Late onset Alzheimer’s disease in older people

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.

Full text

© 2010 Isik, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
Clinical Interventions in Aging 2010:5 307–311
Clinical Interventions in Aging Dovepress
submit your manuscript | www.dovepress.com
Dovepress
307
REVIEW
open access to scientific and medical research
Open Access Full Text Article
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
Introduction
Age is the most important risk factor for AD, with the prevalence rising substantially
between the ages of 65 and 85 years.
1
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.
2
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
three.
3,4
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.
5
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.
6
Pathogenesis
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
LOAD.
7
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.
8
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
Email: atisik@yahoo.com
Number of times this article has been viewed
This article was published in the following Dove Press journal:
Clinical Interventions in Aging
9 October 2010

Clinical Interventions in Aging 2010:5
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
308
Isik
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.
3
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.
9,10
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.
10
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.
9
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.
11,12
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.
13
However,
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.
14
Data
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.
15
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
trafficking.
16
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.
17,18
Furthermore,
Aβ peptides generate oxidative stress via neuroinflammation.
Considerable evidence has supported the hypothesis that neu-
roinflammation is associated with AD pathology.
18
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.
3,19
It has also been
reported that clearance of Aβ along diseased perivascular
channels and through the blood–brain barrier is impeded in
AD atheroma,
20
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.
19,21
Furthermore, insulin resistance and hyperinsulinemia are
implicated in a number of pathophysiologic processes related
to AD.
22,23
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
mellitus,
24,25
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.
22,23–25
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
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
309
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.
3,22,26
Symptoms
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.
27
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.
28–30
Therefore, the
earliest observable symptoms are often mistakenly thought
to be age-related concerns, or manifestations of stress.
31
When AD is suspected, the diagnosis is usually confirmed by
behavioral assessment and cognitive tests, often followed by
a brain scan if possible.
31
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
relationships
• 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.
27
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.
31
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.
32
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
8
and are associated with increased financial
hardship for the caregiver.
33
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.
34
Fewer than 3% of individuals live
more than 14 years after diagnosis.
35
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.
36
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.
37
Furthermore, draft reports presented

Clinical Interventions in Aging 2010:5
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
310
Isik
at the International Conference on Alzheimer’s Disease in
2010 will form the basis of new diagnostic criteria for mild
cognitive impairment and AD.
Treatment
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
death.
38
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.
36
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.
38
In
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.
36
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.
39
However,
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.
Prevention
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.
40
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.
41
Conclusion
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.
Disclosure
The author reports no conflicts of interest in this work.
References
1. Sloane PD, Zimmerman S, Suchindran C, et al. The public health impact
of Alzheimer’s disease, 2000–2050: Potential implication of treatment
advances. Annu Rev Public Health. 2002;23:213–231.
2. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. How common are the
“common” neurologic disorders? Neurology. 2007;68:326–337.
3. Querfurth HW, LaFerla FM. Mechanisms of disease: Alzheimer’s
disease. N Engl J Med. 2010;362:329–344.
4. den Dunnen WF, Brouwer WH, Bijlard E, et al. No disease in the brain
of a 115-year-old woman. Neurobiol Aging. 2008;29:1127–1132.
5. Drachman DA. Aging of the brain, entropy, and Alzheimer disease.
Neurology. 2006;67:1340–1352.
6. Harman D. Alzheimer’s disease pathogenesis: Role of aging. Ann N Y
Acad Sci. 2006;1067:454–460.
7. Schellenberg GD. Genetic dissection of Alzheimer’s disease,
a heterogeneous disorder. Proc Natl Acad Sci U S A. 1995;92:
8552–8559.
8. Holtzman DM. Role of ApoE/Aβ interactions in the pathogenesis of
Alzheimer’s disease and cerebral amyloid angiopathy. J Mol Neurosci.
2001;17:147–155.
9. Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of
dementia: 1. Risk assessment and primary prevention of Alzheimer
disease. CMAJ. 2008;178:548–556.
10. Barnes DE, Covinsky KE, Whitmer RA, et al. Commentary on
“Developing a national strategy to prevent dementia: Leon Thal
Symposium 2009.” Dementia risk indices: A framework for identify-
ing individuals with a high dementia risk. Alzheimers Dement. 2010;6:
138–141.

Clinical Interventions in Aging
Publish your work in this journal
Submit your manuscript here: http://www.dovepress.com/clinical-interventions-in-aging-journal
Clinical Interventions in Aging is an international, peer-reviewed journal
focusing on evidence-based reports on the value or lack thereof of treat-
ments intended to prevent or delay the onset of maladaptive correlates
of aging in human beings. This journal is indexed on PubMed Central,
MedLine, the American Chemical Society’s ‘Chemical Abstracts
Service’ (CAS), Scopus and the Elsevier Bibliographic databases. The
manuscript management system is completely online and includes a
very quick and fair peer-review system, which is all easy to use. Visit
http://www.dovepress.com/testimonials.php to read real quotes from
published authors.
Clinical Interventions in Aging 2010:5
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
Dovepress
311
Late onset Alzheimer’s disease
11. Bussiere T, Giannakopoulos P, Bouras C, et al. Progressive degeneration
of nonphosphorylated neurofilament protein-enriched pyramidal
neurons predict cognitive impairment in Alzheimer’s disease: Stereo-
logic analysis of prefrontal cortex area. J Comp Neurol. 2003;463:
281–302.
12. Garry LW. Neuropathologic changes in Alzheimer’s disease: Potential
target for treatment. J Clin Psychiatry. 2006;67 Suppl 3:3–7.
13. Cotman CW, Su JH. Mechanisms of neuronal death in Alzheimer’s
disease. Brain Pathol. 1996;6:493–506.
14. Braak H, Braak E. Neuropathologic staging of Alzheimer-related
changes. Acta Neuropathol (Berl). 1991;82:239–259.
15. Arendt T. Synaptic degeneration in Alzheimer’s disease. Acta
Neuropathol. 2009;118:167–179.
16. Coleman PD, Yao PJ. Synaptic slaughter in Alzheimer’s disease.
Neurobiol Aging. 2003;24:1023–1027.
17. Lustbader JW, Cirilli M, Lin C. ABAD directly links Abeta to mitochon-
drial toxicity in Alzheimer’s disease. Science. 2004;304:448–452.
18. Newman M, Musgrave FI, Lardelli M. Alzheimer disease: Amyloido-
genesis, the presenilins and animal models. Biochimica Biophysica
Acta. 2007;1772:285–297.
19. Weller RO, Boche D, Nicoll JAR. Microvasculature changes and cerebral
amyloid angiopathy in Alzheimer’s disease and their potential impact
on therapy. Acta Neuropathol. 2009;118:87–102.
20. Price JM, Chi X, Hellermann G, Sutton ET. Physiological levels of
beta-amyloid induce cerebral vessel dysfunction and reduce endothelial
nitric oxide production. Neurol Res. 2001;23:506–512.
21. Deane R, Zlokovic BV. Role of the blood-brain barrier in the pathogen-
esis of Alzheimer’s disease. Curr Alzheimer Res. 2007;4:191–197.
22. Isik AT, Bozoglu E. Insulin resistance in Alzheimer’s disease. In: Aucoin L,
Prideux T, editors. Handbook of Type 1 Diabetes Mellitus: Etiology, Diag-
nosis, and Treatment. Hauppauge, NY: Nova Science; 2010.
23. Isik AT, Celik T, Ulusoy G, et al. Curcumin ameliorates impaired insulin/
IGF signaling and memory deficit in streptozotocin treated rat model.
Age. 2009;31:39–49.
24. Jolivalt CG, Lee CA, Beiswenger KK, et al. Defective insulin signaling
pathway and increased glycogen synthase kinase-3 activity in the brain
of diabetic mice: Parallels with Alzheimer’s disease and correction by
insulin. J Neurosci Res. 2008;86:3265–3274.
25. de la Monte SM, Wands JR. Review of insulin and insulin-like
growth factor expression, signaling, and malfunction in the central
nervous system: Relevance to Alzheimer’s disease. J Alzheimers Dis.
2005;7:45–61.
26. Popescu BO, Toescu EC, Popescu LM, et al. Blood-brain barrier altera-
tions in ageing and dementia. J Neurol Sci. 2009;283:99–106.
27. Alzheimer’s Association. 2010 Alzheimer’s disease facts and figures.
Alzheimers Dement. 2010;6:158–194.
28. Salthouse TA. Memory aging from 18 to 80. Alzheimer Dis Assoc
Disord. 2003;17:162–167.
29. Treitz FH, Heyder K, Daum I. Differential course of executive con-
trol changes during normal aging. Neuropsychol Dev Cogn B Aging
Neuropsychol Cogn. 2007;14:370–393.
30. Isik AT. Approach the elderly patient with forgetfulness. Journal of
Geriatrics and Geriatric Neuropsychiatry. 2009;2:33–38.
31. Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis
and management of Alzheimer’s disease and other disorders associated
with dementia: EFNS guideline. Eur J Neurol. 2007;14(1):e1–e26.
32. Jost BC, Grossberg GT. The evolution of psychiatric symptoms in
Alzheimer’s disease: A natural history study. J Am Geriatr Soc. 1996;44:
1078–1081.
33. Beier MT. Treatment strategies for the behavioral symptoms of
Alzheimer’s disease: Focus on early pharmacologic intervention.
Pharmacotherapy. 2007;27(3):399–411.
34. National Institute on Aging. Understanding stages and symptoms
of Alzheimer’s disease. 2007. Available at: http://www.nia.nih.gov/
alzheimers/publications/stages.htm. Accessed 2008 Feb 21.
35. Mölsä PK, Marttila RJ, Rinne UK. Long-term survival and predictors
of mortality in Alzheimer’s disease and multi-infarct dementia. Acta
Neurol Scand. 1995;91:159–164.
36. Mucke L. Alzheimer disease. Nature. 2009;461:895–897.
37. Dubois B, Feldman F, Jacova C, et al. Research criteria for the diagnosis
of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet
Neurol. 2007;6:734–746.
38. Sabbagh NM. Drug development for Alzheimer’s disease: Where are
we now and where are we headed? Am J Geriatr Pharmacother. 2009;
7:167–185.
39. Isik AT, Celik T, Ural AU, Tosun M, et al. Does the mesenchymal stem
cell therapy improve the streptozotocin induced neurodegeneratıon in
rats? Alzheimers Dement. 2010;6 Suppl 1:569.
40. Szekely CA, Breitner JC, Zandi PP. Prevention of Alzheimer’s disease.
Int Rev Psychiatry. 2007;19:693–706.
41. Tan ZS, Beiser AS, Au R, et al. Physical activity and risk of dementia:
The Framingam study. Alzheimers Dement. 2010;6 Suppl 1:S68.