Article

Physical Exercise Moderates the Relationship of Apolipoprotein E (APOE) Genotype and Dementia Risk: A Population-Based Study

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Abstract

Genetics and lifestyle independently determine dementia risk, but the interaction is unclear. We assessed the interactive relationship of apolipoprotein E (APOE) genotype and physical exercise on dementia risk over a 5-year period in 1,646 older adults from the Canadian Study of Health and Aging who were dementia-free at baseline. Physical exercise moderated the relationship between genotype and dementia (p < 0.01). Specifically, for APOE ɛ4 non-carriers, the odds of developing dementia were higher in non-exercisers than exercisers (OR = 1.98, 95% CI = 1.44, 2.71, p < 0.001), whereas, for APOE ɛ4 carriers, the odds of developing dementia were not significantly different between non-exercisers and exercisers (OR = 0.71, 95% CI = 0.46, 1.31, p = 0.34). Given that most individuals are not at genetic risk, physical exercise may be an effective strategy for preventing dementia.

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... 48 Another large population-based study among relatively old individuals indicated that physical activity significantly reduced the risk of dementia only in APOE noncarriers during a 5 year followup period. 49 The beneficial effects of physical exercise were also absent in APOE4 carriers in another large prospective study among relatively old participants, 50 and findings from three longitudinal cohort studies demonstrated no interaction effect between physical exercise and the APOE genotype in cognitive decline among older adults. 51 Furthermore, although aerobic exercise induced a significant increase in plasma BDNF levels in elderly African patients with MCI carrying no APOE4 allele, this intervention did not affect the BDNF concentration in APOE4 carriers. ...
... It has been suggested that there could be a possible age-related threshold above which the neurodegenerative process among APOE4 carriers might be too extensive for these individuals to benefit from the positive impact of physical activity. 49 Collectively, it seems that increased physical activity may protect against cognitive impairment in older APOE4 noncarriers, whereas in APOE4 carriers, earlier intervention at younger ages and preclinical stages could be beneficial. 53 Longitudinal studies with objective measures of physical exercise in younger and older individuals are needed to clarify its interaction with the APOE allele status and the effects on cognitive decline. ...
... 48 Fenesi 2017 Physical activity reduced the risk of dementia only in APOE noncarriers. 49 ...
... This assumption is not fully supported by empirical findings. There is some evidence that the relationship between physical activity and cognitive decline and dementia is more pronounced in carriers of the ApoE-ε4 allele [27][28][29][30][31][32], but findings have not been consistent [33,34]. ...
... Stratification by APOE genotype suggests moderation of the association between the level physical activity in late adulthood and decline of executive abilities over time. Findings of effect moderation by APOE genotype have been observed previously in prospective cohort studies, but range from more pronounced protective effects of physical activity on cognition in ApoE-ε4 carriers [27,[30][31][32][61][62][63] to protective associations confined to noncarriers [33,34]. These findings call for replication in other cohorts. ...
Article
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Background Research on the association between physical inactivity and cognitive decline and dementia is dominated by studies with short-term follow-up, that might be biased by reverse causality. Objective Investigate the long-term association between physical activity, cognition, and the rate of age-associated cognitive decline. Methods We investigated the association between late-life physical activity and executive functioning and rate of decline of executive abilities during follow-up of up to 16 years, in 3553 participants of the prospective Rotterdam Study cohort. Measurement took place in 1997–1999, 2002–2004, 2009–2011, and 2014–2015. Results At baseline (age ± 72 years), higher levels of physical activity were associated with higher levels of executive functioning (adjusted mean difference = 0.03, 95% CI: 0.00 ; 0.06, p = 0.03). This difference remained intact up to 16 years of follow-up. The level of physical activity at baseline was unrelated to the rate of decline of executive abilities over time, in the whole group (adjusted mean difference in changetime*physical activity = 0.00, 95% CI: -0.00 ; 0.01, p = 0.31). However, stratification by APOE genotype showed that the accelerated decline of executive abilities observed in those with the ApoE-ε4 allele might be attenuated by higher levels of physical activity in late adulthood (ApoE-ε4 carriers: Btime*physical activity = 0.01, 95% CI: 0.00 ; 0.01, p = 0.03). Conclusion Higher levels of physical activity in late adulthood are related to higher levels of executive functioning, up to 16 years of follow-up. Accelerated decline of executive abilities observed in those with the ApoE-ε4 allele might be mitigated by higher levels of physical activity.
... Few exercise studies discriminate between APOE genotypes, and among those who do, results are diverse, as reported by recent systematic reviews [605,606]. Regarding the risk of getting diagnosed with AD, some studies show that the lower risk of developing all-cause dementia and AD among highly active persons is more pronounced in APOE4 non-carriers [586,587,607,608]. In contrast, other studies demonstrate that this association is more valid for people carrying the APOE4 [593], whereas results reported by our research group, and others, do not reveal any impact of the APOE genotype on this relationship [590,609,610]. ...
... Regarding cognition, some studies find that the association between physical activity and preserved cognition is more noticeable among APOE4 carriers [610][611][612]. Opposingly, others reveal an attenuation or even absence of this relationship in APOE4-carriers [608,613,614], while some display no impact of the genotype [609,[615][616][617]. ...
Article
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ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell–cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
... In addition, the Framingham study showed increased risk of dementia in sedentary non-carriers aged 60 years and older, suggesting an inverse association between physical activity and dementia risk [40]. A study of 1646 older adults followed over a 5-year period reported that physical exercise was effective in preventing dementia in non-carriers [41]. No significant differences were observed between active and non-active APOE e4 carriers. ...
... Some studies showed differences between midlife and late-life exercise, suggesting that age plays a crucial role. There are still questions as to whether a threshold related to age exists in the protective effect of exercise on neural pathology accumulation in APOE e4 carriers [41]. However, since the APOE e4 allele causes deleterious effects in neural protection and repair mechanisms, these carriers may be more influenced by lifestyle-related modifications [35]. ...
Article
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease for which no effective treatment exists at present. Previous research has found that exercise reduces the risk of AD. Since the apolipoprotein E (APOE) ε4 allele increases the risk of AD and is associated with faster disease progression than the other isoforms, we aimed to highlight the impact of exercise on AD pathology in APOE ε4 carriers. This review focuses on the effect of exercise on cognitive function, dementia risk, amyloid-β (Aβ) metabolism, lipid metabolism, neuroinflammation, neurotrophic factors and vascularization in APOE ε4 carriers. We searched the literature in the PubMed electronic database using the following search terms: physical activity, exercise, aerobic fitness, training, sport, APOE4, Alzheimer’s disease, AD and dementia. By cross-referencing, additional publications were identified. Selected studies required older adults to take part in an exercise intervention or to make use of self-reported physical activity questionnaires. All included studies were written and published in English between 2000 and 2020. From these studies, we conclude that exercise is a non-pharmacological treatment option for high-risk APOE ε4 carriers to ameliorate the AD pathological processes including reducing Aβ load, protecting against hippocampal atrophy, improving cognitive function, stabilizing cholesterol levels and lowering pro-inflammatory signals. Variation in study design related to age, cognitive outcomes and the type of intervention explained the differences in study outcomes. However, exercise seems to be effective in delaying the onset of AD and may improve the quality of life of AD patients.
... This is because exercise effects occur at the molecular 5,6 , cardiovascular 7 , brain 8,9 , skeletalmuscle 10 , cognitive [11][12][13] , and behavioral levels [14][15][16] . Gene responses to exercise have recently come under investigation as differential effects of gene activation by allele affect human phenotypes at all system levels [17][18][19][20] . ...
... However, BDNF is not the only gene shown to moderate human cognitive phenotypes across the lifespan. The APoE gene comprises three genotypes 29 and they are associated with exercise 18 and cognitive effects that we can test for by age cohort 15,16,30 . Further, APoE and BDNF interact with testable effects on cognition by age cohort 23,31 but these interactions have not been tested in a large, normally aging adult sample . ...
Research Proposal
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Exercise is being marketed as a magic bullet for "what ails ya". Exercise has been associated with better health and clearer thinking from the time of ancient Greece and China and in numerous scientific studies of exercise effects on human cognition in health and disease 1. Due to high variability on most measures across all studies 2 , a precision medicine approach 3 to exercise intervention design, validation, and implementation will support the prescription of exercise in the clinical or wellness setting 4. This is because exercise effects occur at the molecular 5,6 , cardiovascular 7 , brain 8,9 , skeletal-muscle 10 , cognitive 11-13 , and behavioral levels 14-16. Gene responses to exercise have recently come under investigation as differential effects of gene activation by allele affect human phenotypes at all system levels 17-20. This study focuses on gene activations associated with exercise effects by exercise type 21 in normally aging adult humans (30-80, 20s reference group). Two genes that are well-studied in this and impaired populations are brain-derived neurotrophic factor (BDNF) and Apoliopoprotein E (APoE) 22. Their associations with exercise are in the early stages of investigation 23 , and this proposed research is designed to contribute to this important field of inquiry. BDNF is a pleiotropic gene that regulates three key physiological systems required to effect exercise behavior: the brain 24 , metabolism 25 , and all three types of muscle 26. BDNF exists in three main genotypes in the US population that have differential effects on cognitive capacity and response to exercise. 19 and can guide development of precision medicine training programs designed to optimize human cognitive and physical capacity across the lifespan 27,28. However, BDNF is not the only gene shown to moderate human cognitive phenotypes across the lifespan. The APoE gene comprises three genotypes 29 and they are associated with exercise 18 and cognitive effects that we can test for by age cohort 15,16,30. Further, APoE and BDNF interact with testable effects on cognition by age cohort 23,31 but these interactions have not been tested in a large, normally aging adult sample (30-80). This evidence is important because it can inform not only predisposition to exercise and response to exercise (BDNF by allele), but in follow-on studies, precision medicine exercise therapy interventions designed to ameliorate the well-established effects of APoE-4 on the development and severity of Alzheimer's dementia. This set of studies is designed to examine whether there are early signs of genotype effects on phenotypical executive attention capacity by adult human age cohort 32 and exercise by type (movement requiring concentration vs. movement not requiring concentration). 15,16 We hypothesize the genotype combination of BDNF Val/Val+APoE ε2 or ε3 will be associated with better executive function and VO2Max performance compared to all other genotype combinations across all age groups. We hypothesize that any genotype combination that includes APoE ε2 or ε3 will be associated with better executive function by age group compared to the ε4 allele, Experiment 1. We will collect genetic data from a large sample (>500) of normally-aging adults (with a 20s reference group) 30-80 years of age recruited from Lane County, Oregon. Inclusion criteria include normal cognitive and physiological function by age. Exclusion criteria are any illness or injury that impairs cognitive or physiological performance on our predictor and outcome variables. We will document their BDNF and APoE genotype combinations: BDNF (Val/Val, Val/Met, and Met/Met) and APoE (ε2, ε3, and ε4) plus BDNF and APoE genotype combinations. Experiment 2. We will bring all participants in to the lab to undergo a demanding, ecological task switch test (reaction time, local switch costs), 30 and participate in a battery of tests including: 1) estimated VO2Max (Rockport 1-mile Walk) 33 , 2) body mass index (BMI), 3) PHQ-9 depression questionnaire, 4) Mini-mental State Examination,5) Pittsburgh Sleep Scale, and 6) Big-Five Personality Type. Standard demographics will also be collected. We will then evaluate key outcome variables (BDNF/APoE genotype combination, executive function performance and VO2Max) using multivariate analysis of covariance with age as the covariate. Effect sizes seen in all outcome variables will be obtained and the genotype combination capturing the most variance will be identified.
... Lifestyle factors such as diet, physical activity, and education have been suggested to modify the ApoE association with CVD risk and cognitive decline, especially in older populations (4,(15)(16)(17). ...
... Among ApoE E4 carriers, there was no difference in depressive symptoms between the high and low physical activity groups (37). The odds of developing dementia and factors associated with Alzheimer's disease were higher in sedentary than in physically active ApoE E4 non-carriers, but not in carriers (16). Physical activity correlated with a higher Short Mental Status Examination score in non-ApoE E4 carriers (p = .01) ...
Article
Background Studies of longevity examined apolipoprotein E (ApoE), a gene involved in lipoprotein metabolism, which interacts with susceptibility to age-related diseases, and with mortality. We evaluated the association of ApoE isoforms with cardiovascular disease (CVD) and all-cause mortality. Methods A prospective cohort of 949 survivors of the Israel Study of Glucose Intolerance, Obesity, and Hypertension, examined during 1999-2004, mean age 72 years, was followed for mortality until 2017. Participants were interviewed for lifestyle habits and medical history. Anthropometrics and biochemical markers were taken. Logistic regression was used to assess CVD morbidity and Cox proportional-hazard model for mortality. Results The most common genotype in the cohort was ApoE E3 (76.3%), with the other two almost equally distributed (ApoE E2 11.2% and ApoE E4 12.5%). In men only, ApoE E4 associated with CVD (adjusted OR (aOR)=1.46, 95%CI 0.76, 2.80) and with 18-year mortality (adjusted HR (aHR) =1.47, 95%CI 0.95, 2.26), adjusting for age, ethnicity, physical activity, hypertension, diabetes, LDL-cholesterol, HDL-cholesterol, triglycerides and lipid-lowering medications. Low levels of HDL cholesterol, adjusted for ApoE and the above mentioned variables, associated with higher prevalence of CVD (aOR=1.35, 95%CI 1.00, 1.83) and all-cause mortality (aHR=1.42, 95%CI 1.14, 1.78). ApoE E3 and E2 conferred a lower 18-year mortality risk in the physically active individuals, compared to the sedentary (aHR=0.57, 95%CI 0.44, 0.74, and aHR=0.53, 95%CI 0.78, 1.02, respectively) Conclusions In community dwelling older adults, sociodemographic characteristics and physical activity, blood pressure and HDL-cholesterol levels, may outweigh the impact of ApoE polymorphisms on CVD morbidity and all-cause mortality.
... Individual differences influencing age-related decline of memory extend beyond biological aging to include lifestyle factors, such as physical activity (Barnes et al., 2003;Fenesi et al., 2017;Martin Ginis et al., 2017). Indeed, in animal models, aerobic exercise improves high-interference memory (Creer et al., 2010). ...
... Although this may have been a sufficient stimulus for OA to show a positive association with memory, it may not have been enough to evoke a change in YA. OA primarily engage in physical activity at a low intensity (e.g., walking; Rafferty et al., 2002), which reduces their rate of hippocampal atrophy (Varma et al., 2015) and risk of dementia (Fenesi et al., 2017). In contrast, prior work in YA has used high-intensity interval exercise to demonstrate an effect on high-interference memory (Déry et al., 2013;Heisz et al., 2017). ...
Article
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The present study examined the differential effects of aging and fitness on memory. Ninety-five young adults (YA) and 81 older adults (OA) performed the Mnemonic Similarity Task (MST) to assess high-interference memory and general recognition memory. Age-related differences in high-interference memory were observed across the lifespan, with performance progressively worsening from young to old. In contrast, age-related differences in general recognition memory were not observed until after 60 years of age. Furthermore, OA with higher aerobic fitness had better high-interference memory, suggesting that exercise may be an important lifestyle factor influencing this aspect of memory. Overall, these findings suggest different trajectories of decline for high-interference and general recognition memory, with a selective role for physical activity in promoting high-interference memory.
... Therefore, we maximised the UK Biobank cohort and sought to investigate the independent and joint associations of accelerometer-measured TPA and sedentary time with the risk of incident dementia and its subtypes. We further investigated whether the associations of physical activity and sedentary time with dementia are affected by APOE 4-carrying status given the reported interactions between the effects of physical activity and the APOE 4, a well-known genetic risk factor for dementia and AD on dementia risk [26][27][28][29]. ...
Article
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Background Research on the association of physical activity and sedentary time with dementia is accumulating, though elusive, and the interaction effects of the two remain unclear. We analysed the joint associations of accelerometer-measured physical activity and sedentary time with risk of incident dementia (all-cause dementia, Alzheimer’s disease and vascular dementia). Methods A total of 90,320 individuals from the UK Biobank were included. Accelerometer-measured total volume of physical activity (TPA) and sedentary time were measured at baseline and dichotomised by median (low TPA [< 27 milli-gravity (milli-g)], high TPA [≥ 27 milli-g]; low sedentary time [< 10.7 h/day], high sedentary time [≥ 10.7 h/day]). Cox proportional hazards models were used to evaluate the joint associations with incident dementia on both additive and multiplicative scales. Results During a median follow-up of 6.9 years, 501 cases of all-cause dementia were identified. Higher TPA was associated with a lower risk of all-cause dementia, Alzheimer’s disease and vascular dementia; the multivariate adjusted hazard ratios (HRs) (95% CI) per 10 milli-g increase were 0.63 (0.55–0.71), 0.74 (0.60–0.90) and 0.69 (0.51–0.93), respectively. Sedentary time was only found to be linked to all-cause dementia, and the HR for high sedentary time was 1.03 (1.01–1.06) compared with that for low sedentary time. No additive and multiplicative relationship of TPA and sedentary time to incident dementia was found (all P values > 0.05). Conclusion Higher TPA level was related to a lower risk of incident dementia irrespective of sedentary time, which highlighted the implication of promoting physical activity participation to counteract the potential detrimental effect of sedentary time on dementia.
... Besides neurogenesis, Apolipoprotein E type 4 (APOE-E4) is a risk factor for dementia and cognitive decline seen in PD and Alzheimer's disease. Exercise has been hypothesized to reduce mood and cognitive symptoms among APOE-E4 carriers (Fenesi et al., 2017). Ku et al. (2017) measured differences in depressive symptoms among APOE-E4 carriers and noncarriers, and high/low physically active individuals. ...
Article
Objective: Parkinson's disease (PD) is a neurodegenerative disorder caused by disruption of dopamine-producing cells. PD is associated with motor symptoms and nonmotor symptoms including depression and cognitive impairment. Past research suggests an association between depression and cognitive impairment in PD. Physical activity may have a therapeutic effect on both depression and cognitive impairment. The present study investigates if physical activity mediates the association between depressive symptoms and cognition in a longitudinal sample of individuals with PD. Method: Participants include individuals newly diagnosed with PD (N = 487) enrolled in the Parkinson's Progression Marker Initiative (PPMI). Participants completed an array of neuropsychological tests over the course of 5 years, as well as questionnaires of depression and physical activity. Between-person and within-person effects of depression and cognition mediated through physical activity were analyzed using structural equation modeling. Results: A significant direct effect demonstrated depression was associated with worse global cognitive functioning. Furthermore, there was a significant indirect within-person effect, indicating that physical activity fully mediated the association between depression and cognition. Individuals who became more depressed over time became less physically active and subsequently experienced cognitive decline over the 5-year period. Conclusions: Findings have implications for prognostic detection and/or the role of physical activity interventions to buffer effects of depression on cognitive impairment among individuals diagnosed with PD. Physical interventions may potentially be implemented among depressed persons to preserve cognitive functioning. Worsened depression early during PD may be a risk factor for inactivity and cognitive diminishment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
... 18 In addition, the protective effect of physical activity may moderate the predominant genetic risk for AD conveyed by the apolipoprotein E (APOE) genotype that has been associated with a 2-fold risk with each e4 risk allele. 19,20 In the current study, we investigated the association between physical activity and incident ADRD in the population-based Multiethnic Cohort Study (MEC). Using the MEC-Medicare linkage data, we examined whether physical activity assessed at middle to old age was associated with risk of ADRD later in life and whether the associations varied by race and ethnicity, sedentary behavior, and APOE genotypes, as well as the follow-up duration between the MVPA assessment and ADRD diagnosis, age at diagnosis, and body weight status. ...
Article
Introduction: We investigated whether the protective association of physical activity with risk of Alzheimer's disease and related dementias (ADRD) has genetic or behavioral variations. Methods: In the Multiethnic Cohort, we analyzed moderate or vigorous physical activity (MVPA) reported at ages 45 to 75 among 88,047 participants in relation to 13,039 incident diagnoses of late-onset ADRD identified in Medicare claims (1999 to 2014), by five racial and ethnic groups, hours sitting, and in a subset (16%), apolipoprotein E (APOE) genotype. Results: MVPA was inversely associated with ADRD (hazard ratio for ≥14 vs <2.5 hours/week: 0.83, 95% confidence interval [CI]: 0.76 to 0.90 in men; 0.88, 5% CI: 0.81 to 0.95 in women). The association was inverse in all racial and ethnic groups except Black participants (P-heterogeneity = 0.52), but stronger in individuals with lower levels of sitting duration or those who do not carry the APOE e4 risk allele. Discussion: The different effects of physical activity by sitting duration and APOE genotype warrant further research.
... Then, in the reduce phase, the same key will be aggregated to achieve the final purpose of data manipulation. Therefore, in actual programming, developers only need to clarify the meaning of the key and value in each stage of data map/reduce, and then they can convert the existing business to the distributed parallel computing platform [18,19]. Figure 5 depicts the MapReduce workflow. ...
Article
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Physical exercise is very necessary for students, only good physical quality can better study. The mining of physical exercise data is the analysis and integration of physical exercise data. The purpose of this paper is to study the data mining technology of students’ physical exercise. This paper proposes a data mining algorithm for student physical exercise based on Cloud Computing (CdC). In the traditional data mining technology, data regression and clustering are added, and the data is processed through variance and covariance, which can make the data complete the processing steps such as cleaning faster and saves a lot of data processing time. The experiments in this paper show that the algorithm proposed in this paper can analyze the physical exercise data very well. For data samples with sample sizes of 1000 and 2000, the running time is about 20 seconds lower than the original algorithm, and the resource factor of the system is stable at about 82%, which proves that the algorithm has a good load balance.
... In the human population, a sedentary lifestyle is correlated with an increased risk of LOAD (de Rezende et al., 2014;Fenesi et al., 2017;Yan et al., 2020). Therefore, to determine if physical activity influenced transcriptional changes in B6.APOE4.Trem2*R47H mice, a running wheel was provided in the home cage of 22-month-old male mice for 2 months. ...
Article
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Late-onset Alzheimer’s disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression via legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse strains. In addition to extracellular deposits of amyloid plaques and inclusions of the microtubule-associated protein tau, AD is also defined by synaptic/neuronal loss, vascular deficits, and neuroinflammation. These underlying processes need to be better defined, how the disease progresses with age, and compared to human-relevant outcomes. To create more translatable mouse models, MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) groups are identifying and integrating disease-relevant, humanized gene sequences from public databases beginning with APOEε4 and Trem2*R47H, two of the most powerful risk factors present in human LOAD populations. Mice expressing endogenous, humanized APOEε4 and Trem2*R47H gene sequences were extensively aged and assayed using a multi-disciplined phenotyping approach associated with and relative to human AD pathology. Robust analytical pipelines measured behavioral, transcriptomic, metabolic, and neuropathological phenotypes in cross-sectional cohorts for progression of disease hallmarks at all life stages. In vivo PET/MRI neuroimaging revealed regional alterations in glycolytic metabolism and vascular perfusion. Transcriptional profiling by RNA-Seq of brain hemispheres identified sex and age as the main sources of variation between genotypes including age-specific enrichment of AD-related processes. Similarly, age was the strongest determinant of behavioral change. In the absence of mouse amyloid plaque formation, many of the hallmarks of AD were not observed in this strain. However, as a sensitized baseline model with many additional alleles and environmental modifications already appended, the dataset from this initial MODEL-AD strain serves an important role in establishing the individual effects and interaction between two strong genetic risk factors for LOAD in a mouse host.
... Indeed, multiple lines of evidence suggest stronger protective effects of exercise in carriers of the APOE ε4 allele (19,(90)(91)(92), one of the highest genetic risk factors for AD, found in almost half of the late-onset AD cases (93). For example, a population based study of more than 1,600 older adults assessing the interaction between APOE status and exercise on dementia risk over a 5-year period suggests that physical exercise significantly moderated the relationship between genotype and dementia (94). In a posthoc analysis of 200 patients with mild AD, patients who carried the APOE4 allele benefited more from the exercise intervention than non-carriers on cognitive, neuropsychiatric, and physical measures, suggesting that behavioral exercise interventions may also provide benefits after the onset of AD (95). ...
Article
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Regular exercise plays an essential role in maintaining healthy neurocognitive function and central nervous system (CNS) immuno-metabolism in the aging CNS. Physical activity decreases the risk of developing Alzheimer's Disease (AD), is associated with better AD prognosis, and positively affects cognitive function in AD patients. Skeletal muscle is an important secretory organ, communicating proteotoxic and metabolic stress to distant tissues, including the CNS, through the secretion of bioactive molecules collectively known as myokines. Skeletal muscle undergoes significant physical and metabolic remodeling during exercise, including alterations in myokine expression profiles. This suggests that changes in myokine and myometabolite secretion may underlie the well-documented benefits of exercise in AD. However, to date, very few studies have focused on specific alterations in skeletal muscle-originating secreted factors and their potential neuroprotective effects in AD. In this review, we discuss exercise therapy for AD prevention and intervention, and propose the use of circulating myokines as novel therapeutic tools for modifying AD progression.
... Because of the pleiotropic nature of APOE possession, the APOE-ε4 allele can have deleterious effects by influencing multiple biological processes, including lipid metabolism, amyloid beta deposition, neuro-inflammation, neurogenesis, and synaptic function [50,51]. This suggests that the penetrance of the APOE-ε4 allele influences the rate of cognitive dysfunction and the likelihood of transitioning to mild cognitive impairment (MCI) and AD, which is variable and potentially modifiable [52,53]. Therefore, since the difference in the APOE-ε4 allele frequency may affect the results of the present interventional study, it is meaningful to measure the allele frequency. ...
Article
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Oxidative stress plays an important role in age-associated cognitive decline. We recently reported that dietary intake of perilla seed oil (PO), a rich source of α-linolenic acid (LNA, C18:3, ω-3), helps in maintaining good mental health in adults. This study aimed to investigate the impacts of dietary PO intake on cognitive functions and mental health in healthy, elderly Japanese individuals. Seventy-five healthy volunteers aged 64–84 years were randomly divided into two groups: a control group and a PO-administered group. At baseline and at 12 months of intervention, cognitive function, mental health condition, fatty acid profile of the red blood cell plasma membranes (RBC-PM), and serum biochemical parameters were evaluated. Results showed that serum biological antioxidant potential and LNA levels in the RBC-PM at 12 months after the trial were significantly higher in the PO group compared to the control group. Further, both the cognitive function measures, as evaluated by the Frontal Assessment Battery test and the apathy scores, tended to be improved after 12 months in the PO group. Our results demonstrate that dietary PO intake enhances the antioxidant potential and prevents the age-related cognitive and mental decline in healthy elderly individuals by enhancing the blood LNA levels.
... These data support prior work that has reported relationships between exercise-induced improvements in cardiorespiratory fitness and cognitive changes [13,20,22,23]. The highintensity exercise intervention in the current study increased cardiorespiratory fitness levels greater than prior similar RCTs in older adults (typically 10-15% increases) [8,13,24]. It therefore remains puzzling as to why the observed associations between changes in cardiorespiratory fitness and cognition did not yield group-level differences in cognitive outcomes. ...
Article
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Background Physical inactivity has been consistently linked to increased risk of cognitive decline; however, studies examining the impact of exercise interventions on cognition have produced inconsistent findings. Some observational studies suggest exercise intensity may be important for inducing cognitive improvements; however, this has yet to be thoroughly examined in older adult cohorts. The objective of the current study was to evaluate the effect of systematically manipulated high-intensity and moderate-intensity exercise interventions on cognition. Methods This multi-arm pilot randomised clinical trial investigated the effects of 6 months of high-intensity exercise and moderate-intensity exercise, compared with an inactive control, on cognition. Outcome measures were assessed at pre- (baseline), post- (6 months), and 12 months post-intervention. Ninety-nine cognitively normal men and women (aged 60–80 years) were enrolled from October 2016 to November 2017. Participants that were allocated to an exercise group (i.e. high-intensity or moderate-intensity) engaged in cycle-based exercise two times per week for 6 months. Cognition was assessed using a comprehensive neuropsychological test battery. Cardiorespiratory fitness was evaluated by a graded exercise test. Results There was a dose-dependent effect of exercise intensity on cardiorespiratory fitness, whereby the high-intensity group experienced greater increases in fitness than the moderate-intensity and control groups. However, there was no direct effect of exercise on cognition. Conclusions We did not observe a direct effect of exercise on cognition. Future work in this field should be appropriately designed and powered to examine factors that may contribute to individual variability in response to intervention. Trial registration This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000643370). Registered on 3 May 2017—retrospectively registered. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372780
... Because of being associated with a variety of chronic health problems, sedentary lifestyle is emerging as an important public health issue in many countries (Owen et al. 2010). Mounting evidence shows that sedentary habits may be a risk factor for cognitive impairment (Wheeler et al. 2017), while regular exercise can be an useful method for dementia prevention (Fenesi et al. 2017). ...
Article
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Recent investigations have increased the interest on the connection between the microorganisms inhabiting the gut (gut microbiota) and human health. An imbalance of the intestinal bacteria representation (dysbiosis) could lead to different diseases, ranging from obesity and diabetes, to neurological disorders including Alzheimer’s disease (AD). The term “gut-brain axis” refers to a crosstalk between the brain and the gut involving multiple overlapping pathways, including the autonomic, neuroendocrine, and immune systems as well as bacterial metabolites and neuromodulatory molecules. Through this pathway, microbiota can influence the onset and progression of neuropathologies such as AD. This review discusses the possible interaction between the gut microbiome and AD, focusing on the role of gut microbiota in neuroinflammation, cerebrovascular degeneration and Aβ clearance.
... In contrast, other studies have failed to detect any effect of physical exercise on dementia in patients who carry E4 allele. One study showed that the likelihood of developing dementia is not significantly different between those who exercise and those who do not (54). In agreement with that, it has been shown that exercise training did not modify the cognitive function in patients with the APOEE4 allele (55). ...
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We aimed to present an overview of the literature regarding the interaction between physical exercise and APOE gene polymorphism on cognitive function, particularly in patients with Alzheimer’s disease (AD). Firstly, this review focused on the effect of the physical exercise on cognitive function, regardless of APOE gene polymorphism. Some studies have shown that a high level of cardiorespiratory fitness is associated with less neuronal damage with an improvement in memory score tests whereas other studies failed to detect any association between physical exercise and cognitive improvement either in healthy individuals or patients with AD. Taken together, standardized protocols and more longitudinal studies are required to provide a better insight into the effects of physical exercise on cognitive function. Although there is no agreement in the literature regarding the effects of physical exercise on cognitive function, it is well established that it improves social interaction and the feeling of well-being, thereby positively contributing to the quality of life of the elderly. Regarding the influence of physical exercise on cognitive function in APOE E4 allele carriers, the data trend shows that the carriers of allele E4 for APOE gene were more responsive to the beneficial effects of physical exercise on cognitive function compared with non-carriers. Nevertheless, studies with larger sample sizes will provide more accuracy about this relationship.
... These data support prior work that has reported relationships between exercise-induced improvements in cardiorespiratory tness and cognitive changes (13,21,23,24). The high-intensity exercise intervention in the current study increased cardiorespiratory tness levels greater than prior similar RCTs in older adults (typically 10-15% increases) (8,13,25). It therefore remains puzzling as to why the observed associations between changes in cardiorespiratory tness and cognition did not yield group-level differences in cognitive outcomes. ...
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BACKGROUND: Physical inactivity has been consistently linked to increased risk of cognitive decline; however, studies examining the impact of exercise interventions on cognition have produced inconsistent findings. Some observational studies suggest exercise intensity may be important for inducing cognitive improvements; however, this has yet to be thoroughly examined in older adult cohorts. The objective of the current study was to evaluate the effect of systematically manipulated high-intensity and moderate-intensity exercise interventions on cognition. In addition, we investigated individual variability in exercise response by examining effects of relevant genetic factors and changes in cardiorespiratory fitness on cognitive change. METHODS: This multi-arm randomised clinical trial investigated the effects of 6-months of high-intensity exercise and moderate-intensity exercise, compared with an inactive control, on cognition. Outcome measures were assessed at pre- (baseline), post- (6 months), and 12-months post-intervention. Ninety-nine cognitively normal men and women (aged 60 – 80 years) were enrolled from October 2016 to November 2017. Participants that were allocated to an exercise group (i.e., high-intensity or moderate-intensity) engaged in cycle-based exercise two times per week for 6 months. Cognition was assessed using a comprehensive neuropsychological test battery. Cardiorespiratory fitness was evaluated by a graded exercise test. Apolipoprotein e4 genotype and brain-derived neurotrophic factor Val66Met carriage were identified. RESULTS: There was a dose-dependent effect of exercise intensity on cardiorespiratory fitness; whereby the high-intensity group experienced greater increases in fitness than the moderate-intensity and control groups. However, there was no direct effect of exercise on cognition. We observed an association between changes in global cognition and executive function and changes in cardiorespiratory fitness from pre- to post-intervention: this relationship was strongest in brain-derived neurotrophic factor non-Met carriers. CONCLUSIONS We did not observe a direct effect of exercise on cognition. Nevertheless, our data suggests genetics may moderate the relationship between fitness and cognitive change following exercise, and this should be examined further in larger trials. TRIAL REGISTRATION: This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000643370). Registered 3rd May 2017 - retrospectively registered. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372780
... Many studies conclude that physical inactivity is particularly harmful for ε4 carriers [5,32,45,63,66]. Yet, a considerable number of publications fail to find benefits among ε4 carriers, suggesting that the presence of this allele could impair the mechanisms through which PA exerts its action [7,20,56]. Nevertheless, these apparently conflicting results are a consequence of the employment of different study designs to evaluate a wide variety of outcomes. ...
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Background: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer's disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. Methods: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. Results: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. Conclusion: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.
... Three studies found no effects of PA on all-cause dementia risk when examining the entire cohort, or following stratification for APOE ε4 allele carriage (Carlson et al., 2008;Rovio et al., 2007;Hansson et al., 2019). Two studies reported that only ε4 carriers benefited from PA in terms of decreased dementia risk (Kivipelto et al., 2008;Rovio et al., 2005), and five studies reported this effect in ε4 non-carriers only (Tolppanen et al., 2015;Chang et al., 2010;Fenesi et al., 2017;Podewils et al., 2005;Kulmala et al., 2014). Yet APOE ε4 carriers benefit from increased PA levels over time (Tolppanen et al., 2015;Kulmala et al., 2014). ...
Article
Introduction: For decades, researchers have tried to understand the moderating effect of APOE ε4 carriage on the relationship between physical activity (PA), brain health and dementia risk. However, this field has produced inconsistent findings. Method: We conducted a systematic review of the literature, searching for observational and interventional studies examining the effect of APOE ε4 carriage on the relationships between PA, dementia risk and different markers of brain health. Results: Observational studies using dementia risk as a primary outcome measure generally found that in shorter follow-up periods (up to 10 years) both APOE ε4 carriers and non-carriers benefit from PA, although longer follow-ups showed mixed results. In neuroimaging studies, mainly carriers or both groups showed benefits. Additionally, the association between PA and amyloid burden was more evident among carriers. Overall, studies with greater samples of active APOE ε4 carriers are more likely to report benefits within this group in terms of lower dementia risk and reduced brain pathology. Discussion: Although we have identified some patterns for the modulating effect of APOE ε4 on PA and dementia or brain pathology, the available data is, overall, inconclusive. Heterogeneity in study design, methodology, and outcomes blur the ability to detect clear associations.
... There is controversy in the eld regarding whether ε4 carriers and non-carriers bene t to the same extent from PA engagement. Many studies conclude that physical inactivity is particularly harmful for ε4 carriers (Brown et al., 2013;Head et al., 2012;Luck et al., 2014;Rovio et al., 2005;Smith et al., 2013) Yet, a considerable number of publications fail to nd bene ts among ε4 carriers, suggesting that the presence of this allele could impair the mechanisms through which PA exerts its action (Chang et al., 2010;Fenesi et al., 2017;Podewils et al., 2005). Nevertheless, these apparently con icting results are a consequence of the employment of different study designs to evaluate a wide variety of outcomes. ...
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BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer’s disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.
... Our data confirm the exercise responsiveness of BDNF, with levels rising significantly after both moderate and high intensity exercise, and extend the current literature to show that BDNF also appears to be intensity responsive, with high intensity exercise in our platform producing a nearly 30% increase in BDNF levels relative to moderate intensity ( Fig. 2; Supplemental Data File). These findings are particularly salient given the rising prevalence of dementia, the absence of efficacious therapies, and links between sedentary behavior and memory loss 31 . www.nature.com/scientificreports/ ...
Article
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Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise.
... There is controversy in the field regarding whether ε4 carriers and non-carriers benefit to the same extent from PA engagement. Many studies conclude that physical inactivity is particularly harmful for ε4 carriers (Brown et al., 2013;Head et al., 2012;Luck et al., 2014;Rovio et al., 2005;Smith et al., 2013) Yet, a considerable number of publications fail to find benefits among ε4 carriers, suggesting that the presence of this allele could impair the mechanisms through which PA exerts its action (Chang et al., 2010;Fenesi et al., 2017;Podewils et al., 2005). Nevertheless, these apparently conflicting results are a consequence of the employment of different study designs to evaluate a wide variety of outcomes. ...
Preprint
Full-text available
BACKGROUND Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer’s disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS The relationship between PA and alpha power band was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and younger adults only exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.
... Contrary to our aforementioned findings within APOE ε4 carriers, we observed a relationship between decreased FC and greater scores in specific measures of episodic and working memory, but only among APOE ε4 non-carriers. Most studies investigating the relationship between AD incidence and PA have concluded that only APOE ε4 non-carriers benefit from reduced AD risk at greater levels of PA [9,49,50], although there are some exceptions [51,52]. Presently, AD diagnosis is based on clinical progression and cognitive status. ...
Article
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Background: Neuronal hyperexcitability and hypersynchrony have been described as key features of neurophysiological dysfunctions in the Alzheimer's disease (AD) continuum. Conversely, physical activity (PA) has been associated with improved brain health and reduced AD risk. However, there is controversy regarding whether AD genetic risk (in terms of APOE ε4 carriage) modulates these relationships. The utilization of multiple outcome measures within one sample may strengthen our understanding of this complex phenomenon. Method: The relationship between PA and functional connectivity (FC) was examined in a sample of 107 healthy older adults using magnetoencephalography. Additionally, we explored whether ε4 carriage modulates this association. The correlation between FC and brain structural integrity, cognition, and mood was also investigated. Results: A relationship between higher PA and decreased FC (hyposynchrony) in the left temporal lobe was observed among all individuals (across the whole sample, in ε4 carriers, and in ε4 non-carriers), but its effects manifest differently according to genetic risk. In ε4 carriers, we report an association between this region-specific FC profile and preserved brain structure (greater gray matter volumes and higher integrity of white matter tracts). In this group, decreased FC also correlated with reduced anxiety levels. In ε4 non-carriers, this profile is associated with improved cognition (working and episodic memory). Conclusions: PA could mitigate the increase in FC (hypersynchronization) that characterizes preclinical AD, being beneficial for all individuals, especially ε4 carriers.
... In a prospective study among older adults Podewils et al. found an inverse association between physical activity and risk of AD after a 5 year follow-up that was confined to ApoE-ε4 non-carriers, indicating that benefits of exercise may be confined only to ε4 noncarriers (89). A similar finding was reported after a 5 year follow-up in cognitively healthy elders (90). Fenesi et al. found a significant protective effect of physical activity regarding dementia risk in ApoE-ε4 non-carriers, and no significant effect in ApoE-ε4 carriers. ...
Article
Aging is associated with a decrease in body and brain function and with a decline in insulin-like growth factor 1 levels. The observed associations between alterations in insulin-like growth factor 1 levels and cognitive functioning and Mild Cognitive Impairment suggest that altered insulin-like growth factor 1 signaling may accompany Alzheimer’s disease or is involved in the pathogenesis of the disease. Recent animal research has suggested a possible association between insulin-like growth factor 1 levels and the Apolipoprotein E ε4 allele, a genetic predisposition to Alzheimer’s disease. It is therefore hypothesized that a reduction in insulin-like growth factor 1 signaling may moderate the vulnerability to Alzheimer’s disease of human Apolipoprotein E ε4 carriers. We address the impact of age-related decline of insulin-like growth factor 1 levels on physical and brain function in healthy aging and Alzheimer’s disease and discuss the links between insulin-like growth factor 1 and the Apolipoprotein E ε4 polymorphism. Furthermore, we discuss lifestyle interventions that may increase insulin-like growth factor 1 serum levels, including physical activity and adherence to a protein rich diet and the possible benefits to the physical fitness and cognitive functioning of the aging population.
... In a prospective study among older adults Podewils et al. found an inverse association between physical activity and risk of AD after a 5 year follow-up that was confined to ApoE-ε4 non-carriers, indicating that benefits of exercise may be confined only to ε4 noncarriers (89). A similar finding was reported after a 5 year follow-up in cognitively healthy elders (90). Fenesi et al. found a significant protective effect of physical activity regarding dementia risk in ApoE-ε4 non-carriers, and no significant effect in ApoE-ε4 carriers. ...
Article
Full-text available
Aging is associated with a decrease in body and brain function and with a decline in insulin-like growth factor 1 levels. The observed associations between alterations in insulin-like growth factor 1 levels and cognitive functioning and Mild Cognitive Impairment suggest that altered insulin-like growth factor 1 signaling may accompany Alzheimer’s disease or is involved in the pathogenesis of the disease. Recent animal research has suggested a possible association between insulin-like growth factor 1 levels and the Apolipoprotein E ε4 allele, a genetic predisposition to Alzheimer’s disease. It is therefore hypothesized that a reduction in insulin-like growth factor 1 signaling may moderate the vulnerability to Alzheimer’s disease of human Apolipoprotein E ε4 carriers. We address the impact of age-related decline of insulin-like growth factor 1 levels on physical and brain function in healthy aging and Alzheimer’s disease and discuss the links between insulin-like growth factor 1 and the Apolipoprotein E ε4 polymorphism. Furthermore, we discuss lifestyle interventions that may increase insulin-like growth factor 1 serum levels, including physical activity and adherence to a protein rich diet and the possible benefits to the physical fitness and cognitive functioning of the aging population.
... For example, the presence of the apolipoprotein-E4 (ApoE4) allele, a risk factor for Alzheimer's disease (AD) [29], may mediate the magnitude of exercise effects. Accumulation of neuronal and physiological damage in ApoE4 carriers may negate the beneficial effects of physical activity [30,31]. Conversely, ApoE4 carriers may be more responsive to exercise [32], perhaps because lower functional levels at baseline [33][34][35][36] leave more room for improvement. ...
Article
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Background: Potential moderators such as exercise intensity or apolipoprotein-E4 (ApoE4) carriership may determine the magnitude of exercise effects on physical and cognitive functions in patients with dementia (PwD). We determined the effects of a 24-week aerobic and strength training program with a low- and high-intensity phase on physical and cognitive function. Methods: In an assessor-blinded randomized trial, 91 PwD (all-cause dementia, recruited from daycare and residential care facilities, age 82.3 ± 7.0 years, 59 women, Mini-Mental State Examination 20.2 ± 4.4) were allocated to the exercise or control group. In the exercise group, PwD participated in a walking and lower limb strength training program with 12 weeks low- and 12 weeks high-intensity training offered three times/week. Attention-matched control participants performed flexibility exercises and recreational activities. We assessed adherence, compliance, and exercise intensity for each session. We assessed physical (endurance, gait speed, mobility, balance, leg strength) and cognitive (verbal memory, visual memory, executive function, inhibitory control, psychomotor speed) functions with performance-based tests at baseline and after 6, 12, 18, 24, and 36 weeks (follow-up). ApoE4 carriership was determined post-intervention. Results: Sixty-nine PwD were analyzed. Their mean attendance was ~ 60% during the study period. There were no significant effects of the exercise vs. control intervention on endurance, mobility, balance, and leg strength in favor of the exercise group (Cohen's d = 0.13-0.18). Gait speed significantly improved with ~ 0.05 m/s after the high-intensity phase for exercise participants (Cohen's d = 0.41) but declined at follow-up. There were no significant effects of the exercise vs. control intervention on any of the cognitive measures (Cohen's d ~ - 0.04). ApoE4 carriership did not significantly moderate exercise effects on physical or cognitive function. Conclusions: Exercise was superior to control activities for gait speed in our sample of PwD. However, the training effect provided no protection for mobility loss after detraining (follow-up). There were no beneficial effects of the exercise vs. control group on cognitive function. Exercise intensity moderated the effects of exercise on gait speed. ApoE4 carriership moderated the effect of exercise on global cognition only (trend level). Trial registration: Netherlands Trial Register, NTR5035. Registered on 2 March 2015.
... Sedentary lifestyle is becoming a significant public health issue in many countries despite being linked to a number of chronic health conditions (Owen et al., 2010). Accumulating evidence indicates that sedentary behavior can be a risk factor for cognitive decline (Wheeler et al., 2017), while physical exercise may be an effective strategy for preventing dementia (Fenesi et al., 2016). It has been shown that the mechanisms underlying the neuroprotective influence of physical activity on Alzheimer's disease are: the production of antioxidant enzymes and growth factors and decrease in ROS and neuroinflammation, the concentration of Aβ plaques and tau protein in the brain (Chen et al., 2016b). ...
Article
Full-text available
Gut microbiome is a community of microorganisms in the gastrointestinal tract. These bacteria have a tremendous impact on the human physiology in healthy individuals and during an illness. Intestinal microbiome can influence one's health either directly by secreting biologically active substances such as vitamins, essential amino acids, lipids et cetera or indirectly by modulating metabolic processes and the immune system. In recent years considerable information has been accumulated on the relationship between gut microbiome and brain functions. Moreover, significant quantitative and qualitative changes of gut microbiome have been reported in patients with Alzheimer's disease. On the other hand, gut microbiome is highly sensitive to negative external lifestyle aspects, such as diet, sleep deprivation, circadian rhythm disturbance, chronic noise, and sedentary behavior, which are also considered as important risk factors for the development of sporadic Alzheimer's disease. In this regard, this review is focused on analyzing the links between gut microbiome, modern lifestyle, aging, and Alzheimer's disease.
... Some studies suggest a stronger protective effect of PA on dementia in APOE ε 4 carriers compared to non-carriers (18,19). Conversely, findings from Cardiovascular Health Cognition Study and Canadian Study of Health and Aging analyzing the effect of PA on dementia suggest a stronger protective effect of PA in APOE ε 4 non-carriers compared to carriers (20,21). ...
Article
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Background Previous studies have suggested that the association between APOE ɛ4 and dementia is moderated by physical activity (PA), but the results remain inconclusive and longitudinal data on cognitive decline is missing. In this study we examine whether there is a gene-environment interaction between APOE and PA on cognitive decline in older adults using 9-year follow-up data of three cohort studies. Methods We followed 7176 participants from three longitudinal cohort studies: Longitudinal Aging Study Amsterdam (LASA), InCHIANTI and Rotterdam Study for 9 years. PA was assessed with self-reported questionnaires and was categorized in low, moderate and high PA. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and cognitive decline was defined as a decrease of 3 points or more on the MMSE during 3 years follow-up. We fitted logistic regression models using Generalized Estimating Equations adjusting for age, sex, education, depressive symptoms and number of chronic disease. Interaction between APOE and PA was tested on multiplicative and additive scale. Results Cohorts were similar in most aspects but InCHIANTI participants were on average older and had lower education. APOE ɛ4 carriers had higher odds of cognitive decline (OR=1.46, 95% CI (1.29-1.64)) while PA was not significantly associated with cognitive decline overall (Moderate PA: OR 0.87(0.67-1.13); High PA: OR 0.71(0.36-1.40)). There was no evidence for an interaction effect between PA and APOE ɛ4 in cognitive decline in older adults (APOE*Moderate PA: p=0.83; APOE*High PA: p=0.90). Conclusions Previous claims of a gene-environment interaction between APOE ɛ4 and PA in cognitive decline are not supported by our results.
... The engagement in sports or habitual physical activity (PA) has shown an extensive protective role against multiple diseases such as cancer, obesity and type-2 diabetes, and cognitive impairments [1][2][3]. Additionally, PA has also a significant impact on life quality, since it aids with managing stress, preserving cognitive function and memory, and preventing fractures in the elderly [4,5]. Over the last three decades, there has been multiple evidence showing genetic contributions for these traits, such as the variants found in genes involved in the blood pressure control system, which is altered in response to exercise [6,7]. ...
Article
Introduction: The engagement in sports or habitual physical activity (PA) has shown an extensive protective role against multiple diseases such as cancer, obesity, and many others. Additionally, PA has also a significant impact on life quality, since it aids with managing stress, preserving cognitive function and memory, and preventing fractures in the elderly. Objective: Considering there has been multiple evidence showing that genetic variation underpins variation of PA-related traits, we aimed to estimate the heritability (h2) of these phenotypes in a sample from the Brazilian population and assess whether males and females differ in relation to those estimates. Methods: 2,027 participants from a highly admixed population from Baependi, MG, Brazil, had information regarding their PA and sedentary behavior (SB) phenotypes collected through a questionnaire (IPAQ-SF). After data cleaning and transformation procedures, we obtained four variables to be evaluated: total PA (TPA MET), walking time, (WK MET), moderate-vigorous PA (MVPA MET), and SB. A model selection procedure was performed using a single-step covariate inclusion approach. We tested for BMI, waist, hip and neck circumferences, smoking, and depression separately, and performed correlation tests among covariates. Linear mixed models, selection procedure, and the variance components approach to estimate h2 were implemented using SOLAR-Eclipse 8.3.1. Results: We obtained estimates of 0.221, 0.109, 0.226, and 0 for TPA MET, WK MET, MVPA MET, and SB, respectively. We found evidence for gene-sex interactions, with males having higher sex-specific heritabilities than females for TPA MET and MVPA MET. In addition, we found higher estimates of the genetic variance component in males than females for most phenotypes. Discussion/conclusion: The heritability estimates presented in this work show a moderate heritable set of genetic factors affecting PA in a sample from the Brazilian population. The evaluation of the genetic variance component suggests segregating genetic factors in male individuals are more heterogeneous, which can explain why men globally tend to need to practice more intense PA than women to achieve similar health benefits. Hence, these findings have significant implications for the understanding of the genetic architecture of PA and might aid to promote health in the future.
... In conclusion, there does not seem to be a modifying effect of physical activity on the effect of APOE genotype when it comes to hippocampal volume, whereas for aβ, too few studies were identified to reach any definite conclusions, although results are promising. The relationship regarding APOE status and exercise remains undetermined [94,95], and may involve neuroinflammation and neurovascular pathology [96]. ...
Article
Introduction: Observational studies have found that physical activity is associated with a reduced risk of cognitive decline and dementia. Whether physical activity may also reduce the level of AD pathology, remains undetermined. Objective: To examine the relationship between physical activity and AD biomarkers (beta-amyloid1- 42, total tau and phosphorylated tau in CSF, amyloid PET, hippocampal atrophy on MRI and parietotemporal hypometabolism on brain 18F-FDG-PET). Methods: We carried out a systematic review of the observational studies of physical activity and AD biomarkers in healthy subjects, subjective cognitive complaints, mild cognitive impairment (MCI) and AD dementia. Results: We identified a total of 40 papers, which were eligible for inclusion. Thirty-four studies were conducted on healthy subjects, 3 on MCI and healthy subjects, 1 on MCI, and 2 on AD and healthy controls. Six studies reported on CSF biomarkers, 9 on amyloid PET, 29 on MRI and 4 on brain 18FFDG- PET. The majority of studies did not find a significant association between physical activity and AD biomarkers. Conclusion: The quality of included studies with only a few longitudinal studies, limits the conclusions which may be drawn from the present findings especially regarding the biomarkers other than hippocampal volume. However, the majority of the identified studies did not find a significant association.
... GA refers to an individual's average ancestry across his/ her entire genome while LA refers to the ancestral background of a particular (i.e., "local") chromosomal region within an individual genome (Fig 1). GA is predominantly correlated with ethnic, cultural, and environmental factors that are related to broader definitions of race and ethnicity [17][18][19][20]. Conversely, LA is often correlated with ancestry-specific genetic factors that are located in or near the genomic region in question [21,22]. ...
Article
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The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.
... Sedentary lifestyle is becoming a significant public health issue in many countries despite being linked to a number of chronic health conditions (Owen et al., 2010). Accumulating evidence indicates that sedentary behavior can be a risk factor for cognitive decline (Wheeler et al., 2017), while physical exercise may be an effective strategy for preventing dementia (Fenesi et al., 2016). It has been shown that the mechanisms underlying the neuroprotective influence of physical activity on Alzheimer's disease are: the production of antioxidant enzymes and growth factors and decrease in ROS and neuroinflammation, the concentration of Aβ plaques and tau protein in the brain (Chen et al., 2016b). ...
Article
Full-text available
Aims There has been growing interest in fecal microbiota transplantation (FMT) as treatment. Although, frozen donor feces preserved at ‐20°C has been widely used for practical advantages, freezing at ‐20°C can affect bacterial viability. Adequacy evaluation of fresh and frozen feces as the transplant is necessary for the methodological improvement of FMT. Methods and Results The viable bacterial compositions of fecal specimens under fresh and freezing conditions were compared by a microbiome analysis using propidium monoazide (PMA microbiome). In addition, recovery abilities from bacterial reduction by antibiotics were compared between fresh and frozen FMT using a murine model. PMA microbiome results suggested that freezing and freeze‐thawing didn't significantly affect in vitro fecal bacterial viability. However, the recovery effect from antimicrobial cleansing in frozen FMT was reduced in a freezing time‐dependent manner, especially prominent in Actinobacteria and Bacteroidetes phyla. Conclusions Short‐term freezing preservation of feces exhibited maintenance of enteric colonization ability in frozen FMT in comparison to 1 month ‐20°C‐preservation. Significance and impact Long‐term ‐20°C‐preservation of transplanted feces can result in instability of the clinical outcome in FMT therapy. The standardization of practical procedures of FMT therapy according to disease types is desirable. This article is protected by copyright. All rights reserved.
... APOE-ε4 prevalence within global AD populations varies considerably ranging from 41% to 61% (Corbo and Scacchi, 1999;Crean et al., 2011;Farrer et al., 1997) and only half of APOE-ε4 homozygotes develop AD by age 90 years (Henderson et al., 1995). This indicates that the penetrance of the ε4 allele, its influence on the rate of cognitive decline and the likelihood of transitioning to mild cognitive impairment (MCI) and AD, is variable and potentially modifiable (Fenesi et al., 2017;Moser and Pike, 2017;Singh et al., 2006;Ward et al., 2012). ...
Article
An apolipoprotein E ε4 (APOE-ε4) genotype is the strongest common genetic determinant of Alzheimer's disease (AD). The pleiotropic nature of apolipoprotein E has made elucidation of the aetiological basis difficult to establish, which is further complicated by the fact that the penetrance of the APOE-ε4 allele is modulated by sex, age, and nutrition. A greater metabolic consequence of the APOE-ε4 allele is likely to contribute to the fact that two-thirds of AD patients are female. A higher tissue status of the marine n-3 fatty acid docosahexaenoic acid (DHA) is associated with a lower AD risk. However, APOE-ε4 carriers appear less sensitive to the neurocognitive benefits, which may be due to defective blood-brain barrier transport of DHA exacerbated by aging and possibly sex. This suggests higher DHA requirements in this large population subgroup. This narrative review will consider the influence of sex and DHA in modulating APOE-ε4-mediated AD risk.
... There are projects utilizing reaction time as a physiological measure (e.g. [4][5][6]) but to the authors best knowledge, there are no datasets publicly available that contain reaction time data together with other supportive health related data and metadata. ...
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Smoking, excessive drinking, overeating and physical inactivity are well-established risk factors decreasing human physical performance. Moreover, epidemiological work has identified modifiable lifestyle factors, such as poor diet and physical and cognitive inactivity that are associated with the risk of reduced cognitive performance. Definition, collection and annotation of human reaction times and suitable health related data and metadata provides researchers with a necessary source for further analysis of human physical and cognitive performance. The collection of human reaction times and supporting health related data was obtained from two groups comprising together 349 people of all ages - the visitors of the Days of Science and Technology 2016 held on the Pilsen central square and members of the Mensa Czech Republic visiting the neuroinformatics lab at the University of West Bohemia. Each provided dataset contains a complete or partial set of data obtained from the following measurements: hands and legs reaction times, color vision, spirometry, electrocardiography, blood pressure, blood glucose, body proportions and flexibility. It also provides a sufficient set of metadata (age, gender and summary of the participant's current life style and health) to allow researchers to perform further analysis. This article has two main aims. The first aim is to provide a well annotated collection of human reaction times and health related data that is suitable for further analysis of lifestyle and human cognitive and physical performance. This data collection is complemented with a preliminarily statistical evaluation. The second aim is to present a procedure of efficient acquisition of human reaction times and supporting health related data in non-lab and lab conditions.
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Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer’s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-β and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia.
Preprint
INTRODUCTION: APOE4 genotype and lifestyle have been associated with Alzheimer's disease (AD) risk, but how they interact on neuroimaging and cognitive markers of aging and AD remains unclear. METHODS: In 135 cognitively unimpaired older adults from the baseline Age-Well trial, we investigated the interaction between APOE4 status and cognitive activity, diet and physical activity on cognition and neuroimaging markers of neurodegeneration and amyloid. RESULTS: Higher cognitive activity correlated with lower medial temporal lobe (MTL) volume and perfusion in APOE4-carriers, but increased cognitive performance irrespective of APOE4 status. Higher adherence to the Mediterranean diet correlated with higher MTL metabolism and attention scores in APOE4-carriers. Conversely, physical activity correlated with higher MTL perfusion and lower amyloid in APOE4-non-carriers only. DISCUSSION: Genetics and lifestyle factors act through different mechanisms to help APOE4-carriers resist or cope with brain alterations and postpone cognitive decline. Our results support the need of personalized lifestyle-based interventions for AD.
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Background APOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and AD is still missing. Our objective is to assess this question in cognitively normal elderly. Method Baseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well study were analysed. They underwent lifestyle questionnaires (physical and cognitive activity, and diet), neuropsychological assessment (global cognition, memory, attention and executive functions) and multimodal neuroimaging (structural MRI, FDG‐ and Florbetapir‐PET). Interactions between lifestyle and APOE4 status on neuroimaging and cognition were assessed for each lifestyle factor separately. Result There was an interaction between APOE4 status and cognitive activity on neuroimaging measures (p‐values<.04), such that higher cognitive engagement was associated with lower grey matter volume in the parahippocampal cortex and lower brain perfusion in the entorhinal and perirhinal cortices in APOE4 carriers only (Figure 1A). However, greater cognitive engagement was associated with increased cognitive performance (global cognition, executive function and attention, all p‐values<.005), and this irrespective of APOE4 status (i.e., no cognitive activity x APOE4 status interaction; Figure 1B). For diet, interactions were evidenced (p‐values <.04) such that higher adherence to the Mediterranean diet was associated with i) higher brain glucose metabolism in the medial temporal lobe (Figure 2A) and ii) higher performance on attention tests (Figure 2B) in APOE4 carriers only. No interactions were found for physical activity. Conclusion Our results indicate that APOE4 carriers with higher cognitive activity had lower brain outcomes but preserved cognition, suggesting that enriched cognitive engagement promotes cognitive resilience in this population. On the other hand, APOE4 carriers with higher adherence to the Mediterranean diet had greater cerebral metabolism and greater attention capacities. Overall, this suggests that distinct lifestyle factors differentially help APOE4 carriers to resist or cope with brain alteration and postpone cognitive decline. ClinicalTrials.gov Identifier: NCT02977819.
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For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.
Article
Background Both education and cardiovascular risk factors are strongly associated with dementia risk. However, it is not clear whether these associations persist or vary among individuals with high genetic risk for Alzheimer’s Disease. We examined the interactive relationship between lifestyle and genetic dementia risk factors in a prospective cohort study. Methods Our data came from the Atherosclerosis Risk in Communities study participants (n=13,715; baseline age 45-64; 25% Black; 55% female), who were followed for incident dementia from 1987 through 2017. We used Cox proportional hazard models to estimate the risk of dementia (ascertained through in-person examination, telephone cognitive screeners, and/or hospital and death records) associated with baseline education and cardiovascular risk factors (measured using the American Heart Association’s “Life Simple 7”) among ε4 carriers and non-carriers separately. We also examined differences by race and sex. Results 2,226 incident dementia cases occurred over a median 25 years of follow-up. Lower educational attainment and poorer cardiovascular health were associated with greater risk of incident dementia. There was an education by APOE status interaction (p=0.005) whereby the association of education and dementia was weaker for ε4 carriers (HR college graduates vs. less than high school: 0.71 (0.59-0.84) than non-carriers (0.54 (0.47-0.63)). There was no interaction between APOE status and cardiovascular health on dementia risk. These relationships did not vary significantly by race or sex. Conclusions Education and cardiovascular health were associated with lower dementia risk regardless of APOE genotype, though the protective effects of education were somewhat diminished among ε4 carriers.
Article
Background: The global race-dependent association of Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOEɛ4 was a risk factor for AD, whereas APOEɛ2 protected against it. The effects of APOEɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOEɛ4/ɛ4 and lower frequency of APOEɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.
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Adults with Down syndrome (DS) are at risk for Alzheimer's disease. Despite sharing trisomy 21, however, there is variability in the age of disease onset. This variability may mean that other factors, such as lifestyle, influence cognitive aging and disease timing. The present study assessed the association between everyday life physical activity using an actigraph accelerometer and cognitive functioning and early Alzheimer's disease pathology via positron emission tomography amyloid-β and tau and diffusion tension imaging measures of white matter integrity in 61 non-demented adults with DS. Percent time in sedentary behavior and in moderate-to-vigorous activity were associated (negatively and positively, respectively) with cognitive functioning (r = -.472 to .572, p <.05). Neither sedentary behavior nor moderate-to-vigorous activity were associated with amyloid-β or tau, but both were associated with white matter integrity in the superior and inferior longitudinal fasciculus (Fractional Anisotropy: r = -.397 to -.419, p < .05; Mean Diffusivity: r = .400, p < .05). Longitudinal studies are needed to determine if physical activity promotes healthy aging in DS.
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Previous research has shown beneficial cognitive changes following exercise training in older adults. However, the work on the potential moderating effects of Apoliprotein E (APOE) ε4 carrier status has been mixed, and the role of exercise intensity remains largely unexplored. The present study sought to examine the influence of APOE ε4 status and exercise intensity on measures of cognitive performance in a group of older adults. Cross-sectional comparisons between a group of younger inactive adults (n = 44, age = 28.86 ± 0.473 SD, 60.5% female) and a group of older inactive adults (n = 142, age = 67.8 ± 5.4, 62.7% female) were made on baseline measurements of APOE ε4 status, VO2peak, and cognitive performance in the domain of executive functioning. The older adults also participated in a randomized controlled exercise trial, exercising three times per week for 16-weeks in either a low-intensity continuous training (LICT) group or a moderate-intensity continuous training plus interval training (MICT+IT) group at the Center for Health and Neuroscience, Genes, and Environment (CUChange) Exercise Laboratory. Follow-up measurements of VO2peak and cognitive performance were collected on the older adults after the exercise intervention. Cross-sectional comparisons between the older and younger adults demonstrated significant impairments among older adults in Stroop effect on error and time, Category Switch mixing effects, and Keep Track task. This impairment was not moderated by APOE ε4 carrier status. Improvements from pre- to post-exercise intervention were observed in both exercise groups in Stroop effect on error ([F (1, 256) = 9.381, p < 0.01, η² = 0.031]) and Category Switch switching effect reaction time ([F(1, 274) = 4.442, p < 0.05, η² = 0.020]), with no difference between exercise groups. The moderating effects of APOE ε4 carrier status were mixed. Exercise did not improve the Stroop effect on error among ε4 carriers assigned to MICT+IT when improvements were seen in all other groups. Further research is needed to examine the mechanisms of action by which exercise impacts cognitive task performance, and possible moderators such as genetic variability and exercise intensity.
Article
Genetic polymorphisms within physiologically relevant KIF6 and APOE genes were examined in the context of athletic performance. KIF6 and ApoE are involved in cardiovascular health, modulation of lipid level and neurotransmission amongst others. The aim of this study was to examine whether three polymorphisms, KIF6 rs20455 T>C, APOE rs429358 T>C and APOE rs7412 C>T, were associated with athletic status of an athlete defined as performance type (endurance or power). Genotyping was performed using real-time PCR on buccal genomic DNA from 204 Polish athletes including 104 endurance and 100 power athletes, and 161 sedentary individuals. APOE rs429358 genotype frequencies differed significantly between power athletes and sedentary individuals (p = 0.046). KIF6 rs20455 and APOE rs7412 were found to be epistatically associated with the power athletic status (p = 0.032). KIF6 rs20455, APOE rs429358 and APOE rs7412 were associated with athletic status of Polish athletes. In the future, these polymorphisms could contribute to predictive models aimed at assessment of an individual’s athletic status.
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Aerobic exercise may enhance memory in older adults. However, the optimal intensity and underlying mechanism are unclear. This community-based study examined the effect of aerobic exercise intensity on memory and general cognitive abilities. Brain-derived neurotrophic factor (BDNF) was examined as a potential mechanism. Sixty-four sedentary older adults participated in 1 of 3 groups: (i) high-intensity interval training (HIIT); (ii) moderate continuous training (MCT); or (iii) stretching control (CON). Prior to and following the intervention, high-interference memory was assessed using a Mnemonic Similarity task and executive functions were assessed using Go Nogo and Flanker tasks. HIIT led to the greatest memory performance compared with MCT and CON (F [2,55] = 6.04, p = 0.004) and greater improvements in memory correlated with greater increases in fitness (r s (46) = 0.27, p = 0.03). Exercise intensity seemed to matter less for executive functioning, as positive trends were observed for both HIIT and MCT. No significant differences in BDNF were found between groups. Overall, these results suggest that aerobic exercise may enhance memory in older adults, with the potential for higher intensity exercise to yield the greatest benefit. While our findings suggest that BDNF does not regulate these adaptations, the mechanisms remain to be determined. Novelty High-intensity interval training results in the greatest memory performance in inactive older adults compared with moderate continuous training or stretching. Improvement in fitness correlates with improvement in memory performance.
Article
Higher cardiorespiratory fitness has been associated with better cognitive function in older adults; yet, this relationship demonstrates a degree of variability across the older adult population. Thus, it is hypothesised that variation in genetic factors may influence the relationship between fitness and cognitive health. One such genetic factor is the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, which has previously been shown to moderate the relationship between self-reported physical activity and memory performance. In this study we aim to investigate the interaction between BDNF Val66Met polymorphism and objectively-measured cardiorespiratory fitness on performance on tasks assessing verbal and visuospatial memory. Data from ninety-nine cognitively normal men and women aged 60–80 years were used. Fitness was assessed by peak oxygen consumption, and verbal and visuospatial memory were evaluated using well-validated measures. Participants were categorised into: lower-fit Met carriers, higher-fit Met carriers, lower-fit Val/Val, or higher-fit Val/Val. Higher-fit individuals performed better on a task assessing visuospatial memory, compared with lower-fit individuals. Furthermore, an interaction between BDNF Val66Met and fitness was observed in terms of visuospatial memory performance on a continuous paired associate learning task; whereby lower-fit Met carriers performed 1 standard deviation worse than higher-fit Met carriers. No differences were observed between the higher-fit and lower-fit Val/Val homozygotes. Future intervention studies should evaluate the effect of structured exercise on cognitive health between BDNF Val66Met carriers and Val/Val homozygotes.
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Physical activity may decrease the risk of dementia; however, conflicting findings exist. The purpose of the current meta-analysis was to investigate the relationship between physical activity and dementia risk based on physical activity type, amount, and intensity, and to propose an effective minimal physical activity amount for older adults. Forty-four studies were selected for the meta-analysis. Participation in high (a total of >2 hours of activity over the course of three sessions per week) and moderate (a total of >1 hour of activity over the course of two sessions per week) amounts of physical activity showed decreased dementia risks compared to physical inactivity. Vigorous exercise, regular exercise, leisure time physical activities, and gardening showed a positive effect toward lowering dementia risk, but walking was not associated with dementia risk. Physically inactive individuals had a higher dementia risk than those who participated in physical activity. Participation in physical activities produces a favorable effect toward lowering dementia risk. Participating in regular physical activity of >1 hour over the course of two sessions per week and avoiding physical inactivity are recommended for lowering dementia risk. [Journal of Gerontological Nursing, 44(10), 22-29.].
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The APOE4 allele confers greater risk of Alzheimer’s Disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment (MCI) and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in two clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes. At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy (CAA), plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and CAA increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds vs the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.
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This Viewpoint discusses evidence that the beneficial effects of physical activity may vary depending on activity levels.Physical inactivity has been labeled a pandemic due to its increasing global prevalence and its health, economic, environmental, and social consequences. More than half of US adults fail to meet the 2008 physical activity recommendations of 30 minutes of moderate-intensity exercise daily (eg, brisk walking, dancing, and gardening) or 75 minutes of vigorous-intensity exercise weekly (eg, running, fast cycling, and competitive sports). Hence, increasing physical activity is essential for public health because it improves primary and secondary disease prevention across the population.
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The treatment of noncommunicable diseases (NCD), like coronary heart disease or type 2 diabetes mellitus, causes rising costs for the health system. Physical activity is supposed to reduce the risk for these diseases. Results of cross-sectional studies showed that physical activity is associated with better health, and that physical activity could prevent the development of these diseases. The purpose of this review is to summarize existing evidence for the long-term (>5 years) relationship between physical activity and weight gain, obesity, coronary heart disease, type 2 diabetes mellitus, Alzheimer's disease and dementia. Fifteen longitudinal studies with at least 5-year follow up times and a total of 288,724 subjects (>500 participants in each study), aged between 18 and 85 years, were identified using digital databases. Only studies published in English, about healthy adults at baseline, intentional physical activity and the listed NCDs were included. The results of these studies show that physical activity appears to have a positive long-term influence on all selected diseases. This review revealed a paucity of long-term studies on the relationship between physical activity and the incidence of NCD.
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As physical activity may modify the effect of the apolipoprotein E (APOE) ε4 allele on the risk of dementia and Alzheimer's disease (AD) dementia, we tested for such a gene-environment interaction in a sample of general practice patients aged ⩾75 years. Method Data were derived from follow-up waves I-IV of the longitudinal German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). The Kaplan-Meier survival method was used to estimate dementia- and AD-free survival times. Multivariable Cox regression was used to assess individual associations of APOE ε4 and physical activity with risk for dementia and AD, controlling for covariates. We tested for gene-environment interaction by calculating three indices of additive interaction. Among the randomly selected sample of 6619 patients, 3327 (50.3%) individuals participated in the study at baseline and 2810 (42.5%) at follow-up I. Of the 2492 patients without dementia included at follow-up I, 278 developed dementia (184 AD) over the subsequent follow-up interval of 4.5 years. The presence of the APOE ε4 allele significantly increased and higher physical activity significantly decreased risk for dementia and AD. The co-presence of APOE ε4 with low physical activity was associated with higher risk for dementia and AD and shorter dementia- and AD-free survival time than the presence of APOE ε4 or low physical activity alone. Indices of interaction indicated no significant interaction between low physical activity and the APOE ε4 allele for general dementia risk, but a possible additive interaction for AD risk. Physical activity even in late life may be effective in reducing conversion to dementia and AD or in delaying the onset of clinical manifestations. APOE ε4 carriers may particularly benefit from increasing physical activity with regard to their risk for AD.
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Objective: To test for an association between the apolipoprotein E (APOE) ϵ4 allele and dementias with synucleinopathy. Design: Genetic case-control association study. Setting: Academic research. Patients: Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). MAIN OUTCOME MEASURE The APOE allele frequencies. RESULTS The APOE ϵ4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ(2)(4)=185.25; P=5.56 × 10(-39)), and it was higher in the pDLB group than the PDD group (P= .01). In an age-adjusted and sex-adjusted dominant model, ϵ4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). CONCLUSIONS The APOE ϵ4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ϵ4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ϵ4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
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Apolipoprotein E (APOE) genotype was determined in a population of patients with dementia, including 735 patients with Alzheimer's disease (AD), 75 with Frontotemporal Lobar Degeneration (FTLD), 97 with Vascular Dementia (VaD) and 40 with Lewy Body Dementia (LBD), as well as in 506 age- and gender-matched controls (CON). APOE ε2 allele frequency was lower in patients with AD (2.8%) than in CON (6.4%, P≤0.001, OR: 0.41). Similar results were obtained comparing AD with FTLD (6.7%, P≤0.01, OR: 0.37), at difference from VaD (5.6%, P>0.05) or LBD (5.0%, P>0.05). The frequency of the APOE ε4 allele was increased in patients with AD (25.1%) as compared with CON (8.2%, P≤0.001, OR: 4.24), FTLD (11.3%, P≤0.001, OR: 2.67), VaD (11.8%, P≤0.001, OR: 3.02), or LBD (13.8%, P=0.048, OR: 2.07). The frequency of the ε4/ε4 genotype was increased in AD patients compared with controls (6.3 versus 0.8%, P≤0.001, OR: 8.38). The presence of the ε2 allele is a protective factor for AD, whereas the ε4 allele acts as a risk factor for the disease. Both alleles do not influence the susceptibility to FTLD, LBD and VaD.
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The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
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Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n=501), and again at mean ages of 83 (n=284) and 87 (n=187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In non-demented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life.
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The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.
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This study examines cross-sectional age differences, longitudinal age changes, and secular changes in obligatory, committed, and discretionary activities, using activity questionnaire completed by men and women participants in the Baltimore Longitudinal Study of Aging between 1958 and 1992. (1) Time spent, on obligatory activities and passive leisure is greatest, and on committed activities and active leisure least, for older adults. (2) Longitudinal patterns usually mirror cross-sectional ones. There are pronounced exceptions for women whose paid work time has been increasing and housework decreasing, while cross-sectional patterns show the reverse. (3) Over recent decades, time in committed activities shifted in opposite ways for men and women. Men decreased paid work and increased housework, repairs and yardwork, shopping, and child-care, while women increased paid work and decreased housework. In sum, the age structure of activities has persisted in the midst of new social opportunities; gender roles have proven more malleable than age roles.
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Summary points People with mild cognitive impairment are up to 15 times more likely to develop Alzheimer’s disease than those with normal cognitionMemory loss is a presenting symptom in most people who develop Alzheimer’s diseaseThe cause of Alzheimer’s disease is unknown, but genetic and environmental risk factors have been implicatedCholinesterase inhibitors are safe and effective and can be prescribed for people in the moderate stages of Alzheimer’s diseaseAntipsychotic drugs reduce agitation but are linked with an increased risk of mortality and impair cognitionEvidence is growing that some strategies are successful at preventing Alzheimer’s diseaseIn this, the second of two review articles about dementia, we focus on Alzheimer’s disease, which is the most common cause of dementia. Dementia is a clinical syndrome characterised by a cluster of symptoms and signs manifested by difficulties in memory, disturbances in language, psychological and psychiatric changes, and impairments in activities of daily living. Alzheimer’s disease is a specific disease that affects about 6% of the population aged over 65 and increases in incidence with age.1 Patients with Alzheimer’s disease are often identified and managed in primary care, where they may present diagnostic and management challenges. The benefits of early investigation and diagnosis of Alzheimer’s disease include instigation of pharmacological symptomatic treatments and initiation of psychosocial support, plus treatment of comorbid conditions. Here we review the diagnosis and medical management of Alzheimer’s disease, relying where possible on evidence from randomised controlled trials.What is Alzheimer’s disease?Alzheimer’s disease is a chronic progressive neurodegenerative disorder characterised by three primary groups of symptoms. The first group (cognitive dysfunction) includes memory loss, language difficulties, and executive dysfunction (that is, loss of higher level planning and intellectual coordination skills). The second group comprises psychiatric symptoms and behavioural disturbances—for example, depression, hallucinations, delusions, agitation—collectively termed non-cognitive symptoms.2 The third …
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Background: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. Methods: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. Results: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. Conclusions: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory.
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Objective APOE ϵ4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. Design APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11–labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. Setting Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri. Participants A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer’s Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants. Results APOE ϵ4 carriers evidenced higher [11C]PiB binding (P < .001) and lower CSF Aβ42 levels (P < .001) than did noncarriers. Our previous findings of higher [11C]PiB binding (P = .005) and lower CSF Aβ42 levels (P = .009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [11C]PiB binding (P = .008) such that a more sedentary lifestyle was significantly associated with higher [11C]PiB binding for ϵ4 carriers (P = .013) but not for noncarriers (P = .20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments. Conclusion Collectively, these results suggest that cognitively normal sedentary APOE ϵ4–positive individuals may be at augmented risk for cerebral amyloid deposition.
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Vascular dementia is the second common cause of dementia, only second to Alzheimer's disease in later life. The Apolipoprotein E (ApoE) gene polymorphism as a risk factor in vascular dementia has been suggested, but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed this meta-analysis in order to evaluate the relationship between ApoE gene polymorphism and susceptibility to vascular dementia in Chinese population by pooling data from all relevant case-control studies published domestically and abroad from January 1990 to May 2011. 18 case-control studies were selected. Meta-analysis results showed that the pooled OR value of vascular dementia subjects in Chinese population with ε4 allele carriers was 2.07 [95% CI (1.69, 2.53)], and the pooled OR value of vascular dementia subjects with E4/E4 genotype was 3.34 [95% CI (1.89, 5.88)]. These results suggest that ApoE polymorphism is significantly associated with susceptibility to vascular dementia in Chinese population. The subject with at least one ε4 allele or E4/E4 genotype has higher risk suffering from vascular dementia than others.
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This was a prospective study of dementia to elucidate mechanisms of disease risk factors amenable to modification and specifically to determine whether midlife cognitive and physical leisure activities are associated with delayed onset or reduced risk of dementia within older male twin pairs. The co-twin control design used prospectively collected exposure information to predict risk of dementia 20 to 40 years later. The subjects were community-dwelling and nursing home residents living throughout the continental United States. We studied 147 male twin-pairs who were discordant for dementia or age of dementia onset and were members of the National Academy of Sciences-National Research Council Twin Registry of World War II veterans and participants in the Duke Twins Study of Memory in Aging. The main outcome measure was diagnosed dementia by using a two-stage screen and full clinical evaluation. Conditional odds ratios were estimated for the association between midlife leisure activities and late-life dementia. Greater midlife cognitive activity was associated with a 26% risk reduction for dementia onset. Protective effects were most robust in monozygotic twin pairs, where genetic and early-life influences were most tightly controlled, and for activities that were often cognitive and social in nature. Cognitive activity was particularly protective among monozygotic twin pairs carrying the apolipoprotein E epsilon4 allele, with a 30% risk reduction. Midlife physical activity did not modify dementia risk. Participation in a range of cognitively and socially engaging activities in midlife reduced risk for dementia and AD in twins discordant for onset, particularly among twin pairs at elevated genetic risk, and might be indicative of an enriched environment.