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Compensatory mechanisms in higher-educated subjects with Alzheimer's disease: A study of 20 years of cognitive decline
Abstract
A better knowledge of long-term trajectories of cognitive decline is a central feature of the study of the process leading to Alzheimer's dementia. Several factors may mitigate such decline, among which is education, a major risk factor for Alzheimer's disease. The aim of our work was to compare the pattern and duration of clinical trajectories before Alzheimer's dementia in individuals with low and high education within the PAQUID cohort involving 20 years of follow-up. The sample comprises 442 participants with incident Alzheimer's disease (27.2% were male)-171 with low education (mean age = 86.2 years; standard deviation = 5.3 years) and 271 with higher education (mean age = 86.5; standard deviation = 5.4)-and 442 control subjects matched according to age, sex and education. At each visit and up to the 20-year follow-up visit, several cognitive and clinical measures were collected and incident cases of Alzheimer's disease clinically diagnosed. The evolution of clinical measures in pre-demented subjects and matched controls was analysed with a semi-parametric extension of the mixed effects linear model. The results show that the first signs of cognitive decline occurred 15 to 16 years before achieving dementia threshold in higher-educated subjects whereas signs occurred at 7 years before dementia in low-educated subjects. There seemed to be two successive periods of decline in higher-educated subjects. Decline started ∼15 to 16 years before dementia with subtle impairment restricted to some cognitive tests and with no impact during the first 7 to 8 years on global cognition, cognitive complaints, or activities of daily living scales. Then, ∼7 years before dementia, global cognitive abilities begin to deteriorate, along with difficulties dealing with complex activities of daily living, the increase in self-perceived difficulties and depressive symptoms. By contrast, lower-educated subjects presented a single period of decline lasting ∼7 years, characterized by decline concomitantly affecting specific and more global cognitive function along with alteration in functional abilities. This study demonstrates how early cognitive symptoms may emerge preceding Alzheimer's dementia particularly in higher-educated individuals, for whom decline occurred up to 16 years before dementia. It also demonstrates the protective role of education in the clinical trajectory preceding Alzheimer's dementia. We suggest that the initial decline in cognition occurs at the onset of comparable Alzheimer's disease pathology in both groups, and is associated with immediate decline to dementia in the lower education group. In contrast, higher education protects against further cognitive decline for ∼7 years until pathology becomes more severe.
... However, in later stages, the negative cognitive effects of brain damage in people with high reserve could be increased due to the critical overflow of the compensatory capacity of CR. Accordingly, other studies (Amieva et al., 2014;Mungas et al., 2018;Ye et al., 2013;Yu et al., 2012) have shown that with increasing neurodegeneration, the compensatory effects of higher education are lowered as more developed functional networks that support resilience could become more sensitive to brain damage, potentially leading to faster cognitive decline. ...
... Our results also coincide with previous longitudinal studies carried out in participants without cognitive impairment and with those that implement cross-sectional designs in SCD. Thus, Amieva et al. (2014) showed that cognitively normal individuals with higher education exhibited a slower decline over 15 years before meeting the criteria for dementia, whereas those with lower education experienced a more rapid cognitive decline of 7 years before dementia onset. Cross-sectional evidence also suggests that higher education in participants with SCD can reduce the risk of progression to objective cognitive decline, MCI, or dementia (Crumley et al., 2014;Hao et al., 2017Hao et al., , 2019Yang et al., 2020). ...
... The confidence interval leans more favorably toward those with lower education levels, suggesting a comparatively higher likelihood of progression in this subgroup. These results align with the CR hypothesis (Stern et al., 2020) and the available evidence on the reduction in the risk of progression or delay in the cognitive symptoms onset associated with education (Amieva et al., 2014;Ye et al., 2013;Yu et al., 2012), although it does not eliminate the possibility of suffering from dementia. ...
... On the other hand, the risk of dementia in people with ID without DS is not clear. It has been reported that a cognitive reserve, which is formed by education and cognitive stimulation, influences cognitive function in old age [9,10]. Based on previous reports that low cognitive reserve in the general population increases the risk of dementia [9][10][11][12], it is speculated that the prevalence of dementia is higher in populations with ID, which tend to have less developed intellectual functioning and shorter duration of education [5,13]. ...
... It has been reported that a cognitive reserve, which is formed by education and cognitive stimulation, influences cognitive function in old age [9,10]. Based on previous reports that low cognitive reserve in the general population increases the risk of dementia [9][10][11][12], it is speculated that the prevalence of dementia is higher in populations with ID, which tend to have less developed intellectual functioning and shorter duration of education [5,13]. However, the results of previous reports are not consistent. ...
... Many previous studies have consistently documented that individuals who are highly educated or frequently participate in intellectual activity may have better cognitive functioning in old age and a lower risk of developing dementia [9][10][11][12]. On the other hand, one negative effect that may affect the risk of dementia in people with ID is the wear-and-tear phenomenon (proposed under the name of the "weathering hypothesis"), whereby social minorities are subjected to so much stress from socioeconomic disadvantage that they carry an allostatic load, which accelerates biological aging and causes cognitive decline [31,32]. ...
Background
People with intellectual disability (ID) without Down syndrome (DS) are presumed to be at higher risk of developing dementia due to their lower baseline cognitive reserve. We aimed to determine the prevalence of dementia in people with ID without DS and to identify risk factors of dementia.
Methods
This was a cross-sectional survey and multicenter study in Japan. Adults with ID without DS residing in the facilities were included. Caregivers of all participants were interviewed by medical specialists, and participants suspected of having cognitive decline were examined directly. ICD-10 criteria for dementia, DC-LD criteria for dementia, and DSM-5 criteria for neurocognitive disorders were used to diagnose dementia. The severity of ID, educational history, and comorbidities were compared by dividing the groups into those with and without dementia.
Results
A total of 1831 participants were included; 118/1831 (6.44%) were diagnosed with dementia. The prevalence of dementia for each age group was 8.8%, 60–64 years; 9.0%, 65–69 years; 19.6%, 70–74 years; and 19.4%, 75–79 years. Age, severity of ID, duration of education, hypertension, depression, stroke, and traumatic brain injury were significantly associated with the presence of dementia.
Conclusions
Although the prevalence of dementia in people with ID without DS was found to be higher at a younger age than in the general population, the results of this study suggested that adequate education, prevention of head trauma and stroke, and treatments of hypertension and depression may reduce the risk of dementia. These may be potentially important modifiable risk factors for the prevention of dementia in these people.
... On the other hand, the risk of dementia in people with ID without DS is not clear. It has been reported that a cognitive reserve, which is formed by education and cognitive stimulation, in uences cognitive function in old age [9,10]. Based on previous reports that low cognitive reserve in the general population increases the risk of dementia [9,10,11,12], it is speculated that the prevalence of dementia is higher in populations with ID, which tend to have less developed intellectual functioning and shorter duration of education [5,13]. ...
... It has been reported that a cognitive reserve, which is formed by education and cognitive stimulation, in uences cognitive function in old age [9,10]. Based on previous reports that low cognitive reserve in the general population increases the risk of dementia [9,10,11,12], it is speculated that the prevalence of dementia is higher in populations with ID, which tend to have less developed intellectual functioning and shorter duration of education [5,13]. However, the results of previous reports are not consistent. ...
... Many previous studies have consistently documented that individuals who are highly educated or frequently participate in intellectual activity may have better cognitive functioning in old age and a lower risk of developing dementia [9,10,11,12]. On the other hand, there have been no studies that clearly show how the severity of pre-existing ID and educational history are related to the risk of dementia in people with ID [30]. ...
Background
People with intellectual disability (ID) without Down syndrome (DS) are also presumed to be at higher risk of developing dementia due to their lower baseline cognitive reserve. We aimed to determine the prevalence of dementia in people with ID without DS and to identify risk factors of dementia.
Methods
This was a cross-sectional survey and multicenter study in Japan. Adults with ID without DS residing in the facilities were included. Caregivers in all participants were interviewed by medical specialists, and participants suspected of having cognitive decline were examined directly. DSM-5, ICD-10, and DC-LD were used to diagnose dementia. The severity of ID, educational history, and comorbidities were compared by dividing the groups into those with and without dementia.
Results
A total of 1831 participants were included; 118/1831 (6.44%) were diagnosed with dementia. The prevalence of dementia for each age group was 8.8%, 60–64 years; 9.0%, 65–69 years; 19.6%, 70–74 years; 19.4%, 75–79 years. Age, severity of ID, duration of education, hypertension, stroke, and traumatic brain injury were significantly associated with the presence of dementia.
Conclusions
Although the prevalence of dementia in people with ID without DS was found to be higher at a younger age than in the general population, the results of this study suggested that adequate education, prevention of head trauma and stroke, and treatment of hypertension may reduce the risk of dementia. These may be potentially important modifiable risk factors for the prevention of dementia in these people.
... To that end, several researchers have reported that memory complaints and cognitive changes may start even as early as 15 years before the clinical identification of Alzheimer's Disease (AD) [3,4]. However, most studies agree that the majority of those who will eventually develop AD tend to undergo an accelerated course of cognitive decline during the last 3 to 8 years prior to the formal diagnoses of both entities (compared to those who do not develop cognitive impairment) [5,6]. ...
... Previous research has suggested that cognitive changes tend to precede the diagnosis of AD for many years, potentially reflecting the undergoing neurodegenerative alterations which are present even as long as 20-25 years before its onset [3,4]. Episodic memory, language, attention, visuoperceptual and executive skills have all been reported to decline prior to the former identification of AD [10]. ...
... Episodic memory, language, attention, visuoperceptual and executive skills have all been reported to decline prior to the former identification of AD [10]. However, episodic memory dysfunction usually precedes while visuospatial and language decline tend to ensue [3,4,6]. On the other hand, attention and executive function-dependent tasks are affected later in the preclinical course towards the development of AD, typically within the last 3 years before its clinical diagnosis [7,8,45]. ...
Background
The cognitive trajectories of cognitively normal (CN) individuals rapidly progressing to Alzheimer’s disease dementia (AD) have not been investigated.
Aim
To explore the preclinical pattern of cognitive performance heralding the rapid progression from normal cognition to AD.
Methods
The HELIAD cohort underwent comprehensive neuropsychological assessments (memory, language, attention, executive and visuo-perceptual functions) at baseline and after approximately 3-year intervals. The cognitive trajectories of those with normal cognition at baseline were explored according to the follow-up diagnosis using adjusted generalised estimating equations analyses.
Results
A total of 932 predominantly female (61%), older (72.9 ± 4.9), CN participants were followed for 3.09 (± 0.83) years. Among them, 761 individuals remained CN, 29 progressed to AD and 142 developed MCI (33 single-domain amnestic, 41 multidomain amnestic, 37 single-domain non-amnestic and 31 multidomain non-amnestic). Those progressing to AD were already performing worse than the healthy reference in every single cognitive domain at baseline. Cognitive deficits ranged between ~ 0.5SD (attention, executive function and language) and ~ 1.0SD (memory and visuo-perceptual skills). Throughout the 3-year follow-up, memory constantly exhibited the most prominent impairment compared to the remaining cognitive domains while executive function diminished in the most abrupt fashion (~ 0.19SD yearly) separating from the remaining three cognitive functions before the development of full-blown AD. Heterogeneous patterns of cognitive decline clearly differentiated those progressing to MCI from those rapidly converting to AD, as well.
Discussion
Poor performance in every cognitive domain may characterise cognitively normal individuals at high risk of fast progression to AD.
Conclusion
Strict neuropsychological cut-offs fail to detect a considerable number of individuals at high risk of rapid progression to AD.
... [15] Rather, a high cognitive reserve was associated with a faster rate of cognitive decline after the onset of dementia. [14,16] Based on previous reports of the association between educational level and dementia incidence, we inferred that a higher educational level was associated with a later dementia diagnosis and registration. Moreover, we hypothesized that urban residents would be diagnosed and registered with dementia faster because of better access to medical care. ...
... First, we inferred that a higher-level of education conferred greater sensitivity to discover cognitive decline or abnormal behaviors that occurred after the onset of dementia. A study conducted in France by Amieva et al [16] reported that the first sign of cognitive decline was detected 15 to 16 years before being diagnosed with AD in the highly educated patient group, which is much earlier than the average 7 years in the low-education patient group. Our results confirmed that the higher the educational level, the higher is the neurocognitive function when applying for the SDR. ...
In South Korea Long-Term Care Insurance (LTCI) system, the special dementia rating (SDR) is a registration grading for dementia patients who do not have a physical disability or functional restrictions and is the first applicable registration following the diagnosis of dementia. We investigated the differences in age of registration of SDR and age of dementia diagnosis according to the educational level and residential area. This was a retrospective, cross-sectional study using the Korean National Health Insurance Service dataset. Applications for SDR between July 2014 and December 2016 were identified for participant selection, and 32,352 patients with dementia were included. Educational levels were defined as follows: the illiterate, only-reading, 1 to 6 years, 6 to 12 years, and ≥12 years. Urban residents were those who lived in the city, as ascertained from the Korean administrative district system. The primary outcomes were ages at the time of dementia diagnosis and SDR registration. A lower education level significantly correlated with a higher proportion of older adults, but a higher number of years of education significantly increased with the proportion of males and urban residents (P < .001 for all). A higher education level was inversely associated with the age at diagnosis of dementia (P < .001) and at the registration of SDR (P < .001). Urban residents were diagnosed with dementia at a significantly lower age and registered for SDR earlier than rural residents (P < .001 for both). Both urban and rural residents consistently showed that a higher educational level was associated with lower age at the dementia diagnosis and SDR registration. Patients who were highly educated and living in urban areas were diagnosed with dementia and registered on SDR when they were relatively younger, indicating that cognitive decline sensitivity and medical accessibility are related to earlier dementia diagnosis and registration.
... The brain can recruit alternative neural networks to compensate and maintain function despite neurodegeneration. This cognitive reserve is driven by factors such as genetically derived innate cognitive abilities [24], education [25,26], and lifelong cognitive activities [27,28]. Robust evidence suggests that cognitive reserve can delay the clinical symptoms of neurodegeneration, though the subsequent functional decline may be steeper once symptoms manifest [29,30]. ...
Identifying early predictors of cognitive decline and at-risk individuals is essential for timely intervention and prevention of dementia. This study aimed to detect neurobiological changes and factors related to cognitive performance in the Metropolit 1953 Danish male birth cohort. We analyzed data from 582 participants, aged 57–68 years, using machine learning techniques to group cognitive trajectories into four clusters differentiating high- and low-performing groups. These clusters were then evaluated with MRI, EEG, and lifestyle/familial risk factors to identify predictors of cognitive decline. Low education and occupation, alcohol consumption, and type 2 diabetes were associated with lower cognitive performance. Declines in neocortical volume and increases in frontotemporal alpha and temporoparietal gamma activity preceded clinical symptoms of cognitive decline. Neocortical atrophy and disruptions in network activity were prominent in lower-performing groups, with higher education and IQ scores and a lower prevalence of lifestyle factors moderating cognitive decline.
... At the relatively stable decline stage, cognitive reserve may not act obviously to slow down the rate of cognitive decline because the brain has not accumulated enough neural burden at this time, which may show the "preserved differentiation. " However, at older age when individuals start to show a sharp cognitive decline, which is when a significant amount of neural burden has been accumulated, the buffering role of cognitive reserve could become active (Amieva et al., 2014). Therefore, the beneficial influence of SA engagement on slowing down cognitive decline might become more obvious and exaggerated with advancing age, thus showing the "differential preservation. ...
Background
Previous research has indicated that engagement in social activities has proven advantageous for diminishing the likelihood of cognitive decline. However, no study has examined whether such cognitive benefits were to a similar extent for the young-old, the old–old, and the oldest-old groups. The purpose of this research was to determine whether aging would have an impact on the changes in cognitive function that would occur in older adults with varying degrees of social involvement.
Methods
The sample for this study comprised 4,481 older adults who participated in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) during the waves spanning from 2008 to 2018. At baseline, participants were classified into the young-old (60–69 years; Mage = 66.66; SD = 1.87), the old–old (70–79 years; Mage = 74.21; SD = 2.82), and the oldest-old (80 years or older; Mage = 86.46; SD = 5.71) groups.
Results
The level of cognitive function decreased as participants aged. Importantly, compared to those lacking social activities, individuals who were got involved in social engagement at baseline had slower rates of cognitive decline over time. Furthermore, compared with the young-old group and the old–old group, the impact of social activity engagement on slowing cognitive decline was more salient for the oldest-old group.
Conclusion
Active engagement in social activities can slow age-related cognitive decline, particularly for the oldest-old group. To preserve cognitive function with aging, attention and resources should be allocated to encourage social activity engagement.
... All these protective factors increase the cognitive reserve, thus improving tolerance to more neuropathologies without cognitive and functional decline and slowing down the development of dementia. The cognitive reserve is influenced by the anatomical substrate of the brain or the adaptability of cognition, depending on the above-mentioned factors [22][23][24]. ...
The expression of inflamma-miRs and human leukocyte antigen (HLA) haplotypes could indicate mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We used international databases to conduct a systematic review of studies on HLA variants and a meta-analysis of research on microRNAs (miRNAs). We aimed to analyze the discriminative value of HLA variants and miRNAs in MCI, AD and controls to evaluate the protective or causative effect of HLA in cognitive decline, establish the role of miRNAs as biomarkers for the early detection of AD, and find a possible link between miRNAs and HLA. Statistical analysis was conducted using Comprehensive Meta-analysis software, version 2.2.050 (Biostat Inc., Englewood, NJ, USA). The effect sizes were estimated by the logarithm base 2 of the fold change. The systematic review revealed that some HLA variants, such as HLA-B*4402, HLA-A*33:01, HLA-A*33:01, HLA-DPB1, HLA-DR15, HLA-DQB1*03:03, HLA-DQB1*06:01, HLA-DQB1*03:01, SNPs on HLA-DRB1/DQB1, and HLA-DQA1, predisposed to cognitive decline before the occurrence of AD, while HLA-A1*01, HLA-DRB1∗13:02, HLA-DRB1*04:04, and HLA-DRB1*04:01 demonstrated a protective role. The meta-analysis identified let-7 and miR-15/16 as biomarkers for the early detection of AD. The association between these two miRNA families and the HLA variants that predispose to AD could be used for the early screening and prevention of MCI.
... There were also significant negative correlations between educational attainment and AD, supporting consistent findings on education's protective effect on AD (13,14). Higher levels of education seem to play a crucial role in maintaining cognitive function across an extended lifespan (36). Educational attainment significantly contributes to cognitive reserve, an individual's ability to perform tasks and solve problems, even in the presence of amyloid pathology (37). ...
Introduction: People with university degrees have a lower incidence of Alzheimer's Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD.
Method: We used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochran's Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects.
Results: Educational attainment reduced the risk of AD (ORIVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (ORIVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (ORIVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (ORIVW 95% CI= 0.76 [0.62, 0.92], p = 0.006).
Conclusion: Univariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.
... Back in 1994, Stern et al. 67 indicated that individuals with higher level of education or occupational attainment showed reduced risk of developing dementia, such as AD. 68 Further investigations confirmed these findings and added other possible proxies for CR, including IQ, late-life leisure activities, engagement in social networks, and physical activity. 44,69 People with a socially active lifestyle, engaged in demanding and intellectual daily life activities, seem to effectively face cognitive impairment. ...
INTRODUCTION
This review examines the concept of cognitive reserve (CR) in relation to brain aging, particularly in the context of dementia and its early stages. CR refers to an individual's ability to maintain or regain cognitive function despite brain aging, damage, or disease. Various factors, including education, occupation complexity, leisure activities, and genetics are believed to influence CR.
METHODS
We revised the literature in the context of CR. A total of 842 articles were identified, then we rigorously assessed the relevance of articles based on titles and abstracts, employing a systematic approach to eliminate studies that did not align with our research objectives.
RESULTS
We evaluate—also in a critical way—the methods commonly used to define and measure CR, including sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures. The challenges and limitations of these measures are discussed, emphasizing the need for more targeted research to improve the understanding, definition, and measurement of CR.
CONCLUSIONS
The review underscores the significance of comprehending CR in the context of both normal and pathological brain aging and emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation in both healthy and neurologically impaired older individuals.
Highlights
This review examines the concept of cognitive reserve in brain aging, in the context of dementia and its early stages.
We have evaluated the methods commonly used to define and measure cognitive reserve.
Sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures are discussed.
The review emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation.
... 3,6 Memory loss is the main cognitive feature in AD clinical progression. 2 However, other cognitive domains such as language and executive function have shown to be also severely impaired in AD. 7 The rate of progression of cognitive decline in AD, considered the speed at which cognitive decline occurs, has shown to be variable in SAD, 8 and less so in FAD. 9 In both cases, rate of decline can be affected by other factors such as years of education 10 or apolipoprotein E (APOE) haplotype. 11,12 Not all cognitive domains decline at the same rate, and more rapidly declining domains can be disease specific, with memory, language, and executive function showing faster decline rates in AD. 13 Some attempts have been made to find genetic markers for cognitive decline progression in AD, with variable success. ...
INTRODUCTION
Rate of cognitive decline (RCD) in Alzheimer's disease (AD) determines the degree of impairment for patients and of burden for caretakers. We studied the association of RCD with genetic variants in AD.
METHODS
RCD was evaluated in 62 familial AD (FAD) and 53 sporadic AD (SAD) cases, and analyzed by whole‐exome sequencing for association with common exonic functional variants. Findings were validated in post mortem brain tissue.
RESULTS
One hundred seventy‐two gene variants in FAD, and 227 gene variants in SAD associated with RCD. In FAD, performance decline of the immediate recall of the Rey‐Osterrieth figure test associated with 122 genetic variants. Olfactory receptor OR51B6 showed the highest number of associated variants. Its expression was detected in temporal cortex neurons.
DISCUSSION
Impaired olfactory function has been associated with cognitive impairment in AD. Genetic variants in these or other genes could help to identify risk of faster memory decline in FAD and SAD patients.
... This comprehensive approach holds the potential to significantly reduce the burden of gastrointestinal diseases on individuals and society as a whole. There is a strong relationship between intelligence, cognition, and education (2,3). Higher levels of education not only provide access to knowledge and broaden horizons, but also influence the development of intelligence and cognition. ...
Background
Education, intelligence and cognition affect occupational performance and socioeconomic status and may influence virous diseases development. However, the impact of these factors on gastrointestinal diseases and their mediating risk factors remains unclear.
Methods
We utilized genome-wide association studies from European ancestry populations to perform two-sample Mendelian randomization analyses, aiming to estimate genetic instruments associated with education, intelligence, or cognition in relation to 24 gastrointestinal diseases Subsequently, we evaluated 14 potential mediators of this association and calculated the corresponding mediated proportions through two-step Mendelian randomization analyses.
Result
As the dominant factor in gastrointestinal diseases, education had a statistically significant association with 2 gastrointestinal diseases (acute pancreatitis, gastroesophageal reflux) and a suggestive association with 6 diseases (cirrhosis, alcoholic liver disease, cholecystitis, cholelithiasis, chronic gastritis and gastric ulcer). Of the 14 mediators, smoking and adiposity traits played a major role in mediating the effects.
Conclusion
The study demonstrated the causal, independent impact of education on specific gastrointestinal diseases. Smoking and adiposity traits emerged as primary mediators, illuminating potential avenues for targeted interventions for prevention of them.
... This could have induced a more intense AD pathogenesis, which in turn caused neurotoxicity resulting in brain functional hyperactivation. Conversely, another research has suggested that functional hyperactivation may be part of a compensatory mechanism [58], therefore long-term follow-up studies are needed to characterize the nature of the hyperactivation. In this study, the interaction between rFC from DAN seed region and AD risk factors did not have a significant effect on cognitive function. ...
Objective
Cognitive reserve has emerged as a concept to explain the variable expression of clinical symptoms in the pathology of Alzheimer’s disease (AD). The association between years of education, a proxy of cognitive reserve, and resting-state functional connectivity (rFC), a representative intermediate phenotype, has not been explored in the preclinical phase, considering risk factors for AD. We aimed to evaluate whether the relationship between years of education and rFC in cognitively preserved older adults differs depending on amyloid-beta deposition and APOE ε4 carrier status as effect modifiers.
Methods
A total of 121 participants underwent functional magnetic resonance imaging, [¹⁸F] flutemetamol positron emission tomography-computed tomography, APOE genotyping, and a neuropsychological battery. Potential interactions between years of education and AD risk factors for rFC of AD-vulnerable neural networks were assessed with whole- brain voxel-wise analysis.
Results
We found a significant education years-by-APOE ε4 carrier status interaction for the rFC from the seed region of the central executive (CEN) and dorsal attention networks. Moreover, there was a significant interaction of rFC between right superior occipital gyrus and the CEN seed region by APOE ε4 carrier status for memory performances and overall cognitive function.
Conclusion
In preclinical APOE ε4 carriers, higher years of education were associated with higher rFC of the AD vulnerable network, but this contributed to lower cognitive function. These results contribute to a deeper understanding of the impact of cognitive reserve on sensitive functional intermediate phenotypic markers in the preclinical phase of AD.
... On the other hand, clinical assessments offer a readily available cost-effective, easily applicable, non-invasive screening alternative. The core clinical manifestations of AD, cognitive decline and/or neuropsychiatric symptoms, tend to precede the onset of dementia by one to two decades (49,50). While these clinical markers may fall short in terms of predictive potential compared to biological markers, they apparently outcompete laboratory indices in applicability and patient acceptance. ...
BACKGROUND
The utility of neuropsychological measurements as forerunners of Alzheimer’s Disease Dementia (AD) in individuals with normal cognition or mild cognitive impairment (MCI) is undeniable.
OBJECTIVES
To assess the differential prognostic value of cognitive performance in older men versus women.
DESIGN
Longitudinal analysis of data acquired from the National Alzheimer’s Coordinating Center Uniform Data Set.
SETTINGS
Data on older adults (≥60 years) were derived from 43 National Institute on Aging - funded Alzheimer’s Disease Research Centers.
PARTICIPANTS
10,073 cognitively unimpaired (CU) older adults followed for 5.5±3.8 years and 3,925 participants with amnestic MCI monitored for 3.5±2.8 years.
MEASUREMENTS
The domains of episodic memory, verbal fluency, naming, attention, processing speed and executive function were assessed. Cox proportional hazards models examined associations between individual cognitive domains and AD incidence separately for each participant set.
CU and MCI
These predictive models featured individual neuropsychological measures, sex, neuropsychological measure by sex interactions, as well as a number of crucial covariates.
RESULTS
Episodic memory and verbal fluency were differentially related to future AD among CU individuals, explaining a larger proportion of risk variance in women compared to men. On the other hand, naming, attention and executive function were differentially related to future AD among participants with MCI, accounting for a greater fraction of risk variance in men than women.
CONCLUSION
Cognitive performance is differentially related to risk of progressing to AD in men versus women without dementia.
... Brains of individuals with higher education would continue to perform cognitive tasks even if the excessive accumulation of amyloid-beta (Aβ) and tau protein exists (Stern et al., 1994; OPEN ACCESS EDITED BY Indra Adrianto, Henry Ford Health System, United States Dekhtyar et al., 2019). Amieva et al. (2014) followed up 171 lesseducated people and 271 highly educated people for 20 years and found that cognitive performance of highly educated people decreased 15-16 years before reaching the threshold of AD, while the less-educated people developed AD in only 7 years. In other words, EA greatly delays the progression of AD by maintaining cognitive performance. ...
Growing evidence suggests the effect of educational attainment (EA) on Alzheimer’s disease (AD), but less is known about the shared genetic architecture between them. Here, leveraging genome-wide association studies (GWAS) for AD (N = 21,982/41,944), EA (N = 1,131,881), cognitive performance (N = 257,828), and intelligence (N = 78,308), we investigated their causal association with the linkage disequilibrium score (LDSC) and Mendelian randomization and their shared loci with the conjunctional false discovery rate (conjFDR), transcriptome-wide association studies (TWAS), and colocalization. We observed significant genetic correlations of EA (rg = −0.22, p = 5.07E-05), cognitive performance (rg = −0.27, p = 2.44E-05), and intelligence (rg = −0.30, p = 3.00E-04) with AD, and a causal relationship between EA and AD (OR = 0.74, 95% CI: 0.58–0.94, p = 0.013). We identified 13 shared loci at conjFDR <0.01, of which five were novel, and prioritized three causal genes. These findings inform early prevention strategies for AD.
... Previous studies demonstrated that the topographical pattern of amyloid lesions overlaps with some brain networks, especially with the default mode network (DMN) 16 -a network known to support several cognitive functions such as self-referential processes 17 , episodic memory (EM) or executive functioning 18,19 . These cognitive functions have been identified as showing the earliest subtle cognitive decline in the preclinical stage [20][21][22][23][24] . Recent studies have explored the relationship between cMD and cognitive decline. ...
Introduction
Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology.
Methods
122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models.
Results
We find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants.
Conclusions
The combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer’s Disease-related episodic memory decline, suggesting utility in clinical trials.
... Diagnosis of dementia can be prematurely expected within 7 years before. There is about 63-80% of mild cognitive impairment will got development of dementia (10). ...
... Intriguingly, Auriacombe et al. have specifically investigated the preclinical course of repetitions and intrusions and reported that the rate of repetitions on the SVF task increases steeply shortly (about 2 years) before the diagnosis of AD [11]. Considering that episodic memory, language, and visuo-perceptual impairment tend to manifest as early as 4-8 years prior to the formal identification of AD [44][45][46], the detection of perseverations could represent a pivotal turning point in the preclinical neuropathological courses of older adults towards the development of AD (a prominent implication of frontal operations), ultimately leading to full-blown dementia of the AD type [47]. ...
Background and Objectives: The aim of the present study was to investigate the prognostic value of the qualitative components of verbal fluency (clustering, switching, intrusions, and perseverations) on the development of mild cognitive impairment (MCI) and dementia. Materials and Methods: Participants were drawn from the multidisciplinary, population-based, prospective HELIAD (Hellenic Longitudinal Investigation of Aging and Diet) cohort. Two participant sets were separately analysed: those with normal cognition and MCI at baseline. Verbal fluency was assessed via one category and one letter fluency task. Separate Cox proportional hazards regressions adjusted for important sociodemographic parameters were performed for each qualitative semantic and phonemic verbal fluency component. Results: There were 955 cognitively normal (CN), older (72.9 years ±4.9), predominantly female (~60%) individuals with available follow-up assessments after a mean of 3.09 years (±0.83). Among them, 34 developed dementia at follow-up (29 of whom progressed to Alzheimer’s dementia (AD)), 160 developed MCI, and 761 remained CN. Each additional perseveration on the semantic condition increased the risk of developing all-cause dementia and AD by 52% and 55%, respectively. Of note, participants with two or more perseverations on the semantic task presented a much more prominent risk for incident dementia compared to those with one or no perseverations. Among the remaining qualitative indices, none were associated with the hazard of developing all-cause dementia, AD, and MCI at follow-up. Conclusions: Perseverations on the semantic fluency condition were related to an increased risk of incident all-cause dementia or AD in older, CN individuals.
... Elles ont de plus des durées de suivi différents (allant de 1.7 à 20 ans), utilisent des outils de mesure variés, spécifiques du déclin cognitif (score MMSE ou scores neuropsychologiques) et/ou du déclin fonctionnel (ADAScog, IADL, CDR). Elles s'intéressent à des population à des stades différents de la maladie, allant de l'analyse des stades précliniques (Amieva et al., 2008(Amieva et al., , 2014Verlinden et al., 2016) aux stades évolués (Wattmo et al., 2013). ...
La maladie d’Alzheimer (MA) est la première cause de démence dégénérative. Elle est définie par l’accumulation anormale des protéines Tau et myloïdes, constituant des plaques amyloïdes. Alors que l’atteinte neuro-pathologique de la MA est stéréotypée chez les malades, son expression clinique et son pronostic sont hétérogènes. Les facteurs modulant l’expression de la maladie sont actuellement peu connus. Dans ce travail, nous avons analysé deux facteurs modulateurs de l’expression de la maladie : l’âge et l’activation microgliale que nous avons étudié au sein d’une population de sujets atteints de la MA (aux stades débutant et sévère) et de témoins, définis sur des critères diagnostiques clinico-biologiques. Nous avons tout d’abord analysé l’effet de l’âge sur la modification de la morphologie des sillons corticaux au cours de la MA. Nous avons mesuré l’ouverture des sillons corticaux ainsi que le volume hippocampique sur l’IRM cérébrale de sujets MA jeunes (<65 ans), de sujets MA plus âgés (>65 ans) ainsi que chez des sujets témoins appariés à l’âge. Dans un second temps, nous étudié l’activation microgliale en quantifiant la fixation du ligand [18F]-DPA-14, grâce à la tomographie par émission de positrons (TEP) au sein d’une population de sujets MA et de témoins suivis cliniquement pendant deux ans. Finalement, nous avons mesuré et comparé l’évolution de l’activation microgliale au cours du temps entre des sujets MA et des témoins, qui ont bénéficié de la réalisation d’un second examen TEP. Nos hypothèses étaient (1) que l’étude de la morphologie des sillons corticaux était plus performante que la mesure du volume hippocamique pour distinguer les formes jeunes de MA des formes du sujet âgé, (2) qu’en comparaison aux témoins, l’activation microgliale était plus importante chez les sujets MA et qu’elle influait sur la progression clinique de la maladie, et (3) qu’il existait différents profils évolutifs d’activation microgliale. Nos résultats montrent (1) que la mesure de l’ouverture des sillons corticaux est un meilleur marqueur diagnostique que la mesure du volume hippocampique dans le groupe de sujets MA jeune, dès le stade débutant de la maladie. A l’inverse, elle entraîne un risque de diagnostic par excès chez le patient de plus de 65 ans, où l’effet de l’âge se confond avec celui de la maladie ; (2) l'activité microgliale est augmentée précocement au cours de la MA et est associée à une stabilité cognitive et fonctionnelle de la MA. Finalement, (3) qu’il existe différents profils d’activation microgliale au cours du temps, avec des retentissements distincts sur la progression de la MA. Au total, ces travaux confirment l'hétérogéneité de la maladie d'Alzheimer. L'étude des effets de l'âge et de l'activation microgliale au sein d'une population atteinte d'une MA met en évidence des sous-types de malades avec une expression et des trajectoires évolutives distinctes ; les sujets jeunes présentent une expression corticale de la maladie plus étendue et les sujets avec une faible activation de la microglie ont une dégradation fonctionnelle et cognitive plus sévère. Ces facteurs de variabilité ouvrent des pistes de recherche clinique mais aussi thérapeutiques. Ils pourraient être pris en compte dans les protocoles thérapeutiques ultérieurs.
... Therefore, we can infer that an adequate exercise level is a significant protective factor against cognitive decline over time even after controlling for unique individual characteristics. One supportive evidence recently published reported that patients with Alzheimer's disease did not develop dementia symptoms, supporting the fact that cognitive function has resilience (22)(23)(24). It is hypothesized that a healthy lifestyle delays the onset of dementia and its symptoms by increasing the brain's resilience. ...
Purpose
To investigate the longitudinal effects of adequate exercise, defined as an exercise duration of ≥150 min/week by the World Health Organization (WHO), on cognitive function in middle-aged adults.
Methods
This study was a longitudinal panel analysis using secondary data obtained from the Korean Longitudinal Study of Aging (KLoSA) database, with 4,825 participants registered and comprising five rounds of survey data in 2-year intervals from 2010 to 2018. The participants were divided into the adequate exercise (≥150 min/week), deficient exercise (<150 min/week), and no exercise groups according to the WHO definition, and their cognitive decline over the 8-year period was analyzed. Further, we investigated the longitudinal effects of exercise using a fixed effects model with cognitive function as the dependent variable.
Results
In the dementia group, both deficient (<150 min/week) and adequate (≥150 min/week) exercises had statistically significantly positive effects on cognitive function. However, the coefficient size was not significantly larger in the adequate exercise group than in the deficient exercise group. In the participants with mild cognitive impairment (MCI), an adequate exercise level had significantly positive effects on cognitive function, while a deficient exercise level did not. In the participants with normal cognition, an adequate exercise level was not significantly associated with changes in cognitive function.
Conclusion
Continuous exercise can have a positive influence on cognitive function scores in middle-aged and older adults with MCI or dementia, but the findings cannot substantiate that adequate exercise (≥150 min/week) is more effective compared to deficient exercise (<150 min/week).
... While there is considerable evidence that there is a protective effect of CR on cognitive performance and cognitive impairment in older age (e.g., Amieva et al., 2014;Brayne et al., 2010;Stern et al., 1994;Zahodne et al., 2011), it is less clear whether CR might safeguard against focal neuropathology and moderate cognitive impairment on socio-cognitive tasks. Such measures assess the higher-order cognitive processes that allow individuals to interpret the behaviors of others (Adolphs, 2009). ...
The Cognitive Reserve (CR) hypothesis accounts for individual differences in vulnerability to age- or pathological-related brain changes. It suggests lifetime influences (e.g., education) increase the effectiveness of cognitive processing in later life. While evidence suggests CR proxies predict cognitive performance in older age, it is less clear whether CR proxies attenuate age-related decline on social cognitive tasks. This study investigated the effect of CR proxies on unimodal and cross-modal emotion identification. Sixty-six older adults aged 60-78 years were assessed on CR proxies (Cognitive Reserve Index Questionnaire, NART), unimodal(faces only, voices only), and cross-modal (faces and voices combined) emotion recognition and executive function (Stroop Test). No CR proxy predicted performance on emotion recognition. However, NART IQ predicted performance on the Stroop test; higher NART IQ was associated with better performance. The current study suggests CR proxies do not predict performance on social cognition tests but do predict performance on cognitive tasks.
... IADL place greater demand on cognitive resources and therefore represent a more sensitive outcome to assess early functional loss than BADL ( Figure 1B) (8). Notably, decline in IADL can be masked by compensatory mechanisms in very early stages of AD, presenting a challenge for accurate and complete clinical assessment (15). ...
As the focus of Alzheimer's disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.
... Further, our sample was also highly educated with an average of 15.8 years of education. This is relevant because research suggests that education influences the impact of cognitive aging on memory (Amieva et al., 2014;Katzman et al., 1989;Rentz et al., 2010;Stern et al., 1995Stern et al., , 1992 such that memory problems occur later in people with more education. Future studies should aim to have more diverse oldest-old samples to more accurately represent the broader population. ...
Episodic memory is widely recognized as a critically important aspect of cognition that is often impacted by cognitive and brain aging. Prior work has shown that episodic memory is related to the presence of teeth-like folds on the dentate gyrus, called dentation. We hypothesized that episodic memory performance relates to overall hippocampal structure (i.e., dentation and volume) in an oldest-old cohort. We used data from the McKnight Brain Aging Registry, which consisted of cognitively healthy 85+-year-old adults. We conducted a canonical correlation analysis on 111 participants between a set of episodic memory tests and a set of characterizations of hippocampal structure. The analysis yielded a strong canonical correlation between episodic memory and hippocampal structure (r = 0.491, p = <0.001). The results suggest there is a connection between hippocampal morphology and function in the oldest-old. Our findings suggest that dentation may play an important role in relation to the individual differences observed in episodic memory performance among the oldest old and that hippocampal structure supports healthy cognitive aging.
Highlights
We characterized hippocampal dentation in a healthy oldest-old sample.
Hippocampal structure is related to episodic memory in healthy oldest-old adults.
Memory functioning is related to both hippocampal volume and dentation.
Objective
With an increasing prevalence, Alzheimer's Disease (AD) is the most common cause of dementia. However, a percentage of potentially modifiable cases have been reported. This article describes the prevalence of four of these potentially modifiable risk factors: hearing loss, diabetes mellitus (DM), obesity, and hypertension.
Methods
Descriptive cross‐sectional study with data from 2018 to 2022, using the Colombian health system database SISPRO. The population of this study consisted of all people within the age range 50–100 with a main diagnosis of AD according to the ICD‐10 codes. Subjects were divided by decades, and the prevalence ratio (PR) for the outcome of AD and each of its potentially modifiable risk factors was then calculated and adjusted by age using the Mantel‐Haenszel formula.
Results
167,556 cases of AD were identified, with 66.4% being females. Peak age was in octogenarians, and the five‐years period prevalence for people older than 50 was 12.6 cases/1000 people. The PRs showed a positive association for all risk factors, except obesity. Following age correction, obesity's PR value shifted to positive in males and overall population but remained negative for females. The highest post‐correction PR in the overall population was hypertension (1.44), followed by DM (1.34), hearing loss (1.31) and obesity (1.12). Notably, PRs had a greater magnitude in younger and male age groups.
Conclusion
The results of this study are consistent with the fact that the prevalence of potentially modifiable risk factors is higher within the group of people with AD as their main diagnosis.
Analyzing longitudinal data in health studies is challenging due to sparse and error‐prone measurements, strong within‐individual correlation, missing data and various trajectory shapes. While mixed‐effect models (MM) effectively address these challenges, they remain parametric models and may incur computational costs. In contrast, functional principal component analysis (FPCA) is a non‐parametric approach developed for regular and dense functional data that flexibly describes temporal trajectories at a potentially lower computational cost. This article presents an empirical simulation study evaluating the behavior of FPCA with sparse and error‐prone repeated measures and its robustness under different missing data schemes in comparison with MM. The results show that FPCA is well‐suited in the presence of missing at random data caused by dropout, except in scenarios involving most frequent and systematic dropout. Like MM, FPCA fails under missing not at random mechanism. The FPCA was applied to describe the trajectories of four cognitive functions before clinical dementia and contrast them with those of matched controls in a case‐control study nested in a population‐based aging cohort. The average cognitive declines of future dementia cases showed a sudden divergence from those of their matched controls with a sharp acceleration 5 to 2.5 years prior to diagnosis.
Aging is often associated with decline in brain processing power and neural predictive capabilities. To challenge this notion, we used magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to record the whole-brain activity of 39 older adults (over 60 years old) and 37 young adults (aged 18–25 years) during recognition of previously memorised and varied musical sequences. Results reveal that when recognising memorised sequences, the brain of older compared to young adults reshapes its functional organisation. In fact, it shows increased early activity in sensory regions such as the left auditory cortex (100 ms and 250 ms after each note), and only moderate decreased activity (350 ms) in medial temporal lobe and prefrontal regions. When processing the varied sequences, older adults show a marked reduction of the fast-scale functionality (250 ms after each note) of higher-order brain regions including hippocampus, ventromedial prefrontal and inferior temporal cortices, while no differences are observed in the auditory cortex. Accordingly, young outperform older adults in the recognition of novel sequences, while no behavioural differences are observed with regards to memorised ones. Our findings show age-related neural changes in predictive and memory processes, integrating existing theories on compensatory neural mechanisms in non-pathological aging.
Background:
A screening tool sensitive to Alzheimer's disease (AD) risk factors, such as amyloid-β (Aβ) deposition, and subtle cognitive changes, best elicited by complex everyday tasks, is needed.
Objective:
To determine if grocery shopping performance could differentiate older adults at elevated risk of developing AD (OAer), older adults at low risk of developing AD (OAlr), and young adults (YA), and if amount of Aβ deposition could predict grocery shopping performance in older adults (OA).
Methods:
Twenty-one OAer (78±5 years), 33 OAlr (78±5 years), and 28 YA (31±3 years) performed four grocery shopping trials, with the best and worst performances analyzed. Measures included trial time, number of correct items, number of grocery note fixations, and number of fixations and percentage of time fixating on the correct shelving unit, correct brand, and correct shelf. Linear mixed effects models compared measures by performance rank (best, worst) and group (OAer, OAlr, YA), and estimated the effect of Aβ deposition on measures in OA.
Results:
Relative to their best performance, OAer and OAlr exhibited more correct shelving unit fixations and correct brand fixations during their worst performance, while YA did not. Within OA's worst performance, greater Aβ deposition was associated with a smaller percentage of time fixating on the correct shelving unit, correct shelf, and correct brand. Within OA, greater Aβ deposition was associated with more grocery note fixations.
Conclusions:
OA with elevated Aβ deposition may exhibit subtle working memory impairments and less efficient visual search strategies while performing a cognitively demanding everyday task.
Objective
To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer’s disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD).
Methods
Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer’s Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed – attention and executive function – cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline.
Results
There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder.
Conclusions
Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.
Instrumental variable methods, which handle unmeasured confounding by targeting the part of the exposure explained by an exogenous variable not subject to confounding, have gained much interest in observational studies. We consider the very frequent setting of estimating the unconfounded effect of an exposure measured at baseline on the subsequent trajectory of an outcome repeatedly measured over time. We didactically explain how to apply the instrumental variable method in such setting by adapting the two‐stage classical methodology with (1) the prediction of the exposure according to the instrumental variable, (2) its inclusion into a mixed model to quantify the exposure association with the subsequent outcome trajectory, and (3) the computation of the estimated total variance. A simulation study illustrates the consequences of unmeasured confounding in classical analyses and the usefulness of the instrumental variable approach. The methodology is then applied to 6224 participants of the 3C cohort to estimate the association of type‐2 diabetes with subsequent cognitive trajectory, using 42 genetic polymorphisms as instrumental variables. This contribution shows how to handle endogeneity when interested in repeated outcomes, along with a R implementation. However, it should still be used with caution as it relies on instrumental variable assumptions hardly testable in practice.
Introduction:
Commonly occurring dementias include those of Alzheimer's, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective is to determine how many years in advance of a dementia diagnosis cognitive scores begin to change.
Methods:
14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990-1992, mean age 57±5.72), and in 11,244 at visit 4 (1996-1998), 5,640 at visit 5 (2011-2013), and 3,574 at visit 6 (2016-2017) with surveillance for dementias of all causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit.
Results:
During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6 respectively. Adjusted DWRT z-scores were significantly lower 20-25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25-30 years and 3-test combination z-scores were significantly lower as early as 30-31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was -0.20 at 30-31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0-5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score was -0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants.
Conclusion:
DWRT, DSST and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites.
Society within the Brain provides insightful accounts of scientific research linking social connection with brain and cognitive aging through state-of-the-art research. This involves comprehensive social network analysis, social neuroscience, neuropsychology, psychoneuroimmunology, and sociogenomics. This book provides a scientific discourse on how a society, community, or friends and family interact with individuals' cognitive aging. Issues concerning social isolation, rapidly increasing in modern societies, and the controversy in origins of individual difference in social brain and behaviour are discussed. An integrative framework is introduced to explicate how social networks and support alleviate the effects of aging in brain health and reduce dementia risks. This book is of interest and useful to a wide readership: from gerontologists, psychologists, clinical neuroscientists and sociologists, to those involved in developing community-based interventions or public health policy for brain health, to people interested in how social life influences brain aging or in the prevention of dementia.
The menopausal transition has been proposed to put women at risk for undesirable neurological symptoms, including cognitive decline. Previous studies suggest that alterations in the hormonal milieu modulate brain structures associated with cognitive function. This structured review provides an overview of the relevant studies that have utilized MRI to report volumetric differences in the brain following menopause, and its correlations with the evaluated cognitive functions. We performed an electronic literature search using Medline (Ovid) and Scopus to identify studies that assessed the influence of menopause on brain structure with MRI. Fourteen studies met the inclusion criteria. Brain volumetric differences have been reported most frequently in the frontal and temporal cortices as well as the hippocampus. These regions are important for higher cognitive tasks and memory. Additionally, the deficit in verbal and visuospatial memory in postmenopausal women has been associated with smaller regional brain volumes. Nevertheless, the limited number of eligible studies and cross-sectional study designs warrant further research to draw more robust conclusions.
Cerebral small vessel disease is common in older adults and increases the risk of stroke, cognitive impairment, and dementia. While often attributed to midlife vascular risk factors such as hypertension, factors from earlier in life may contribute to later small vessel disease risk. In this review, we summarize current evidence for early-life effects on small vessel disease, stroke and dementia focusing on prenatal nutrition, and cognitive ability, education, and socioeconomic status in childhood. We discuss possible reasons for these associations, including differences in brain resilience and reserve, access to cognitive, social, and economic resources, and health behaviors, and we consider the extent to which these associations are independent of vascular risk factors. Although early-life factors, particularly education, are major risk factors for Alzheimer disease, they are less established in small vessel disease or vascular cognitive impairment. We discuss current knowledge, gaps in knowledge, targets for future research, clinical practice, and policy change.
PURPOSES
To establish a normative range of MemTrax (MTx) metrics in the Chinese population.
METHODS
The correct response percentage (MTx‐%C) and mean response time (MTx‐RT) were obtained and the composite scores (MTx‐Cp) calculated. Generalized additive models for location, shape and scale (GAMLSS) were applied to create percentile curves and evaluate goodness of fit, and the speed‐accuracy trade‐off was investigated.
RESULTS
26,633 subjects, including 13,771 (51.71%) men participated in this study. Age‐ and education‐specific percentiles of the metrics were generated. Q tests and worm plots indicated adequate fit for models of MTx‐RT and MTx‐Cp. Models of MTx‐%C for the low and intermediate education fit acceptably, but not well enough for a high level of education. A significant speed‐accuracy trade‐off was observed for MTx‐%C from 72 to 94.
CONCLUSIONS
GAMLSS is a reliable method to generate smoothed age‐ and education‐specific percentile curves of MTx metrics, which may be adopted for mass screening and follow‐ups addressing Alzheimer's disease or other cognitive diseases.
Highlights
GAMLSS was applied to establish nonlinear percentile curves of cognitive decline.
Subjects with a high level of education demonstrate a later onset and slower decline of cognition.
Speed‐accuracy trade‐off effects were observed in a subgroup with moderate accuracy.
MemTrax can be used as a mass‐screen instrument for active cognition health management advice.
Objective:
Disparities in Alzheimer disease (AD) and differences in help seeking (HS) across sociodemographic groups warrant public health concern. Research addressing such disparities must shift toward the earliest clinical manifestations of AD to optimize diagnosis, intervention and care planning. Subjective cognitive decline (SCD), a risk state for AD, provides an important context in which to examine sociodemographic-related disparities in HS.
Participants and methods:
One hundred sixty-seven cognitively healthy older adults (Mage=73, Meducation=16) (26.4% Black, Asian, or "Other") completed SCD questionnaire, HS questions, and mood measures (depression and anxiety). Binary logistic adjusted regressions examined: (a) the association between SCD and HS; and (b) the extent to which education moderated the relationship between SCD and HS. SCD [b = 0.06, SE=0.13, P<0.001, odds ratio=1.06, 95% CI (1.03, 1.08)] and education [b=0.32, SE=0.09, P<0.001, odds ratio=1.37, 95% CI (1.15, 1.64)] were independently associated with HS, with significant interaction between education and SCD on HS [b=0.2, SE=0.01, P=0.01, odds ratio=1.02, 95% CI (1.00, 1.03)].
Conclusions:
Findings elucidate the importance of tailoring SCD-related psychoeducational resources depending on educational background as a preliminary stepping-stone in encouraging HS among older adults who may be at particular risk for developing dementia.
Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We employed a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET.
In this multicenter study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease-dementia with baseline [18F]flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning.
We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness.
In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
Alzheimer's disease (AD) is generally diagnosed using advanced imaging, but recent research suggests early screening using biomarkers in peripheral blood is feasible; among them, plasma tau proteins phosphorylated at threonine 231, threonine 181, and threonine 217 (p-tau217) are potential targets. A recent study indicates that the p-tau217 protein is the most efficacious biomarker. However, a clinical study found a pg/ml threshold for AD screening beyond standard detection methods. A biosensor with high sensitivity and specificity p-tau217 detection has not yet been reported. In this study, we developed a label-free solution-gated field effect transistor (SGFET)-based biosensor featuring a graphene oxide/graphene (GO/G) layered composite. The top layer of bilayer graphene grown using chemical vapor deposition was functionalized with oxidative groups serving as active sites for forming covalent bonds with the biorecognition element (antibodies); the bottom G could act as a transducer to respond to the attachment of the target analytes onto the top GO conjugated with the biorecognition element via π-π interactions between the GO and G layers. With this unique atomically layered G composite, we obtained a good linear electrical response in the Dirac point shift to p-tau217 protein concentrations in the range of 10 fg/ml to 100 pg/ml. The biosensor exhibited a high sensitivity of 18.6 mV/decade with a high linearity of 0.991 in phosphate-buffered saline (PBS); in human serum albumin, it showed approximately 90% of the sensitivity (16.7 mV/decade) in PBS, demonstrating high specificity. High stability of the biosensor was also displayed in this study.
The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal gradients into functionally related cortical networks. To understand the cognitive relevance of this functional embedding, we acquired fMRI data while participants viewed brief news clips, either containing or lacking recently familiarized cues. Participants were 188 healthy mid-life adults and 31 adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We employed a recently developed technique - connectivity gradientography - to study gradually changing patterns of voxel to whole brain functional connectivity and their sudden transitions. We observed that functional connectivity gradients of the anterior hippocampus map onto connectivity gradients across the default mode network during these naturalistic stimuli. The presence of familiar cues in the news clips accentuates a stepwise transition across the boundary from the anterior to the posterior hippocampus. This functional transition is shifted in the posterior direction in the left hippocampus of individuals with MCI or AD. These findings shed new light on the functional integration of hippocampal connectivity gradients into large-scale cortical networks, how these adapt with memory context and how these change in the presence of neurodegenerative disease.
A small number of robust studies have explored the association between cognitive tests and marital status levels of mild cognitive impairment (MCI) patients using the TADPOLE dataset. Rey Auditory Verbal Learning Test (RAVLT) cognition performance combined with marital status levels is associated with increased odds of MCI than either RAVLT in isolation. The cross-sectional association between RAVLT performance in immediate response, learning, forgetting, and perception of forgetting with marital status and MCI was evaluated using TADPOLE data. We included participants with MCI and normal cognition in our study. Based on our logistic regression model, four RAVLT subgroups are associated with MCI (low and high response performance, immediate response with learning, immediate response with learning and forgetting, immediate response with learning, forgetting, and perception of forgetting). We adjusted models for sex, age, race, marital status, education, ethnicity, APOE4 genotype, hippocampus, whole brain, ventricles, and ICV. A mean age of 77/67 years was observed in the sample (n = 6560), 44% of participants were females, and 58% had mild cognitive impairment. Subgroups whose ages are 61 to 70 (OR 0.26, 95% CI 0.15–0.45) and older (OR 0.07, 95% CI 0.04–0.12), as well as race: black/African American (OR 0.13, 95% CI 0.03–0.52), multiple races (OR 0.05, 95% CI 0.01–0.24), and never married (OR 0.2, 95% CI 0.12–0.34) were negatively associated with immediate response and forgetting subgroup tests. There is a need for studies that evaluate other cognitive tests in the TADPOLE dataset with missing data as a predictive tool that aligns with the factors associated with MCI.
Background:
High educational attainment may protect individuals, particularly middle-aged and older adults, against a wide range of health risks, including memory decline with age; however, this protection is less clear in patients with Alzheimer's disease (AD). In addition, this effect may differ across racial groups. According to the Marginalized-Related Diminished Return (MDR) theory, for example, the protective effect of high educational attainment on mental and physical health shows a weaker protective effect for racial minority groups, particularly Black people compared to White individuals.
Objectives:
This longitudinal study used data of middle-aged and older adults with AD with two aims: first, to test the association between educational attainment and memory, and second, to explore racial differences in this association in the USA.
Methods:
Data came from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The total sample was 1673 American middle-aged and older adults. The independent variable was educational attainment measured as years of education. The main outcome was memory operationalized as Rey Auditory Verbal Learning Test (RAVLT) Verbal Forgetting percentage (VF%). Age, gender, and follow-up duration were covariates. Race was the effect modifier. Linear regression model was utilized to analyze the data.
Results:
Of all participants, 68 (4.1%) were Black, and the remaining were White, with a mean age of 75 years old. In the pooled sample, educational attainment did not show a significant association with memory, independent of confounders. Educational attainment showed a significant interaction with race on memory, with higher educational attainment having a different effect on memory in White patients compared to Black patients.
Conclusion:
The effect of higher educational attainment on memory differs for Black patients with AD compared to White patients. To prevent cognitive disparities by race, we need to go beyond racial inequality in access to resources (e.g., education) and minimize diminished returns of educational attainment for racial minorities. To tackle health inequalities, social policies should not be limited to equalizing socioeconomic status but also help minority groups leverage their available resources, such as educational attainment, and secure tangible outcomes.
Introduction
Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them.
Methods
We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE).
Results
Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM.
Discussion
Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.
Introduction:Few robust studies have analyzed association between cognitive tests and the marital status of Mild Cognitive Impairment (MCI) group with ADNI dataset. To test the hypothesis that Rey Auditory Verbal Learning test (RAVLT) cognition performance with marital status is associated with greater odds of MCI group than either RAVLT independently, we used TADPOLE data to evaluate cross-sectional associations between RAVLT performance in immediate response, learning, forgetting, and perception of forgetting with marital status and MCI. Methods: Subjects with MCI and Normal Cognition were included. Logistic regression models indicate associations between four RAVLT subgroups (low and high performance of immediate response, immediate response with learning, performance of immediate response with learning and forgetting, performance of immediate response with learning, forgetting and perception of forgetting) and MCI group. Models adjust for age, sex, race, marital status, ethnicity, education, APOE4 genotype, hippocampus, whole-brain, ventricles and ICV. Results: The sample (n=6560) had a mean age of 77 / 67 years, 44% were female, 58% in MCI group. Only all RAVLT subgroups test with age 61 to 70(OR 0.26, 95% CI 0.15-0.45), age 71 or older(OR 0.07, 95% CI,0.04-0.12), race:black/african american(OR 0.13, 95% CI 0.03-0.52)race:more than one(OR 0.05, 95% CI 0.01-0.24), marital status:never married(OR 0.2, 95% CI 0.12-0.34). Conclusion: Studies are needed to evaluate other cognitive test with missing data within TADPOLE dataset as modifiable risk factor for MCI.
Introduction:
The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps.
Methods:
A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke.
Results:
Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier.
Discussion:
Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.
The results of a community study dealing with the ecological distribution of intellectual and various perceptual-motor deficits, presumed to be functionally related to neurological status, are presented. Ss were 158 White and 60 Black 3rd graders of public and parochial schools. Measures included a parents' questionnaire, school achievement data, behavioral ratings, and such tests as the Culture Fair Intelligence Test, Wepman Auditory Discrimination Test, and the Bender Gestalt Test. Results suggest that levels of neurological integrity vary along a socioeconomic gradient and between ethnic groups. An environmentally based model of social causation is presented as the most appropriate explanation of the patterned distribution of neurological pathology across social class and ethnic-group lines. This model focuses on such factors as malnutrition/undernutrition, adverse conditions of environmental stimulation, inadequate obstetrical and pediatric care, and environmental deterioration. (105 ref)
Objective To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11–labeled Pittsburgh Compound B ([11C]PiB), in healthy older individuals.
Design Cross-sectional clinical study.
Setting Berkeley, California.
Participants Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.
Main Outcome Measures Cortical [11C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.
Results Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [11C]PiB uptake (P < .001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [11C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [11C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [11C]PiB uptake.
Conclusions Individuals with greater early- and middle- life cognitive activity had lower [11C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [11C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
Age impacts multiple neural measures and these changes do not always directly translate into alterations in clinical and cognitive measures. This partial protection from the deleterious effects of age in some individuals is referred to as cognitive reserve (CR) and although linked to variations in intelligence and life experiences, its mechanism is still unclear. Within the framework of a theoretical model we tested two potential mechanistic roles of CR to maintain task performance, neural reserve and neural compensation, in young and older adults using functional and structural MRI. Neural reserve refers to increased efficiency and/or capacity of existing functional neural resources. Neural compensation refers to the increased ability to recruit new, additional functional resources. Using structural and functional measures and task performance, the roles of CR were tested using path analysis. Results supported both mechanistic theories of CR and the use of our general theoretical model.
To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association.
In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies.
We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test.
Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment.
The concept of reserve has been proposed to account for the disjunction between the degree of brain damage and its clinical outcome. This paper attempts to produce a coherent theoretical account the reserve in general and of cognitive reserve in particular. It reviews epidemiologic data supporting the concept of cognitive reserve, with a particular focus of its implications for aging and dementia. It then focuses on methodologic issues that are important when attempting to elucidate the neural underpinnings of cognitive reserve using imaging studies, and reviews some of our group's work in order to demonstrate these issues.
the investigation of cognitive decline in the older population has been hampered by analytical considerations. Most studies of older people over prolonged periods suffer from loss to follow-up, yet this has seldom been investigated fully to date. Such considerations limit our understanding of how basic variables such as education can affect cognitive trajectories.
we examined cognitive trajectories in a population-based cohort study in Cambridge, UK, of people aged 75 and over in whom multiple interviews were conducted over time. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Socio-demographic variables were measured, including educational level and social class. An age-based quadratic latent growth model was fitted to cognitive scores. The effect of socio-demographic variables was examined on all latent variables and the probability of death and dropout.
at baseline, age, education, social class and mobility were associated with cognitive performance. Education and social class were not related to decline or its rate of change. In contrast, poor mobility was associated with lower cognitive performance, increased cognitive decline and increased rate of change of cognitive decline. Gender, age, mobility and cognitive ability predicted death and dropout
contrary to much of the current literature, education was not related to rate of cognitive decline or change in this rate as measured by MMSE. Higher levels of education do not appear to protect against cognitive decline, though if the MMSE is used in the diagnostic process, individuals with less education may be diagnosed as having dementia somewhat earlier.
Paquid is an epidemiological study designed to gather and follow-up a cohort of 3,777 elderly subjects (65 years and older) living at home. In order to study normal and pathological brain ageing, these subjects were randomly chosen in the general population of 75 communities of Gironde and Dordogne, two administrative areas of South-Western France. The subjects were interviewed at home by trained psychologists and followed-up with the same procedure at 1, 3 and 5 years after the initial data collection. The identification of the demented cases is made with a two-stage design: the first stage is a systematic screening by the psychologists with application of the DSM-IIIR criteria and the second stage consists in a confirmation of the diagnosis by a neurologist according to the NINCDS-ADRDA criteria. Paquid is complemented by the study of a random sample of 357 subjects living in institutions in Gironde.
Paquid is an epidemiological study designed to gather and follow up a cohort of 4,000 elderly subjects (65 years and older) living at home in order to study normal and pathological brain aging. These subjects were randomly chosen in the general population of 75 communities of South-Western France. We present the results of the data collected from 2,792 subjects on the prevalence and the correlates of clinically diagnosed dementia. The DSM III criteria for dementia were met by 101 subjects (3.62 p. 100). These cases were reviewed by a neurologist to confirm the diagnosis and to determine the cause of dementia using the NINCDS-ADRDA criteria. Forty-three subjects were classified as probable Alzheimer's disease; 8 as possible Alzheimer's disease; 5 as vascular dementia; 5 as Parkinson's disease with dementia; 2 as alcoholic dementia; 2 as "dementified psychosis"; and 1 unclassified. Fifteen patients refused to be examined by the neurologist, 18 were false-positives, and 2 died before the neurologists visit. Using the NINCDS-ADRDA criteria, the prevalence of dementia was as low as 1.6 p. 100. The prevalence of probable Alzheimer's disease decreased dramatically as educational level increased, lung 5.4 p. 100 for subjects with no education, 1.7 p. 100 for subjects with grade school level, 0.4 p. 100 for subjects with high school level and 0.4 p. 100 for subjects with university degrees. The relationship between dementia and educational level is still controversial in the literature. In this study the sample was large and randomly selected; all the demented cases fulfilled the NINCDS-ADRDA criteria. This suggests that educational level is indeed an important correlate of dementia in the French elderly community.
The relations between reading time and memory span were studied in four languages: English, Spanish, Hebrew, and Arabic. Reading rate was measured either in speeded reading of digits or in normal-pace reading of stories. Faster speeded reading and normal-pace reading rates for a given language were associated with larger memory span for speakers of that language. These relations, which were shown to be monotonically related to the number of syllables or phonemes per item, extend the within-language word-length effect reported by Baddeley, Thomson and Buchanan (1975), across languages. In addition, these findings demonstrate a form of linguistic relativity: a relation between simple surface-structural features of language (number of syllables) and cognitive processing (memory span and reading rate). It is argued that this linguistic relativity may be limited by trade-offs between surface features and common linguistic practice.
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In this study, the authors evaluated whether the association between low educational level and increased risk of Alzheimer's disease (AD) and dementia may be explained by occupation-based socioeconomic status (SES). A cohort of 931 nondemented subjects aged ≥75 years from the Kungsholmen Project, Stockholm, Sweden, was followed for 3 years between 1987 and 1993. A total of 101 incident cases of dementia, 76 involving AD, were detected. Less-educated subjects had an adjusted relative risk of developing AD of 3.4 (95% confidence interval: 2.0, 6.0), and subjects with lower SES had an adjusted relative risk of 1.6 (95% confidence interval: 1.0, 2.5). When both education and SES were introduced into the same model, only education remained significantly associated with AD. Combinations of low education with low or high SES were associated with similar increased risks of AD, but well-educated subjects with low SES were not at high risk. Low SES at 20 years of age, even when SES was high at age 40 or 60 years, was associated with increased risk; however, this increase disappeared when education was entered into the model. In conclusion, the association between low education and increased AD risk was not mediated by adult SES or socioeconomic mobility. This suggests that early life factors may be relevant.
Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.
Objective.
—Several cross-sectional studies have found an association between Alzheimer's disease (AD) and limited educational experience. It has been difficult to establish whether educational experience is a risk factor for AD because educational attainment can influence performance on diagnostic tests. This study was designed to determine whether limited educational level and occupational attainment are risk factors for incident dementia.Design.
—Cohort incidence study.Setting.
—General community.Participants.
—A total of 593 nondemented individuals aged 60 years or older who were listed in a registry of individuals at risk for dementia in North Manhattan, NY, were identified and followed up.Interventions.
—We reexamined subjects 1 to 4 years later with the identical standardized neurological and neuropsychological measures.Main Outcome Measure.
—Incident dementia.Results.
—We used Cox proportional hazards models, adjusting for age and gender, to estimate the relative risk (RR) of incident dementia associated with low educational and occupational attainment. Of the 593 subjects, 106 became demented; all but five of these met research criteria for AD. The risk of dementia was increased in subjects with either low education (RR, 2.02; 95% confidence interval [CI], 1.33 to 3.06) or low lifetime occupational attainment (RR, 2.25; 95% CI, 1.32 to 3.84). Risk was greatest for subjects with both low education and low life-time occupational attainment (RR, 2.87; 95% CI, 1.32 to 3.84).Conclusions.
—The data suggest that increased educational and occupational attainment may reduce the risk of incident AD, either by decreasing ease of clinical detection of AD or by imparting a reserve that delays the onset of clinical manifestations.(JAMA. 1994;271:1004-1010)
Five experiments are reported. These demonstrate that, in bilingual subjects, Welsh digits take longer to articulate than their English equivalents, and this difference is paralleled by the finding that digit span in Welsh is significantly smaller than that in English. These differences are attributable to bilingual word-length differences, and it is this, rather than intellectual differences, which explains why the norms for Welsh children on the digit span test of the Welsh Children's Intelligence Scale are reliably less than those for the same age American children tested on the similar digit span procedure of the Wechsler Intelligence Scale for Children. These findings lead to the prediction that mental calculation in the Welsh language will be more difficult than that in English.
An interaction between translation and storage in working memory is demonstrated. This finding accords with the working memory formalization of Baddeley & Hitch (1974). It is shown that translation towards the language of preference is faster than that in the reverse direction.
The CES-D scale is a short self-report scale designed to measure depressive symptomatology in the general population. The items of the scale are symptoms associated with depression which have been used in previously validated longer scales. The new scale was tested in household interview surveys and in psychiatric settings. It was found to have very high internal consistency and adequate test- retest repeatability. Validity was established by pat terns of correlations with other self-report measures, by correlations with clinical ratings of depression, and by relationships with other variables which support its construct validity. Reliability, validity, and factor structure were similar across a wide variety of demographic characteristics in the general population samples tested. The scale should be a useful tool for epidemiologic studies of de pression.
The NINCDS-ADRDA criteria for the diagnosis of Alzheimer's disease (AD) (G. McKhann et al, 1984) have gained widespread acceptance because of their clinical utility. However, the present criteria for the neuropsychological component of the evaluation are conservative and maximize specificity instead of sensitivity, making it difficult to identify early cases of dementia. There is considerable overlap between many of the 8 cognitive domains specified and a lack of consensus as to the types and numbers of tests to be used for each domain. Other problems are the lack of normative data for different age groups as well as diverse ethnic and cultural groups, and the need for objective assessment of the patient's functional capacities. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Senile dementia was the third most common admission diagnosis for New York psychiatric hospitals at the start of the twentieth century and the distinction between vascular and senile dementia was understood by psychiatrists even then. The term Alzheimer's disease (AD) was originally introduced to distinguish a pre-senile dementia from the common general paresis, but Alzheimer raised the possibility that pre-senile AD might not be distinguishable in clinical or histological terms from senile dementia. By the late 1970s it had become clear that the most common disorder producing dementia in elderly people was clinically and pathologically identical to pre-senile AD. AD is malignant, reducing remaining life expectancy by almost half and raising the risk of death over five years threefold (cancer raises it fourfold). Synapse loss associated with beta amyloid oligomers is a strong determinant of cognitive decline in patients with AD. Tau-containing neurofibrillary tangles usefully track disease severity. Unmodifiable risk factors include mutations in three genes which affect the production or metabolism of beta amyloid, the risk factor gene for Apolipoprotein 4 and female gender. The overriding risk factor is age, the prevalence of AD doubling with every five years of age until 90. Low education, head injury and low folate levels are examples of potentially modifiable risk factors. Since a delay of onset of five years would halve the number of patients with the disease, clinical trials for such putative protective factors as estrogens, folic acid, vitamin E, statins, and NSAIDs have begun. Cognitive and leisure activity may be protective against the development of AD but any protective function can only be confirmed by clinical trials.
Longitudinal studies of ageing make repeated observations of multiple measurements on each subject. Change point models are often used to model longitudinal data. We demonstrate the use of Bayesian and profile likelihood methods to simultaneously estimate different change points in the longitudinal course of two different measurements of cognitive function in subjects in the Bronx Aging Study who developed Alzheimer's disease (AD). Analyses show that accelerated memory decline, as measured by Buschke Selective Reminding, begins between seven and eight years before diagnosis of AD, while decline in performance on speeded tasks as measured by WAIS Performance IQ begins slightly more than two years before diagnosis, significantly after the decline in memory. Copyright © 2001 John Wiley & Sons, Ltd.
A number of experiments explored the hypothesis that immediate memory span is not constant, but varies with the length of the words to be recalled. Results showed: (1) Memory span is inversely related to word length across a wide range of materials; (2) When number of syllables and number of phonemes are held constant, words of short temporal duration are better recalled than words of long duration; (3) Span could be predicted on the basis of the number of words which the subject can read in approximately 2 sec; (4) When articulation is suppressed by requiring the subject to articulate an irrelevant sound, the word length effect disappears with visual presentation, but remains when presentation is auditory. The results are interpreted in terms of a phonemically-based store of limited temporal capacity, which may function as an output buffer for speech production, and as a supplement to a more central working memory system.
Although the relationship between education and cognitive status is well-known, evidence regarding whether education moderates the trajectory of cognitive change in late life is conflicting. Early studies suggested that higher levels of education attenuate cognitive decline. More recent studies using improved longitudinal methods have not found that education moderates decline. Fewer studies have explored whether education exerts different effects on longitudinal changes within different cognitive domains. In the present study, we analyzed data from 1014 participants in the Victoria Longitudinal Study to examine the effects of education on composite scores reflecting verbal processing speed, working memory, verbal fluency, and verbal episodic memory. Using linear growth models adjusted for age at enrollment (range, 54-95 years) and gender, we found that years of education (range, 6-20 years) was strongly related to cognitive level in all domains, particularly verbal fluency. However, education was not related to rates of change over time for any cognitive domain. Results were similar in individuals older or younger than 70 at baseline, and when education was dichotomized to reflect high or low attainment. In this large longitudinal cohort, education was related to cognitive performance but unrelated to cognitive decline, supporting the hypothesis of passive cognitive reserve with aging.
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
To study the predictive value of memory complaints resulting in consultation with a GP as to the risk of subsequent dementia, we analysed the data from the follow-up of the Paquid cohort study carried out around Bordeaux. A sample of 1503 elderly people over 65, living at home and non-demented at the baseline screening, was considered. The risk of dementia was measured two and four years after the baseline screening: 60.8 per cent of subjects themselves perceived a memory impairment and 15.6 per cent expressed this complaint to their GP. Forty-eight developed a subsequent dementia. Taking the group without memory complaint as the reference set, three groups of elderly people could be recognized as at high risk of dementia: subjects with self-perceived memory impairment, consulting a GP with low memory performance or with normal memory performances, and subjects with memory complaints not resorting to a GP but with low memory performance. In non-demented elderly people, memory complaints expressed to the GP may be a strong predictor of dementia and should not be neglected.
The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review and revise its first (2006) Guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A to D, with A having the strongest evidence base (from randomized controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and brain imaging can improve diagnostic accuracy (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for mild to moderate Alzheimer's disease (A) and memantine for moderate to severe Alzheimer's disease (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), especially for neuropsychiatric symptoms (A). Cholinesterase inhibitors and memantine can produce cognitive improvements in DLB (A). There is no clear evidence that any intervention can prevent or delay the onset of dementia. Although the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition are in progress. Although results of pivotal studies are awaited, results to date have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use.
The influence of education, occupation, and leisure activities on the passive and active components of reserve capacity remains unclear. We used the voxel-based morphometry (VBM) technique in a population-based sample of 331 nondemented people in order to investigate the relationship between these factors and the cerebral volume (a marker of brain reserve). The results showed a positive and significant association between education, occupation, and leisure activities and the cognitive performances on Isaac's set test. Among these factors, only education was significantly associated with a cerebral volume including gray and white matter (p = 0.01). In voxel-based morphometry analyses, the difference in gray matter volume was located in the temporoparietal lobes and in the orbitofrontal lobes bilaterally (a p-value corrected <0.05 by false discovery rate [FDR]). Although smaller, the education-related difference in white matter volume appeared in areas connected to the education-related difference in gray matter volume. Education, occupation attainment, and leisure activities were found to contribute differently to reserve capacity. Education could play a role in the constitution of cerebral reserve capacity.
Ordinal and quantitative discrete data are frequent in biomedical and neuropsychological studies. We propose a semi-parametric model for the analysis of the change over time of such data in longitudinal studies. A threshold model is defined where the outcome value depends on the current value of an underlying Gaussian latent process. The latent process model is a Gaussian linear mixed model with a non-parametric function of time, f(t), to model the expected change over time. This model includes random-effects and a stochastic error process to flexibly handle correlation between repeated measures. The function f(t) and all the model parameters are estimated by penalized likelihood using a cubic-spline approximation for f(t). The smoothing parameter is estimated by an approximate cross-validation criterion. Confidence bands may be computed for the estimated curves for the latent process and, using a Monte Carlo approach, for the outcome in its natural scale. The method is applied to the Paquid cohort data to compare the time-course over 14 years of two cognitive scores in a sample of 350 future Alzheimer patients and in a matched sample of healthy subjects.
White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve.
Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively.
Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume.
For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition.