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Is Dementia Inevitable?
Does the incidence of dementia steadily increase as we grow older? Or is there a decrease
or plateau in risk? To answer these questions, this article reviews the epidemiology of
dementia in extremely old age and examines the distribution of specific causes of dementia.
Important risk factors for and possible mechanisms of dementia also are discussed.
by Chris MacKnight, MD, MSc, FRCPC
M any diseases are either age-
related or aging-related. An
age-related disease is a disease
also will review explanations for
some of the conflicting findings.
• The Kame project.6 This study
evaluated Japanese-Americans
in Washington State and found
that typically occurs around a Epidemiology of a steady increase in the preva-
specific age (e.g., Hodgkin’s dis- Dementia in Late Life lence of dementia with increas-
ease, rheumatoid arthritis). An Early epidemiologic studies of ing age, with over 70% of men
aging-related disease is a disease dementia included very few sub- and women aged 95 years and
that typically occurs with increas- jects older than 95 years of age. older having dementia.
ing age, and often is considered to For example, the EURODEM- • The MRC-ALPHA project.7,8
be caused, at least in part, by prevalence-research-group analy- This study took place in
degeneration of and/or “wear and ses, which included close to Liverpool, England and found
tear” on the body’s cells and tis- 16,000 subjects, had only 69 sub- only a 47% prevalence of dem-
sues (e.g., osteoarthritis, athero- jects older than 95 years of age.2 entia in centenarians.
sclerosis). Aging-related diseases An early systematic review did not • Ritchie and Kildea.9 This 1995
are diseases that many of us can attempt to draw conclusions about meta-analysis concentrated on
expect to develop, if we live long the extremely elderly, because of the extremely elderly and ana-
enough. Into which category does their under-representation in the lyzed data from 1,388 subjects
dementia—specifically Alzheim- 47 studies reviewed.3 aged 90-94 years and 317 sub-
er’s disease (AD)—fall? Several large, recent epidemio- jects aged 95-99 years. The
The prevalence and incidence of logic studies have reported the prevalence of dementia did not
AD increase exponentially with prevalence of dementia in their increase exponentially com-
age, and some studies have reported eldest participants: pared to younger ages; rather,
a prevalence of dementia close to • The Kungsholmen study.4 In- the rate of increase in dementia
100% in people around 100 years of vestigators from this study prevalence was found to fall in
age (centenarians).1 Most of these found a 30% prevalence of the age range 80-84 years;
types of epidemiologic studies, dementia in men and a 50% around the age of 95 years,
however, have included very few prevalence of dementia in prevalence was seen to level
people older than 90 years of age. women ≥ 95 years of age, with off. The prevalence of dementia
This review will briefly discuss another 12% of subjects having at age 95-99 years was 44.8%.
studies that have evaluated the eld- questionable dementia. Unfortunately these cross-
est of the elderly population, and • Canadian Study of Health sectional studies are plagued with
and Aging (CSHA).5 This biases. Sample sizes often are very
study reported a 59% preva- small and non-response rates are
Dr. MacKnight is Assistant lence of dementia in those aged very high. For example, the Kung-
Professor, Division of Geriatric 95 years and older, with 86% sholmen study had a 40% non-
Medicine, Dalhousie University, of those aged 100 years and response rate in the ≥ 95-year age
Halifax, Nova Scotia. older having dementia. group. And in the CSHA study, the
10 • The Canadian Alzheimer Disease Review • April 2003
extremely elderly were almost all Table 1
nursing-home residents. Subjects Population-based Centenarian Studies
with dementia are more likely to
refuse participation in such stud- Complete Non-response
Place Examinations Rate Prevalence
ies,10,11 and since dementia increas-
es mortality,12-14 cross-sectional Leiden15 34 — 41%
Finland16 185 32% 36% male/17% female
studies may underestimate the true
Japan17 47 6% 70%
burden of disease, through both Italy18 92 60% 70% male/50% female
non-response bias and selective Netherlands19 15 12% 87% male/100% female
mortality. Sweden20 100 39% 30% male/16% female
A more useful approach may be Tokyo20 218 67% 71% male/43% female
to conduct studies specifically Denmark21,22 207 19% 51%
aimed at the extremely elderly. This New England23 34 21% 64%
may decrease the non-response bias
and improve the appropriateness of Several studies suggest that the for mortality and, perhaps, com-
any cognitive examinations used. extent of neuropathologic changes paring multiple cohorts. Unfortu-
A number of centenarian stud- and degree of cognitive impair- nately, even longitudinal studies
ies have investigated cognition in ment are poorly correlated in the are vulnerable to non-response, as
detail. Table 1 summarizes the extremely elderly.26,27 In the New drop-outs from these studies are
results of population-based cente- England Centenarian Study,28,29 more likely to be cognitively
narian studies.15-23 The prevalence infarcts were common, but few impaired.30
of dementia in these studies is patients met neuropathologic cri- The longitudinal studies that
most often between 30% to 60%, teria for AD (even among those have reported results in extremely
with women generally having a with a clinical diagnosis of AD). old age generally show a decline
higher prevalence than men.
When causes of dementia are When causes of dementia are reported, AD emerges as
reported, AD emerges as the most
common, with over 75% of cases
the most common, with over 75% of cases in Italy,
in Italy, Finland and Japan having Finland and Japan having that diagnosis.16-18
that diagnosis.16-18 The exception is
Denmark, where 50% of dementia Several patients had no cognitive in incidence of dementia for men,
cases are classified under vascular impairment, despite extensive with the decline in women, if
dementia.22 Many of the studies neuropathologic abnormalities, present, occurring later.31-37 How-
also include a cognitive impair- and conversely, several patients ever, several studies have shown
ment—not dementia—category; with significant cognitive impair- no decline in incidence.7,38-40
20% to 30% of cases are classi- ment had no identified neu- When examining subtypes, most
fied under this diagnosis. ropathologic abnormality. studies showed a decrease in the
Some centenarian studies in- Even the centenarian studies incidence of AD, particularly in
clude neuropathologic examina- have significant non-response and men, even when the incidence of
tions. A small series of studies cannot account for any mortality all dementias continued to
evaluating cognitively normal bias. Additionally, surveys of par- increase.32,33,36,37,39,40
Japanese centenarians found that ticular age groups, at particular The investigators from the
92% had incurred at least one points in time, are vulnerable to Cache County study37 performed a
infarct, but few had any changes cohort effects, where the findings particularly thorough analysis. This
associated with AD, such as may be due to something common study included a largely Mormon
plaques or tangles.24 Furthermore, to that cohort of subjects, rather and rural population with AD and
a small French study found no than reflecting some biological other forms of dementia. The inves-
relationship between the density property of aging. Longitudinal tigators found a decrease in the
of senile plaques and the degree studies can overcome some of incidence of all dementias in men
of cognitive impairment.25 these weaknesses by accounting and women in the oldest age group
The Canadian Alzheimer Disease Review • April 2003 • 11
(≥ 93 years). Careful examination even in the presence of the epsilon and cognition in extremely late
suggested that this decline was not 4 allele.46,47 Investigators from the life.
a methodologic artifact. Possible Adult Changes in Thought study
explanations for the results include: found similar results.40 Conclusions
unusual aspects of the population; This review, in effect, raises more
heterogeneity, such that an “early-” Is There a Primary questions than answers:
onset group disappears, leaving an Dementia of Aging? 1) Is the decline in incidence of
impervious group; or the interac- Terry and Katzman48 argue that AD in men a true finding, or is
tion of vascular and dementia risk there is a primary dementia of it due to the frequency of coex-
factors (i.e., those at highest risk aging. They believe that with isting stroke and the difficulty
die younger). ongoing neuronal and, most operationalizing standard crite-
importantly, synaptic losses, we ria in the extremely elderly?
Apolipoprotein E and all will develop dementia. Their 2) How can the disconnection bet-
Dementia in Late Life hypothesis suggests that humans ween neuropathologic findings
The presence of an apolipoprotein gain synapses in early life (a and dementia be explained?
E (ApoE) epsilon 4 allele may process accelerated by education) 3) How appropriate are neuropsy-
increase one’s risk of AD, however and then, after adolescence, inex- chologic examinations in these
its effect in late life is controver- orably lose synapses. Any nega- subjects, who often have severe
sial. Several centenarian studies tive effects of these synapse loss- vision and hearing impairment,
have demonstrated no increased es are not seen until a critical and functional impairment un-
risk of AD with an ApoE epsilon 4 threshold is reached—a threshold related to their cognition?
allele,16,17,41 but results from other that is far past most people’s ex- 4) Does the effect of ApoE truly
studies conflict.42 Studies also have pected life span. People with less disappear?
shown that the epsilon 4 allele may education and/or neuronal loss 5) Are cholinesterase inhibitors
not impair cognition in very old due to other factors (e.g., alcohol safe and effective in the ex-
people who are not demented,42,43 abuse, head injury, hypertension) tremely elderly—an age group
but again, results from other stud- may exhibit this primary dementia which is typically excluded
ies suggest otherwise.44 Interesting of aging at a younger age. from clinical trials?
results from a Finnish study45 Although this is an interesting 6) Can lifestyle changes and
found that ApoE status did not cor- hypothesis, there is little hard chronic-disease management
relate with clinical dementia, but evidence to support it at this prevent dementia even in
did correlate with neuropathologic time. However, sophisticated extremely old age?
AD (i.e., 42% of participants car- magnetic-resonance-imaging Despite the need for further
rying the epsilon 4 allele, who (MRI) studies suggest that “con- investigations to answer these ques-
were not demented, had neuro- nectivity” is lower in older, tions, the results of this review are
pathologic AD). Investigators also healthy subjects compared to hopeful in the sense that there is
have found that, although the younger, healthy subjects.49 Terry definitely a substantial minority of
epsilon 4 allele predicts early onset and Katzman’s hypothesis cer- centenarians who remain cogni-
of dementia, there is a peak after tainly is one method to explain tively intact. Therefore, there is one
which both the incidence and the apparent “disconnection” bet- final question we can answer:
prevalence of dementia decrease, ween neuropathologic changes Is dementia inevitable? No.
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The Canadian Alzheimer Disease Review • April 2003 • 13
