ArticlePDF AvailableLiterature Review

Changing perspectives regarding late-life dementia



Individuals over 80 years of age represent the most rapidly growing segment of the population, and late-life dementia has become a major public health concern worldwide. Development of effective preventive and treatment strategies for late-life dementia relies on a deep understanding of all the processes involved. In the centuries since the Greek philosopher Pythagoras described the inevitable loss of higher cognitive functions with advanced age, various theories regarding the potential culprits have dominated the field, ranging from demonic possession, through 'hardening of blood vessels', to Alzheimer disease (AD). Recent studies suggest that atrophy in the cortex and hippocampus-now considered to be the best determinant of cognitive decline with aging-results from a combination of AD pathology, inflammation, Lewy bodies, and vascular lesions. A specific constellation of genetic and environmental factors (including apolipoprotein E genotype, obesity, diabetes, hypertension, head trauma, systemic illnesses, and obstructive sleep apnea) contributes to late-life brain atrophy and dementia in each individual. Only a small percentage of people beyond the age of 80 years have 'pure AD' or 'pure vascular dementia'. These concepts, formulated as the dynamic polygon hypothesis, have major implications for clinical trials, as any given drug might not be ideal for all elderly people with dementia.
Nature Reviews
Center for Memory and
Brain Health, The
Sandra and Malcolm
Berman Brain & Spine
Institute, Baltimore,
MD, USA (M. Fotuhi).
Department of Clinical
Neurological Sciences,
University Hospital,
University of Western
Ontario, London, ON,
Canada (V. Hachinski).
Department of
Neurology, Case
Western Reserve
University, Cleveland,
(P. J. Whitehouse).
M. Fotuhi, Center for
Memory and Brain
Health, The Sandra and
Malcolm Berman Brain
& Spine Institute, 5051
Greenspring Avenue,
Baltimore, MD 21209,
Changing perspectives regarding
late-life dementia
Majid Fotuhi, Vladimir Hachinski and Peter J. Whitehouse
Abstract | Individuals over 80 years of age represent the most rapidly growing segment of the population, and
late-life dementia has become a major public health concern worldwide. Development of effective preventive
and treatment strategies for late-life dementia relies on a deep understanding of all the processes involved.
In the centuries since the Greek philosopher Pythagoras described the inevitable loss of higher cognitive
functions with advanced age, various theories regarding the potential culprits have dominated the field, ranging
from demonic possession, through ‘hardening of blood vessels’, to Alzheimer disease (AD). Recent studies
suggest that atrophy in the cor tex and hippocampus—now considered to be the best determinant of cognitive
decline with aging—results from a combination of AD pathology, inflammation, Lewy bodies, and vascular
lesions. A specific constellation of genetic and environmental factors (including apolipoprotein E genotype,
obesity, diabetes, hypertension, head trauma, systemic illnesses, and obstructive sleep apnea) contributes
to late-life brain atrophy and dementia in each individual. Only a small percentage of people beyond the age
of 80 years have ‘pure AD’ or ‘pure vascular dementia’. These concepts, formulated as the dynamic polygon
hypothesis, have major implications for clinical trials, as any given drug might not be ideal for all elderly people
with dementia.
Fotuhi, M. et al. Nat. Rev. Neurol. advance online publication XX Month 2009; doi:10.1038/nrneurol.2009.175
Memory loss, dementia, and Alzheimer disease (AD)
are major public health concerns worldwide. In recent
years, AD has become almost synonymous with late-
life dementia. 100 years ago, however, senile dementia
(mostly attributed to ‘hardening of the blood vessels’)
was considered to be the dominant etiology for cog-
nitive impairment in elderly individuals over the age
of 80 years. 1,000 years ago, demonic possession was
blamed for the same set of dementia symptoms. Clearly,
scientists in each era have tried to untangle the complex
etiology of late-life dementia, and still no specific effec-
tive remedy has emerged.
In this critical Review of the dementia literature, we
trace the development of various dominant concepts and
theories and outline a set of key discoveries that have
brought us to our current state of knowledge in this field.
We focus on the most recent studies, which suggest that
cognitive impairment among the oldest old results from
a dynamic complex of genetic and environmental factors.
We discuss the implications of these developments for
the design of future clinical trials and summarize some
of the key questions that we must answer in the coming
years. For example, is late-life dementia an extension of
AD pathology, or is it qualitatively and quantitatively
different from early-onset AD? Also, what are the best
and most specific biomarkers and imaging techniques
to detect presymptomatic cognitive impairment and to
monitor the rate of clinical progression in elderly indivi-
duals with dementia?
Evolution of concepts
Greco-Roman period to 1907
Cognitive decline with aging was described by Western
philosophers and clinicians as early as the 7th century
BC.1 The Greek philosopher Pythagoras observed that
the pattern of development of new skills early in life
reverses toward the end of life. ‘Normal’ regression of
mental faculties, according to Pythagoras, would begin
in one’s 60s and, by one’s 80s, would lead to the “imbecil-
ity of infancy”. These concepts persisted until the Early
Renaissance period, when patients with dementia were
treated as witches. In the 18th century, ‘senile demen-
tia’ was recognized as a distinct condition from normal
aging, and patients with this condition were shown to
have smaller brains, on average, than their cognitively
healthy counterparts.2 In the 1890s, Alois Alzheimer
and Otto Binswanger extensively described and empha-
sized the critical roles of atherosclerosis and stroke in the
development of brain atrophy and senile dementia.2
Alois Alzheimer’s findings of plaques and tangles during
the autopsy evaluation of a young patient with progres-
sive confusion and hallucination were published in 1907
as a case report entitled “About a peculiar disease of the
cerebral cortex”. In 1910, Emil Kraepelin, in part for
political purposes in the context of rivalry between two
Competing interests
The authors declare no competing interests.
Nature Reviews
voluME 5
major academic institutions in Europe, included this case
report in his leading textbook of psychiatry and used
the term ‘Alzheimer’s disease.1 Alzheimer himself did
not consider amyloid to be the primary cause of senile
dementia, and he wrote, “plaques are not the cause of
senile dementia, but only an accompanying feature of
senile involution of the central nervous system.3
For much of the early 20th century, AD was con sidered
to be a rare condition that affected young people with
presenile dementia. By contrast, ‘hardening of the blood
vessels’ was considered to be the main pathology for
cognitive decline in the last decades of life. In the 1940s
and 1950s, a group of psychiatrists, including David
Rothschild, promoted the idea that late-life dementia
was a consequence of society’s choice to isolate elderly
individuals and deprive them of meaningful inter actions
with friends and relatives.4 David Wilson wrote, “lone-
someness, lack of responsibility, and a feeling of not being
wanted all increase the restricted view of life, which in
turn leads to restricted blood flow.”5 In 1974, the increas-
ing realization that strokes can be the primary etiology for
brain atrophy and confusion in older patients led to the
formulation of the ‘multi-infarct dementia’ diagnosis.6
A gradual shift of focus from vascular issues to AD
pathology began with reported findings of extensive
amyloid plaque loads in the brains of elderly people
with dementia.7 The discovery of mutations in the genes
encoding γ-secretase and amyloid precursor protein in
familial forms of early-onset AD put amyloid at the
center of the pathological processes of dementia, and
the amyloid cascade hypothesis attracted substantial
attention.8 This hypothesis proposes that aggregation
of amyloid-β (Aβ) protein in the cortex (which begins
as toxic dimers and oligomers that later turn into diffuse
and then fibrillar ‘insoluble plaques’) triggers oxidative
injury and synaptic loss; these, in turn, bring about
hyperphosphorylation of tau protein, which leads to
Key points
Over the past 27 centuries, the perception of cognitive impairment with aging
has changed from a normal inevitable part of aging to being mostly attributable
to Alzheimer disease (AD)
Alois Alzheimer was one of the first clinician–scientists to describe the
importance of vascular pathology and to de-emphasize the role of amyloid
plaques in brain atrophy and late-life dementia
Clinicopathological studies have consistently shown that individuals over
80 years of age generally have ‘mixed’ pathologies (infarcts, plaques, tangles,
Lewy bodies and inflammation) rather than ‘pure AD’
The size of the cortex and hippocampus—more than AD or any other single
pathological finding—correlates with the degrees of cognitive decline and
dementia in elderly individuals
Appreciating the link between midlife risk factors and late-life size of the cortex
and hippocampus has serious implications for disease diagnosis, patient
management, and interpretation of research findings
The dynamic polygon hypothesis provides a new framework for thinking about
aging and dementia that departs from the linear model proposed by the amyloid
cascade hypothesis
formation of tangles, triggering widespread neuronal
dysfunction and dementia.9,10 Interest in this hypo thesis
grew rapidly, and the term senile dementia was soon
changed to ‘senile dementia of Alzheimer’s type’ and,
eventually, simply to ‘Alzheimer disease’.
With increasing interest in plaques and tangles and
with the hope of finding a ‘cure’ for late-life dementia,
experts in neurology and psychiatry convened and estab-
lished a set of criteria for a clinical diagnosis of AD.11,12 In
parallel, minimal microscopic criteria were established
for a postmortem histological diagnosis of AD. The
Khachaturian criteria, reflecting the opinion of a panel
of experts who met in 1984, attempted to standardize the
pathological diagnosis of AD on the basis of density of
senile plaques (both neuritic and diffuse) found in cor-
tical areas.13 Higher densities of plaques were required
for a positive AD diagnosis as the age of the indivi-
duals increased from <50 years, through 50–75 years,
to >75 years.13 In 1991, the CERAD (Consortium to
Establish a Registry for AD) criteria were established to
provide further specificity for an AD diagnosis. Under
these criteria, densities of neuritic (not diffuse) plaques
above a defined normal value were assigned to three cat-
egories, A, B and C, with category C representing the
highest plaque density.14 CERAD used an age-related
plaque score, and the diagnostic categories also incor-
porated clinical information.
The CERAD criteria fulfilled an important need for
confirmation of an AD diagnosis in research and clini-
cal centers around the world. However, this widely used
classification had two important limitations. First, the
pathological distinctions were based on the brains of 142
patients with dementia (average age 76 years) compared
with those of only eight much younger ‘control’ indivi-
duals (average age 65 years). If the authors had selected
patients and controls in their 80s, their cut-off criteria
could have been quite different. Second, the quantity
and distribution of neurofibrillary tangles—a promi-
nent feature of AD—were not taken into account. These
limitations resulted in a great deal of disagreement, even
among neuropathologists viewing the same pathological
The Braak and Braak criteria (stages I–VI), which were
based on distribution and progression of neurofibrillary
tangles (not plaques) from limbic areas to frontal lobes,
showed a close correlation between stages of dementia
and the severity of pathological findings.16 The National
Institute on Aging–Reagan criteria, which were intro-
duced in 1997, incorporated information about the sever-
ity of the burden of both plaques and tangles along with
clinical information regarding dementia, and removed
the criteria for age.17 AD pathology was highly likely to
be the underlying cause of dementia if both frequent
neuritic plaques (CERAD category C) and widespread
neurofibrillary tangles (Braak stage V and VI) were
Clinical and pathological consensus guidelines have
been proposed for other forms of dementia, such as
Nature Reviews
dementia with Lewy bodies, vascular dementia, and
normal pressure hydrocephalus.18–21 The possibility that
cerebral amyloid angiopathy could contribute to dementia
through mechanisms other than paren chymal AD pathol-
ogy was also recognized.22 A major challenge acknow-
ledged by the consensus guidelines was the determination
of boundaries between normal aging and dementia among
elderly individuals (especially those beyond the age of
80 years), as those without considerable cognitive decline
often had some degree of pathology in their brains.15,23
Reflecting these challenges, one study showed that the
frequency of diagnosed cases of dementia in the same
patient population of 1,879 men and women over 65 years
of age varied by an order of magnitude (from 3.1% to
29.1%), depending on the clinical criteria used.24
The description of a clinical stage called mild cognitive
impairment (MCI) defined a major turning point in
dealing with the challenge of dichotomization of patients
into normal or dementia categories.25 Initially, the pro-
posed diagnostic criteria for MCI required significant,
objectively measured memory loss that was corroborated
by the patient’s family. Further progress in refining the
definition of MCI came with the recognition that some
elderly individuals can have a nonamnestic presenta-
tion that leads to vascular or other forms of dementia.26
Pathology, imaging and cerebrospinal fluid studies all
pointed to MCI as a transitional stage along the trajec-
tory of cognitive decline—a stage that could be targeted
for intervention in patients with a high likelihood of
developing dementia within 2–3 years.
Despite these new developments, the main focus
remained on AD. Throughout the 1990s, a consensus
had taken shape among clinicians and researchers in the
field that plaques and tangles eventually cause AD, and
that AD is the predominant cause of dementia among
the elderly.9 A major assumption that was made in 100s
of published studies, and which prevailed until recently,
was that most patients had either vascular dementia or
AD, but not both.
The Nun Study in 1997 reignited interest in the impor-
tance of adequate blood supply to the brain (Figure 1)
and the role of vascular disease and stroke in late-life
dementia.27,28 Examination of the brains of elderly nuns
revealed a distinct dissociation between the load of AD
plaques and tangles and the degree of cognitive impair-
ment that was evident before their deaths. It became
clear from the Nun Study that lacunar strokes magni-
fied the effects of any given load of AD pathology, and
vice versa. A large, multicenter, longitudinal study in
England and Wales published in 2001 also showed that
most patients with late-onset dementia had a mixture
of cerebro vascular and AD-type lesions.29 Patients who
had either mild subclinical (silent) AD pathology or mild
sub clinical cerebrovascular disease seemed to remain free
of dementia for a longer period of time than those who
had a combination of these two pathologies.23,27,28,30
Numerous other clinical, pathological and radio logical
findings have confirmed a close link between vascular
risk factors, the development of strokes (ranging from
microscopic to large), and late-onset cognitive decline
(Box 1).28,31,32 Some longitudinal epidemiological studies
that monitored participants from midlife to late life
revealed that a combination of risk factors could increase
the likelihood of dementia more than 16-fold.33 As vas-
cular lesions could range from a few microscopic infarcts
or mild white matter c hanges to large strokes and marked
atrophy (with varying contribution to cognitive decline),
Figure 1 | High density of blood vessels in the brain. To reveal the density of
cerebral blood vessels, the brain was injected with a plastic emulsion and the
parenchymal tissue was dissolved. As this specimen illustrates, the brain is a
highly vascular organ. Thus, vascular risk factors that impede adequate cerebral
flow can substantially impair all aspects of cognitive function with aging.
Permission obtained from Wolters Kluwer Health © Zlokovic, B. V. &
Apuzzo, M. L. J. Strategies to circumvent vascular barriers of the central nervous
system. Neurosurgery 43(4), 877–878 (1998).
Box 1 | Factors associated with cognitive function late in life
The summary below is semi-quantitative: performing a quantitative meta-analysis
for these associations remains challenging owing to marked heterogeneity in
selection of participants for longitudinal and interventional studies, and the wide
range of outcome measures selected in individual reports.28,30,32,33,49,52,53,58,60,65,67,
Factors associated with better cognitive function with aging
Strong associations: education, walking (physical activity)
Moderate association: leisure activities
Mild associations: alcohol (one or two glasses per day), challenging occupation,
eating fish, eating fruit and vegetables
Factors associated with worse cognitive function with aging
Strong associations: apolipoprotein E ε4 genotype, silent or large strokes,
midlife hypertension, obesity
Moderate associations: depression, diabetes, excessive alcohol use, high
homocysteine levels, high midlife cholesterol levels, obstructive sleep apnea
Mild associations: chronic stress, head trauma, impaired insulin response, low
folate and vitamin B12 levels, smoking
Nature Reviews
voluME 5
no consensus could be reached for a widely accepted
diagnosis of vascular dementia.20
With the realization that even small vascular lesions
have profound effects on the brain and can substantially
modify the link between AD pathology and dementia,
some researchers began to question the accuracy of AD
diagnoses in population studies.34 In a retrospective
analysis, when ‘pure AD’ was defined as dementia in the
absence of any vascular risk factors (as a way of excluding
individuals with coexisting vascular lesions), the number
of cases previously diagnosed with AD dropped by more
than 50%.34 In parallel, examination of brains of patients
with late-onset dementia revealed that the link between
plaques and tangles and symptoms of clinical dementia
was strong in patients younger than 75 years and poor
for those older than 90 years.35,36 Thus, skepticism grew
over the simplistic view that the common form of late-
life dementia among the oldest old is primarily attribut-
able to the accumulation of plaques and tangles in the
2007 to the present day
An important study from 2007 confirmed that the load
of AD plaques and tangles in elderly individuals with
dementia could be similar to that found in cognitively
healthy individuals without dementia (30% and 24.2%,
respectively), and that the brains of patients with
dementia often had a combination of AD lesions, vas-
cular pathology and Lewy bodies.41 A subsequent study
from the same group, along with several other reports,
showed that the presence of multiple pathologies sig-
nificantly increases the likelihood of conversion from
cognitively normal to MCI, and from MCI to demen-
tia (Box 2, Supplementary Table 1 online).36,38,42–47 The
odds ratio for a clinically probable AD diagnosis was 4.7
in the presence of AD pathology alone, but it increased
to 16.2 in the presence of a combination of AD patho-
logy, infarcts and Lewy bodies.44 Another study showed
that AD lesions fully account for dementia among the
‘young old’ (60–80 years) but not among the oldest old
(beyond 90 years).46 In the Honolulu–Asia Aging Study,
only 18.6% of elderly patients with a clinical diagnosis
of dementia had pure AD pathology.43 These and other
independent clinicopathological studies concluded that
late-life dementia reflects the convergence of several dif-
ferent pathological processes on the brain areas that are
important for memory and higher cognitive function;
that is, the cortex and hippocampus.48
Two studies reported in 2009 have highlighted the size
of the cortex and hippocampus as the main determi-
nants of late-life dementia. Erton-Lyons and colleagues
analyzed the brains of 36 individuals (12 with normal
cognitive function and 24 with a diagnosis of AD before
death), all of whom met the standard pathological cri-
teria for AD (Braak stage V or VI, and moderate to fre-
quent neuritic plaques according to the CERAD criteria.
Larger cortical and hippocampal volumes were associ-
ated with preserved cognition, even in the presence of
a high burden of AD lesions.47 Another clinicopatho-
logical study showed that the load of neuritic plaques in
the hippocampus rises with each decade of life beyond
the age of 70 years in individuals without dementia,
but decreases in those with dementia.42 The degree of
atrophy in the cortex and hippocampus remained the
most consistent correlate of dementia in the last decades
of life.
Box 2 | Neuropathological findings in individuals aged >80 years
Crystal et al. (2000)38
Many patients >80 years with dementia do not meet pathological criteria for
Alzheimer disease (AD), dementia with Lewy bodies (DLB) or frontotemporal
Incidence of non-AD pathology progressively increases beyond 70 years of age,
approaching 50% in nonagenarians
White et al. (2005)36
Japanese American men—especially those diagnosed with AD—showed
considerable discrepancies between clinical diagnosis and pathological findings
Late-life cognitive impairment and dementia often involve a combination of AD,
microvascular lesions, cortical Lewy bodies, hippocampal sclerosis, and diffuse
atrophy and/or neuronal loss
Schneider et al. (2007)41
Patients with multiple pathologies were three times more likely to exhibit
dementia than those with only one pathology
Mixed brain pathologies accounted for most dementia cases in patients aged
>80 years
Sonnen et al. (2007)45
Independent correlates of dementia include Braak stage V or VI, more than two
infarcts, and Lewy bodies
Interventions to reduce infarct risk might prevent or delay dementia onset
Haroutunian et al. (2008)46
Individuals aged >80 years old show different neuropathological features of
dementia from septuagenarians
Infarcts, DLB, hippocampal sclerosis, or factors yet to be identified, might
contribute to dementia in people aged >80 years
Savva et al. (2009)42
Neocortical and hippocampal atrophy was a better predictor of dementia than
was AD pathology
Therapeutic interventions targeting AD pathology might be effective for
septuagenarians but not octagenarians or nonagenarians
White (2009)43
Certain lesion combinations, such as AD plus infarcts, were more closely
associated with dementia than were individual pathological lesions
Infarcts were the dominant finding in many cases, perhaps because the
participants were elderly men
Schneider et al. (2009)44
Odds ratios of clinically probable AD increase significantly when different
neuropathological lesions are combined
Most elderly people with clinically diagnosed AD exhibit mixed pathologies
Erten-Lyons et al. (2009)47
Large hippocampal and total brain volume allows elderly people to remain
cognitively healthy despite a high AD pathology burden
Nature Reviews
With the goal of finding effective strategies for preven-
tion and treatment of cognitive impairment with aging,
new avenues of research are now focusing on all the
patho logical and physiological processes that can poten-
tially affect the cortex and hippocampus.47 Some midlife
risk factors are associated with marked late-life dementia
and with a smaller cortex and hippocampus.33 Extensive
research is now underway to elucidate the mechanisms
through which midlife factors might modulate the likeli-
hood of dementia in the last decades of life (Box 1), and
to establish how vascular conditions might interact with
each other and with neurodegenerative processes such
as AD.49
The dynamic polygon hypothesis
Late-life dementia, in contrast to early-onset AD, can
reflect damage to the brain by a wide range of vascular
and nonvascular factors (Figure 2). To varying degrees,
obesity, hypertension, diabetes, atrial fibrillation, high
cholesterol, congestive heart failure, inflammatory con-
ditions (such as lupus), obstructive sleep apnea (OSA),
education, exercise, chronic stress, and depression can all
alter brain architecture transiently or permanently at the
cellular or macroscopic level (Figure 3).50–61 This broad
view, integrating brain function, cardiovascular function,
neuroplasticity, and eventual development of cognitive
impairment in late life, highlights a dynamic inter-
action between genetically determined, non modifiable
pathological processes, and processes that are potentially
reversible (for example, environmental exposures). This
model, which we have termed the ‘dynamic polygon
hypothesis’, departs from a primary focus on plaques
and tangles (Figure 3). For example, small-vessel disease
and AD pathology are both linked to loss of neurons in
the CA1 area of the hippocampus.62 In turn, high blood
pressure, diabetes, obesity, smoking, and sedentary
lifestyle are prominent triggers for small-vessel disease
and might, therefore, influence the ultimate size of the
hippocampus. Moreover, an individual vascular factor
such as obesity could have nonlinear and heterogeneous
consequences that affect the brain through numerous
mediators, including hypertension, infarcts and white
matter changes, as well as increased sympathetic acti-
vity, interleukins, neurotrophins, growth factors, adipo-
cytokines, adipose-derived leptin, and satiety factors (see
Hypertension—a prominent feature of obesity—is
likely to lead to atrophy in the cortex and hippocampus
through vascular lesions; that is, atherosclerosis, white
matter changes, or infarcts.64 OSA, another condition
that is commonly associated with obesity, probably
causes marked cortical atrophy through chronic noctur-
nal cerebral hypoxia over a period of several decades.65
The severity of cortical atrophy in patients with OSA
approaches 18% in the frontal lobes, hippocampus, para-
hippocampal gyri, parietal cortex, and cingulate cortex—
many of the same cortical areas that are known to be
affected by AD pathology.66
Midlife obesity might lower the threshold for late-
life dementia through mechanisms other than hyper-
tension and/or hypoxic-induced brain atrophy due to
OSA.67 In a study that controlled for high blood pres-
sure, myo cardial infarction and strokes, these factors
did not fully explain the strong association between
midlife excessive abdominal fat accumulation and cog-
nitive decline 30 years later.67 Other potential mediators
include insulin resistance, insulin-like growth factor,
inflammation, ghrelin, leptin, or other as yet unidenti-
fied hormones.68–70 High insulin levels could suppress the
insulin-degrading enzyme and lead to higher levels of Aβ
oligomers, as well as reducing Aβ clearance and increas-
ing tau hyper phosphorylation.69,70 In the setting of meta-
bolic syndrome or diabetes, obesity can heighten levels
Cortical atrophy
Plaques and tangles
White matter abnormalities?
Obstructive sleep apnea
Diabetes mellitus
Traumatic brain injury
Congestive heart failure
Hippocampal atrophy
Hippocampal sclerosis
Obstructive sleep apnea
White matter abnormalities?
Plaques and tangles
Chronic depression or stress
Reduced cerebral blood ow
Diabetes mellitus
Cerebral amyloid angiopathy
White matter abnormalities
Diabetes mellitus
Congestive heart failure
Kidney or liver disease?
Thyroid disease
Vitamin B12 deciency Lacunar stroke
Diabetes mellitus
High cholesterol?
Figure 2 | Factors that could cause brain atrophy and cognitive impairment. Blood
vessels are shown in red. Cortical and hippocampal volumes correlate well with
the degree of cognitive decline and dementia. Some processes lead directly to
atrophy in these structures, whereas others contribute to white matter
abnormalities and strokes (cortical or subcortical, small or large), and might
indirectly hasten volume loss in the cortex and hippocampus. Further
investigations will be required to ascertain the relative contributions of the various
processes—especially those indicated by question marks—to brain atrophy and
cognitive impairment.
Nature Reviews
voluME 5
of inflammatory processes in the brain and, either inde-
pendently or in conjunction with degenerative processes,
modulate the size of the cortex and hippocampus.58,71 The
obesity–dementia link, therefore, illustrates how various
vascular and nonvascular processes might interact in a
dynamic and complex network of factors encompassing
both genes and environment.
The apolipoprotein E ε4 (APOE ε4) genotype, a major
genetic susceptibility factor for AD, increases the risk of
dementia between twofold and 12-fold.72 The presence of
APOE ε4 lowers the efficiency of cellular repair mecha-
nisms, reduces the clearance of plaques and tangles in the
brain, and decreases gray matter volume.73,74 The impact
of APOE ε4 on the brain is not limited to plaques and
tangles, however, as the Apo-E4 protein can interact with
and directly modify the severity of vascular conditions
such as hypercholesteremia. Apo-E4 has also been shown
to directly interact with the LDL cholesterol receptor.75
Other forms of Apo-E might also have roles in both
AD and non-AD processes. The APOE ε2 genotype
is believed to exert neuroprotective effects through a
lowering of levels of Aβ in the brain. A recent study,
however, showed that elderly individuals beyond the age
of 90 years who possess APOE ε2 tend to remain cog-
nitively intact even in the presence of a high burden of
plaques and tangles, suggesting involvement of non-AD-
related neuroprotective mechanisms against dementia.76
Thus, presence of the APOE ε4 or APOE ε2 allele might
alter the course of cognitive decline with aging through
changes in levels of both AD and vascular injury, as well
as through modifications in compensatory repair mecha-
nisms that deal with both types of pathology.
In contrast to early-onset AD, which cannot be modi-
fied with any known interventions, late-life dementia
might be preventable. Some preliminar y—and still
controversial—findings indicate that a number of pro-
tective factors, including exercise, education, participat-
ing in brain-stimulating activity, having a cognitively
challenging occupation, eating an antioxidant-rich diet,
and consuming fish or omega-3 fatty acid supplements,
are associated with improved cognitive function and a
reduced risk of late-life dementia (Box 1).30 These factors
are believed to increase synaptic density in the brain (that
is, create stronger cognitive reserve), perhaps in part
through angiogenesis and in part through increasing
levels of brain-derived neurotrophic factor (BDNF).77,78
In animals, exercise selectively increases BDNF gene
expression in the hippocampus and reduces the load of
amyloid plaques throughout the brain.79,80
Results from studies of neuroplasticity in the adult
animal brain are beginning to be replicated in humans.
Sensitive MRI measurements reveal that the size of the
Apolipoprotein E
Amyloid plaques
Low cognitive
The amyloid cascade hypothesis
Missense mutations in APP, PS1 or PS2 genes
Increased Aβ42 production and accumulation
Aβ42 oligomerization and deposition as diffuse plaques
Subtle effects of Aβ oligomers on synapses
Microglial and astrocytic activation
(for example, by complement factors, cytokines)
Progressive synaptic and neuritic injury
Altered neuronal ionic homeostasis; oxidative injury
Widespread neuronal and neuritic dysfunction
and cell death with transmitter decits
Altered kinase and phosphatase activities Tangles
Alzheimer disease
aThe dynamic polygon hypothesis
Figure 3 | Models to account for late-life cognitive impairment. a | According to the amyloid cascade hypothesis, a chain of
processes that begins with plaques, which in turn cause the formation of tangles, leads to synaptic loss and dementia. In
this model, no distinction is made between early-onset and late-life dementia. b | According to the dynamic polygon
hypothesis, early-onset dementia results from toxicity associated with aggregation of plaques and tangles (although not
necessarily in a linear fashion). Late-life dementia, on the other hand, is considered to be a more complex disease: a set
of pathological processes that affect the size of the cortex and hippocampus (for example, tauopathy, inflammation,
synucleinopathy, amyloid aggregation, and strokes) is interlinked with positive or negative consequences of environmental
exposures (for example, education, exercise, leisure activities, or obesity). In this model, plaques and tangles are two
components among a larger set of factors that modulate synaptic density and the size of the cortex and hippocampus,
and eventually determine the level of cognitive agility or frailty toward the end of life. More studies are needed to establish
which model best fits the existing data in this field. Abbreviations: Aβ, amyloid-β; APP, amyloid precursor protein;
PS, presenilin.
Nature Reviews
human cortex and hippocampus can expand signifi-
cantly with exercise or intense brain stimulation. In a
placebo-controlled study, healthy elderly people who
participated in a walking program 3 days a week for
6 months experienced a 3% increase in cortical brain
volume in their frontal lobes, as determined by MRI
findings before and after the exercise program.81,82 In
medical students preparing for their national certifica-
tion examinations, intensive brain stimulation over a
period of 3 months was shown to increase the volume of
the cortex and hippocampus.83 These observations might
partly account for resistance to injury triggered by AD
pathology, which is observed in individuals with high
levels of fitness and cognitive reserve; these individuals
could have optimal cerebral blood flow in their brains
and a relatively high density of synapses in their cortex
and hippocampus.84,85
In summary, the primary focus on AD pathology to
account for late-life dementia is being superseded by
a focus on understanding potentially modifiable pro-
cesses.86 According to the dynamic polygon hypothesis,
a balance of positive and negative environmental factors,
together with a balance of positive and negative genetic
factors, seems to affect the brain throughout early life
and midlife to determine the degree of cognitive agility
or impairment in late life (Box 1, Figure 2).84,85 These
factors increase or decrease cerebral blood flow, oxidative
stress, inflammation, insulin-signaling components, size
and frequency of infarcts, and concentrations of growth
factors, cortisol or other hormones.
Preliminary reports suggest that the load of amyloid
plaques, which is determined to some extent by genetic
background, can potentially be altered by environ-
mental factors such as exercise, traumatic brain injury or
diet.80,87–89 In animal studies, consumption of apple juice
or curcumin seemed to lower amyloid levels.90,91 Thus,
like the degree of microvascular disease in the brain,
amyloid levels might depend on lifestyle choices. These
observations have provided a strong impetus to establish
the profile of risk factors for dementia in late life and
to initiate early preventive strategies in individuals with
a high likelihood of developing cognitive decline with
aging.92 These preventive strategies would aim to modify
both vascular and AD pathology in the brain through
changes in lifestyle and use of disease-modifying drugs.
Future prospects
Ongoing trials
Over the past two decades, important refinements in
defining the pathophysiology of dementia have paved
the way for developing effective preventive and treat-
ment strategies. In particular, our understanding of the
factors that could cause brain atrophy in late life has
expanded substantially over the past 2–3 years. New
imaging techniques, such as PET scans using 11C-labeled
Pittsburgh compound B (PIB) have unveiled the distribu-
tion of amyloid in the brain in patients with or without
dementia.93 Studies are now in progress that correlate
PIB imaging data with cerebrospinal fluid findings.94
Standard MRI techniques have enabled us to establish
that hippocampal volume is an excellent predictor of
further deterioration in patients with MCI and demen-
tia.95,96 New MRI techniques, such as diffusion tensor
imaging, are beginning to reveal the degree and relevance
of white matter changes with aging.97
More than 100 clinical trials of approaches to prevent
and treat patients with varying degrees of cognitive
impairment are currently underway.98,99 Drugs being
tested include immune-related medications (for example,
immunoglobulin or vaccines), inhibitors of amyloid and
tau, and nerve-growth-factor-like agents.99,100 Despite the
fact that an initial active immunization trial to reduce
levels of amyloid in patients with dementia was stopped
owing to encephalitic complications, and the preliminary
(and incomplete) results were disappointing, passive
immunization clinical trials are still in progress.101,102
Research is also underway to detect ‘cognitively normal’
individuals at risk of late-life dementia at the pre-
symptomatic stage, and to determine the ideal disease-
modifying medications for these individuals.60 Treatment
of vascular risk factors is associated with a reduced rate
of cognitive decline, and preventive strategies in this area
are starting to move from ideas and suggestions to real-
life recommendations for clinical practice.92 The ultimate
goal is to determine early-life or midlife interventions,
such as factors that enhance cognitive reserve and synap-
tic density, that would enable people to remain cogni-
tively intact in their 80s and 90s, even if they develop a
high load of AD pathology in their brains (Figure 3b).
Remaining questions
Serial PIB and MRI studies in normal individuals and
those with MCI or AD demonstrate a clear dissociation
between the annual rate of amyloid deposition and the
rate of brain atrophy and neurodegeneration, consistent
with previous observations that progression of clinical
symptoms in dementia is not coupled to amyloid depo-
sition.103,104 Consequently, is amyloid still a valid target
for the treatment of elderly individuals with late-life
dementia and, if so, should research focus on the natural
compensatory mechanisms that confront amyloid, on
amyloid itself, or on both?105 Alternatively, should the
focus shift toward the dissolution of tau aggregates, given
that the density of neurofibrillary tangles correlates more
closely with the degree of cognitive impairment than
does amyloid pathology?39
Strong evidence in support of the amyloid cascade
hypothesis links toxic soluble amyloid dimers and oli-
gomers to AD.106 However, attempts to demonstrate a
cascade process from amyloid aggregation to tangle-
related neuronal dysfunction have been disappoint-
ing, and no convincing causal link has been established
between plaques and tangles.102 These findings have
called the amyloid cascade into question, and investiga-
tors must now consider how, and indeed whether, this
hypothesis should be tested further.102,107–111
Nature Reviews
voluME 5
A body of literature—albeit controversial—suggests
that anti-inflammatory and antioxidant medications can
lead to better cognitive function and a lower risk of cog-
nitive impairment with aging.112 Future studies should
address whether inflammation is a common denomi-
nator in AD, dementia with Lewy bodies, white matter
changes and infarcts, and whether late-life dementia is a
primary neuroinflammatory condition that is aggravated
by other coexisting pathologies.
Another important issue to address is the
relationship—if any—between late-life dementia and
early-onset AD. Is the common form of late-life demen-
tia simply an extension of early-onset AD, or is it a sepa-
rate condition, perhaps triggered by genes and proteins
that have yet to be discovered?40,46 Atrophy in the cortex
and hippocampus correlates better with the severity and
progression of late-life dementia than do white matter
changes, infarcts, plaques, tangles or Lewy bodies.47 The
pathogenetic basis of this atrophy is currently unclear:
could it result from processes other than strokes, AD,
inflammation, and Lewy body pathology? Given the
large number of clinicopathological studies that point to
the presence of multiple classes of pathology in brains of
the oldest old (with or without dementia), a case could
be made for re-evaluating the diagnostic criteria for AD
in patients beyond the age of 80 years.
Numerous midlife risk factors have been associated
with late-life dementia, ranging from early-life educa-
tion, smoking, choice of hobbies and head trauma, to the
presence of medical conditions such as obesity (Box 1).
The pathophysiological mechanisms that underlie these
associations, and the factors that are most relevant for
identifying targets for early intervention, remain to
be determined. Future research should also focus on
which biomarkers are the best candidates for detect-
ing presymptomatic patients who are at risk of late-life
Given that a number of environmental risk factors
have been implicated in late-life dementia, and consider-
ing that rates of obesity and hypertension are rising at
a rapid rate among children, efforts to prevent demen-
tia should perhaps start early in life. Numerous studies
have examined a possible role for omega-3 fatty acids in
reducing the risk of dementia, but the results obtained
to date have been heterogeneous.89 One explanation for
the marked variation in findings from dozens of studies
in this field—and perhaps the explanation for the failure
of most clinical trials in patients with AD—could be the
selection and monitoring of participants with various
brain pathologies, all of whom were diagnosed with AD.
Given the observed heterogeneity of the pathological
process in patients with cognitive decline, candidates for
clinical trials should perhaps be selected more rigorously,
and be subdivided into groups with primary AD, primary
vascular pathology, or primary mixed pathology.
The last question is one of terminology. Some
researchers consider the word ‘dementia’ to be obsolete
and derogatory.113 Should we replace this diagnostic
terminology with a more respectful label such as ‘cog-
nitive impairment? The progressive deterioration in
cognitive function might be labeled on a scale ranging
from MCI, which already has its own established cri-
teria, through intermediate cognitive decline (patients
who have developed difficulty in performing instrumen-
tal activities of daily living such as shopping), to severe
cognitive impairment (patients who have developed dif-
ficulties performing their basic activities of daily living
such as managing personal hygiene).
The dominant conceptual views of late-life memory
loss and confusion have shifted considerably through-
out history. These symptoms were considered ‘normal’
as early as 700 BC, as signs of being ‘possessed by evil’
in the early Renaissance period, as evidence of ‘harden-
ing of blood vessels’ throughout most of the 20th
century, and as manifestations of AD since the 1990s.
Clinicopathological studies conducted over the past few
years agree that most individuals with cognitive impair-
ment over the age of 80 years have a mixture of several
coexisting abnormalities, and only a small proportion
have pure pathology (for example, dementia with Lewy
bodies, AD, or hippocampal sclerosis) in their brains.
Technological advances in brain imaging, along with
advances in the field of neuroscience, have opened up
new possibilities for studying the brain with aging, and
have provided an opportunity for researchers to ask
more-definitive questions. An enormous amount of
progress has been made, but more research is required
before specific recommendations to prevent late-life
dementia can be formulated.
Alois Alzheimer was one of the first scientists to exten-
sively describe the importance of vascular lesions in
brain atrophy in late-life dementia (and to de-emphasize
the relevance of amyloid plaques). It is noteworthy that
a century later, reduction of vascular risk factors (along
with improvement of physical and cognitive fitness)
remains the most reasonable recommendation that we
can offer to members of the public who strive toward
better brain health and successful aging.28,33,92,114,115
Review criteria
MEDLINE was searched for articles published in
English from January 1980 to August 2009, with the
following keywords: “dementia”, “cognitive impairment”,
“memory”, “Alzheimer disease”, “amyloid hypothesis”,
“aging” and “clinicopathologic”. Abstracts were reviewed,
and papers with a focus on the link between clinical
manifestation of cognitive decline and diagnostic
criteria for dementia, as well as those with an emphasis
on historical development of concepts in the field of
dementia, were further analyzed in detail. In addition,
the reference sections of these articles, along with
relevant chapters in standard neuropathology textbooks,
were consulted.
Nature Reviews
1. Berchtold, N. C. & Cotman, C. W. Evolution in the
conceptualization of dementia and Alzheimer’s
disease: Greco-Roman period to the 1960s.
Neurobiol. Aging 19, 173–189 (1998).
2. Mast, H., Tatemichi, T. K. & Mohr, J. P. Chronic
brain ischemia: the contributions of Otto
Binswanger and Alois Alzheimer to the
mechanisms of vascular dementia. J. Neurol. Sci.
132, 4–10 (1995).
3. Alzheimer, A. On peculiar cases of disease at
higher age [German]. Neurologie und Psychiatrie
4, 256–286 (1911).
4. Ballenger, J. F. Progress in the history of
Alzheimer’s disease: the importance of context.
J. Alzheimers Dis. 9, 5–13 (2006).
5. Wilson, D. C. The pathology of senility. Am. J.
Psychiatry 111, 902–906 (1955).
6. Hachinski, V. C., Lassen, N. A. & Marshall, J.
Multi-infarct dementia. A cause of mental
deterioration in the elderly. Lancet 2, 207–210
7. Blessed, G., Tomlinson, B. E. & Roth, M. The
association between quantitative measures of
dementia and of senile change in the cerebral
grey matter of elderly subjects. Br. J. Psychiatry
114, 797–811 (1968).
8. Hardy, J. A. & Higgins, G. A. Alzheimer’s disease:
the amyloid cascade hypothesis. Science 256,
184–185 (1992).
9. Cummings, J. L. Alzheimer’s disease. N. Engl. J.
Med. 351, 56–67 (2004).
10. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of
Alzheimer’s disease: progress and problems on
the road to therapeutics. Science 297, 353–356
11. McKhann, G. et al. Clinical diagnosis of
Alzheimer’s disease: report of the NINCDS-ADRDA
Work Group under the auspices of Department of
Health and Human Services Task Force on
Alzheimer’s Disease. Neurology 34, 939–944
12. American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders, 4th edn
(American Psychiatric Association, Washington,
D. C., 1994).
13. Khachaturian, Z. S. Diagnosis of Alzheimer’s
disease. Arch. Neurol. 42, 1097–1105 (1985).
14. Mirra, S. S. et al. The Consortium to Establish a
Registry for Alzheimer’s Disease (CERAD). Part II.
Standardization of the neuropathologic
assessment of Alzheimer’s disease. Neurology
41, 479–486 (1991).
15. Jellinger, K. A. Criteria for the neuropathological
diagnosis of dementing disorders: routes out of
the swamp? Acta Neuropathol. 117, 101–110
16. Braak, H. & Braak, E. Neuropathological stageing
of Alzheimer-related changes. Acta Neuropathol.
82, 239–259 (1991).
17. [No authors listed] Consensus recommendations
for the postmortem diagnosis of Alzheimer’s
disease. The National Institute on Aging, and
Reagan Institute Working Group on Diagnostic
Criteria for the Neuropathological Assessment of
Alzheimer’s Disease. Neurobiol. Aging 18 (4
Suppl.), S1–S2 (1997).
18. McKeith, I. G. Dementia with Lewy bodies. Br. J.
Psychiatry 180, 144–147 (2002).
19. McKeith, I. G. et al. Consensus guidelines for the
clinical and pathologic diagnosis of dementia with
Lewy bodies (DLB): report of the Consortium on
DLB International Workshop. Neurology 47,
1113–1124 (1996).
20. Hachinski, V. et al. National Institute of
Neurological Disorders and Stroke-Canadian
Stroke Network vascular cognitive impairment
harmonization standards. Stroke 37, 2220–2241
21. Relkin, N., Marmarou, A., Klinge, P., Bergsneider,
M. & Black, P. M. Diagnosing idiopathic normal-
pressure hydrocephalus. Neurosurger y 57 (3
Suppl.), S4–S16 (2005).
22. Yoshimura, M. et al. Dementia in cerebral amyloid
angiopathy: a clinicopathological study. J. Neurol.
239, 441–450 (1992).
23. Nagy, Z. et al. The effects of additional pathology
on the cognitive deficit in Alzheimer disease. J.
Neuropathol. Exp. Neurol. 56, 165–170 (1997).
24. Erkinjuntti, T., Ostbye, T., Steenhuis, R. &
Hachinski, V. The effect of different diagnostic
criteria on the prevalence of dementia. N. Engl. J.
Med. 337, 1667–1674 (1997).
25. Petersen, R. C. et al. Mild cognitive impairment:
clinical characterization and outcome. Arch.
Neurol. 56, 303–308 (1999).
26. Petersen, R. C. & Negash, S. Mild cognitive
impairment: an overview. CNS Spectr. 13, 45–53
27. Snowdon, D. A. et al. Brain infarction and the
clinical expression of Alzheimer disease. The Nun
Study. JAMA 277, 813–817 (1997).
28. Viswanathan, A., Rocca, W. A. & Tzourio, C.
Vascular risk factors and dementia: how to move
forward? Neurology 72, 368–374 (2009).
29. Neuropathology Group. Medical Research
Council Cognitive Function and Aging Study.
Pathological correlates of late-onset dementia
in a multicentre, community-based population in
England and Wales. Neuropathology Group of the
Medical Research Council Cognitive Function and
Ageing Study (MRC CFAS). Lancet 357, 169–175
30. Fotuhi, M. Preserving memory: tips to help baby
boomers stay in the game. Practical Neurology
March/April, [ED: is this volume number
correct?] 34–40 (2009).
31. Troncoso, J. C. et al. Effect of infarcts on dementia
in the Baltimore longitudinal study of aging. Ann.
Neurol. 64, 168–176 (2008).
32. Kivipelto, M. et al. Obesity and vascular risk
factors at midlife and the risk of dementia and
Alzheimer disease. Arch. Neurol. 62, 1556–1560
33. Kivipelto, M. et al. Risk score for the prediction of
dementia risk in 20 years among middle aged
people: a longitudinal, population-based study.
Lancet Neurol. 5, 735–741 (2006).
34. Aguero-Torres, H., Kivipelto, M. & von Strauss, E.
Rethinking the dementia diagnoses in a
population-based study: what is Alzheimer’s
disease and what is vascular dementia? A study
from the Kungsholmen project. Dement. Geriatr.
Cogn. Disord. 22, 244–249 (2006).
35. Prohovnik, I. et al. Dissociation of
neuropathology from severity of dementia in late-
onset Alzheimer disease. Neurology 66, 49–55
36. White, L. et al. Recent clinical–pathologic
research on the causes of dementia in late life:
update from the Honolulu–Asia Aging Study.
J. Geriatr. Psychiatry Neurol. 18, 224–227
37. Schmitt, F. A. et al. “Preclinical” AD revisited:
neuropathology of cognitively normal older adults.
Neurology 55, 370–376 (2000).
38. Crystal, H. A. et al. The relative frequency of
“dementia of unknown etiology” increases with
age and is nearly 50% in nonagenarians. Arch.
Neurol. 57, 713–719 (2000).
39. Nelson, P. T., Braak, H. & Markesbery, W. R.
Neuropathology and cognitive impairment in
Alzheimer disease: a complex but coherent
relationship. J. Neuropathol. Exp. Neurol. 68, 1–14
40. Korczyn, A. D. The amyloid cascade hypothesis.
Alzheimers Dement. 4, 176–178 (2008).
41. Schneider, J. A., Arvanitakis, Z., Bang, W. &
Bennett, D. A. Mixed brain pathologies account
for most dementia cases in community-dwelling
older persons. Neurology 69, 2197–2204
42. Savva, G. M. et al. Age, neuropathology, and
dementia. N. Engl. J. Med. 360, 2302–2309
43. White, L. Brain lesions at autopsy in older
Japanese-American men as related to cognitive
impairment and dementia in final years of life:
a summary report from the Honolulu–Asia Aging
Study. J. Alzheimers Dis. doi:10.3233/
44. Schneider, J. A., Arvanitakis, Z., Leurgans, S. E. &
Bennett, D. A. The neuropathology of probable
Alzheimer disease and mild cognitive impairment.
Ann. Neurol. 66, 200–208 (2009).
45. Sonnen, J. A. et al. Pathological correlates of
dementia in a longitudinal, population-based
sample of aging. Ann. Neurol. 62, 406–13
46. Haroutunian, V. et al. Role of the neuropathology
of Alzheimer disease in dementia in the oldest-
old. Arch. Neurol. 65, 1211–1217 (2008).
47. Erten-Lyons, D. et al. Factors associated with
resistance to dementia despite high Alzheimer
disease pathology. Neurology 72, 354–360
48. Jagust, W. J. et al. Neuropathological basis of
magnetic resonance images in aging and
dementia. Ann. Neurol. 63, 72–80 (2008).
49. Helzner, E. P. et al. Contribution of vascular risk
factors to the progression in Alzheimer disease.
Arch. Neurol. 66, 343–348 (2009).
50. Korf, E. S., White, L. R., Scheltens, P. &
Launer, L. J. Midlife blood pressure and the risk of
hippocampal atrophy: the Honolulu Asia Aging
Study. Hyper tension 44, 29–34 (2004).
51. Du, A. T. et al. Age effects on atrophy rates of
entorhinal cortex and hippocampus. Neurobiol.
Aging 27, 733–740 (2006).
52. Sapolsky, R. M. Chickens, eggs and hippocampal
atrophy. Nat. Neurosci. 5, 1111–1113 (2002).
53. Sapolsky, R. M. Depression, antidepressants, and
the shrinking hippocampus. Proc. Natl Acad. Sci.
USA 98, 12320–12322 (2001).
54. Knecht, S. et al. Atrial fibrillation in stroke-free
patients is associated with memory impairment
and hippocampal atrophy. Eur. Heart J. 29,
2125–2132 (2008).
55. den Heijer, T. et al. Type 2 diabetes and atrophy of
medial temporal lobe structures on brain MRI.
Diabetologia 46, 1604–1610 (2003).
56. Appenzeller, S., Carnevalle, A. D., Li, L. M.,
Costallat, L. T. & Cendes, F. Hippocampal atrophy
in systemic lupus er ythematosus. Ann. Rheum.
Dis. 65, 1585–1589 (2006).
57. Tate, D. F. & Bigler, E. D. Fornix and hippocampal
atrophy in traumatic brain injury. Learn. Mem. 7,
442–446 (2000).
58. Biessels, G. J., De Leeuw, F. E., Lindeboom, J.,
Barkhof, F. & Scheltens, P. Increased cortical
atrophy in patients with Alzheimer’s disease and
type 2 diabetes mellitus. J. Neurol. Neurosurg.
Psychiatry 77, 304–307 (2006).
59. Sheline, Y. I., Gado, M. H. & Kraemer, H. C.
Untreated depression and hippocampal volume
loss. Am. J. Psychiatry 160, 1516–1518 (2003).
60. Barnes, D. E. et al. Predicting risk of dementia in
older adults. The late-life dementia risk index.
Neurology 73, 173–179 (2009).
Nature Reviews
voluME 5
61. Jefferson, A. L. et al. Lower cardiac output is
associated with greater white matter
hyperintensities in older adults with
cardiovascular disease. J. Am. Geriatr. Soc. 55,
1044–1048 (2007).
62. Kril, J. J., Patel, S., Harding, A. J. & Halliday, G. M.
Patients with vascular dementia due to
microvascular pathology have significant
hippocampal neuronal loss. J. Neurol. Neurosurg.
Psychiatry 72, 747–751 (2002).
63. Gustafson, D. Adiposity indices and dementia.
Lancet Neurol. 5, 713–720 (2006).
64. Wiseman, R. M. et al. Hippocampal atrophy, whole
brain volume, and white matter lesions in older
hypertensive subjects. Neurology 63, 1892–1897
65. Minoguchi, K. et al. Silent brain infarction and
platelet activation in obstructive sleep apnea. Am.
J. Respir. Crit. Care Med. 175, 612–617 (2007).
66. Macey, P. M. et al. Brain morphology associated
with obstructive sleep apnea. Am. J. Respir. Crit.
Care Med. 166, 1382–1387 (2002).
67. Whitmer, R. A. et al. Central obesity and increased
risk of dementia more than three decades later.
Neurology 71, 1057–1064 (2008).
68. Diano, S. et al. Ghrelin controls hippocampal
spine synapse density and memory performance.
Nat. Neurosci. 9, 381–388 (2006).
69. LeRoith, D. Insulin-like growth factors and the
brain. Endocrinology 149, 5951 (2008).
70. Neumann, K. F. et al. Insulin resistance and
Alzheimer’s disease: molecular links & clinical
implications. Curr. Alzheimer Res. 5, 438–447
71. Yaffe, K. et al. The metabolic syndrome,
inflammation, and risk of cognitive decline. JAMA
292, 2237–2242 (2004).
72. Farrer, L. A. et al. Effects of age, sex, and ethnicity
on the association between apolipoprotein E
genotype and Alzheimer disease. A meta-analysis.
APOE and Alzheimer Disease Meta Analysis
Consortium. JAMA 278, 1349–1356 (1997).
73. Tiraboschi, P. et al. Impact of APOE genotype on
neuropathologic and neurochemical markers of
Alzheimer disease. Neurolog y 62, 1977–1983
74. Drzezga, A. et al. Effect of APOE genotype on
amyloid plaque load and gray matter volume in
Alzheimer disease. Neurolog y 72, 1487–1494
75. Cheng, D. et al. Functional interaction between
APOE4 and LDL receptor isoforms in Alzheimer’s
disease. J. Med. Genet. 42, 129–131 (2005).
76. Berlau, D. J., Corrada, M. M., Head, E. &
Kawas, C. H. APOE ε2 is associated with intact
cognition but increased Alzheimer pathology in
the oldest old. Neurology 72, 829–834 (2009).
77. Cotman, C. W., Berchtold, N. C. & Christie, L. A.
Exercise builds brain health: key roles of growth
factor cascades and inflammation. Trends
Neurosci. 30, 464–472 (2007).
78. Helzner, E. P., Scarmeas, N., Cosentino, S.,
Portet, F. & Stern, Y. Leisure activity and cognitive
decline in incident Alzheimer disease. Arch.
Neurol. 64, 1749–1754 (2007).
79. Neeper, S. A., Gomez-Pinilla, F., Choi, J. &
Cotman, C. W. Physical activity increases mRNA
for brain-derived neurotrophic factor and nerve
growth factor in rat brain. Brain Res. 726, 49–56
80. Adlard, P. A., Perreau, V. M., Pop, V. &
Cotman, C. W. Voluntary exercise decreases
amyloid load in a transgenic model of Alzheimer’s
disease. J. Neurosci. 25, 4217–4221 (2005).
81. Erickson, K. I. et al. Training-induced plasticity in
older adults: effects of training on hemispheric
asymmetry. Neurobiol. Aging 28, 272–283 (2007).
82. Colcombe, S. J. et al. Aerobic exercise training
increases brain volume in aging humans.
J. Gerontol. A Biol. Sci. Med. Sci. 61, 1166–1170
83. Draganski, B. et al. Temporal and spatial
dynamics of brain structure changes during
extensive learning. J. Neurosci. 26, 6314–6317
84. Drachman, D. A. Aging of the brain, entropy, and
Alzheimer disease. Neurolog y 67, 1340–1352
85. Drachman, D. A. Nature or nurture: education and
the trajectory of declining brain function with age
and Alzheimer disease. Neurology 70, 1725–
1727 (2008).
86. McGurn, B., Deary, I. J. & Starr, J. M. Childhood
cognitive ability and risk of late-onset Alzheimer
and vascular dementia. Neurology 71,
1051–1056 (2008).
87. Ambrée, O. et al. Reduction of amyloid angiopathy
and Aβ plaque burden after enriched housing in
TgCRND8 mice: involvement of multiple
pathways. Am. J. Pathol. 169, 544–552 (2006).
88. Hartman, R. E. et al. Pomegranate juice
decreases amyloid load and improves behavior in
a mouse model of Alzheimer’s disease. Neurobiol.
Dis. 24, 506–515 (2006).
89. Fotuhi, M., Mohassel, P. & Yaffe, K. Fish
consumption, long-chain omega-3 fatty acids and
risk of cognitive decline or Alzheimer disease:
a complex association. Nat. Clin. Pract. Neurol. 5,
140–152 (2009).
90. Yang, L. et al. Inhibition of the expression of
prostate specific antigen by curcumin [Chinese].
Yao Xue Xue Bao 40, 800–803 (2005).
91. Chan, A. & Shea, T. B. Dietary supplementation
with apple juice decreases endogenous amyloid-β
levels in murine brain. J. Alzheimer s Dis. 16,
167–171 (2009).
92. Kivipelto, M. & Solomon, A. Preventive neurology:
on the way from knowledge to action. Neurology
73, 168–169 (2009).
93. Aizenstein, H. J. et al. Frequent amyloid
deposition without significant cognitive
impairment among the elderly. Arch. Neurol. 65,
1509–1517 (2008).
94. Mathis, C. A. Amyloid imaging fundings from
multicenter studies. Alzheimer’s & Dementia 5,
IC-S1-01 (2009).
95. van der Flier, W. M. & Scheltens, P. Alzheimer
disease: hippocampal volume loss and
Alzheimer disease progression. Nat. Rev. Neurol.
5, 361–362 (2009).
96. Driscoll, I. et al. Longitudinal pattern of regional
brain volume change differentiates normal aging
from MCI. Neurolog y 72, 1906–1913 (2009).
97. Salmond, C. H. et al. Diffusion tensor imaging in
chronic head injury survivors: correlations with
learning and memory indices. Neuroimage 29,
117–124 (2006).
98. Cummings, J. L., Doody, R. & Clark, C. Disease-
modifying therapies for Alzheimer disease:
challenges to early inter vention. Neurology 69,
1622–1634 (2007).
99. Salloway, S. & Correia, S. Alzheimer disease: time
to improve its diagnosis and treatment. Cleve.
Clin. J. Med. 76, 49–58 (2009).
100. Fillit, H., Hess, G., Hill, J., Bonnet, P. & Toso, C.
IV immunoglobulin is associated with a reduced
risk of Alzheimer disease and related disorders.
Neurology 73, 180–185 (2009).
101. Holmes, C. et al. Long-term effects of Aβ42
immunisation in Alzheimer’s disease: follow-up of
a randomised, placebo-controlled phase I trial.
Lancet 372, 216–223 (2008).
102. Hardy, J. The amyloid hypothesis for Alzheimer’s
disease: a critical reappraisal. J. Neurochem.
110, 1129–1134 (2009).
103. Jack, C. R., Jr et al. Serial PIB and MRI in normal,
mild cognitive impairment and Alzheimer’s
disease: implications for sequence of
pathological events in Alzheimer’s disease. Brain
132, 1355–1365 (2009).
104. Giannakopoulos, P. et al. Tangle and neuron
numbers, but not amyloid load, predict cognitive
status in Alzheimer’s disease. Neurology 60,
1495–1500 (2003).
105. Jagust, W. Will neuroimaging help us understand
Alzheimer’s disease? Alzheimer’s & Dementia 5,
IC-PL-01 (2009).
106. Shankar, G. M. et al. Amyloid-β protein dimers
isolated directly from Alzheimer’s brains impair
synaptic plasticity and memor y. Nat. Med. 14,
837–842 (2008).
107. Lee, H. G. et al. Amyloid-β in Alzheimer disease:
the null versus the alternate hypotheses.
J. Pharmacol. Exp. Ther. 321, 823–829 (2007).
108. Seabrook, G. R., Ray, W. J., Shearman, M. &
Hutton, M. Beyond amyloid: the next generation
of Alzheimer’s disease therapeutics. Mol. Interv.
7, 261–270 (2007).
109. Abbott, A. Neuroscience: the plaque plan. Nature
456, 161–164 (2008).
110. Small, S. A. & Duff, K. Linking Aβ and tau in late-
onset Alzheimer’s disease: a dual pathway
hypothesis. Neuron 60, 534–542 (2008).
111. Williams, M. Progress in Alzheimer’s disease drug
discovery: an update. Curr. Opin. Investig. Drugs
10, 23–34 (2009).
112. Fotuhi, M. et al. Better cognitive performance in
elderly taking antioxidant vitamins E and C
supplements in combination with nonsteroidal
anti-inflammatory drugs: the Cache County Study.
Alzheimers Dement. 4, 223–227 (2008).
113. Trachtenberg, D. I. & Trojanowski, J. Q. Dementia:
a word to be forgotten. Arch. Neurol. 65, 593–595
114. Hachinski, V. World Stroke Day 2008: “little
strokes, big trouble”. Stroke 39, 2407–2420
115. Hachinski, V. Shifts in thinking about dementia.
JAMA 300, 2172–2173 (2008).
116. Knopman, D. S. Go to the head of the class to
avoid vascular dementia and skip diabetes and
obesity. Neurology 71, 1046–1047 (2008).
117. Kivipelto, M. & Solomon, A. Cholesterol as a risk
factor for Alzheimer’s disease—epidemiological
evidence. Acta Neurol. Scand. Suppl. 185, 50–57
118. Kivipelto, M., Solomon, A., Blennow, K.,
Olsson, A. G. & Winblad, B. The new cholesterol
controversy—a little bit of history repeating? Acta
Neurol. Scand. Suppl. 185, 1–2 (2006).
V. Hachinski is funded by the Alzheimer Association,
Award Number IIRG-08-91792. P. J. Whitehouse
received support from the National Institute on Aging,
Shigeo and Megumi Takayama, and the Greenwall
Foundation. Barbara Crain, Miia Kivipelto and Michael
Williams made significant suggestions, and we very
much appreciate their critical and thoughtful
comments. We thank Tzipora Sofare, Medical Editor at
the Sandra and Malcolm Berman Brain & Spine
Institute, for her help with the preparation of the
tables and figures.
Supplementary information
Supplementary information is linked to the online
version of the paper at
... Lobar CMBs might be the "tip of iceberg" of widespread CAA-related dysfunction in cortical small vessels. Of note, lobar CMBs might serve as an intriguing link between cerebrovascular and neurodegenerative pathology (32). In addition, the correlation of lobar CMBs with working memory is partial because that lobar CMBs had a predilection for the temporal lobes (29). ...
Full-text available
Purpose Combined the number, volume, and location of cerebral microbleeds (CMBs), this study aimed to explore the different features of CMBs and their correlation with cognitive ability in patients with type 2 diabetes mellitus (T2DM). Methods This study recruited 95 patients with T2DM and 80 healthy control (HC) individuals. AccuBrain ® , an automated tool, was used to obtain the number and volume of CMBs. The scores on global cognition and five cognitive domains were derived from a battery of cognitive tests. The logistic regression and multivariate linear regression were conducted to determine the relationship between the CMBs (number, volume, and location) and cognitive ability in patients with T2DM. Results After adjusting for several variables, the total volume of CMBs (OR = 0.332, 95%CI: 0.133–0.825, and p = 0.018) was independent risk factor for cognitive impairment, whereas the total number of CMBs was not (OR = 0933, 95%CI: 0.794–1.097, and p = 0.400). Furthermore, the volume of CMBs in lobar regions was independently associated with working memory (β = −0.239, 95%CI: −0.565 to −0.035, and p = 0.027). However, no significant correlation between the number of CMBs (both lobar and deep/infratentorium) and any cognitive domains was observed. Conclusions Lobar CMBs was related with cognitive impairment in patients with T2DM and might be a potential early warning signal. Compared with the counting analysis, the quantitative method offered a more sensitive and objective measurement for studying imaging features of CMBs.
... We selected age, sex, dialysis vintage, and various comorbidities listed in Table 1, which have been proven to be risk factors for dementia in previous studies as candidates for predictors [21][22][23]. Age was calculated by the difference between the birthday and the index date. Dialysis vintage was calculated from the date at which maintenance dialysis therapy was initiated to the index date of the case and control subjects. ...
Full-text available
Background Dementia is prevalent and underdiagnosed in the dialysis population. We aimed to develop and validate a simple dialysis dementia scoring system to facilitate identification of individuals who are at high-risk for dementia. Methods We applied a retrospective nested case-control study design using a national dialysis cohort derived from the National Health Insurance Research Database in Taiwan. Patients aged between 40-80 years were included and 2,940 patients with incident dementia were matched to 29,248 non-dementia controls. All subjects were randomly divided into the derivation and validation sets with a ratio of 4:1. Conditional logistic regression models were used to identify factors contributing to the risk score. The cutoff value of the risk score was determined by Youden's J statistic and the graphic method. Results The dialysis dementia risk score(DDRS) finally included age and ten comorbidities as risk predictors. The C-statistics of the model is 0.71(95% confidence interval(CI):0.70-0.72). Calibration revealed a strong linear relationship between predicted and observed dementia risk(R²:0.99). At a cutoff value of 50 points, the high-risk patients had approximately 3-fold increased risk of having dementia compared to those with low risk(odds ratio:3.03,95% CI: 2.78-3.31). The DDRS performance, including discrimination(c-statistic:0.71,95% CI:0.69-0.73) and calibration(p-value of Hosmer-Lemeshow test for goodness of fit=0.18), was acceptable during validation. The value of odds ratio(2.82, 95% CI:2.37-3.35) was similar to those in the derivation set. Conclusions The DDRS system has the potential to serve as an easily accessible screening tool to determine the high-risk groups who deserve subsequent neurological evaluation in the daily clinical practice.
... Alzheimer's brains can be differentiated from healthy brains by a large loss in brain weight and volume associated with a shrinkage and loss of neuronal functions ( Figure 1a) (Gomez-Isla et al., 1996). In addition, AD brains have a significant atrophy of the hippocampus and the cortex, which is elevated sixfold comparing with normal elderly people (Fox et al., 2000;Fotuhi et al., 2009). ...
Full-text available
Morbus Alzheimer (AD) is a neurodegenerative disease, characterized by steady loss of cognitive functions, behavioral changes and neuropsychological symptoms. Today, AD can be treated only symptomatically. There is no drug available, which stops or reverses the pathological changes in AD. Alzheimer's disease is characterized by two pathological hallmarks, amyloid plaques and neurofibrillary tangles (NFTs). NFTs are composed of aggregated tau protein. The accumulation of tau into NFTs reduces normal tau function and causes neuronal dysfunction. The formation of tau aggregates is triggered by two hexapeptide sequences within tau: VQIINK (PHF6*), which is located at the beginning of the second repeat (R2) and VQIVYK (PHF6), which is located at the beginning of the third repeat (R3). PHF6* segment has recently been described as a more potent driver of tau aggregation than PHF6. Peptides that inhibit the pathological aggregation of tau are potentially useful candidates for future therapies in AD. The use of the molecular biology screening technique, phage display, allows fast and simple selection of peptides that bind to a desired target protein. The aim of this study was to develop specific D-enantiomeric peptides that inhibit the pathological aggregation of tau. D-enantiomeric peptides were chosen as they are protease stable and considerably less immunogenic than L-peptides. Another objective of this project was to investigate which of the both sequences within tau, PHF6 or PHF6*, is the more effective target for the development of tau aggregation inhibiting peptides. Employing phage display and mirror image phage display, we selected specific peptides to inhibit tau fibril formation. Two selections were performed; the first selection was conducted using monomers of L-enantiomeric full-length tau as a target for phage display. In addition, we performed a second selection using fibrils of the D-enantiomeric hexapeptide VQIINK (PHF6*) as a target for mirror image phage display. PHF6* segment was targeted in our second selection since PHF6* was recently reported as a more powerful driver for tau aggregation as PHF6. The most interesting obtained peptide, designated MMD3, was found both in the selection against tau monomer and in the selection against D-PHF6* fibrils. MMD3 and its retro-inverso form, designated MMD3rev, clearly inhibited PHF6* aggregation as well as full-length tau aggregation in Thioflavin T (THT) assays. In addition, we performed preliminary experiments to investigate which of the both sequences, PHF6 or PHF6*, is the more effective target for inhibitors of tau fibril formation. We compared the tau aggregation inhibiting effects of MMD3 and MMD3rev with other peptides, which were previously described in the literature and target either PHF6 or PHF6*, respectively. From our early preliminary data, it seems likely that PHF6 and PHF6* aggregation inhibitors are comparably effective in inhibiting the aggregation of full-length tau. However, further characterization using different biochemical and biophysical methods is still required. Our selected peptides MMD3 and MMD3rev present promising candidates for therapeutic and diagnostic applications in AD research. Currently, MMD3 and MMD3rev are further characterized in the German Center for Neurodegenerative Diseases (DZNE).
... С учетом патогенеза SARS-CoV-2 одной из причин прогрессирования этих нарушений могут быть выраженная дыхательная недостаточность с гипоксией и гипоксемией, дисметаболические нарушения, сопровождающие этот процесс, сладж-синдром, глутаматная эксайтотоксичность; усиление выработки оксида азота, развитие оксидантного стресса; реакция местного воспаления, микровезикулярные изменения; повреждение гематоэнцефалического барьера, некроз клеток; апоптоз [8,9]. Своевременное выявление КН и адекватная реабилитация снизят риски их прогрессирования в более позднем возрасте [10,11]. ...
Full-text available
Objective of the Review: To summarise and analyse references published during COVID-19 pandemic regarding possible pathogenic mechanisms of neuropsychiatric and cognitive disorders (CD) in COVID patients, based on their manifestations, changes in severity and course of the disease associated with comorbid CD. Key Points. CDs following an acute COVID-19 period, especially in combination with comorbid cognitive disorders, are often diagnosed in various age groups of patients. Since the risk that mild CDs progress and transform to moderate and severe CDs in these patients is higher than the statistically average value, clinicians should be aware of the significance of early diagnosis of cognitive disorders. In selecting methods for psychological diagnostics and correction, it is advisable to rely of the data and lessons learnt from earlier SARS-CoV and MERS-CoV pandemics. Conclusion. A multi-disciplinary approach to organisation of medical rehabilitation involving physiological and cognitive screening will allow personifying neuropsychologic rehabilitation programs, thus improving both short-term and long-term rehabilitation outcomes. Keywords: cognitive disorders, SARS-CoV-2, COVID-19, medical rehabilitation.
Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as a sole energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.
Dementia is increasingly being recognised as a public health priority and poses one of the largest challenges we face as a society. At the same time, there is a growing awareness that the quest for a cure for Alzheimer's disease and other causes of dementia needs to be complemented by efforts to improve the lives of people with dementia. To gain a better understanding of dementia and of how to organize dementia care, there is a need to bring together insights from many different disciplines. Filling this knowledge gap, this book provides an integrated view on dementia resulting from extensive discussions between world experts from different fields, including medicine, social psychology, nursing, economics and literary studies. Working towards a development of integrative policies focused on social inclusion and quality of life, Dementia and Society reminds the reader that a better future for persons with dementia is a collective responsibility.
Résumé Objectifs Dans la pratique clinique, nous constatons une forte propension à interpréter tout trouble du sujet âgé sur un mode démentiel. L’objectif de ce travail est d’en cerner les origines, les mécanismes opératoires ainsi que les conséquences subjectives. Il s’agit également de proposer un modèle pour appréhender et traiter cette doxa gérontologique. Méthode En nous appuyant sur notre expérience clinique en institution, nous analysons l’articulation entre l’idéologie gériatrique actuelle et les assignations subjectives démentielles en pratiques gérontologiques. Nous effectuons tout d’abord un repérage théorique et contextualisé de la reconceptualisation de la maladie d’Alzheimer, du vieillissement et du symptôme cognitif. Ensuite, nous repérons l’incidence de ces conceptions dans les pratiques auprès des sujets âgés. Enfin, nous identifions les postures singulières et institutionnelles qui peuvent en découler. Résultat Jusque dans les années 1970, la diversité des conceptions gériatriques internationales était proportionnelle à la complexité clinique du processus de vieillesse et de l’état démentiel du sujet âgé. La reconceptualisation de la démence sénile et pré-sénile en maladie spécifique au vieillissement associée à des transformations socioculturelles décisives va imposer une lecture biomédicale des problématiques du vieillissement. Issu d’un leadership états-unien qui va totalement façonner l’orientation du discours dominant émergeant, le modèle d’une maladie d’Alzheimer expansée conditionne aujourd’hui les manières monocentrées d’aborder la variété des tableaux cliniques gériatriques. Sur le terrain, il en résulte que les manifestations de l’adulte âgé sont soumises à une interprétation démentielle commune qui opère comme démentification subjective. Discussion La démentification subjective est ce que nous désignons comme effets psychiques délétères de cette interprétation démentielle appliquée aux situations cliniques du sujet vieillissant, avec ou sans problématique cérébrale probable. Elle est le produit d’un double mécanisme que nous dénommons décérébration psychique et pousse-à-la-démence. Le phénomène de soustraction à la faculté de penser s’articule ainsi au processus de vidage de sens des manifestations du sujet âgé puis de remplissage par des éléments identitaires démentiels via les discours et attitudes de l’entourage. Selon la situation clinique, cette double opération aura des effets subjectifs divers oscillant entre deux pôles : majoration des symptômes en cas de pathologie neurodégénérative probable, création d’un tableau d’allure démentielle artificiel plus ou moins marqué en cas de diagnostic erroné ou d’étiquetage abusif. Dans ce contexte, accompagner le sujet âgé en passe par la nécessité de traiter l’Autre. Dans la veine du modèle étiologique soutenu par le psychiatre britannique Martin Roth à l’aube de la psychogériatrie, nous avançons que seul un questionnement simultané des dimensions organique, psychique et toxique articulé à une clinique inscrite dans le rapport à l’Autre peut efficacement saisir les problématiques et défis gériatriques. Conclusion Face à la diversité des troubles du vieillissement, la clinique gériatrique se doit avant tout d’être une clinique introspective. La garantie de la dignité et de la liberté du sujet est en effet conditionnée par la faculté de résistance à l’idéologie Alzheimer de ceux qui entourent et accompagnent l’adulte âgé.
Full-text available
Alzheimer's disease (AD) is the most common type of dementia responsible for more than 121,499 deaths from AD in 2019 making AD the sixth-leading cause in the United States. AD is a progressive neurodegenerative disorder characterized by decline of memory, behavioral impairments that affects a person's ability to function independently ultimately leading to death. The current pressing need for a treatment for (AD) and advances in the field of cell therapy, has rendered stem cell therapeutics a promising field of research. Despite advancements in stem cell technology, confirmed by encouraging pre-clinical utilization of stem cells in AD animal models, the number of clinical trials evaluating the efficacy of stem cell therapy is limited, with the results of many ongoing clinical trials on cell therapy for AD still pending. Mesenchymal stem cells (MSCs) have been the main focus in these studies, reporting encouraging results concerning safety profile, however their efficacy remains unproven. In the current article we review the latest advances regarding different sources of stem cell therapy and present a comprehensive list of every available clinical trial in national and international registries. Finally, we discuss drawbacks arising from AD pathology and technical limitations that hinder the transition of stem cell technology from bench to bedside. Our findings emphasize the need to increase clinical trials towards uncovering the mode of action and the underlying therapeutic mechanisms of transplanted cells as well as the molecular mechanisms controlling regeneration and neuronal microenvironment.
Dementia and frailty increase health adversities in older adults, which are topics of growing research interest. Frailty is considered to correspond to a biological syndrome associated with age. Frail patients may ultimately develop multiple dysfunctions across several systems, including stroke, transient ischemic attack, vascular dementia, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, cortico-basal degeneration, multiple system atrophy, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. Patients with dementia and frailty often develop malnutrition and weight loss. Rigorous nutritional, pharmacological, and non-pharmacological interventions generally are required for these patients, which is a challenging issue for healthcare providers. A healthy diet and lifestyle instigated at an early age can reduce the risk of frailty and dementia. For optimal treatment, accurate diagnosis involving clinical evaluation, cognitive screening, essential laboratory evaluation, structural imaging, functional neuroimaging, neuropsychological testing is necessary. Diagnosis procedures best apply the clinical diagnosis, identifying the cause(s) and the condition(s) appropriate for treatment. The patient's history, caregiver's interview, physical examination, cognitive evaluation, laboratory tests, structural imaging should best be involved in the diagnostic process. Varying types of physical exercise can aid the treatment of these disorders. Nutrition maintenance is a particularly significant factor, such as exceptionally high-calorie dietary supplements and a Mediterranean diet to support weight gain. The core purpose of this article is to investigate trends in the management of dementia and frailty, focusing on improving diagnosis and treatment. Substantial evidence builds the consensus that a combination of balanced nutrition and good physical activity is an integral part of treatment. Notably, more evidence-based medicine knowledge is required.
Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
Background We have undertaken a large unselected, community-based neuropathology study in an elderly (70–103 years) UK population in relation to prospectively evaluated dementia status. The study tests the assumption that dementing disorders as defined by current diagnostic protocols underlie this syndrome in the community at large. Methods Respondents in the Medical Research Council Cognitive Function and Ageing Study were approached for consent to examine the brain at necropsy. Dementia status was assigned by use of the automated geriatric examination for computer-assisted taxonomy algorithm. Neuropathological features were standardised by use of the protocol of the Consortium to Establish a Registry of Alzheimer's Disease, which assesses the severity and distribution of Alzheimer-type pathology, vascular lesions, and other potential causes of dementia. A statistical model of dementia risk related predominantly to Alzheimer-type and vascular pathology was developed by multivariate logistic regression. Findings We report on the first 209 individuals who have come to necropsy. The median age at death was 85 years for men, and 86 years for women. Cerebrovascular (78%) and Alzheimer-type (70%) pathology were common. Dementia was present in 100 (48%), of whom 64% had features indicating probable or definite Alzheimer's disease. However, 33% of the 109 non-demented people had equivalent densities of neocortical neuritic plaques. Some degree of neocortical neurofibrillary pathology was found in 61% of demented and 34% of non-demented individuals. Vascular lesions were equally common in both groups, although the proportion with multiple vascular pathology was higher in the demented group (46% vs 33%). Interpretation Alzheimer-type and vascular pathology were the major pathological correlates of cognitive decline in this elderly sample, as expected, but most patients had mixed disease. There were no clear thresholds of these features that predicted dementia status. The findings therefore challenge conventional dementia diagnostic criteria in this setting. Additional factors must determine whether moderate burdens of cerebral Alzheimer-type pathology and vascular lesions are associated with cognitive failure.
Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally.Design A prospective, longitudinal inception cohort.Setting General community clinic.Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
Early and accurate diagnosis of Alzheimer's disease (AD) has a major impact on the progress of research on dementia. To address the problems involved in diagnosing AD in its earliest stages, the National Institute on Aging, the American Association of Retired Persons, the National Institute of Neurological and Communicative Disorders and Stroke, and the National Institute of Mental Health jointly sponsored a workshop for planning research. The purpose of the meeting was to identify the most important scientific research opportunities and the crucial clinical and technical issues that influence the progress of research on the diagnosis of AD. The 37 participants included some of the most knowledgeable and eminent scientists and physicians actively involved in the study of AD. The participants were divided among six panels representing the disciplines of neurochemistry, neuropathology, neuroradiology, neurology, neuropsychology, and psychiatry. Within each of the panels, participants discussed specific areas of research requiring further
Objective. —To determine the relationship of brain infarction to the clinical expression of Alzheimer disease (AD). Design. —Cognitive function and the prevalence of dementia were determined for participants in the Nun Study who later died. At autopsy, lacunar and larger brain infarcts were identified, and senile plaques and neurofibrillary tangles in the neocortex were quantitated. Participants with abundant senile plaques and some neurofibrillary tangles in the neocortex were classified as having met the neuropathologic criteria for AD. Setting. —Convents in the Midwestern, Eastern, and Southern United States. Participants. —A total of 102 college-educated women aged 76 to 100 years. Main Outcome Measures. —Cognitive function assessed by standard tests and dementia and AD assessed by clinical and neuropathologic criteria. Results. —Among 61 participants who met the neuropathologic criteria for AD, those with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. Participants with lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without infarcts (the odds ratio [OR] for dementia was 20.7,95% confidence interval [95% CI], 1.5-288.0). Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter than in those without infarcts. In contrast, among 41 participants who did not meet the neuropathologic criteria for AD, brain infarcts were only weakly associated with poor cognitive function and dementia. Among all 102 participants, atherosclerosis of the circle of Willis was strongly associated with lacunar and large brain infarcts. Conclusion. —These findings suggest that cerebrovascular disease may play an important role in determining the presence and severity of the clinical symptoms of AD.