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108
Epidemiological of and risk factors for Alzheimer‘s disease: A review
Jana Povovaa
, Petr Ambroza
, Michal Barb
,Veronika Pavukovaa
, Omar Seryc
, HanaTomaskovaa
,Vladimir Janouta
Background. Alzheimer’s disease (AD) is the most common form of dementia. It is a degenerative, incurable and terminal
disease.The increasing prevalence of AD is, among other reasons, due to population aging, which is, to a certain
extent, seen worldwide. Continuous advances in health care keep increasing life expectancy. Official statistics are likely
to significantly underestimate the actual prevalence of AD. Alzheimer’s disease represents an important public health
problem. Its aetiology is still unknown and for this reason, it is necessary to study all potential risk factors which may
contribute to the development of this disease.
Methods.We searched original and review articles addressing Alzheimer´s disease using key words Alzheimer’s disease,
epidemiology, risk factors and prevention. We found and used one hundred and four references.
Conclusions. Based on epidemiological studies, genetic studies, neuroimaging methods and neuropathology research,
three basic etiological hypotheses of the development of AD have been formulated: genetic, vascular and psychosocial.
At present, the level of evidence is insufficient for the etiological role of other factors, such as nutrition, occupational
exposure to various substances and inflammation. From the point of view of early diagnosis and application of primary
or secondary prevention principles, genetic factors are the most important.
Key words: Alzheimer’s disease, epidemiology, risk factors, prevention
Received: September 9, 2011; Accepted with revision: May 17, 2012; Available online: June 14, 2012
http://dx.doi.org/10.5507/bp.2012.055
a
Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Czech Republic
b
Department of Clinical Studies, Faculty of Medicine, University of Ostrava
c
Department of Biochemistry, Faculty of Science, Masaryk University Brno
Corresponding author: Jana Povova, e-mail: Jana.povova@osu.cz
INTRODUCTION
Alzheimer’s disease (AD) is the most common form
of dementia. It is a degenerative, incurable and terminal
disease. Although it is mostly diagnosed in people over
65 years, a less prevalent early-onset form may develop
much earlier.
Alzheimer’s disease affects most (up to 75%) of the
more than 35 million people suffering from dementia
worldwide. The prevalence is believed to double every 20
years. Thus, it is estimated that approximately 115 million
people may be affected by AD in 2050. The disease has a
major impact not only on the sufferers but also on persons
caring for them as well as the entire society.
The etiological factors are mostly unknown. There
is increasing evidence of the role that certain risk factors
play in the development of the disease, such as genetic
and vascular factors or disorders. Also known are
psychosocial factors which may positively influence the
pathogenesis and clinical manifestation of the disease.
Therefore, intervention in these areas may lower the risk
of its development or at least delay the clinical manifesta-
tion.
The increasing prevalence of AD is, among other
reasons, due to population aging, which is, to a certain
extent, seen worldwide.
OCCURRENCE
Prevalence
Aggregate data from studies on the prevalence of AD
in Europe reported the age-standardized prevalence of
AD in people aged 65 or more to be 4.4% (ref.1
). A US
study performed in a representative sample of persons
over 70 years of age reported AD prevalence of 9.7%
(ref.2
). The global prevalence of AD is estimated at 3.9%
in people older than 60 years, with regional variations in
individual continents3
.
In developed countries, approximately 1 in 10 persons
over 65 years of age suffers from a form of dementia
compared with more than one third of those older than
85 years4,5
.
Incidence
Two US studies of persons aged 65 or more reported
an AD incidence of 15.0 per 1,000 person-years. The incidence
rates for males and females were 13.0 and 16.9
per 1,000 person-years, respectively6,7
.
In a 3 year follow-up, a Swedish prospective study involving
987 persons aged 75 years or older found the incidence
rates of dementia in the age group of 75-79 years
to be 19.6 and 12.4 per 1,000 person-years in females
and males, respectively. In those aged 90 or more, the
incidence rates of dementia were 86.7 per 1,000 personyears
in females and 15.0 per 1,000 person-years in males.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):108–114.
109
A similar distribution by age and gender was seen in AD.
The risk of the development of any form of dementia is
reported to be approximately twice as high in females as
in males and the risk of Alzheimer’s disease is as much
as three times higher in females8
.
Numerous other studies report the incidence rates of
dementia and AD as the number of persons per year.
For example, in a British prospective cohort study of
1,070 persons aged 65 or more and followed for 3 years,
the incidence of all types of dementia was 9.2 per 1,000
population and year, of which the AD incidence was 6.3
per 1,000 population and year9
.
Koukolík reported approximately 35,000 AD patients
aged 65 years or more in former Czechoslovakia in 1983
(ref.10
).
According to the Czech Alzheimer Society, approximately
130,000 people in the Czech Republic currently
suffer from dementia, two thirds of which have AD.
RISK FACTORS
Hypotheses
Based on epidemiological studies, neuroimaging
methods and neuropathology research, three etiological
hypotheses of the development have been reported, with
moderate or strong evidence11
:
– genetic,
– vascular, and
– psychosocial.
At present, the level of evidence is insufficient for the
etiological role of other factors, such as nutrition, occupational
exposure to various substances and inflammation.
Genetic hypothesis
Early-onset familial AD is usually caused by autosomal
dominant mutations in the genes for amyloid precursor
protein (APP), presenilin 1 and presenilin 2. This form of
AD accounts for approximately 2–5% of all AD cases12
.
First-degree relatives of patients with AD are at higher
lifetime risk of developing the disease than the rest of
the population13
. Both genetic and other factors contribute
to the increased risk and familial aggregation of AD
cases. As far as genetic factors are concerned, this risk
may be partly due to the presence of the apolipoprotein
E (APOE) apoE4 allele. Other genes also contribute to
the pathogenesis of this mental disorder14
. The apoE4
allele is the only proven genetic factor so far identified in
the development of both the early- and late-onset forms
of AD. This factor increases susceptibility to AD but it
is neither necessary nor sufficient for the development
of this disease. The higher the number of the apoE4 alleles,
the higher the risk of AD and the lower the age of
onset. The risk effect of the presence of the apoE4 allele
decreases with age. Generally, approximately 15-20% of
AD cases may be attributed to this risk15
.
Tens of other candidate genes with polymorphisms
affecting the risk of the development of AD have been
studied. Predominantly, these are secretase genes – e.g.
BACE1 (beta-site amyloid precursor protein-cleaving
enzyme 1), presenilin 1, peptidase genes – e.g. ECE1
(endothelin-converting enzyme), IDE (insulin-degrading
enzyme), microtubule and cytoskeletal genes – e.g. MAPT
(microtubule-associated protein tau), synaptic genes – e.g.
ABCA1 (ATP-binding cassette A1 transporter), anti-apoptotic
genes – e.g. IL-1 (interleukin 1), protease genes -e.g.
ACE (angiotensin-converting enzyme) and other genes
such as the gene for APP.
Vascular hypothesis
Vascular risk factors, such as smoking, obesity and
high total cholesterol levels, together with vascular morbidity,
such as hypertension, diabetes mellitus and asymptomatic
cerebral infarction, are associated with a higher
risk of dementia including Alzheimer’s disease.
Smoking
Earlier cross-sectional studies often reported a lower
prevalence of AD among smokers compared with non-
smokers16
. This seemingly protective effect was probably
due to survivor bias since the proportion of smokers
among the prevalent cases was smaller.
When incident cases of AD were studied, however,
the situation was completely reversed17-19
. That is, numerous
analytical studies found a significantly increased risk
of AD associated with cigarette smoking, especially in
apoE4 allele non-carriers20-22
. Meta-analyses of these analytical
studies concluded that current smoking was associated
with an increased risk of the development of AD,
with RR=1.79; 95% CI 1.43–2.23 (ref.23,24)
.
Alcohol
It is well recognized that alcohol abuse causes alcohol
dementia. Moreover, middle-aged heavy drinkers, especially
apoE4 allele carriers, were found to have a more
than 3-fold higher risk of dementia and AD later in their
lives25
. On the other hand, the risk of developing dementia
and AD was reduced in light and moderate alcohol
consumers26,27
.
In heavy consumers, alcohol clearly damages the
brain. Even light to moderate alcohol consumption was
found to be related to brain atrophy and volume loss28,29
.
Overweight and obesity
Higher BMI in middle age is a risk factor for AD and
other dementias. Higher BMI or obesity (in particular
abdominal obesity) at around the age of 50 years means
an increased risk of dementia 20-25 years later30-33
. Several
analytical studies in the elderly suggested that a significant
decrease in BMI was associated with a higher risk of AD
in the following 5-6 years37,38
.
Blood pressure and management of hypertension
Increased blood pressure in middle age, especially if
uncontrolled, was associated with a higher risk of the later
development of AD in several observational studies39,40
.
Findings from analytical studies of the association
between blood pressure and the risk of dementia are not
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):108–114.
110
consistent. Studies with a relatively short follow-up (less
than 3 years) found no or even an inverse association
between blood pressure values and the risk of dementia
and AD (ref.41
). Since dementia has a long latent period
and blood pressure may drop in its pre-clinical stage, an
absent or inverse association may be interpreted as a result
of the process42,43
.
However, analytical studies with a longer follow-up
(e.g. more than 6 years) reported an inverse associa-
tion44-46
, suggesting that low blood pressure later in the
life may contribute to the development or clinical manifestation
of dementia including AD (ref.41,47
).
Longitudinal studies have repeatedly shown a protective
effect of antihypertensive drugs against the development
of dementia and AD (ref.41,48,49
). Recent analytical
studies have suggested that the protective effect of antihypertensive
therapy may depend on its duration and
the patient’s age. Greater protective effects were found
in the younger elderly (e.g. under 75 years of age) and
in those with long-term treatment50,51
. Antihypertensive
therapy may protect against dementia and AD by delaying
the atherosclerotic process, decreasing the number of
atherosclerotic lesions and improving cerebral perfusion41
.
Hypercholesterolemia and statin therapy
High total serum cholesterol levels in middle age were
found to be a risk factor for the development of AD at a
later age52,53
. High total cholesterol in middle age is a risk
factor for the development of AD and other dementias
20 years later but decreasing serum cholesterol levels in
late middle age may be due to ongoing disease processes
and may represent a marker for later AD and other de-
mentias54
.
According to several cross-sectional and case-control
studies, the use of statins significantly decreases the prevalence
of AD (ref.55,56
). Whereas an analytical study (the
Rotterdam Study) showed that the use of statins was associated
with a lower risk of AD (ref.57
), other prospective
studies found either no beneficial effect or only a slightly
decreased risk of AD related to the use of statins58,59
.
Experimental studies have suggested that statins may decrease
the production of beta amyloid both in vitro and
in vivo. Statins also have various other effects that may be
beneficial for the CNS and thus may lower the risk of AD.
Nutritional factors
Several analytical studies showed a decreased risk of
AD associated with higher intake of antioxidants such as
vitamins E and C (ref.60,61
), either in the diet or in dietary
supplements. However, some studies found a negative ef-
fect62
. Yet other studies showed that the Mediterranean
diet (high intake of fish, fruit and vegetables rich in antioxidants)
was associated with a lower risk of AD, independent
of vascular risk factors63,64
. A Cochrane systematic
review concluded that supplementation with folic acid
and vitamin B12 had no beneficial effect on cognitive
functions despite the fact that folic acid and vitamin B12
effectively decrease serum homocysteine levels65
.
It was also reported that a diet rich in saturated fats
and cholesterol increased the risk of AD (ref.66
) whereas
polyunsaturated fatty acids and fish may be protective
against dementia67,68
.
Diabetes mellitus
Many longitudinal studies found an increased risk of
not only neurodegenerative but also vascular dementia in
people with diabetes69–71
. This risk was confirmed by a systematic
review72
. The presence of diabetes in middle age
or a longer duration of diabetes may play a key role in the
development of AD and other dementias73,74
. Moreover,
borderline conditions, prediabetes or impaired glucose
tolerance are also related to an increased risk of AD and
other dementias in very old people75
. This relationship
may be partly explained by diabetic comorbidities such
as hypertension and dyslipidaemia76–78
.
A relationship was also found between a higher
prevalence of AD in an elderly population in Finland79
,
although an analytical study of a multiethnic cohort of
the elderly in the USA found no association between the
metabolic syndrome and either the prevalence or incidence
of AD, despite the fact that two components of
the syndrome, i.e. diabetes and hyperinsulinaemia, were
associated with increased risk of incident AD (ref.80
).
Cardiovascular and cerebrovascular diseases
A significantly increased risk of dementia and AD was
found in patients who had suffered a stroke as well as
clinically silent cerebral infarction confirmed by magnetic
resonance imaging81,82
.
Also cardiovascular diseases are associated with an
increased incidence of dementia and AD, with the highest
risk of dementia in persons with peripheral artery disease,
suggesting that extensive peripheral atherosclerosis is a
risk factor for AD (ref.83,84
).
Neuropathological studies have suggested that cerebrovascular
lesions, atherosclerosis and neurodegenerative
changes often coexist with each other in the brain, producing
a clinical manifestation of the dementia syndrome85,86
.
Psychosocial hypothesis
A systematic review found that psychosocial factors
and an active lifestyle throughout life may decrease the
risk of dementias including AD (ref.87
).
Education and socioeconomic status
Lower education is tied to increased risk of dementia
and AD. This link has been confirmed by many crosssectional
and longitudinal studies88,89
. Although education
and socioeconomic status are highly correlated with each
other, when studied separately, an independent association
was only found for education90
.
Social network and social engagement
Longitudinal observational studies suggest that a poor
social network or a lack of social engagement are associated
with decreased cognitive functions and dementia87,91
.
The risk of dementia was also higher in elderly persons
with increased social isolation and less frequent and unsatisfactory
contacts with relatives and friends. Persons
with low neuroticism combined with high extraversion
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):108–114.
111
had a lower risk of dementia92
. Low levels of social engagement
in late life and decreased social engagement
from middle to late life were associated with a two-fold
increase in the risk of the development of dementia and
AD later in life93,94
.
Physical activity
Regular physical exercise is associated with a delay in
onset of dementia and AD in the elderly without cognitive
impairment95
. Physical activity in the form of various
leisure activities rather than sports or specific physical
exercise led to a decrease in the risk of dementia96
. Even
low-intensity physical activity such as walking may lower
the risk of dementia and cognitive impairment97
. A significant
protective effect of regular physical activity in
middle age, with respect to the development of dementia
and AD later in the life, was found especially in persons
with the apoE4 allele98
.
Mental activity
Various activities requiring a mental effort, such as
reading, social and cultural activities, knitting, gardening,
dancing, tabletop games, playing musical instruments,
watching specific TV programmes, showed a protective
effect against dementia and AD (ref.99,72
). A study
of Swedish twins showed that complexity of work, in
particular more complex work with people, may reduce
the risk of AD (ref.100
). A recent neuroimaging study suggested
that a high level of complex mental activity across
the lifespan was correlated with reduced hippocampal
atrophy101
.
PREVENTION
Primary prevention
Although the mechanisms of action of vascular and
psychosocial factors participating in the pathogenesis and
clinical manifestation of AD have not been fully understood,
primary prevention is possible since most vascular
and psychosocial factors including lifestyle factors are
modifiable11,102
.
Primary prevention strategies addressing the vascular
pathway in the development of AD include:
– measures against hypertension, obesity, increased glucose
levels and diabetes mellitus in middle age,
– measures against cardiac failure and preventing very
low blood pressure and thus maintaining sufficient
cerebral perfusion.
Primary prevention strategies focused on maintaining
an active and socially integrated lifestyle:
– ensuring an extensive social network,
– frequent participation in social physical and intellectual
stimulating activities11,87
.
Secondary prevention
AD is characterized by a pre-clinical stage lasting
several years during which progressive neurodegenerative
changes occur in the brain, even before the onset of
typical clinical signs103
. However, this pre-clinical stage
is difficult to identify although some clinical markers,
neuroimaging biomarkers and biochemical markers are
available104
:
– mild cognitive impairment (isolated memory loss),
– biochemical markers in the serum and cerebrospinal
fluid (beta amyloid and tau protein),
– neuroimaging methods are considered an effective tool
for diagnosing AD in the pre-clinical stage (amyloid
positron emission tomography is able to measure beta
amyloid in the brain in vivo),
– volumetric magnetic resonance imaging detecting medial
temporal lobe atrophy.
Tertiary prevention
The goal of tertiary prevention of AD is to rule out
functional disability and, if possible, improve the quality
of life:
– cognitive training,
– treatment with cholinesterase inhibitors (donepezil,
rivastigmine, galantamine),
– treatment with N-methyl D-aspartate receptor antagonists
(memantine).
CONCLUSION
Alzheimer’s disease represents an important public
health problem. Its aetiology is still unknown and for this
reason, it is necessary to study all potential risk factors
which may contribute to its development.
From the point of view of early diagnosis and potential
application of primary or secondary prevention, genetic
factors are the most important.
ABBREVIATIONS
AD, Alzheimer’s disease.
ACKNOWLEDGMENT
Supported by the Czech Ministry of Health grant project
no. NT11152-6/2010.
CONFLICT OF INTEREST STATEMENT
Author’s conflict of interest diclosure: The authors
stated that there are no conflicts of interest regarding the
publication of this article.
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