Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease

Abstract

In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.
We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.
Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer's disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E).
Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias 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 of risk modification.

Full text

DOI:
Practice
CMAJ • February 26, 2008 • 178(5)
© 2008 Canadian Medical Association or its licensors
554488
The case
Mr. A, a 45-year-old professional, presents for a routine
health check-up, during which he states “I am quite worried
about getting Alzheimer disease, just like my mother.” He
goes on to say “As you know, our family has been caring for
her while she slowly deteriorated. A month ago, we had to
move her to a long-term care facility. It is really taking a toll
on our family. So I want to know what my chances are of es-
caping this terrible disease. I want to do everything I can to
avoid my mother’s fate.” Mr. A then goes on to say that his
mother, who is alive, had her first symptoms of dementia at
the age of 74 years. To his knowledge, no other family mem-
bers, including aunts and uncles, have been affected by
dementia. Mr. A is relatively healthy. He has never smoked
and rarely drinks alcohol. However, he has been taking med-
ication for hypertension for over a year and has hyperlipi-
DOI:10.1503/cmaj.070796
Diagnosis and treatment of dementia: 1. Risk assessment
and primary prevention of Alzheimer disease
Review
Background: In addition to nonmodifiable genetic risk fac-
tors, potentially modifiable factors such as hypertension, hy-
perlipidemia and environmental exposures have been identi-
fied as risk factors for Alzheimer disease. In this article, we
provide physicians with practical guidance on risk assess-
ment and primary prevention of Alzheimer disease based on
recommendations from the Third Canadian Consensus Con-
ference on the Diagnosis and Treatment of Dementia, held in
March 2006.
Methods: We developed evidence-based guidelines using
systematic literature searches, with specific criteria for study
selection and quality assessment, and a clear and transpar-
ent decision-making process. We selected studies published
from January 1996 to December 2005 that met the following
criteria: dementia (all-cause, Alzheimer disease or vascular
dementia) as the outcome; longitudinal cohort study; study
population broadly reflective of Canadian demographics;
and genetic risk factors and general risk factors (e.g., hyper-
tension, education, occupation and chemical exposure)
identified. We graded the strength of evidence using the cri-
teria of the Canadian Task Force on Preventive Health Care.
Results: Of 3424 articles on potentially modifiable risk fac-
tors for dementia, 1719 met our inclusion criteria; 60 were
deemed to be of good or fair quality. Of 1721 articles on ge-
netic risk factors, 62 that met our inclusion criteria were
deemed to be of good or fair quality. On the basis of evi-
dence from these articles, we made recommendations for
the risk assessment and primary prevention of Alzheimer dis-
ease. For the primary prevention of Alzheimer’s disease, there
is good evidence for controlling vascular risk factors, espe-
cially hypertension (grade A), and weak or insufficient evi-
dence for manipulation of lifestyle factors and prescribing of
medications (grade C). There is good evidence to avoid estro-
gens and high-dose (> 400 IU/d) of vitamin E for this purpose
(grade E). Genetic counselling and testing may be offered to
at-risk individuals with an apparent autosomal dominant in-
heritance (grade B). Screening for the apolipoprotein E geno-
type in asymptomatic individuals in the general population is
not recommended (grade E).
Abstract
Christopher Patterson MD, John W. Feightner MD MSc, Angeles Garcia MD PhD,
G.-Y. Robin Hsiung MD MHSc, Christopher MacKnight MD MSc, A. Dessa Sadovnick PhD
From the Division of Geriatric Medicine (Patterson), McMaster University,
Hamilton, Ont.; the Department of Family Medicine (Feightner), University
of Western Ontario, London, Ont.; the Department of Medicine (Garcia),
Queen’s University, Kingston, Ont.; the Departments of Medicine (Hsiung,
Sadovnick) and Medical Genetics (Sadovnick), University of British Colum-
bia, Vancouver, BC; and the Department of Medicine (MacKnight), Dal-
housie University, Halifax, NS
Interpretation: Despite the personal and societal burden of
dementia, our understanding of genetic predisposition to
dementias 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 im-
pact of risk modification.
CMAJ
2008;178(5):548-56
Une version française de ce résumé est disponible à l’adresse
www.cmaj.ca/cgi/content/full/178/5/548/DC1
This series is based on recommendations from the Third Canadian Consen-
sus Conference on the Diagnosis and Treatment of Dementia.
Series editor:
Howard Chertkow MD, Department of Neurology, McGill Uni-
versity and the Bloomfield Centre for Research in Aging, Lady Davis Institute,
Sir Mortimer B. Davis–Jewish General Hospital, Montréal, Que.

Practice
CMAJ • February 26, 2008 • 178(5)
554499
demia. On this visit, his blood pressure is 145/90 mm Hg. His
total cholesterol level is 5.7 mmol/L, high-density lipoprotein
(HDL) cholesterol level 1.39 mmol/L, low-density lipoprotein
cholesterol level 4.31 mmol/L, triglyceride level 2.34 mmol/L
and total cholesterol:HDL ratio 4.1.
What should you advise Mr. A about his risk of dementia?
More importantly, what should you tell him about preventing
or decreasing his chances of getting dementia?
T
his hypothetical patient’s story and concerns are all
too familiar. Dementia is a devastating illness for pa-
tients. For families, the emotional, physical and fi-
nancial burden of this illness is also substantial. Because 1 in
12 Canadians over the age of 65 years may be affected by de-
mentia,
1
there are also important consequences for society as
a whole.
Why does dementia occur in some people and not others?
How can patients minimize their chances of facing a future
with dementia? In recent years, a number of longitudinal
studies have better defined risk factors for various types of de-
mentia.
2
Lifestyle factors such as tobacco use, diet and alco-
hol as well as vascular risk factors have emerged as important
predictors. Several genetic factors have also been identified.
3
In this article, we provide physicians with practical guidance
on risk assessment and primary prevention of Alzheimer dis-
ease supported by evidence-based recommendations from
the Third Canadian Consensus Conference on the Diagnosis
and Treatment of Dementia (Box 1). A description of the
process used to generate these recommendations is provided
in the first article of this series
1
and in an online appendix ac-
companying this article (available at www.cmaj.ca/cgi
/content/full/178/5/548/DC2).
Approach to risk assessment
Like Mr. A, many patients ask about their baseline risk of de-
mentia. Family physicians should appreciate that they are at-
tempting to predict the onset of a heterogeneous group of
diseases. As a consequence, it is possible that some risk fac-
tors may predispose to some types of dementia while having
little influence on predicting the onset of other types. In this
article we focus on Alzheimer disease, first considering ge-
netic aspects, then vascular, lifestyle and finally sociodemo-
graphic risk factors (Table 1).
Genetic risk factors
To assess genetic risk in an individual or family, it is critical to
obtain an accurate family history with as much information
as possible about the diagnosis of dementia and age of onset
in reportedly affected family members. Obtaining reliable an-
swers to these questions is not a trivial task. If it is not possi-
ble to examine the affected family members, confirmation of
diagnosis by review of clinical reports and neuropathologic
findings, if available, adds to diagnostic certainty. In addition
to confirming the diagnosis in relatives, attempting to estab-
lish the age of onset is also important. Often the medical his-
tory of a person’s parents is unknown because of distance,
life circumstance such as divorce, reticence of the previous
generation to discuss personal issues, or death from other
causes at a young age. Furthermore, the person may have no
siblings, or have no information on siblings’ health status.
Incomplete family histories can be a major hurdle in assess-
ing genetic risk.
Early-onset Alzheimer disease, which may have a signifi-
cant genetic component, is generally defined as occurring be-
fore 60 years of age. It accounts for only 6%–7% of all cases of
Alzheimer disease.
19,20
From this small pool of patients, only
13% clearly exhibit autosomal dominant transmission over
more than one generation, which means that a sibling, a par-
ent and a grandparent also has Alzheimer disease.
20,21
To date,
all 3 known causative gene mutations (changes that almost al-
ways result in Alzheimer disease if the patient lives long
enough) lead to the early-onset form.
3
The first of these genes
to be identified was the amyloid precursor protein gene, lo-
cated on chromosome 21. Mutations in this gene cause exces-
sive cleavage by the β- and γ-secretase enzymes, instead of
normal cleavage by the α-secretase enzyme. The result is in-
creased production of toxic β-amyloid fragments, which are
converted into insoluble aggregates that form senile plaques
in brain tissue (Figure 1 and Figure 2). Two other genes that
cause familial early-onset Alzheimer’s disease are presenilin-1,
located on chromosome 14, and presenilin-2, located on chro-
mosome 1. Both of these genes are involved in the γ-secretase
complex, and mutations lead to excessive cleavage by the γ-
secretase enzyme, which results in increased production and
accumulation of β-amyloid fragments (Figure 1). These mech-
anisms are not known to be associated with late-onset or spo-
radic Alzheimer disease.
Table 1: Risk factors for Alzheimer disease
Factor Risk (95% CI)
Systolic hypertension > 160 mm/Hg
RR: 1.5 (1.0–2.3)
4
OR: 2.3 (1.0–5.5)
5
Serum cholesterol > 6.5 mmol/L
RR: 2.1 (1.0–4.4)
5
RR: 3.1 (1.2–8.5)
6
Moderate wine consumption
(250–500 mL/d) compared with more
or less than this amount RR: 0.53 (0.3–0.95)
7
High level of physical activity*
compared with little or no regular
exercise
RR: 0.5 (0.28–0.90)
8
RR: 0.55 (0.34–0.88)
9
RR: 0.69 (0.5–0.96)
10
Smoking, current
RR: 1.74 (1.21–2.50)
11
RR: 1.99 (1.33–2.98)
12
Head injury, with loss of consciousness
Moderate HR: 2.32 (1.04–5.1)
13
Severe HR: 4.51(1.77–11.47)
13
Education > 15 yr (v. < 12 yr) RR: 0.48 (0.27–0.84)
14
Statin drugs
RR: 0.82 (0.46–1.46)
15
HR: 1.19 (0.35–2.96)
16
Nonsteroidal anti-inflammatory drugs RR: 0.42 (0.26–0.66)
17
RR: 0.51 (0.37–0.70)
18
Note: CI = confidence interval, RR = relative risk, OR = odds ratio, HR = hazard
ratio.
*See section on lifestyle factors for details about physical activity.

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Box 1: Recommendations for the assessment and management of risk factors for, and the primary prevention
of, Alzheimer disease*
Genetic risk factors
1. Predictive genetic testing, with appropriate pre-and post-testing counselling, may be offered to the following
at-risk individuals with an apparent autosomal dominant inheritance when a family-specific mutation has been
identified [grade B recommendation, level 2 evidence; new recommendation]
a. First-degree relatives (e.g., children and siblings) of an affected person with the mutation
b. First cousins of an affected person if the common ancestors (parents who were siblings) died before the
average age of onset of dementia in the family
c. Nieces and nephews of an affected person whose parent (sibling of the affected person) died before the
average age of onset of dementia in the family
d. Minors are not usually referred for predictive genetic testing in Canada, but occasionally such testing may be
considered on a case-by-case basis by the relevant medical ethics committee(s)†
2. Genetic screening for the apolipoprotein E (APOE) genotype in asymptomatic individuals in the general
population is not recommended because of the low specificity and sensitivity [grade E recommendation, level 2
evidence; revised recommendation]. Note: This is also true of other putative susceptibility genes such as the
sortilin-related receptor 1 gene (SORL1).
Vascular risk factors
1. There is good evidence to treat systolic hypertension (> 160 mm Hg) in older individuals (age > 60 years). In
addition to reducing the risk of stroke, the incidence of dementia may be reduced. The target systolic blood
pressure should be ≤ 140 mm Hg [grade A recommendation, level 1 evidence; new recommendation].
2. Although acetylsalicylic acid and statin therapy following myocardial infarction, antithrombotic therapy for
nonvalvular atrial fibrillation, and correction of carotid artery stenosis > 60% have been shown to reduce the risk
of stroke, there is insufficient evidence to recommend for or against these measures for the specific purpose of
reducing the risk of dementia [grade C recommendation, level 1 evidence; revised recommendation]
3. Although there are many reasons for treating type 2 diabetes mellitus, hyperlipidemia and
hyperhomocysteinemia, there is insufficient evidence to recommend for or against treatment of these conditions
for the specific purpose of reducing the risk of dementia [grade C recommendation, level 2 evidence; revised
recommendation]
Lifestyle risk factors
1. Although there is insufficient evidence to make a firm recommendation for the primary prevention of dementia,
physicians may advocate for strategies, including legislation, to reduce the risk of serious head injuries [grade C
recommendation, level 2 evidence; new recommendation]
2. Although there is insufficient evidence to make a firm recommendation for the primary prevention of dementia,
physicians may advise their patients about, and advocate for, the wearing of appropriate protective clothing
during the administration of pesticides, fumigants, fertilizers and defoliants [grade C recommendation, level 2
evidence; new recommendation]
3. Although recommendations may be made on other grounds (e.g., as part of a healthy lifestyle), there is
insufficient evidence to recommend for or against higher levels of physical or mental activity for the specific
purpose of reducing the risk of dementia [grade C recommendation, level 2 evidence; new recommendation]
4. Although there is insufficient evidence to make a firm recommendation for the primary prevention of dementia,
physicians may advocate for appropriate levels of education and strategies to retain students in appropriate
learning environments [grade C recommendation, level 2 evidence; new recommendation]
5. Although there is insufficient evidence to make a firm recommendation for the primary prevention of dementia,
physicians may choose to advise their patients about the potential advantages of increased consumption of fish,
reduced consumption of dietary fat and moderate consumption of wine [grade C recommendation, level 2
evidence; new recommendation]
Medications
1. There is insufficient evidence to recommend for or against the prescription of nonsteroidal anti-inflammatory
drugs for the sole purpose of reducing the risk of dementia [grade C recommendation, level 2 evidence; new
recommendation]
2. There is good evidence to avoid the use of estrogen, alone or in combination with progesterone, for the
sole purpose of reducing the risk of dementia [grade E recommendation, level 1 evidence; new
recommendation]
3. There is insufficient evidence to recommend for or against supplementation with vitamins E or C for the
prevention of dementia [grade C recommendation, level 2 evidence). High-dose vitamin E (≥ 400 IU/d) is
associated with excess mortality and should not be recommended [grade E recommendation, level 1 evidence;
new recommendation]
*Based on recommendations from the Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia, held in March 2006.
†Prenatal diagnostic testing is not offered in Canada.

Practice
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Among families in which causal genetic mutations for
early-onset Alzheimer disease have been identified, 30%–
70% of mutations are in the presenilin-1 gene, 10%–15% are
in the amyloid precursor protein gene, and less than 5% are
in the presenilin-2 gene.
23
Many cases of early-onset Alzheim-
er disease do not have an identified genetic mutation, possi-
bly because the specific genes have not yet been identified or
because some cases may have different causes.
To date, no single causal genetic mutation has been identi-
fied for late-onset Alzheimer disease. Most cases are believed
to be complex and likely influenced by a mixture of genetic
risk factors (e.g., the apolipoprotein E gene [
APOE
] and the
sortilin-related receptor 1 gene [
SORL1
]) and by acquired risk
factors such as hypertension and diabetes, and probably many
other factors yet to be defined. The risk to a person who has a
first-degree relative (parent or sibling) with late-onset Alz-
heimer disease is slightly higher than the risk in the general
population but much lower than the risk to someone with a
familial pedigree of early-onset disease (see “Risk estimation”
on page 554).
For late-onset Alzheimer disease, several genes have been
implicated as risk factors. These genes increase the probability
of, but do not guarantee the development of, Alzheimer disease.
However, their absence does not guarantee that Alzheimer dis-
ease will not develop. Currently only
APOE
has been confirmed
as a genetic risk factor in multiple large, population-based stud-
ies.
3
The
APOE
gene has 3 common allele forms: ε2 (which oc-
curs in 8% of white populations), ε4 (in 15%) and ε3 (in about
75%). The association of the ε4 allele with late-onset Alzheimer
disease is well established (Table 2).
APOE
is involved in choles-
terol transport and β-amyloid formation, but its exact mecha-
nism in promoting Alzheimer disease is unclear.
24
The strength of the association between the
APOE
ε4 allele
and Alzheimer disease is stronger among women than
among men. It also diminishes with age, being stronger
among people between 55 and 65 years old and less so
among older people. This is likely because the risk of Alz-
heimer disease rises sharply in older age, whether or not the
ε4 allele is present. Given the uncertainties surrounding po-
tential increased risk for Alzheimer disease in an individual
rather than in a population, screening for the
APOE
genotype
is not recommended for clinically asymptomatic people as
part of routine clinical practice.
Recently, the sortilin-related receptor gene (
SORL1
) has
been associated with late-onset Alzheimer’s disease in several
populations of different ethnic backgrounds in the United
States.
25,26
SORL1
is involved in amyloid precursor protein
processing, which adds further support to the role of the
Oligomer
aggregate
α-secretase
Normal cleavage of
amyloid precursor protein
Abnormal cleavage of amyloid precursor protein
leading to excess amyloid accumulation
APP
β-secretase
APP mutations
increase
β-secretase
cleavage
PSEN1/PSEN2
mutations increase
γ-secretase
activity
Aβ peptide
Extracellular space
Cytoplasm
Aβ
γ-secretase
C
e
l
l
m
e
m
b
r
a
n
e
Figure 1: The amyloid precursor protein (APP) is a transmembrane protein that can undergo a series of proteolytic cleavage by secre-
tase enzymes. When it is cleaved by α-secretase in the middle of the β-amyloid domain (Aβ), it is not amyloidogenic. However, when
APP is cleaved by β- and γ-secretase enzymes, neurotoxic Aβ peptides are released, which can accumulate into oligomer aggregate.
Mutations in the
APP
gene tend to inhibit cleavage by α-secretase and consequently enable preferential cleavage by β-secretase. Mu-
tations in the presenilin-1 and presenilin-2 genes (
PSEN1
and
PSEN2
), which are components of the γ-secretase complex, increase
cleavage by γ-secretase at this site. In both situations, the result is excess Aβ peptide production. The current Aβ hypothesis suggests
that the soluble oligomers can impair synaptic function between neurons. Simultaneously, the oligomers may aggregate into insolu-
ble β-sheet amyloid fibrils, which can trigger a local inflammatory response.
22
Over time, the subsequent oxidative stress and bio-
chemical changes ultimately lead to neuronal death and the development of neuritic plaques typical of Alzheimer disease.
Lianne Friesen and Nicholas Woolridge

Practice
CMAJ • February 26, 2008 • 178(5)
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amyloid cascade in the pathogenesis of Alzheimer disease.
The utility of
SORL1
in clinical risk assessment has yet to be
determined, and testing for this gene is not yet available.
Although it is relatively straightforward to distinguish
early-onset from late-onset Alzheimer disease when the age
of onset is well below 60 or well above 65 years, there is ambi-
guity when the illness begins between 60 and 65 years, and a
clear distinction between the 2 conditions is not always possi-
ble. There are well-documented cases of Alzheimer disease
with proven pathogenic mutations in which symptoms first
appeared after 65 years of age in some familial pedigrees of
early-onset disease.
27–30
Early-onset Alzheimer disease and fa-
milial Alzheimer disease are not synonymous. Sporadic cases
of early-onset Alzheimer disease can occur with no family
history and no genetic mutations, and familial late-onset
pedigrees can occur with no responsible genes identified.
31–33
A strong family history of dementia should trigger further
investigation and referral to a specialist for consultation
(Box 2). All patients suspected of having familial early-onset
Alzheimer disease should be referred to a specialty memory
clinic or genetic clinic for further evaluation (a list of Can-
adian centres offering clinical genetic services is available at
http://ccmg.medical.org/clinical.html).
Before any testing is performed, genetic counselling is
considered essential. The discovery of an inherited causative
gene for Alzheimer disease is likely to be extremely distress-
ing. Thus, genetic testing should not take place unless all of
the potential risks and benefits have been clearly explained
and considered.
To help determine whether there is a causative gene in
Mr. A’s family, we must consider 2 important questions.
First, at what age did Mr. A’s mother first experience symp-
toms of Alzheimer disease? Second, do any of his other family
members have dementia and, if so, at what age was the onset
and how are they related to Mr. A? In this instance, Mr. A ap-
pears to be a reliable informant about his mother’s health his-
tory. There is nothing in Mr. A’s reported family history to
suggest autosomal dominant multi-generational transmis-
sion. Therefore, Mr. A needs no further work-up or assess-
ment for the genetic aspect of his risk assessment.
Nongenetic risk factors
Vascular risk factors
Considerable evidence from longitudinal cohort studies has in-
dicated that the relation between blood pressure and subse-
quent development of dementia is somewhat complex.
2
Al-
though a number of studies have shown that elevated systolic
blood pressure is associated with an increased risk of both
Alzheimer disease and all-cause dementia, curiously some
studies have shown that a systolic blood pressure below
140 mm Hg is also associated with an increased risk.
4
Notwith-
standing these and other apparently contradictory findings, the
results of the Systolic Hypertension in Europe (SYST-EUR)
study revealed a reduced risk of dementia among participants
receiving antihypertensive treatment.
34
In this trial, more than
3000 patients over 60 years old who had systolic blood pres-
sures of 160–219 mm Hg and diastolic pressures below 95 mm
Hg, measured while seated, were randomly assigned to receive
either nitrendipine (10–40 mg/d), with added enalapril or hy-
drochlorothiazide, titrated to reduce the blood pressure by at
least 20 mm Hg to reach a value below 150 mm Hg, or match-
ing placebo.
34
The participants were free of dementia at base-
line and were subsequently monitored by means of the Mini-
Mental State Examination
35
and further diagnostic tests to
reach a definitive diagnosis of dementia (according to the crite-
ria of the Diagnostic and Statistical Manual of Mental Disor-
ders, third edition, revised [DSM-III-R]) if the score fell below
Figure 2: Images of normal hippocampus (A) and hippocampus
of a patient with Alzheimer disease (B) [Bielschowsky stain]. The
numerous dark brown spots seen in the abnormal hippocampus
are the neuritic plaques typical of Alzheimer disease. At higher
magnification (C), these plaques (black arrows) and tangles
(white arrows) seen in Alzheimer disease are clearly visible.
Images courtesy of Dr. Ian R.A. MacKenzie, Department of Pathology, University of British Columbia

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23. After a median follow-up of 2 years, the incidence of de-
mentia was reduced by 50%, from 7.7 to 3.8 cases per 1000 pa-
tient-years in the treatment group, an absolute risk reduction of
0.39%. The relative risk of dementia was 0.47 (95% confidence
interval [CI] 0.28–0.78), and most cases were diagnosed as
probable Alzheimer disease. In absolute terms, the number of
cases of hypertension needed to treat for 5 years to prevent
1 case of dementia is about 53. No other randomized con-
trolled trial has shown such convincing results, and a meta-
analysis of 4 trials concluded that the relative risk for dementia
after treatment of hypertension was 0.80 (95% CI 0.63–1.02),
just missing statistical significance.
36
In the case of Mr. A, de-
pending on the severity of his hypertension, appropriate treat-
ment will reduce his risk of stroke, heart failure and myocardial
infarction. Although there is no definitive evidence in his age
group, his risk of dementia may also be reduced.
Epidemiologic studies have established an association be-
tween hyperlipidemia and subsequent development of demen-
tia. Longitudinal studies have established that midlife eleva-
tion of the total serum cholesterol level is associated with an
increased risk of subsequent Alzheimer disease (relative risk
2.1–3.1).
2
However, 2 large randomized controlled trials failed
to show that use of 3-hydroxy-3-methylglutaryl–coenzyme A
(HMG–CoA) reductase inhibitors (statins) reduced the inci-
dence of dementia. One trial compared pravastatin (40 mg/d)
with placebo in nearly 6000 men and women aged 70–80 years
who had a baseline total cholesterol level of 4.0–9.0 mmol/L;
the mean duration of follow-up was 3.2 years.
37
By the end of
the trial, there were no significant differences in the Mini-
Mental State Examination scores between the pravastatin and
placebo groups (mean difference 0.06 [out of 30], 95% CI
0.04–0.16;
p
= 0.59). Neither was there any difference in
scores on instrumental activities of daily living, a sensitive
marker for dementia. The other study compared simvastatin
(40 mg/d) with placebo in over 20 000 men and women aged
40–80 years who had a baseline total cholesterol level greater
than 3.5 mmol/L and who were followed for 5 years.
38
By the
end of the trial, the incidence of dementia was 0.3% in each of
the 2 groups.
Although there may be compelling reasons to treat hyper-
lipidemia in Mr. A, especially if he had additional risk factors
such as smoking, and a strong family history of premature vas-
cular disease, there is no evidence that treatment of hyperlipi-
demia will reduce his risk of subsequent Alzheimer disease.
39
Lifestyle factors
For Mr. A, and indeed for all healthy middle-aged and elderly
patients worried about memory loss, a pressing issue is
whether there are lifestyle factors that could (or should) be
modified in an attempt to preserve memory function with ag-
ing. Although a “healthy lifestyle” in general can be recom-
mended to all patients, the question is whether there is an evi-
dence base to support specific recommendations to Mr. A in
order to preserve his memory.
Early case–control studies had suggested that tobacco
smoking actually reduced the risk of dementia, but longitudi-
nal cohort studies have identified a significantly increased
risk of all-cause dementia and Alzheimer disease among to-
bacco smokers.
12
A pooled analysis of results from 4 Euro-
pean population-based studies involving over 28 000 people
concluded that current smokers, but not former smokers,
were at increased risk for Alzheimer disease.
11
Although there
is no conclusive evidence that smoking cessation will lessen
his risk of Alzheimer disease, the mere possibility provides
yet another reason to discourage Mr. A from smoking.
Both total dietary fat intake and reduced levels of omega 3
fatty acids have been linked to an increased risk of dementia in
epidemiologic studies.
40
A recent longitudinal study has also
suggested that adherence to a Mediterranean-style diet is asso-
ciated with a decreased risk of Alzheimer disease,
41
as is con-
sumption of fish.
2
In the absence of evidence from random-
ized controlled trials, we cannot offer unequivocal advice
regarding diet for the primary prevention of dementia. How-
ever, in Mr. A’s case, the presence of hyperlipidemia mandates
that counselling to reduce intake of both saturated and total
dietary fat should constitute part of his overall management
regardless of any potential impact on his risk of dementia.
Increased levels of physical activity have been linked to a re-
duced risk of subsequent dementia. Data from the Canadian
Study of Health and Aging have associated regular physical activ-
ity (defined by a simple “yes/no” question) with a reduced risk of
Alzheimer disease (relative risk 0.69, 95% CI 0.50–0.96).
10
In an-
other analysis of the data from this study, the level of physical
activity was assessed by combining 2 questions regarding fre-
Table 2: Risk of Alzheimer disease by apolipoprotein E
genotype
3
Genotype Odds ratio (95% CI)*
ε3/ε3
1.0 [ref]
Single ε4
3.2 (2.9–3.5)
ε4/ε4
11.6 (8.9–15.4)
ε2/ε3
0.6 (0.5–0.8)
Note: CI = confidence interval, ref = reference group.
*Compared with white people, the strength of the association is weaker among
black and Hispanic people and stronger among people of Japanese descent.
The association is stronger among women than among men.
Box 2: Asymptomatic people at high risk for familial
Alzheimer disease for whom genetic testing may be
considered
• Child of a person in whom a causative mutation has been
identified
• Sibling of a person in whom a causative mutation has been
identified, especially if the sibling is younger than the
affected person was at the age of dementia onset
• Niece or nephew of a person in whom a causative
mutation has been identified and whose parent (sibling of
the affected person) died before the age of onset of
disease in the affected person
• Minors are not usually referred for predictive genetic
testing in Canada, but occasionally such testing may be
considered on a case-by-case basis by the relevant
medical ethics committee(s)*
*Prenatal diagnostic testing is not offered in Canada.

Practice
CMAJ • February 26, 2008 • 178(5)
555544
quency and intensity of exercise for participants who reported
regular physical activity. A high level of exercise was defined as 3
or more times weekly at an intensity greater than walking. When
compared with those who reported no regular exercise, those re-
porting a high level of exercise had a decreased risk of Alzheimer
disease developing in 5 years (odds ratio 0.50, 95% CI 0.28–
0.90).
8
In the Cardiovascular Health Study, conducted in the
United States, participants who expended the highest quartile of
energy (calculated at more than 1657 kcal/wk) had a lower risk of
all-cause dementia (adjusted relative risk 0.58, 95% CI 0.41–
0.83) and of Alzheimer disease (adjusted relative risk 0.55, 95%
CI 0.34–0.88) compared with participants who expended the
lowest quartile of energy (estimated at less than 248 kcal/wk).
9
In
Mr. A’s case, even in the absence of evidence from randomized
controlled trials on this topic, it is reasonable to recommend reg-
ular physical activity given his stated risk factors.
Intellectually challenging activity of various types has been
associated with a reduced risk of dementia in longitudinal stud-
ies. Daily mental activities were associated with a decreased risk
of all-cause dementia (relative risk 0.59) in the Kungsholmen
study.
42
Similarly, the Washington Heights Study (New York)
showed a reduced risk of all-cause dementia (relative risk 0.62)
among participants who engaged in a higher level of leisure ac-
tivity (self-reported participation in > 6 of 13 activities v. < 6 ac-
tivities [low level] in the previous month).
43
There is emerging
evidence that cognitive training, especially involving novel or
unfamiliar tasks, may delay cognitive decline. A recently pub-
lished follow-up study of a randomized controlled trial of cogni-
tive training appeared to show sustained improvement in spe-
cific cognitive performance up to 5 years after the intervention.
44
Whether this type of endeavour translates into a reduced risk of
dementia remains to be proven.
Epidemiologic evidence has established that moderate con-
sumption of wine (250–500 mL/d), compared with an intake of
more or less than this amount, is associated with a reduced risk
of subsequent all-cause dementia (relative risk 0.56, 95% CI
0.36–0.92) and of Alzheimer disease (relative risk 0.53, 95% CI
0.30–0.95).
7
Advice about alcohol consumption should be tem-
pered by the known risks of excessive use in terms of neurologic
and other organ damage, as well as increased risk of injury from
intoxication. In the absence of evidence from randomized con-
trolled trials, a firm recommendation for the use of alcohol to
reduce the risk of Alzheimer disease cannot be offered, neither
can we recommend that a nondrinker begin to drink alcohol.
There has been controversy in the literature concerning the
contribution of head injury to subsequent development of de-
mentia. Long-term follow-up of a cohort of World War II US
Navy and Marine servicemen who were admitted to hospital dur-
ing military service has shed light on this issue. Those who were
admitted with moderate or severe head injury with loss of con-
sciousness experienced an increased risk of subsequent Alz-
heimer disease (hazard ratio 2.32, 95% CI 1.04–5.17, for moder-
ate head injury and 4.51, 95% CI 1.77–11.47, for severe head
injury) compared with those admitted because of other causes.
13
It is therefore appropriate to encourage Mr. A to wear appropri-
ate head protection should he engage in contact sports or in ac-
tivities that could result in head injuries such as bicycling.
Sociodemographic risk factors
There is evidence from longitudinal cohort studies that the risk
of Alzheimer disease is increased among people who have re-
ceived shorter periods of education. For example, in an Ameri-
can longitudinal cohort study, participants who had more than
15 years of education had a reduced risk of Alzheimer disease
(relative risk 0.48, 95% CI 0.27–0.84) when compared with
those who had less than 12 years of education.
14
Although stud-
ies of occupation and dementia risk are inconclusive, a longitu-
dinal study from Manitoba showed that occupational exposure
to environmental toxins such as pesticides, fertilizers, fumi-
gants and defoliants was associated with an increased risk of
Alzheimer disease (relative risk 4.35, 95% CI 1.05–17.90).
45
Risk estimation
A 20-year follow-up analysis of the Cardiovascular Risk Factor,
Aging and Dementia (CAIDE) study population in Scandinavia
was recently published.
46
Data on midlife risk factors were en-
tered into a logistic regression model, with dementia as the out-
come, and a simple scoring system was devised. Two models
were proposed: one included
APOE
status, but its inclusion did
not increase the accuracy of the predictive model. The scoring
system and risk of late-onset dementia are shown in Table 3 and
Table 4. For Mr. A, if he is physically inactive, has a systolic
Table 3: Logistic regression model for dementia risk in 20 years,
based on scores for midlife risk factors*
Risk factor Odds ratio (95% CI) Score
Age, yr
< 47 1 [ref] 0
47–53 2.958 (1.261–6.938) 3
> 53 5.825 (2.192–15.476) 4
Education, yr
≥ 10
1 [ref] 0
7–9 2.485 (0.982–6.291) 2
< 6 3.599 (1.453–8.913) 3
Systolic blood pressure, mm Hg
≤ 140
1 [ref] 0
> 140 2.206 (1.169–4.161) 2
Body mass index, kg/m
2
≤ 30
1 [ref] 0
> 30 2.296 (1.263–4.173) 2
Total cholesterol, mmol/L
≤ 6.5
1 [ref] 0
> 6.5 1.879 (1.012–3.491) 2
Physical activity
Active 1 [ref] 0
Inactive 1.693 (0.953–3.009) 1
Note: CI = confidence interval, ref = reference group.
*Adapted, with permission, from Kivipelto et al.
46
Copyright © 2006 Elsevier.
The original table included 2 predictive models. The model reproduced here
does not include apolipoprotein E ε4 allele status, the inclusion of which did
not increase the accuracy of the predictive model.

Practice
CMAJ • February 26, 2008 • 178(5)
555555
blood pressure above 140 mm Hg and a total serum cholesterol
level less than 6.5 mmol/L, his 20-year risk of dementia is less
than 2%. Investigators in the REVEAL study calculated risk
curves using data from 12 630 first-degree relatives of people
with Alzheimer disease.
47
Using this method, we can estimate
that, by age 80, Mr. A’s risk will be about 13%, compared with
5% if he had no first-degree relative with Alzheimer disease.
47
Prevention of Alzheimer disease
Epidemiologic studies have suggested that the consumption of
several medications is associated with a reduced risk of demen-
tia. These products include nonsteroidal anti-inflammatory
drugs,
17
vitamin supplements,
48
and estrogens in women.
49
In
the case of nonsteroidal anti-inflammatory drugs, the most re-
cent meta-analysis, of 25 observational studies, concluded that
the risk of all-cause dementia was significantly lower among
study participants exposed to these drugs than among those who
had not taken them.
18
However, a recently published random-
ized controlled trial of celecoxib (200 mg twice daily), naproxen
(220 mg twice daily) and placebo in cognitively healthy partici-
pants was ended early because of concerns about drug safety and
lack of effect, since no delay or reduction in the onset of demen-
tia was observed.
50
Thus, there is no justification for recom-
mending the use of nonsteroidal anti-inflammatory drugs for the
primary prevention of Alzheimer disease. Recent systematic re-
views have also concluded that, in the absence of evidence from
randomized controlled trials, there is no justification for con-
suming antioxidant vitamins C and E with the intention of reduc-
ing the risk of subsequent Alzheimer disease.
51
Furthermore,
doses of vitamin E greater than 400 IU/d have been shown to
have negative cardiovascular effects.
52
Studies of B vitamins are
inconclusive and are considered in a later article in this series.
Recommendations based on studies other than randomized
controlled trials must be made with extreme caution. Estrogen
hormone replacement therapy was widely recommended for
the prevention of cardiovascular disease on the basis of case–
control, epidemiologic and biological studies. Definitive, ran-
domized controlled trials such as the Women’s Health Initia-
tive proved that the risks of myocardial infarction and stroke
were actually increased with the use of such therapy. The
Women’s Health Initiative Memory Study, a large randomized
controlled trial of estrogen and progesterone replacement ther-
apy in over 7000 women aged 65–79 years, revealed that the
risk of dementia was increased with the use of estrogen either
alone or in combination with progesterone. This finding effec-
tively extinguishes recommendations for hormone replace-
ment therapy for the prevention of dementia.
53
Knowledge gaps
This review highlights significant gaps in our current knowl-
edge of risk factors for Alzheimer disease. Although we now
know much about individual risk factors for dementia, we do
not know how they interact or which risk factors account for
what proportion of dementia cases. Also lacking is a clear pic-
ture of which specific interventions can lower this risk, and at
what age and in whom they need to be implemented. Large
(and expensive) longitudinal intervention studies are needed to
define the optimal preventive strategies. For primary preven-
tion, treatment of hypertension offers the best chance of reduc-
ing or delaying the onset of dementia. It seems likely that
lifestyle interventions (regular exercise, both physical and men-
tal, moderate alcohol intake, and avoidance of tobacco and
head injuries) may also reduce the risk of dementia. Because of
the logistical challenges involved, it is unlikely that the present
level of evidence, based on longitudinal cohort studies, will
soon be superseded by randomized controlled trials to test
these interventions. Given the very large numbers of healthy
people who would need to participate in dementia prevention
trials, attention has been increasingly focused on those at high-
est risk, especially those with mild cognitive impairment. Thus
far, no pharmaceutical agents have been shown to delay or pre-
vent conversion to dementia, although mentally stimulating
activities are showing promise. Agents that interfere with the
production of insoluble amyloid fragments in the brain, or ac-
celerate their clearance, are being actively pursued. Despite pre-
vious disappointments, it is possible that a vaccine may eventu-
ally be found. With regard to genetic risk factors, new
susceptibility genes for late-onset Alzheimer’s disease continue
to be found with increasing regularity.
The case revisited
Based on an empirical estimation from epidemiologic data,
Mr. A’s family physician can inform him that his risk of
Alzheimer disease by the age of 80 is increased from 5% (base-
line risk) to 13%, because he has a first-degree relative with
late-onset Alzheimer disease.
47
Because nothing in Mr. A’s
family history suggests autosomal dominant multigenerational
transmission, he does not require genetic testing. Mr. A should
be advised to control his cardiovascular risk factors, including
his hypertension and cholesterol levels, using evidence-based
strategies.
54,55
However, Mr. A cannot be assured that these in-
terventions will decrease his risk of Alzheimer disease despite
other proven health benefits. Other than those outlined in this
article, there are no high-quality clinical trials that have evalu-
ated the effectiveness of modifying risk factors, and there are
no proven therapies that will prevent dementia.
This article has been peer reviewed.
Competing interests: None declared.
Table 4: Probability of dementia in late life according to the
midlife risk scores*
Score† Risk (95% CI), %
0–5 1.0 (0.0–2.0)
6–7 1.9 (0.2–3.5)
8–9 4.2 (1.9–6.4)
10–11 7.4 (4.1–10.6)
12–15 16.4 (9.7–23.1)
Note: CI = confidence interval.
*Adapted, with permission, from Kivipelto et al.
46
Copyright © 2006 Elsevier.
†Total scores are derived from individual scores for risk factors in Table 3.

Practice
CMAJ • February 26, 2008 • 178(5)
555566
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Acknowledgements: Christopher Patterson received support from the Insti-
tute of Advanced Studies, University of Bologna (Italy), during the prepara-
tion of this work. Chris MacKnight is supported by a New Investigator Award
from the Canadian Institutes of Health Research.
Editor’s Note: The background papers with supporting evidence for
the recommendations from the Third Canadian Consensus Conference
on the Diagnosis and Treatment of Dementia were published in the
October 2007 issue of
Alzheimer's and Dementia
and are available at
www.alzheimersanddementia.org. These articles are also freely
available at www.cccdtd.ca (through agreement with Elsevier).
Contributors: All of the authors contributed to the study conception and de-
sign, revised the manuscript critically for important intellectual content and
approved the final version submitted for publication.
Correspondence to: Dr. Christopher Patterson, Division of Geriatric
Medicine, Chedoke Hospital, Hamilton Health Sciences, Sanatorium
Rd., PO Box 2000, Hamilton ON L8N 3Z5; pattec@hhsc.ca
Articles to date in this series
• Chertkow H. Diagnosis and treatment of dementia: Intro-
duction. Introducing a series based on the Third Canadian
Consensus Conference on the Diagnosis and Treatment of
Dementia.
CMAJ
2008;178:316-21.