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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

				
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