Epidemiología del envejecimiento y trastornos cognitivos asociados prevalencia e incidencia de la enfermedad de Alzheimer y otras demencias

1. Chapter 9
Epidemiology of aging and associated cognitive disorders:
Prevalence and incidence of Alzheimer’s disease and other
dementias
OSCAR L. LOPEZ1,2
* AND LEWIS H. KULLER3
1
Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
2
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
3
Graduate School of Public Health, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
Abstract
The study of the incidence and prevalence of dementia is important to understand the distribution of
dementing illness among age and sex groups, and for the detection of possible causes of these disorders.
A variation in the incidence or prevalence of dementia, especially Alzheimer’s disease (AD) by region or
specific populations can be because of greater or lesser exposure to the causal agents of dementia. For
example, in the past the striking differences in the incidence of coronary heart disease (CHD) led to
the understanding of the relationship between dietary factors, such as saturated fat and dietary cholesterol,
and the incidence of CHD. However,thereisahighprevalenceofdementiainelderlyindividualsaroundthe
world, and multiple studies conducted in industrialized and nonindustrialized countries have shown an age-
standardized prevalence of dementia ranging from 5% to 7% in most countries. Dementia is not a specific
disease but rather a constellation of cognitive changes and disability due to several “causes,” i.e., AD, Lewy
bodies, vascular disease, drugs, and alcohol. Whether there is a trend for reduced incidence of dementia has
to be further evaluated. It is possible that the improvement in the treatments of risk factors, especially vas-
cular disease, has resulted in decreased incidence. However, this could result in an increase in prevalence,
since the improved therapies for risk factors will lead to increased longevity in patients with dementia.
THE STUDY OF COGNITIVE DISORDERS
IN EPIDEMIOLOGIC STUDIES
There have been significant advances in the determina-
tion of prevalence and incidence of dementia, especially
Alzheimer’s disease (AD), over the past decades.
Because the identification of a “case” is critical in epide-
miologic studies, one of the most important advances in
this area has been the implementation of standardized
diagnostic criteria that are widely accepted by the
research community and used across multiple studies.
For example, the Diagnostic and Statistical Manual of
Mental Disorders (DSM) 4th Edition (APA, 1994),
and the NINDS-ADRDA criteria for AD (McKhann
et al., 1984), have shown high accuracy in clinical-
pathologic studies (Lopez et al., 1999). In addition, there
have been significant improvements in the clinical diag-
nosis of non-AD dementia syndromes, e.g., dementia
with Lewy bodies (DLB) (McKeith et al., 2017), fronto-
temporal dementia (FTD) (Neary et al., 1998; Mckhann
et al., 2001), and vascular dementia (VaD) (Chui et al.,
1992; Roman et al., 1993).
The epidemiologic methodology developed over the
past decades has allowed researchers to determine
the prevalence and incidence of dementing disorders in
the general population, as well as the distribution by
*Correspondence to: Oscar L. Lopez, M.D., 3501 Forbes Avenue, Suite 830, Pittsburgh, PA 15213, United States.
Tel: + 1-412-246-6970, Fax: +1-412-246-6873, E-mail: lopezol@upmc.edu
Handbook of Clinical Neurology, Vol. 167 (3rd series)
Geriatric Neurology
S.T. DeKosky and S. Asthana, Editors
https://doi.org/10.1016/B978-0-12-804766-8.00009-1
Copyright © 2019 Elsevier B.V. All rights reserved

2. age, sex, and education level. The prevalence of demen-
tia doubles every 5 years in individuals between the ages
of 65 and 85 (Hebert et al., 1995; Ferri et al., 2005; Rocca
et al., 2011; Prince et al., 2013), and continues increasing
after age 90 (Corrada et al., 2010). It is estimated that,
globally, 4.7 million individuals aged 65 years or older
with AD dementia. This include 0.7 million were
between 65 and 74 years, 2.3 million age 75–84 years,
and 1.8 million 85 years and older (Hebert et al.,
2013). This figure is projected to rise to 13.8 million in
the United States and may reach 130 million worldwide
by 2050 (Alzheimer’s, 2015).
The introduction of neuroimaging (i.e., MRI) in large
population studies has represented a significant step for-
ward in understanding the pathobiology of dementing
processes (Longstreth et al., 1996; Kuller et al., 2004);
it has especially enabled better examination of the rela-
tionship between AD and vascular disease. The recent
introduction of amyloid (Klunk et al., 2004) and tau
(Johnson et al., 2016) protein ligands utilizing positron
emission tomography (PET) will expand the knowledge
of the etiology of neurodegenerative disorders in the
adult. The Australian Imaging, Biomarkers and Lifestyle
(AIBL) Study of Aging showed that 30% of the nonde-
mented participants age >65 had amyloid deposition in
their brains, and the Mayo Clinic Aging Study found that
48% of nondemented subjects between the ages of 70 and
74 were PETAb positive or/and neurodegeneration pos-
itive (hippocampal volume) by MRI (Jack et al., 2014).
In addition, it found that tau positivity by PET 18
F-AV-
1451 was 18% in cognitively normal individuals at age
65 and 42% at age 80 (Jack et al., 2017). These new
methodologies bring to the field a significant advance
and a challenging dilemma, namely, whether the neuro-
degenerative process should be diagnosed at the time
the image is found to be “positive” regardless of the
presence or evidence of clinical symptomatology or
by a clinical syndrome. It is possible that AD pathology
based only on in vivo measurements and the AD pathol-
ogy associated with a clinical syndrome are separate
entities.
The measurement of blood amyloid and tau protein
levels has the potential to be used as a biomarker to con-
firm the clinical diagnosis of AD as the cause of the
dementia syndrome (Zetterberg et al., 2013; Palmqvist
et al., 2019) or as a predictor of future AD dementia given
AD pathology (van Oijen et al., 2006; Lopez et al., 2019).
This area of research has been evolving over the past two
decades, and there are promising new techniques that are
making the use of blood biomarkers more accurate
(Nakamura et al., 2018; Nabers et al., 2019). However,
there is still a long road to the widespread use of periph-
eral biomarkers in the clinic. It is still not clear how they
will be used, whether the blood biomarker by itself will
be enough for the diagnosis of AD, or whether a
“positive” blood biomarker will be the initial step before
neuroimaging or obtaining another laboratory measure
(e.g., CSF). The hope is that only one highly sensitive test
will be necessary for the clinical diagnosis of AD. Blood
biomarkers for AD are urgently needed as a cost-
effective and noninvasive diagnostic tool.
EVOLUTION AND LIMITATIONS OF THE
DIAGNOSTIC CRITERIA FOR DEMENTIA
A definitive diagnosis of dementia and AD requires
histopathologic confirmation, but most epidemiologic
studies of AD rely on clinical criteria to define cases.
Over the past 30 years, the diagnoses of dementia have
been based on the criteria proposed by the Diagnostic
and Statistical Manual of Mental Disorders (DSM),
from the 3rd to the 4th edition (APA, 1980, 1987,
1994, 2000). These criteria require that for the diagnosis
of dementia impairments must be present in memory
and in one additional cognitive domain (e.g., language,
executive function). In addition, these cognitive deficits
should have caused significant impairment in social or
occupational functioning and represent a significant
decline from previous levels of functioning. These
DSM criteria are still being used in research studies,
although the DSM 5th edition, introduced in 2013
(APA, 2013), has modified the definition of dementia
(see following text).
The International Classification of Diseases (ICD) has
been widely used to identify cases with dementia (WHO,
1993), especially in epidemiologic settings. These cri-
teria have a stricter definition for dementia. They require
that memory, abstract thinking, judgment, and problem
solving must all be impaired, along with impairment
of one additional cognitive domain. Although these cri-
teria have a high specificity for dementia, they have low
sensitivity because cases with mild disease are usually
missed (Erkinjuntti et al., 1997). Therefore, we expect
a lower prevalence and incidence of dementia when these
criteria are used.
Given that there have been some criticisms of the
diagnostic criteria of dementia based on memory deficits,
a less restrictive definition has been used in research
settings (Lopez et al., 2011). Consequently, several stud-
ies have based the diagnosis of dementia on the presence
of impairments in two cognitive domains, but not neces-
sarily memory (Lopez et al., 2000, 2003). These criteria
have shown a sensitivity for AD of 98% and specificity
of 88% relative to autopsy (Lopez et al., 2000). The
National Institute on Aging—Alzheimer’s Association
(NIA-AA) criteria for all-cause dementia has taken a
similar approach requiring deficits in two of the fol-
lowing domains: memory, judgment/problem solving,
140 O.L. LOPEZ AND L.H. KULLER

3. visuospatial, language, and behavior (e.g., agitation, apa-
thy, socially unacceptable behaviors) (McKhann et al.,
2011). The DSM-5th edition has proposed similar cri-
teria for dementia (APA, 2013), and created two diagnos-
tic classifications based on the severity of the cognitive
syndrome, Mild and Major Neurocognitive Disorder.
Diagnostic criteria will continue to evolve to identify
the specific causes of dementia with the incorporation of
techniques for in vivo measurement of neuropathology
such as amyloid PET scanning or CSF determination
of amyloid and tau abnormalities (Sperling et al.,
2011; Jack et al., 2016), which will allow for more pre-
cise antemortem diagnoses (Clark et al., 2011). The cost
of these new technologies poses challenges for the devel-
opment of large-scale epidemiologic studies, however,
limiting sample sizes and selectivity of the populations
being studied.
PREVALENCE OF DEMENTIA AND AD
There is a high prevalence of dementia in elderly individ-
uals around the world, and there have been multiple stud-
ies conducted in industrialized and nonindustrialized
countries to examine this issue. The age-standardized
prevalence of dementia ranges from 5% to 7% in most
countries (Ferri et al., 2005; Sosa-Ortiz et al., 2012). In
the United States, prevalence of dementia was higher
in African Americans and Latinos than in non-Latino
Whites (Gurland et al., 1999). In the United Kingdom,
there was a higher prevalence in African-Caribbean par-
ticipants compared to Whites (Adelman et al., 2011). The
estimated prevalence of dementia in people age 60 years
and older ranged from a low of 4.7% in central Europe to
a high of 8.5% in Latin America and 8.7% in North
Africa and the Middle East (Prince et al., 2013;
Alzheimer’s, 2015). Studies conducted in nonindus-
trialized countries have documented lower incidence
and prevalence in Nigeria (1.4%) (Hendrie et al., 1995;
Hendrie et al., 2001) and rural India (1.1%) (Chandra
et al., 1998; Ganguli et al., 2000; Ferri et al., 2005),
although rates have increased in Africa and Asia over
the last few years (Alzheimer’s, 2015). Ascertainment
methodologies and high mortality rates may explain
the lower prevalence and incidence in these elderly popu-
lations. However, it is possible that differences in diet,
exercise, or other lifestyle exposures account for the
reported differences.
Dementia, especially AD, is present in all populations
around the world. Whether there is a difference in the
prevalence of dementia between industrialized countries
and less industrialized populations remains an unan-
swered question. However, it is estimated that the
decreased mortality in nonindustrialized countries will
lead to an increase in the number of older individuals
at risk for dementia after age 60 in these populations;
58% of the individuals with dementia are living in
low-middle income countries, and it is projected that this
proportion will increase to 71% in 2050 (Prince et al.,
2013; Alzheimer’s Disease International, 2015).
INCIDENCE OF DEMENTIA AND AD
Estimates of dementia incidence after age 60 years dou-
ble every 10 years (Jorm and Jolley, 1998; Prince et al.,
2013). There is very little difference between the sexes in
the incidence of dementia or AD, although by absolute
numbers there are more women than men with the dis-
ease, particularly over the age of 85 years, due to differ-
ences in life expectancy (Fitzpatrick et al., 2004). Studies
conducted in the United States showed that incidence
rates were higher in African Americans and Latinos than
Whites (Tang et al., 2001; Yaffe et al., 2013). However,
after adjustment for education level or socioeconomic
status these differences disappeared (Yaffe et al.,
2013). A large study conducted in China showed that
the incidence of dementia was 9.87/1000 person-years,
which is similar to that observed in the United States
and Europe (Chan et al., 2013).
There is a great variability in the estimates of inci-
dence of dementia among studies. In a large meta-
analysis of 24 longitudinal studies, the age-specific
incidence of dementia ranged from as low as 5/1000
for individuals from 65 to 70 years and as high as
60 to 80/1000 for those 85 years and older (Sosa-Ortiz
et al., 2012). The disparity in the results may stem from
multiple causes. A study using the Kaiser Permanente
database in northern California reported that at age
>64, the incidence of dementia was highest for African
Americans and lowest for Asian Americans, mostly
Japanese, 15.2/1000 person-years (Mayeda et al.,
2016). An important limitation of the study is that it
was based on ICD codes on electronic medical records
of inpatient and outpatient encounters and likely under-
estimated the extent of dementia, especially among
healthy individuals.
The Cardiovascular Health Study Cognition Study
(CHS-CS) followed over 3068 adults who were free of
dementia at baseline from 1992–93 to 1998–99 and
found that the incidence estimates varied from 32/1000
person-years age 75 to 79 at entry to 96/1000 person-
years age 85, with little sex difference (Fitzpatrick
et al., 2004). The incidence of dementia continues to
increase after age 90+ (Corrada et al., 2010). A study
conducted in a subgroup of the CHS-CS showed that
only 2% of the nondemented participants in 1992–93
were alive and had normal cognition at the end of the
study in 2013 (Kuller et al., 2016).
EPIDEMIOLOGY OF AGING AND ASSOCIATED COGNITIVE DISORDERS 141

4. DEMENTIA AND MORTALITY
Dementia has been increasingly reported as a common
cause of death in older adults in industrialized and non-
industrialized countries (Sousa et al., 2009). In a Medi-
care survey of 22,896 adults age 65 years and older,
dementia accounted for 19% of all deaths (Tinetti
et al., 2012); it was second to heart failure. Traditional
mortality statistics are not a good measure of deaths
attributed to dementia or AD; these figures underestimate
the contribution of dementia to mortality (Tinetti et al.,
2012; James et al., 2014). While individuals do not die
of AD per se, advanced dementia increases vulnerability
for other disorders (e.g., common infections), which
ultimately lead to death, or decisions not to treat aggres-
sively in severely demented patients.
LIMITATION IN THE ASCERTAINMENT
OF DEMENTIA CASES
The use of medical records, i.e., hospital discharge,
physicians’ office records, nursing homes, and death
certificates to identify “dementia cases” to quantify inci-
dence, prevalence, and risk factors has severe limitations.
Patients do not usually seek health care for “early
dementia” but rather are evaluated because they are seen
by a doctor for another disease, i.e., heart disease, stroke,
lung disease, and so on. Therefore, there is an increased
likelihood that a dementia diagnosis becomes a function
of the frequency of medical care for other causes, severity
of cognitive deficits and disability, and physician spe-
cialty. Thus, the sensitivity, i.e., identification of all
dementia cases is severely low and specificity, i.e., iden-
tification of dementia that does not exist is high. There
will also be greater likelihood of association of comor-
bidities with dementia, i.e., reason for physician visit,
and higher case-fatality because of severity of diagnosis.
TEMPORAL TRENDS
Several recent studies have reported that the incidence of
dementia may be declining over time, especially in high-
income countries (Schrijvers et al., 2012; Grasset et al.,
2016; Matthews et al., 2016; Satizabal et al., 2016).
A population-based study in Rotterdam reported a
decreased incidence of dementia in all age groups
between 1990 and 2000 as well as an increase in brain
volume as a percent of intracranial volume (Schrijvers
et al., 2012). Similarly, the Framingham Heart Study in
the United States found that the cumulative 5-year hazard
rate of dementia fell from 3.6 per 100 persons during the
late 1970s to 2.0 per 100 persons in the late 2000s
(Satizabal et al., 2016). The magnitude of the decline
was greater for VaD than for AD dementia, and rates
of hypertension, atrial fibrillation, and stroke also fell
over the same period.
The MRC Cognitive Function and Aging Study com-
pared incidence of dementia in populations aged 65 in
England and Wales in 1989–94 and 2008–11, and found
a 20% drop in the incidence of dementia primarily among
men (Matthews et al., 2016). The decline was greatest in
the upper social class (least deprived) with little change
in lower social class (most deprived). This was also noted
in the Framingham Heart Study in the United States.
A study in France of two large longitudinal cohorts
age 65 reported a significant decline in the incidence
of dementia in women, age-adjusted HR 0.62 (CI:
0.48–0.80) but not for men, independent of differences
in education, vascular risk factors, and depression
(Grasset et al., 2016).
While the incidence is declining, the prevalence will
increase, because improvements in healthcare will result
in decreased mortality in patients living with dementia
(Ahmadi-Abhari et al., 2017). Indeed, the Kungsholmen
Study did not find a change in prevalence from 1987 to
2008, and this was interpreted in the context of decreased
incidence with increased prevalence due to better
survival of the population (Qiu et al., 2013).
The decline in incidence is not observed in other
populations. Interestingly, the Hisayama Study found
that the incidence of dementia exhibited a dramatic
increase of 170% from 1985 to 2012, and the prevalence
increased from 6.8% in 1985 to 11.2% in 2012 (Ohara
et al., 2017). The incidence of AD increased, while
VaD and hypertension rates remained stable. In addition,
a population-based study in the northern United States
found no change in the incidence of dementia over time
in a relatively homogenous highly educated population
(Rocca et al., 2011). In addition, the prevalence rates
of AD in two populations of African Americans in Indi-
ana showed no decline between 1992 and 2001, despite
significant differences in medical care (Hall et al., 2009).
The reasons for an apparent decline in incidence may
include improved educational levels of the more recent
birth cohorts who are reaching the age of dementia risk,
or improved prevention and treatment of risk factors,
especially for vascular disease. Importantly, the impro-
vements in education levels in the population can influ-
ence the methodology used to detect dementia. Studies
using global cognitive measures (e.g., Mini Mental State
Examination) as a screening instrument or as a tool for
diagnosis, most likely, will miss the early dementia cases,
especially in those with a high level of education, who
most likely will have scores within the normal range. It
is important to point out that the cycle of evaluations
could also influence incident studies. Studies that exam-
ine participants every 4 or 5 years will miss dementia
cases, especially in the older groups. The CHS-CS found
that the mean time with mild cognitive impairment (MCI:
a transitional state between normal to dementia) is
3.5 years (Lopez et al., 2012). This means that an
142 O.L. LOPEZ AND L.H. KULLER

5. individual can go from normal to MCI to dementia to
death within a 4–5-year period and be considered normal
in the statistical analysis.
It is possible that the apparent decline is an artifact
introduced by the definition of dementia as a specific
level of cognitive impairment, especially memory, and
related disability, rather than a relative change. Better
educated, cognitively higher-functioning individuals
can tolerate a greater extent of neuropathologic change
prior to reaching the threshold of the manifestation of
early symptoms of dementia (this concept is termed
cognitive reserve) (Stern, 2012). If dementia is defined
as a change in cognition to below an absolute level
and education improves over time, the prevalence of
dementia may appear to decline when the only thing that
has changed is the higher level of education of the
participants in the incidence and prevalence studies
(Rocca et al., 2011). The French population-based
Personnes Ag
ees Quid (PAQUID) study compared cog-
nitive performance of two generations of participants
recruited 10 years apart and found that the second-
generation group performed better on global cognitive
measures and on specific cognitive tests than the first-
generation group due to improvements in education
levels (Grasset et al., 2018), and there was an increased
proportion of individuals performing intellectual occu-
pations (8.2% vs 15.5%) in the second-generation group
compared to the first-generation group.
Whether this declining trend is reflected in pathology
remains to be determined. A study from Switzerland sug-
gests that there has been a decline over time in amyloid
deposition in the brain. The authors examined a series
of autopsy cases, mean age 828 years, without clin-
ical diagnosis of dementia or cognitive disorders, and
the average amyloid stage decreased by approximately
24% over the study period from 1972 to 2006, espe-
cially in the 85 age group (Kovari et al., 2014). How-
ever, pathologic studies that examined older cohorts
found that the dementia symptoms can be caused
by multiple pathologies in the elderly—amyloidosis,
neurodegeneration, and vascular disease (Kawas
et al., 2015).
DEMENTIA IN YOUNG INDIVIDUALS
Alzheimer’s disease is the most frequent form of demen-
tia after age 65, as well as in those whose age 65.
There are not many population-based studies on
young-onset dementia. A study conducted in the United
Kingdom showed that the prevalence of dementia with
onset between the ages of 30 and 65 years was 54 per
100,000 (95% CI: 45–64) and 98 per 100,000
(81–118) between the ages of 45 and 65 years (Harvey
et al., 2003). AD was the most frequent diagnosis
followed by vascular disease and frontotemporal demen-
tia. A study conducted in Japan showed similar preva-
lence rates (Ikejima et al., 2009), although the most
frequent form of dementia was vascular disease, fol-
lowed by AD. Studies conducted in referral clinics indi-
cated that head trauma and metabolic and autoimmune
disorders are the most frequent cause of dementia in indi-
viduals whose age 45 (Harvey et al., 2003).
VASCULAR DEMENTIA
Clinical and neuropathologic studies have shown that
cerebrovascular disease is considered the second most
common cause of dementia in the elderly (Ott et al.,
1995; Knopman et al., 2002). However, the heterogene-
ity of the clinical presentation and progression of VaD
makes it a difficult diagnosis (O’brien and Thomas,
2015). It is traditionally recognized that VaD can develop
after a single or multiple stroke and can have a stepwise
progression. However, VaD can also develop in individ-
uals without clinical strokes and can have a gradual pro-
gression (Hulette et al., 1997), and a significant
proportion of the patients with VaD have concomitant
AD. The prevalence and incidence of VaD tend to be
higher in Asian than in Western populations (Ott et al.,
1995; Ohara et al., 2017), and in African Americans than
in Whites in the United States (Tang et al., 2001;
Fitzpatrick et al., 2004).
Because of the heterogeneity of the clinical presenta-
tion of VaD it is difficult to classify individuals in the bor-
der zone between “pure” vascular cases vs those where
the vascular phenomena occur in combination with other
disease processes. The Rotterdam Study found that 72%
of the dementia cases were AD, 16% were VaD, and 12%
other dementias (Ott et al., 1995), while the CHS found
that 12% of the all dementia cases met criteria for VaD,
and of that group 27% met criteria for “pure” VaD, and
63% exhibited different degrees of cerebrovascular dis-
ease associated with other disease processes, mainly
AD (Lopez et al., 2005).
The use of MRI in large population cohorts has
improved our detection of VaD and has allowed us to bet-
ter understand the difficulties in the determination of its
incidence and prevalence. A study that examined
incidence of VaD using MRI found that the incidence
was 3.8/1000 person-years before the MRI and 5.4 when
the MRI was used for diagnosis (Lopez et al., 2005).
However, discrepancies still exist. The use of four diag-
nostic criteria in a large epidemiologic study (i.e., DSM-
IV (APA, 1994), the National Institute of Mental and
Neurological Disorders and the Association Internatio-
nale pour la Recherche et l’Enseigment en Neurosci-
ences [NINDS-AIREN] (Roman et al., 1993), and the
State of California Alzheimer’s Disease Diagnostic
and Treatment Centers (ADDTC) criteria for VaD
EPIDEMIOLOGY OF AGING AND ASSOCIATED COGNITIVE DISORDERS 143

6. (Chui et al., 1992) showed that the agreement ranged
from fair to substantial, indicating that none of these
criteria identified the same group of individuals (Lopez
et al., 2005).
LEWY BODY DEMENTIA
DLB is considered the second most frequent form of
neurodegenerative dementia in the elderly. Because of
the identification of the core symptomatology (i.e., visual
hallucinations, parkinsonism, fluctuations of the senso-
rium) (McKeith et al., 2017) requires careful evaluations
and information from proxies, the true prevalence and
incidence in the population could be underestimated.
In addition, the core symptomatology can also be present
in patients with Parkinson’s disease and dementia (PDD)
(Emre et al., 2007). The temporal sequence of the symp-
toms may distinguish DLB from PDD; in DLB the motor
and cognitive symptoms tend to develop within the same
year, while in PDD the cognitive symptoms develop after
the patient has had motor symptoms for several years.
The pathology of both DLB and PDD appears the same,
a finding yet to be explained.
A review of population and clinical studies showed
that the prevalence of DLB ranged from 0.3% to 24%
in the general population (Vann Jones and O’brien,
2014; Hogan et al., 2016a), and 3%–7% of the patients
with dementia were found to meet criteria for DLB. Point
and period prevalence estimates ranged from 0.02 to 63.5
per 1000 persons. The annual incidence ranged from
3.2% to 4.5% cases/1000 person-years. There was an
association with old age, and there were more males than
females with DLB. Overall, DLB seems to have a low
prevalence in the population, but has a high representa-
tion in referral clinics, most likely due to the complexity
of the symptomatology.
PARKINSON’S DISEASE WITH
DEMENTIA
The prevalence of Parkinson’s disease (PD) in industri-
alized countries ranges from 0.3% to 1%, with an inci-
dence of 8–18 per 100,000 person-years (de Lau and
Breteler, 2006). PD is usually more frequent in males
than females, and studies conducted in the United States
show that the prevalence is lower for African Americans
than for Whites, Asians, and Latinos (Mayeux et al.,
1995; Van Den Eeden et al., 2003). The proportion of
patients with PD who are diagnosed PDD ranged from
10% to 15%. Longitudinal studies have shown that the
incidence of PDD in nondemented PD subjects was
69/1000 person-years, and the highest increase occurs
between age 65 and 75 (Mayeux et al., 1995). However,
approximately 65% of the PD patients who survived after
age 85 developed PDD.
A study of 221 PD patients showed that 78%
showed PDD after 8-year follow up (Aarsland et al.,
2003). A review of the medical records of individuals
with parkinsonism showed that the incidence of DLB
was 3.5/100,000 person-years, and of PDD was 2.5.
The Combined incidence of DLB and PDD was
5.9/100,000 person-years. DLB patients developed
symptoms at a younger age, and men had a higher
incidence of dementia than women across the age
spectrum (Savica et al., 2013).
FRONTOTEMPORAL DEMENTIA
Frontotemporal dementia (FTD) is characterized by
behavioral, executive, and language deficits, and is
considered the third most frequent form of neurodegen-
erative dementias across all age groups (Neary et al.,
1998; McKhann et al., 2001). However, 70% of the cases
occur in individuals whose age 65 (Bang et al., 2015).
The clinical diagnosis is challenging because the behav-
ioral symptoms are similar to those seen in late onset
psychiatric disorders, and the language deficits (e.g.,
logopenic aphasia) can also be seen in early onset AD
(Gorno-Tempini et al., 2011; Rascovsky and
Grossman, 2013). Consequently, more sophisticated
methods are used for its clinical characterization (e.g.,
FDG-PET, specific neuropsychologic tests). FTD
patients can also present with motor neuron disease
(MND), and FTD can coexist with corticobasal degener-
ation (CBD) or progressive supranuclear palsy (PSP)
symptoms (Dickson et al., 2011; Armstrong et al., 2013).
Because of the younger age at which FTD develops, it
is difficult to determine accurate prevalence and inci-
dence rates in the population. Most of the studies were
based on assessments of neuropsychiatric institutions,
municipal surveys, dementia registries, practitioners’
reports, or medical records review (Hogan et al.,
2016b), which may explain the different prevalence rates
in different countries. A systematic review of prevalence
and incidence studies of FTD showed that FTD
accounted for 2.5% of the dementias across all age
groups, and 10.2% in those aged 65 (Hogan et al.,
2016b). The prevalence estimates ranged from 0.01 to
4.6 per 1000 person-years, and the incidence from 0.0
to 0.3 person-years. Sex differences have not been
identified.
The combined prevalence of FTD, PSP, and CBD
(Aarsland et al., 2003) in two counties in the United
Kingdom was 10.8/100,000 across all age groups, and
the incidence was 1.61/100,000 (Coyle-Gilchrist et al.,
2016). A study conducted in two Italian provinces
showed an incidence rate of 3.05/100,000 (Logroscino
et al., 2019). The prevalence increased with age and
peaked between age 65 and 69 in the United Kingdom
144 O.L. LOPEZ AND L.H. KULLER

7. and between age 75 and 79 in Italy; both studies identi-
fied cases after age 85. The individual pathologies in the
spectrum of FTD have a very low prevalence; the esti-
mated prevalence of PSP was 1.0 per 100,000 (95% CI
0.9–1.0) (Nath et al., 2001). Thirty-eight of 234 cases
identified as having FTD met criteria for CBD over a
period of 2 years in a population of 1.9 million in the
United Kingdom (Coyle-Gilchrist et al., 2016). In Italy,
out of 63 incident cases with FTD, identified during a
period of 12 months, 23 (36.5%) had the behavioral
variant, 19 (30%) had the nonfluent variant of primary
progressive aphasia, 7 (11%) had CBD, 9 (14%) PSP, 2
(3%) MND, and 3 (4.7%) were diagnosed as having
nonspecific primary progressive aphasia (Logroscino
et al., 2019).
SUMMARY
Almost all diseases have a low or high distribution
in populations of incidence and prevalence because
of the differences in exposure to specific environ-
ments, i.e., lifestyle determinants of disease and genet-
ics (host susceptibility). The major exceptions are
monogenic diseases, such as homozygous familial
hypercholesterolemia or rare monogenic dominant dis-
orders of amyloid metabolism that cause early age AD
(Rogaev et al., 1995). Therefore, evaluating the geo-
graphic variations of disease often leads to identifica-
tion of “possible causal agents” of AD or other types of
dementia. The changes in these lifestyle variables over
time may result in a decrease in incidence of AD. Bet-
ter treatment may lead to reduced case fatality and case
morbidity without changing incidence and may result
in an increase in prevalence because of improved
survival.
The failure to date to demonstrate substantial vari-
ation in “dementia” incidence or prevalence across
geographic areas is likely because of the failure to mea-
sure the specific causal pathways that contribute to
dementia syndromes. The previous studies have focused
primarily on older individuals who often have multiple
pathologies in the brain that “cause dementia.” The eval-
uation of specific determinants of “dementia syndrome”
based on MRI, PET, and other biomarkers will likely
result in better evaluation of geographic variation in
specific dementia diagnoses, especially for younger
populations 80 years old, and then possibly identifica-
tion of causal agents for specific dementia(s).
The reported decline in incidence of “dementia” may
reflect the substantial improvements in prevention
because of changes in lifestyle, such as changes in diet,
smoking, and exercise, and better treatment of CVD risk
factors, such as elevated BP, diabetes, and hyperlipid-
emia. However, much of the decline in incidence may
just be to the result of improved education and “IQ” of
populations over time, i.e., cohort effects, that are a func-
tion of better early age nutrition, reduction of infectious
diseases, better educational opportunities, and reduction
of early life environmental exposures, such as lead, air
pollution, and pesticides. Thus, environmental and life-
style factors that evolved 40–50 or more years ago
may now be contributing to a substantial decline in inci-
dence of “dementia.”
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