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Dementia has become a common diagnosis in aging populations, and the numbers will increase in the forthcoming years. Alzheimer's disease (AD) is the most common form of dementia in the elderly, accounting for 50%-56% of cases at autopsy and in clinical series. Nowadays, the number of people affected by AD is rapidly increasing, and more than 35 million people worldwide have AD, a condition characterized by deterioration of memory and other cognitive domains, and leading to death 3-9 years after diagnosis. The number of patients with AD, the most common cause of disability in the elderly, is set to rise dramatically. Therefore, it is important for clinicians to recognize early signs and symptoms of dementia and to note potentially modifiable risk factors and early disease markers.
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DOI: 10.2147/CIA.S11718
Late onset Alzheimer’s disease
in older people
Ahmet Turan Isik
Department of Internal Medicine,
Division of Geriatric Medicine,
Gulhane School of Medicine,
Ankara, Turkey
Abstract: Dementia has become a common diagnosis in aging populations, and the numbers
will increase in the forthcoming years. Alzheimer’s disease (AD) is the most common form
of dementia in the elderly, accounting for 50%–56% of cases at autopsy and in clinical series.
Nowadays, the number of people affected by AD is rapidly increasing, and more than 35 million
people worldwide have AD, a condition characterized by deterioration of memory and other
cognitive domains, and leading to death 3–9 years after diagnosis. The number of patients with
AD, the most common cause of disability in the elderly, is set to rise dramatically. Therefore,
it is important for clinicians to recognize early signs and symptoms of dementia and to note
potentially modifiable risk factors and early disease markers.
Keywords: Alzheimer disease, dementia, elderly
Age is the most important risk factor for AD, with the prevalence rising substantially
between the ages of 65 and 85 years.
The incidence of the disease doubles every five
years after 65 years of age, with diagnosis of 1275 new cases per year per 100,000
persons older than 65 years, so that AD affects 30%–50% of all people by the age
of 85 years.
Data on centenarians show that AD is not necessarily the outcome
of aging, but the odds of receiving a diagnosis of AD after 85 years exceed one in
Despite its remarkable prevalence among the elderly, AD has been regarded
as a specific disease, distinct from normal aging. This view is supported in large part
by clinical and pathologic similarities to early-onset, dominantly inherited familial
AD, where genetic mutations related to amyloids have been identified. There is much
evidence that early onset (sporadic) AD (LOAD) overlaps with normal aging in many
clinical and pathologic respects.
Interestingly, early onset AD accounts only for 5%
of total AD cases. The majority of AD patients (90%–95%) are LOAD, and it usually
develops after 65 years of age.
While early onset AD is almost certainly genetically based, there are no specific gene
mutations that are associated with inheritance of the disease in LOAD. The expres-
sion of the apolipoprotein E (ApoE) 4 allele is one of the risk factors identified for
In the central nervous system, ApoE is synthesized by astrocytes, microglia,
and, to a lesser extent, by neurons. The role of ApoE in LOAD pathogenesis is not
fully elucidated, but it has been suggested that ApoE is important in trafficking of
amyloid β (Aβ) peptide.
In addition, apolipoprotein J (clusterin), an amyloid β-peptide
Correspondence: Ahmet Turan Isik
Department of Internal Medicine,
Division of Geriatric Medicine, Gulhane
School of Medicine, Ankara, Turkey
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This article was published in the following Dove Press journal:
Clinical Interventions in Aging
9 October 2010
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chaperone, TOMM40, a transporter of proteins across the
mitochondrial membrane, and Sortillin-related receptor,
which functions to partition amyloid precursor protein away
from β-secretase and γ-secretase, are recently discovered
proteins encoded by the risk genes for LOAD.
In addition to
nonmodifiable genetic risk factors, potentially modifiable fac-
tors, such as hypertension, diabetes mellitus, hyperlipidemia,
hyperhomocysteinemia, coronary and peripheral artery
diseases, alcohol, smoking, obesity, levels of physical or men-
tal activity, levels of education, and environmental exposures
have been investigated to identify risk factors for LOAD.
Furthermore, it has been reported that risk index methods
including these risk factors provide a practical, flexible, and
objective framework for identifying the optimal combina-
tion of measures for identification of high-risk individuals
for prevention and early intervention efforts.
Despite the
personal and societal burden of LOAD, our understanding of
the genetic predisposition to LOAD and the contribution of
other risk factors remains limited. More importantly, there are
few data to explain the overall risks and benefits of prevention
strategies or their impact on risk modification.
AD is characterized by extensive atrophy of the brain
caused by a series neuropathologic changes, including
neuronal loss, formation of amyloid plaques, appearance of
neurofibrillary tangles, and synaptic loss.
Amyloid plaques
and neurofibrillary tangles result from an aberration in depo-
sition of the Aβ peptide and the hyperphosphorylated tau
protein, respectively, and these depositions lead to neuronal
loss and neurotoxicity in the brain affected by AD.
these changes in the brain are not found throughout the brain
and preferentially affect specific brain areas in a manner
that is essentially consistent from patient to patient.
obtained by electron microscopy and immunocytochemical
and biochemical analysis on synaptic marker proteins in
AD biopsies and autopsies indicate that synaptic loss in the
hippocampus and neocortex is an early event and the major
structural correlate of cognitive dysfunction. From all cortical
areas analyzed, the hippocampus appears to be the most
severely affected by the loss of synaptic proteins, while the
occipital cortex is affected least.
In addition, it was reported
that synaptic loss is currently the best neurobiologic correlate
of cognitive deficits in AD. Also, there is evidence that living
neurons lose their synapses in AD. Furthermore, synaptic
function is impaired in living neurons, as demonstrated
by decrements in transcripts related to synaptic vesicle
Although new imaging techniques and powerful animal
models have helped understanding the time course and the
mechanisms of the lesions, the relationship between Aβ
accumulation and tau pathology is still badly understood and
the mechanism of LOAD continues to be debated. Accumula-
tion of Aβ peptides may be the key event in the pathogenesis
of AD. The exact mechanism by which Aβ peptide deposition
induces neurotoxicity is unclear, but it appears that oxidative
stress plays an important role. Oxidative stress is extensive
in AD, and Aβ peptides stimulate oxidative stress by both
direct and indirect mechanisms. Aβ peptides by themselves
may act as enzymes and can bind to mitochondrial proteins,
resulting in the generation of free radicals.
Aβ peptides generate oxidative stress via neuroinflammation.
Considerable evidence has supported the hypothesis that neu-
roinflammation is associated with AD pathology.
In addition,
in AD, vascular injury and parenchymal inflammation per-
petuate the cycle of protein aggregation and oxidation in
the brain, and diffuse pathologic changes include cerebral
amyloid angiopathy, affecting more than 90% of patients
with AD, capillary abnormalities, disruption of the blood–
brain barrier, and large-vessel channels.
It has also been
reported that clearance of Aβ along diseased perivascular
channels and through the blood–brain barrier is impeded in
AD atheroma,
and that deregulation of Aβ transport across
the capillary blood–brain barrier is caused by the imbalanced
expression of low-density lipoprotein receptor-related pro-
teins and receptors for advanced glycation end products.
Furthermore, insulin resistance and hyperinsulinemia are
implicated in a number of pathophysiologic processes related
to AD.
It has been demonstrated that reduced brain insulin
signaling is associated with increased tau phosphorylation
and Aβ levels in a streptozotocin-induced model of diabetes
and also that insulin promotes the release of
intracellular Aβ in neuronal cultures and accelerates Aβ
trafficking to the plasma membrane. Similarly, intravenous
insulin infusion also raises plasma Aβ42 levels in patients with
AD but not in normal adults, an effect that is exaggerated in
patients with AD and a higher body mass index. In addition,
impaired insulin or insulin-like growth factor-1 signaling can
result in hyperphosphorylation of tau, which can cause cell
death mediated by apoptosis, mitochondrial dysfunction, or
necrosis, and promote oxidative stress, which contributes
to the neurodegeneration cascade, and leads to dementia-
associated behavioral and cognitive deficits. For this reason,
it seems that insulin resistance causes tau phosphorylation,
neurofibrillary tangle formation, and increased beta amyloid
aggregation in LOAD.
Therefore, we think that the insu-
lin resistance should be taken into account, both in explaining
the pathophysiologic mechanisms and the managing of the
Clinical Interventions in Aging 2010:5
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Late onset Alzheimer’s disease
LOAD. In short, the current pathophysiologic approach to
LOAD is based on a number of common mechanisms of neu-
rodegeneration, including accumulation of abnormal proteins,
mitochondrial dysfunction, and oxidative stress, impaired
insulin signaling, calcium homeostasis dysregulation, early
synaptic disconnection, and late apoptotic cell death. Aging
itself is associated with mild cognitive deterioration, probably
due to subtle multifactorial changes resulting in a global
decrease of functional brain reserve.
AD can affect different people in different ways, but the most
common symptom pattern begins with gradually worsen-
ing difficulty remembering new information. In the early
stages, the most commonly recognized symptom is inability
to acquire new memories, such as difficulty in recalling
recently observed facts.
Cognitive profiles of normal aging
emphasize a decline in skills, including learning efficiency,
working memory, and psychomotor speed. Although memory
impairment is the earliest cognitive change in AD, distin-
guishing early disease from normal aging can be difficult,
and making a decision as to whether a memory complaint is
associated with the normal aging process or is a precursor
sign for dementia, is difficult for the doctor.
Therefore, the
earliest observable symptoms are often mistakenly thought
to be age-related concerns, or manifestations of stress.
When AD is suspected, the diagnosis is usually confirmed by
behavioral assessment and cognitive tests, often followed by
a brain scan if possible.
As the damage spreads, individuals
also experience confusion, disorganized thinking, impaired
judgment, trouble expressing themselves, and disorientation.
The following are warning signs of Alzheimer’s disease:
• Memory loss that disrupts daily life
• Challenges in planning or solving problems
• Difficulty completing familiar tasks at home, at work, or
at leisure
• Confusion in time or place
• Trouble understanding visual images and spatial
• New problems with words in speaking or writing
• Misplacing things and losing the ability to retrace steps
• Decreased or poor judgment
• Withdrawal from work or social activities
• Changes in mood and personality.
As the disease advances, symptoms include confusion,
irritability, and aggression, mood swings, language
breakdown, long-term memory loss, and the general
withdrawal of the sufferer as their senses decline.
As the
disease progresses, cognitive impairment becomes profound
and daily functioning skills decline. Although typically
thought of as indicative of late-stage disease, behavioral
symptoms can appear early in the course of the disease, well
before clinical diagnosis. These symptoms can include social
withdrawal, depression, paranoia, and mood changes. As the
disease advances, symptoms such as anxiety, irritability, and
agitation become more pronounced.
Behavioral symptoms
are also a major source of stress for the caregiver. Behavioral
disturbances have been shown to be a strong predictor of
caregiver burden
and are associated with increased financial
hardship for the caregiver.
Physical functions are gradually
lost, ultimately leading to death. Individual prognosis is
difficult to assess, because the duration of the disease varies.
AD develops for an indeterminate period of time before
becoming fully apparent, and it can progress undiagnosed
for years. The mean life expectancy following diagnosis is
approximately 7 years.
Fewer than 3% of individuals live
more than 14 years after diagnosis.
There is an increasing interest in the identification of patients
in the earliest stage of AD, prior to clinical manifestation of
dementia, in order to provide effective early intervention
that aims at delaying significant impairment. A definitive
diagnosis of AD requires a detailed post-mortem micro-
scopic examination of the brain. But nowadays, AD can be
diagnosed with more than 95% accuracy in living patients
by using a combination of tools. These include taking a care-
ful history from patients and their families, and assessing
cognitive function by neuropsychologic tests. Other causes
of dementia must be ruled out, such as low thyroid function,
vitamin deficiencies, infections, cancer, and depression. It is
also crucial to differentiate AD from other neurodegenera-
tive dementias.
The National Institute of Neurological and Communica-
tive Disorders and Stroke and the Alzheimer’s Disease and
Related Disorders Association (NINCDS-ADRDA) and the
Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR) criteria for AD
are the prevailing diagnostic standards in research. However,
they have now fallen behind the unprecedented growth of
scientific knowledge. Moreover, NINCDS-ADRDA was
reported in 1984 and the subsequent DSM-IV-TR in 2000.
For this reason, to improve the specificity for diagnosis of AD,
the criteria were revised by Dubois to offer a new diagnostic
approach including genetic testing, molecular imaging, and
body fluid biomarkers.
Furthermore, draft reports presented
Clinical Interventions in Aging 2010:5
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at the International Conference on Alzheimer’s Disease in
2010 will form the basis of new diagnostic criteria for mild
cognitive impairment and AD.
There was no effective therapy for AD before the approval
of the cholinesterase inhibitors and memantine. These
agents are associated with detectable symptomatic improve-
ment, and have a modest effect on the progression of AD
from mild cognitive impairment to disabling dementia and
Medicines currently prescribed for AD fall into three
groups, ie, inhibitors of acetylcholinesterase (according to
the cholinergic hypothesis of AD, memory impairments
result from death of cholinergic neurons in the basal fore-
brain), an antagonist of a receptor for the neurotransmitter
glutamate, and drugs from the psychiatric toolbox to control
depression and behavioral abnormalities.
The clinical development of new agents for symptomatic
and disease-modifying treatment of AD has resulted in both
promise and disappointment. Despite the fact that no new
compound for the treatment of AD has been introduced
since the approval of memantine in 2002, the variety of drug
targets and mechanisms of action, and the total number of
compounds under investigation make it highly likely that
important new pharmacotherapeutic options will become
available for the treatment of AD over the next decade.
Moreover, research into the underlying etiology and
pathophysiology of AD is likely to facilitate identification
of additional targets for future drug development.
addition, stem cell therapy for AD might be used to replace
destroyed neurons, but AD poses particular challenges
in this regard because it affects diverse types of neurons
in different brain regions.
However, our experience has
demonstrated that mesenchymal stem cell therapy might
provide neuronal replacement and improved cognitive func-
tion in streptozotocin-induced neurodegeneration in rats,
but adjunctive therapies with mesenchymal stem cells in
this type of neurodegeneration need to be tried.
the development of bone marrow mesenchymal stem cell
therapy for the replacement of cells and tissues lost due to
neurodegeneration in AD is still in the early stages, and fur-
ther studies will be needed before it can be tested in humans.
Nonetheless, these improving effects of mesenchymal stem
cells give us hope for the future.
Nowadays, there is no definitive evidence to support any
particular measure being effective in prevention of AD.
Global studies of measures to prevent or delay the onset
of AD have often produced inconsistent results. However,
epidemiologic studies have proposed relationships between
certain modifiable factors, such as diet, cardiovascular risk,
pharmaceutical products, or intellectual activities, among
others, and a population’s likelihood of developing AD. Only
further research, including clinical trials, will reveal whether
these factors can help to prevent AD.
In addition, at the
International Conference on Alzheimer’s Disease in 2010,
it was also reported that moderate to heavy physical activity
is associated with a reduced risk of dementia, with up to two
decades of follow-up.
In summary, AD is increasingly being diagnosed as one of
the most important medical problems in the elderly, and
the management of elderly patients with AD is complex.
A comprehensive approach is required that focuses on
both the patient and caregiver. Despite all developments,
our treatment options for prevention and treatment of the
cognitive, behavioral, and psychologic symptoms of AD
are still lacking. Therefore, it is important for clinicians to
recognize early signs and symptoms of AD and to determine
potentially modifiable risk factors.
The author reports no conflicts of interest in this work.
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... Whereas neuropsychiatric syndromes have been associated with memory dysfunction (12), risk of dementia (13), and earlier onset of dementia (14), it is unclear whether psychotropic drugs may affect clinical changes in AD. Even though APOE «4 noncarriers appear to be more susceptible to the effects of cognitive enhancement therapy (15), the impact of APOE «4 carrier status as a mediator of effects of psychotropic drugs on clinical changes in AD is not fully understood. ...
... All cognitive and functional scores (but not caregiver burden) were significantly changed after 1 year, but only MMSE score changes were different according to APOE «4 carrier status. Although behavioral burden may be even higher in other dementia syndromes (51), behavioral symptoms, rather than cognition, are the primary determinants of caregiver burden (14) and correlate better with functionality than with cognitive decline (33). Yet cognition has been known to have an impact on functionality in all stages of AD (52). ...
Objective: Neuropsychiatric syndromes have been associated with memory dysfunction and risk of and earlier onset of dementia, but how psychotropic drugs affect clinical changes in Alzheimer’s disease is not entirely clear. This study aimed to assess the prospective effects of psychotropic drugs on cognitive and functional changes in Alzheimer’s disease according to APOE ε4 carrier status. Methods: The study included consecutive outpatients with late-onset Alzheimer’s disease (N=193) and examined score variations at 1 year on the following tests: Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, Severe Mini-Mental State Examination (SMMSE), Brazilian version of the Zarit Caregiver Burden Interview, Index of Independence in Activities of Daily Living, and Lawton’s Instrumental Activities of Daily Living Scale. Analyses of score variations accounted for the use of psychotropic drugs or the number of different medications in use, as well as APOE ε4 carrier status, with significance at p<0.05. Results: For APOE ε4 noncarriers (N=90), cholinesterase inhibitors were beneficial regarding caregiver burden (p=0.030) and basic functionality (p=0.046), memantine was harmful regarding SMMSE score changes (p=0.032), second-generation antipsychotics had nonsignificant harmful effects on SMMSE score changes (p=0.070), and antiepileptic therapy (p=0.001) and the number of different medications in use (p=0.006) were harmful in terms of basic functionality. APOE ε4 carriers (N=103) did not experience any effects of isolated psychotropic drugs on clinical changes, including antidepressants. Conclusions: Results support the harmful prospective effects of second-generation antipsychotics and antiepileptic drugs on cognitive and functional changes in Alzheimer’s disease, particularly for APOE ε4 noncarriers, whereas antidepressants may be safer options for behavioral enhancement.
... Alzheimer's disease (AD; OMIM 104300) is a progressive neurodegenerative disorder and the most frequent cause of dementia in the elderly, with prevalence rising substantially between 65 years and older [1,2]. The incidence of AD doubles every five years beyond the Biomedicines 2022, 10 age of 65, with the diagnosis of 1275 new cases/year/100,000 individuals over 65 years, such that 30%-50% of all people become affected by the age of 85 [2,3]. ...
... Alzheimer's disease (AD; OMIM 104300) is a progressive neurodegenerative disorder and the most frequent cause of dementia in the elderly, with prevalence rising substantially between 65 years and older [1,2]. The incidence of AD doubles every five years beyond the Biomedicines 2022, 10 age of 65, with the diagnosis of 1275 new cases/year/100,000 individuals over 65 years, such that 30%-50% of all people become affected by the age of 85 [2,3]. Although 60-80% of AD is inherited in elderly populations, genetic and environmental factors also play a crucial role in the onset, progression, and severity of phenotype [4,5]. ...
Full-text available
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by a progressive loss of cognitive functions at a higher level than normal aging. Although the apolipoprotein (APOE) gene is a major risk factor in developing AD, other genes have also been reported to be linked with complex phenotypes. Therefore, this genome-wide expression study explored differentially expressed genes as possible novel biomarkers involved in AD. The mRNA expression dataset, GSE28146, containing 15 sample data composed of 8 AD cases from the hippocampus region with age-matched control (n = 7, >65 years), was analyzed. Using “affy” R-package, mRNA expression was calculated, while pathway enrichment analysis was performed to determine related biological processes. Of 58 differentially expressed genes, 44 downregulated and 14 upregulated genes were found to be significantly (p < 0.001) altered. The pathway enrichment analysis revealed two altered genes, i.e., dynein light chain 1 (DYNLL1) and kalirin (KLRN), associated with AD in the elderly population. The majority of genes were associated with retrograde endocannabinoid as well as vascular endothelial growth factors affecting the complex phenotypes. The DYNLL1 and KLRN genes may be involved with AD and Huntington’s disease (HD) phenotypes and represent a common genetic basis of these diseases. However, the hallmark of AD is dementia, while the classic motor sign of HD includes chorea. Our data warrant further investigation to identify the role of these genes in disease pathogenesis
... Both EOAD and LOAD have the same treatment options. The use of cholinesterase inhibitors (ChEI), which are antagonists of a receptor for the neurotransmitter glutamate and drugs usually prescribed to combat depression and other illnesses (Isik, 2010), is the main option for therapy in AD cases that are considered mild to moderate for EOAD and LOAD (Wattmo and Wallin, 2017). Overall, cognitive response in patients treated with ChEIs showed better outcomes in patients diagnosed with LOAD than EOAD (Li and Singh, 2014). ...
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Objective This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer’s disease (LOAD) and Early-onset Alzheimer’s disease (EOAD). Method Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer’s patients’ registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD. Results In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175–2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221–3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799–0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834–0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627–0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462–0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424–0.660, p < 0.001] were associated with LOAD. Conclusion Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.
... The diagnosis is based on a formal evaluation of cognitive function, neuropsychiatric tests, and interviews with the patient and family. Imaging methods and laboratory tests are routinely ordered to exclude other organic causes of impaired mental state (Falk et al. 2012;Houmani et al. 2018;Isik 2010;McBride et al. 2013), which may be amenable to more definitive intervention. Although not included in the standard clinical workup of AD, early subtle and later more overt abnormalities (e.g., slow waves) can often be seen on electroencephalography (EEG) at initial presentation and advanced stages of AD, respectively. ...
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Electroencephalography (EEG) may detect early changes in Alzheimer's disease (AD), a debilitating progressive neurodegenerative disease. We have developed an automated AD detection model using a novel directed graph for local texture feature extraction with EEG signals. The proposed graph was created from a topological map of the macroscopic connectome, i.e., neuronal pathways linking anatomo-functional brain segments involved in visual object recognition and motor response in the primate brain. This primate brain pattern (PBP)-based model was tested on a public AD EEG signal dataset. The dataset comprised 16-channel EEG signal recordings of 12 AD patients and 11 healthy controls. While PBP could generate 448 low-level features per one-dimensional EEG signal, combining it with tunable q-factor wavelet transform created a multilevel feature extractor (which mimicked deep models) to generate 8,512 (= 448 × 19) features per signal input. Iterative neighborhood component analysis was used to choose the most discriminative features (the number of optimal features varied among the individual EEG channels) to feed to a weighted k-nearest neighbor (KNN) classifier for binary classification into AD vs. healthy using both leave-one subject-out (LOSO) and tenfold cross-validations. Iterative majority voting was used to compute subject-level general performance results from the individual channel classification outputs. Channel-wise, as well as subject-level general results demonstrated exemplary performance. In addition, the model attained 100% and 92.01% accuracy for AD vs. healthy classification using the KNN classifier with tenfold and LOSO cross-validations, respectively. Our developed multilevel PBP-based model extracted discriminative features from EEG signals and paved the way for further development of models inspired by the brain connectome.
... Alzheimer's disease and other dementias were found to be more common among women than among men. AD and other dementias are among the three leading neurological disorders (Isik 2010). Cholinergic dysfunction, cognitive impairment, memory loss, neuronal death, and behavioral problems are all symptoms of AD. ...
Abstract: Neurological illnesses disrupt brain function and are one of the primary causes of disability and mortality around the world. Nutritional factors have a significant impact on brain function. Some nutrients have been found to help prevent the onset of prevalent neurological illnesses like Alzheimer’s and Parkinson’s disease. Certain diets, such as carbohydrate-rich diets, can assist to prevent neurological diseases from developing. As a result, nutrition and neurological problems are linked, which could lead to the development of a novel treatment strategy that slows disease progression.
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The United Nations projects that one in every six people will be over the age of 65 by the year 2050. With a rapidly aging population, the risk of Alzheimer's disease (AD) becomes a major concern. AD is a multifactorial disease that involves neurodegeneration in the brain with mild dementia and deficits in memory and other cognitive domains. Additionally, it has been established that individuals with Human Immunodeficiency Virus-1 (HIV-1) experience a 5 to 10-year accelerated aging and an increased risk of developing HIV-associated neurocognitive disorders (HAND). Despite a significant amount of clinical evidence pointing towards a potential overlap between neuropathogenic processes in HAND and AD, the underlying epigenetic link between these two diseases is mostly unknown. This study is focused on identifying differentially expressed genes observed in both AD and HAND using linear regression models and a more robust significance analysis of microarray. The results established that the dysregulated type 1 and 2 interferon pathways observed in both AD and HAND contribute to the similar pathologies of these diseases within the brain. The current study identifies the important roles of interferon pathways in AD and HAND, a relationship that may be useful for earlier detection in the future.
Alzheimer's disease (AD) is one of the progressive neurodegenerative disorders and the most common cause of dementia in the elderly worldwide causing difficulties in the daily life of the patient. AD is characterized by the aberrant accumulation of β‐amyloid plaques and tau protein‐containing neurofibrillary tangles (NFTs) in the brain giving rise to neuroinflammation, oxidative stress, synaptic failure, and eventual neuronal cell death. The total cost of care in AD treatment and related health care activities is enormous and pharmaceutical drugs approved by Food and Drug Administration have not manifested sufficient efficacy in protection and therapy. In recent years, there are growing studies that contribute a fundamental understanding to AD pathogenesis, AD‐associated risk factors, and pharmacological intervention. However, greater molecular process‐oriented research in company with suitable experimental models is still of the essence to enhance the prospects for AD therapy and cell lines as a disease model are still the major part of this milestone. In this review, we provide an insight into molecular mechanisms, particularly the recent concept in gut‐brain axis, vascular dysfunction and autophagy, and current models used in the study of AD. Here, we emphasized the importance of therapeutic strategy targeting multiple mechanisms together with utilizing appropriate models for the discovery of novel effective AD therapy. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Current understanding of mechanisms underlying AD pathogenesis and some common non‐rodent study models (Created with
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Alzheimer's disease (AD) is an incurable neurodegenerative disorder and the leading cause of death among older individuals. Available treatment strategies only temporarily mitigate symptoms without modifying disease progression. Recent studies revealed the multifaceted neurobiology of AD and shifted the target of drug development. Established animal models of AD are mostly tailored to yield a subset of disease phenotypes, which do not recapitulate the complexity of sporadic late-onset AD, the most common form of the disease. The use of human induced pluripotent stem cells (HiPSCs) offers unique opportunities to fill these gaps. Emerging technology allows the development of disease models that recapitulate a brain-like microenvironment using patient-derived cells. These models retain the individual's unraveled genetic background, yielding clinically relevant disease phenotypes and enabling cost-effective, high-throughput studies for drug discovery. Here, we review the development of various HiPSC-based models to study AD mechanisms and their application in drug discovery.
Aim: Alzheimer's disease (AD) and dementia with Lewy body (DLB) constitute the most common types of dementia, and are two common geriatric syndromes; however, sarcopenia has not been elaborately evaluated in DLB so far. Therefore, this study aimed to investigate the relationship between sarcopenia and DLB in older adults. Methods: In this retrospective and cross-sectional study, 662 participants, who were followed in a memory clinic at the Geriatrics department of a university hospital, were included. Comprehensive Geriatric Assessment, including the activities of daily living, malnutrition and malnutrition risk, frailty, cognition, and sarcopenia were assessed. Sarcopenia was defined according to the revised European Working Group on Sarcopenia in Older People-2 criteria. Results: A total of 662 participants (461 healthy controls, 133 with AD and 68 with DLB) with a mean age of 73.60 ± 7.50 years were included. The prevalence of probable sarcopenia and sarcopenia was 53.4% and 19.5%, respectively, in patients with AD, whereas it was 55.9% and 19.1%, respectively, in patients with DLB. After adjustment analyses, probable sarcopenia, sarcopenia and low muscle mass were related to AD (P < 0.001, P = 0.001, P < 0.001, respectively). Probable sarcopenia and slow gait speed were associated with DLB (P < 0.01, P < 0.001, respectively). Conclusions: Sarcopenia is common in patients with DLB and in those with AD, and seems to be closely related to low muscle strength and slow gait speed in DLB patients. Considering sarcopenia-related negative health outcomes in older adults, the evaluation of sarcopenia, therefore, should also be among the follow-up and treatment goals of DLB patients. Geriatr Gerontol Int 2022; ••: ••-••.
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This paper examined the toxins naturally produced by marine dinoflagellates and their effects on increases in β-amyloid plaques along with tau protein hyperphosphorylation, both major drivers of Alzheimer’s disease (AD). This approach is in line with the demand for certain natural compounds, namely those produced by marine invertebrates that have the potential to be used in the treatment of AD. Current advances in AD treatment are discussed as well as the main factors that potentially affect the puzzling global AD pattern. This study focused on yessotoxins (YTXs), gymnodimine (GYM), spirolides (SPXs), and gambierol, all toxins that have been shown to reduce β-amyloid plaques and tau hyperphosphorylation, thus preventing the neuronal or synaptic dysfunction that ultimately causes the cell death associated with AD (or other neurodegenerative diseases). Another group of toxins described, okadaic acid (OA) and its derivatives, inhibit protein phosphatase activity, which facilitates the presence of phosphorylated tau proteins. A few studies have used OA to trigger AD in zebrafish, providing an opportunity to test in vivo the effectiveness of new drugs in treating or attenuating AD. Constraints on the production of marine toxins for use in these tests have been considered. Different lines of research are anticipated regarding the action of the two groups of toxins.
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Alzheimer’s disease (AD) is the sixth leading cause of all deaths in the United States, and the fifth leading cause of death in Americans aged 65 and older. Whereas other major causes of death have been on the decrease, deaths attributable to AD have been rising dramatically. Between 2000 and 2006, heart disease deaths decreased nearly 12%, stroke deaths decreased 18%, and prostate cancer-related deaths decreased 14%, whereas deaths attributable to AD increased 47%. An estimated 5.3 million Americans have AD; the approximately 200,000 persons under age 65 years with AD comprise the younger-onset AD population. Every 70 seconds, someone in America develops AD; by 2050, this time is expected to decrease to every 33 seconds. Over the coming decades, the "baby-boom" population is projected to add 10 million people to these numbers. In 2050, the incidence of AD is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million people. Significant cost implications related to AD and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (e.g., decreased business productivity) costs. Not included in these figures is the $94 billion in unpaid services to individuals with AD provided annually by an estimated 10 million caregivers. Mild cognitive impairment (MCI) is an important component in the continuum from healthy cognition to dementia. Understanding which individuals with MCI are at highest risk for eventually developing AD is key to our ultimate goal of preventing AD. This report provides information meant to increase an understanding of the public-health impact of AD, including incidence and prevalence, mortality, lifetime risks, costs, and impact on family caregivers. This report also sets the stage for a better understanding of the relationship between MCI and AD. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Background and aim: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are one of the sources of adult stem cells being explored for potential use in repairing neurodegenerative disorders. In this study, it was aimed to investigate the useful effects of BM-MSCs therapy on the streptozotocin-induced neurodegeneration in rats. Materials and methods: Adult female Wistar rats were bilaterally injected intra-cerebroventricularly with streptozotocin (3 mg/kg) for neurodegeneration. Water maze tests were used to monitor spatial learning and memory. One or two intravenous injections of BM-MSCs were administrated to rat via the tail veins. At the end of the study, all rats were sacrificed for histological evaluation and immunohistochemistry. Results: Streptozotocin group demonstrated a significant increase in escape latency in comparison with both control groups (Sham and Saline), whereas rats treated with BM-MSCs exhibited a decrease in escape latency in comparison with streptozotocin group. The percentage of time spent in the target quadrant and the mean number of platform crossings did not change in all the groups. BM-MSCs administration improved spatial learning but not memory. However, improvement in neuronal cells in hippocampal CA1 region was only observed in the rats treated with BM-MSCs twice as opposed to the rats treated with BM-MSCs once or with saline. Conclusions: In this study, mesenchymal stem cells therapy failed to improve the streptozotocin-induced neurodegeneration like Alzheimer's disease in rats.
Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.
There is growing consensus in the field of Alzheimer's disease (AD) research that it may be difficult to develop drugs that can reverse the neuronal damage caused by the disease once symptoms are severe enough to be diagnosable. Therefore, the goal has shifted toward identification of individuals earlier in the disease process, when symptoms are very mild, as well as identification of asymptomatic, high-risk individuals so that they can be targeted for prevention and early intervention. In other fields, risk indices are often used to identify individuals who are asymptomatic but high-risk. Risk indices, also known as prognostic models, are tools that are used to predict the likelihood that an individual will experience a given event within a given time frame. Usually, this is accomplished by combining information from several different individual risk factors into a summary score. The prognostic accuracy of risk indices is typically assessed based on the area under the receiver operating characteristic (ROC) curve, also known as the c statistic [1]. The ROC curve is a graph of the true-positive rate (sensitivity) by the false-positive rate (1-specificity), and it is related to the relative probability that in all possible pairs of subjects in which one had the outcome and one didn't, the one with the outcome would receive a higher risk score. The c statistic may range from 0 to 1, with 0.5 reflecting predictive accuracy no better than chance and 1 reflecting perfect discrimination. The Framingham Heart Index is one of the most commonly used risk indices. It uses a combination of age, sex, blood pressure, cholesterol, and smoking status to identify individuals who are currently free of overt coronary heart disease but, based on their risk factor profile, have a high risk of experiencing a major coronary event within 10 years (c statistic, 0.79) [2,3]. Similarly, the Breast Cancer Risk Assessment Tool uses information about a woman's age, race, reproductive history, family history of breast cancer, and biopsy history to predict her risk of developing invasive breast cancer within five years (c statistic, 0.58) [4,5]. Risk indices also are available to predict risk of mortality [6,7], disability [8], nursing home placement [9], and diabetes [10,11], among many other conditions and disorders.
The neurodegenerative disorder Alzheimer's disease is becoming more prevalent in ageing populations worldwide. The identification of effective treatments will require a better understanding of the physiological mechanisms involved, and innovative approaches to drug development and evaluation.