Alzheimer Disease Including Focal Presentations PDF

213
Alzheimer’s Disease Including Focal Presentations

Nicolas Villain, MD, PhD1,2,3 Bruno Dubois, MD2,3
1 Alzheimer Precision Medicine, Sorbonne Université, Paris, Address for correspondence Nicolas Villain, MD, PhD, Alzheimer
France Precision Medicine, Sorbonne Université, GRC n° 21, Paris, France
2 Department of Neurology, Institute of Memory and Alzheimer’s (e-mail: [email protected]).
Disease, Assistance Publique - Hopitaux de Paris, Pitié-Salpêtrière
Hospital, Paris, France
3 Institut du Cerveau et de la Moëlle Epinière, Paris, France
Semin Neurol 2019;39:213–226.
Abstract Alzheimer’s disease (AD) is the commonest neurodegenerative disease and the most
frequent cause of dementia. It affects 30 million people worldwide. Current research
criteria focus on biomarkers’ status for amyloid and tau using positron emission
tomography and cerebrospinal fluid analysis, independent of clinical status. Current
epidemiological data, which mostly rely on biomarker-undetermined AD cases, have
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highlighted ApoE4 and age as the main risk factors. Rare autosomal dominant
mutations also account for a small fraction of early-onset AD. The main clinical
phenotype at presentation is the amnestic phenotype targeting episodic memory.
This is followed by rarer phenotypes such as posterior cortical atrophy, logopenic
variant of primary progressive aphasia, frontal variant AD, corticobasal syndrome, and
other even rarer presentations mimicking language variants of frontotemporal demen-
tia. Main differential diagnoses include hippocampal sclerosis with TDP-43, primary
age-related tauopathy, argyrophilic grain disease, frontotemporal lobar degeneration,
Keywords Lewy body disease, chronic traumatic encephalopathy as well as nondegenerative
► Alzheimer’s disease disorders such as cerebrovascular disease, chronic alcohol consumption, limbic ence-
► diagnosis phalitis, medial temporal lobe epilepsy, and others. Co-occurrence of AD pathology
► CSF with other neurodegenerative and vascular diseases is common and increases with age.
► epidemiology This presents a challenge in current clinical practice due to a lack of reliable biomarkers
► dementia for non-AD neurodegenerative diseases.
Alzheimer’s disease: History, Evolution of

Concepts, and Current Definition dementia in the general population by the medical and
scientific community . We will start with a review of this
Age-related dementia has been known since ancient times history to understand the evolution of the concepts and
(►Fig. 1). Alzheimer’s disease (AD) pathology was first definitions of AD from 1907 to the 21st century to put in
described in the early 20th century. Alois Alzheimer context the scientific literature on AD of the past 30 years.
described it at the beginning of the 20th century,1,2 and
AD was integrated in medical textbooks only a few years Alzheimer’s Disease and Dementia: A Long-Lasting
later.3 However, it was not until the last quarter of the 20th 20th Century Debate
century that AD was recognized as the major cause of Descriptions of dementia precede the discoveries of Alois
Alzheimer, going back to ancient Egyptians who acknowl-
edged age to be accompanied by memory decline.4 Ancient
Villain Nicolas’s ORCID is http://orcid.org/0000-0002-7429-4289.
Issue Theme Dementia; Guest Editor, Copyright © 2019 by Thieme Medical DOI https://doi.org/
Arash Salardini, MD Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1681041.
New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
214 Alzheimer’s Disease Including Focal Presentations Villain, Dubois

Fig. 1 Conceptual evolution of Alzheimer’s disease (AD) and its diagnosis criteria since its first description by Alois Alzheimer in 1907.
Romans give us the current English word “dementia,” which name after Alzheimer presenile dementia cases he identified
they used with similar meaning. as distinct from senile dementia. As discussed elsewhere, it is
Alzheimer’s first patient with dementia had the early not entirely clear what led Kraepelin to do so.7–9 The
onset form of AD. In an oral communication in 1906, pub- distinguishing characteristics he cites for early-onset AD
lished in 1907, he reported the case of Auguste Deter, a 51- (EOAD) are patients’ relative youth, severe dementia, focal
year-old woman with delusions, severe memory loss, disor- signs, and language disturbances. These characteristics we
ientation, language deficits, and behavioral disturbances. She acknowledge today distinguish EOAD and late-onset AD
had been institutionalized in Frankfurt for these symptoms (LOAD). Alzheimer himself objected to the link Fischer
but continued to decline until she was bedridden and died claimed existed between presbyophrenic dementia (aging-
4.5 years later.1 Autopsy revealed a diffuse atrophic brain related dementia) and plaques.10 While he concurred with
without macroscopic focal degeneration. Microscopic exam- the fact that plaques occurred more frequently in cases of
ination showed “tangles of fibrils,” neuronal loss, and presbyophrenic dementia, he did not believe them to be
“deposition of a special substance in the cortex [that] can pathognomonic for this condition. Plaques in his view were a
be observed without dye, but it is very refractory to dyeing.” marker of senile dementia, but without causing the condi-
We have here the complete picture of AD as is currently tion. In line with this point of view, Kraepelin’s textbook
defined: a progressive cognitive decline focusing on memory established a distinction which remained predominant
leading to dementia, associated with neurofibrillary tangles within the scientific and medical circles for much of the
(revealed later to be the result of hyperphosphorylated tau 20th century, and commentators continued to rely on the old
protein deposits) and the special substance that was found diagnostic categories of senility or senile dementia to
later to be an accumulation of amyloid A-β proteins (see describe a rather wide variety of commonly recognized
chapter on Neuropathology and the work by Hyman et al).5 symptoms and behaviors. They traced the etiology of these
Alzheimer thought this condition was “eine eigenartige clinical symptoms to an equally wide variety of causes, all
Erkrankung der Hirnrinde” (title of the 1907 Alzheimer’s more or less loosely related to the phenomenon of old age.8
article), i.e., an unusual illness of the cerebral cortex. The The “Fischer/Alzheimer–Kraepelin debate” finally ree-
following years saw many more descriptions of the same merged and was eventually settled in favor of Fischer’s point
brain lesions identified both in early- and late-onset cases of view during the last quarter of the 20th century. Furthered
(i.e., senile dementia). Remarkably, Oskar Fischer’s clinico- by demographic, political, and scientific developments (see
pathological study of 16 patients diagnosed with senile Boller’s4 study for a review), senile dementia became
dementia came out in the very same year as Alzheimer’s. It increasingly common within the aging population, beyond
is in this study that we find the first description of neuritic what could be explained by the arteriolosclerotic lesions or
plaques.6 In spite of this, 3 years later Kraepelin decided to other known phenomena of old age. In reaction to the
Seminars in Neurology Vol. 39 No. 2/2019

Alzheimer’s Disease Including Focal Presentations Villain, Dubois 215
situation, particular attention was given to the pathological intermediate stage. On the Global Deterioration Scale (GDS),
hallmarks of senile dementia and Fischer‘s work in the area MCI status was defined as fulfilling the criteria for stage 3.13
was met with renewed interest. For example, the white Peterson and colleagues refined the concept further by
paper authored by Robert Katzman, Robert Terry, and requiring a memory complaint, recognizing that awareness
Katherine Bick at the conclusion of a 1977 workshop con- of decreasing mnemonic capabilities suggests that the sub-
ference, co-organized by National Institute on Aging (NIA), ject is still at an early stage.14,15 In addition, GDS stage 3 MCI
National Institute of Neurological and Communicative Dis- admitted the occurrence of executive level functional defi-
orders and Stroke (NINCDS), and National Institute of Mental cits, which Petersen’s MCI leaves aside as not sufficiently
Health (NIMH) and held in Bethesda, concluded: “there is specific to early-stage AD. The mild symptomatic phase of
increasing recognition that most patients with clinically AD, which precedes the fully developed clinical syndrome of
defined senile dementia (onset after age 65) manifest the dementia, had, at that time, no official clinical standing and
same pathological changes in their brains as do patients in was artificially included in the spectrum of MCI. The hetero-
their presenium (under age 65) with Alzheimer’s disease.”11 geneity of pathologies sharing clinical features but having
A growing consensus following the same lines helped bring different etiologies which were regrouped under the label
Alzheimer research into the modern era by “officially“ MCI represented an important limitation. Subtyping MCI was
acknowledging AD as a condition affecting patients in old proposed according to the type and number of cognitive
age. domains impaired (e.g., amnestic vs. nonamnestic MCI and
single vs. multiple-domain MCI15,16) as a possible solution.
AD as a Clinicopathological Entity and Cause of However, only 70% of amnestic MCI cases (the most specific
Dementia cases regarding AD phenotype) who have progressed to

Seven years later, the publication of the NINCDS–Alzheimer’s dementia actually met neuropathological criteria for AD.17
Disease and Related Disorders Association (NINCDS-ADRDA) In parallel, NINCDS-ADRDA criteria for probable AD were
criteria of AD confirmed AD as a disease, independent of age found to suffer from much the same lack of specificity, with
of presentation, and therefore as a cause of senile demen- sensitivity of the criteria in a tertiary center estimated to be
tia.12 Three cornerstones of these criteria were that: (1) any 70.9 to 87.3%, and its specificity 44.3 to 70.8%.18
antemortem clinical diagnosis of AD could be made merely
on a “probable“ basis, while (2) final and definite diagnosis From a Clinicopathological Definition to a
was possible upon postmortem examination only, and (3) Clinicoradiobiological Definition
the diagnosis could only be applied when the disease was NINCDS-ADRDA and MCI criteria enabled researchers to
advanced to the functional disability threshold of dementia. follow clinical cases and to better characterize the disease.
The NINCDS-ADRDA criteria established a two-step proce- First, the clinical phenotype of AD was elucidated: in more
dure for the diagnosis of probable AD. First, establishing the than 85% of cases, AD presents as a progressive amnestic
existence of a dementia syndrome by means of medical disorder with a specific episodic memory impairment
examination and neuropsychological testing, revealing def- profile characterized by low free recall that is not improved
icits in at least two areas of cognition, one of which had to be by cueing. This distinguishes AD from normal aging and
memory. These deficits were required to be sufficiently non-AD disorders. It is also useful for predicting conversion
pronounced as to significantly impact patients’ daily func- to AD in MCI patients19 (see below). Second, postmortem
tioning. Upon this initial identification of a dementia syn- studies of AD patients showed a specific hierarchical pat-
drome, the second step consisted of the exclusion of other tern of tau pathology, which begins in the memory-related
possible etiologies of dementia with blood/cerebrospinal areas of medial temporal lobe structures (entorhinal cortex,
fluid (CSF) investigations to rule out infectious, inflamma- hippocampal formations, parahippocampal gyrus).20,21 In
tory, or metabolic diseases, and with brain neuroimaging contrast, β amyloid deposits are more diffuse in the neo-
(computed tomography [CT] scan or magnetic resonance cortex before spreading to the deep nuclei, the pons, and
imaging [MRI]) to exclude small vessel diseases, strategic the cerebellum.20,22 The AD-specific episodic memory pro-
lacunar infarcts, large vessel infarcts and/or cerebral hemor- file proved to correlate significantly with hippocampal
rhages, brains tumors, hydrocephalus, or/and other similar volume and, more precisely, with the CA1 field.23,24 Third,
causes. diagnostic accuracy of AD was also improved because of a
better characterization of non-AD neurodegenerative dis-
The Concept of Mild Cognitive Impairment eases through specific criteria. These other dementias
With time, it became obvious that the established classifica- included primary progressive aphasias, corticobasal syn-
tion of AD as purely a dementia had important drawbacks, drome, frontotemporal dementias, and Lewy body demen-
especially in dealing with the early and prodromal stages of tia. The identification of these diseases, which were
the disease. The concept of mild cognitive impairment (MCI) previously highly confused with AD, has consequently
is a response to this conundrum, allowing to label objective decreased its apparent heterogeneity. Finally, reliable bio-
memory loss and/or cognitive impairment that has not yet markers for AD were isolated and have now become avail-
advanced to the point of impacting activities of daily living. able at least in expert centers. The incremental gains in
The term MCI was introduced in the late 1980s by Reisberg diagnostic accuracy due to biomarkers is now well
and colleagues to characterize subjects who were at this established.25–27

Hence, a new conceptual framework for the diagnosis of In line with the conceptual evolution, the NIA/AA pub-
AD has been proposed by the International Working Group lished diagnostic criteria in 2011,29 which refined the
(IWG)28 and later by the NIA/Alzheimer’s Association (NIA/ NINCDS-ADRDA framework to broaden the coverage of
AA)29 based on two requirements: (1) earlier diagnosis and different stages of disease from the asymptomatic (preclini-
(2) greater specificity. In 2007, the IWG provided a new cal), through the predementia stages (MCI due to AD), to the
conceptual framework, according to which AD moves from a most severe stages of dementia. These shared many features
clinicopathological entity to a clinicoradiobiological entity.28 with the IWG criteria, including the recognition of an
The 2007 IWG criteria stipulated that AD can be recognized asymptomatic but biomarker-positive phase and of a pre-
in vivo in the presence of two associated features. The first is dementia symptomatic phase of AD. Biomarkers were given
the evidence of an “amnestic syndrome of the hippocampal an important place in the diagnostic process, first in identi-
type” seen in the typical form of the disease. The importance fying amyloid abnormalities and second in identifying
of a specific memory pattern was highlighted because it downstream neurodegeneration. These biomarkers also
occurs early in the course of the disease and it is fairly had the advantage of being usable in both clinical and
specific, though not pathognomonic, for AD. The second research settings. The most interesting contribution of the
necessary feature was supportive evidence from biomarkers NIA/AA criteria pertains to the preclinical stages of the
that were proposed for the first time for the diagnosis of AD. disease. Based on the hierarchical biomarker model pro-
The biomarkers of AD were divided into two groups: (1) the posed by Jack and colleagues31 (itself in line with the amyloid
pathophysiologic markers—positive positron emission cascade hypothesis32), it was proposed33 that (1) Aβ accu-
tomography (PET)-amyloid scan or CSF AD profile (low Abeta mulation biomarkers become abnormal first and a substan-
42 level, high total tau, and high phospho-tau); these mar- tial Aβ load accumulates before the appearance of clinical

kers identified AD pathology since they were strongly cor- symptoms; (2) biomarkers of synaptic dysfunction, including
related with postmortem AD histopathological changes; (2) FDG and functional MRI, may demonstrate abnormalities
topographical markers: hippocampal atrophy on volumetric very early, particularly in APOE gene allele carriers, who may
MRI or cortical regional hypometabolism on fluorodeoxy- manifest functional abnormalities before detectable Aβ
glucose-PET (FDG-PET) especially the posterior associative fibrillar deposition;34,35 (3) structural MRI was thought to
areas including the posterior cingulate cortex (see chapter on become abnormal a bit later, as a marker of neuronal loss,
Neuroimaging). These reflected downstream damage and and MRI retained a close relationship with cognitive perfor-
were rather markers of progression, more targeted at asses- mance through the clinical phases of MCI and dementia;36
sing change over time and predicting outcomes. As a con- and (4) none of the biomarkers was static—rates of change in
sequence, CSF and MRI investigations were no longer simply each biomarker changed over time and followed a nonlinear
for excluding other etiologies of brain dysfunction but were time course.
central to detecting AD-related changes. There are several important differences between the NIA/
An important clarification of the above criteria was AA criteria and those from IWG. The NIA/AA framework held
brought forward in 2010, introducing the concept of “atypi- that the presence of Alzheimer pathology indicates the
cal forms of AD” and proposing corresponding criteria and a diagnosis of AD, and that this diagnosis is applicable at
diagnostic framework.30 An amnestic presentation for AD this “in situ” stage for research purposes. At the predementia
may not always be the case, and other specific clinical MCI stage, the framework applied a probabilistic likelihood
phenotypes could be associated with postmortem evidence based on the presence of AD biomarkers with designation
of AD pathology. These specific clinical phenotypes included either of biomarkers that reflect amyloidosis (CSF Abeta or
nonamnestic focal cortical syndromes, such as logopenic amyloid PET) or those that are “downstream” indicative of
aphasia, biparietal atrophy, posterior cortical atrophy neuronal degeneration (CSF phospho or total tau, FDG glu-
(PCA), and frontal variant AD (see below). These clinical cose, and volumetric MRI). Based on positive, negative, or
disorders were more commonly seen and treated as atypical intermediate results on the “amyloid” and “downstream”
AD, as biomarkers began to allow in vivo confirmation of biomarkers—or the absence thereof—a probabilistic likelihood
Alzheimer’s pathology. Individuals without clinical symp- of “high” or “intermediate” was applied to the diagnosis. In
toms but with positive biomarkers of Alzheimer pathology contrast to IWG criteria, the MCI stage of AD was formally
were considered “asymptomatic at risk of AD.” “Asympto- distinguished from the dementia stage, which had its own
matic at risk for AD” was used for subjects without cognitive diagnostic criteria. In the dementia stage, 10 categories of
dysfunction but evidence of amyloidosis in the brain (on PET dementia of the AD type were established, including probable
amyloid) or AD-related changes in the CSF. The stage “pre- AD dementia, possible AD dementia, probable or possible AD
symptomatic AD” was ascribed to individuals carrying auto- dementia with evidence of the AD pathophysiological process,
somal dominant monogenic AD mutations (see below) who and pathophysiologically proved AD dementia. The probable
would with time inevitably develop clinical AD, provided or possible AD dementia stages retained most of the features of
they lived long enough. Finally, topographical markers were the 1984 NINCDS-ADRDA diagnosis of probable AD12 despite
no longer used because of their lack of specificity regarding the low specificity, limited positive predictive value, and poor
AD. Thus, the only validated biomarkers for AD diagnosis negative predictive value of these criteria.18
were defined as CSF low Aβ42 and high T-tau or P-tau levels On the basis of the 2010 preliminary paper, the IWG
or evidence of amyloid retention in amyloid PET. formalized its criteria in 2014.37 In addition, they refined the

definition of the typical amnestic AD, identified with the use senting neurodegeneration are structural MRI, FDG-PET, and
of list-learning and other episodic memory tests . They also CSF total tau. Nonetheless, no technical measures or thresh-
introduced the notion of a copathology in AD with the olds are settled in these criteria, and it is clearly stated that
diagnosis of mixed AD when a patient had in addition to these biomarkers will be evolving as research progresses.
AD a coexisting disorder identified by evidence of specific Clinical definitions are restricted to the clinical phase of
clinical and biological features of another disease, such as AD: cognitively unimpaired (normal performing subjects on
parkinsonism (for Lewy body disease) or cerebrovascular cognitive testing, may report subjective cognitive decline),
disease. Additional formalizations concerned the preclinical MCI (evidence of cognitive impairment and evidence of
state of AD, including the “asymptomatic at risk of AD” and decline in cognitive performance from baseline in an indivi-
“presymptomatic AD” previously described. dual who performs daily living activities independently), and
We can conclude that the main contribution of the IWG dementia (substantial progressive cognitive impairment that
and NIA/AA criteria lies in the refinement they brought to the affects several domains and/or neurobehavioral symptoms
diagnosis of AD prior to the onset of dementia and their and results in a clearly evident functional impact on daily
inclusion of biomarkers of Alzheimer’s pathology into the life).
diagnostic framework. Beyond this, their methodology As a whole, individuals who fulfill both the A and T
proved useful with clinical trials and possibly with regula- biomarker criteria qualify as having AD (preclinical AD or
tory decisions. They could also set the stage for primary AD with MCI or AD with dementia). Individuals who fulfill
and secondary prevention. the A biomarker criteria without the T biomarker are classi-
fied as Alzheimer’s pathologic change (preclinical, with MCI
From a Clinicoradiobiological Definition to a Pure or with dementia),31,41 while individuals who fulfill the T

Biological Definition biomarker criteria without the A biomarker are classified as
In 2016, the joint IWG/AA meeting furthered the integration non-Alzheimer’s pathologic change (such as the A negative, T
of biomarkers into the definition of AD and decided to apply negative, and N positive individuals), in keeping with the
this definition independent of the clinical status.38 Indeed, NIA/AA pathologic definition of primary age-related tauo-
the new definition of AD is now purely biological and is based pathy (PART) as not AD.45 There is currently no data regard-
on the positivity of biomarkers of both amyloidosis and ing the risk of developing subsequent AD amongst
tauopathy independent of the clinical status. The cognitive individuals diagnosed with PART. In line with the mixed
changes are now considered as a stage of the disease which AD concept introduced by the IWG criteria, the NIA/AA
refers to a degree of disease progression (preclinical ¼ criteria also allow for this concept under the term “suspected
asymptomatic, prodromal ¼ cognitive deficit with no Alzheimer’s” and concomitant suspected non-Alzheimer’s
impact in the daily living activity, and dementia ¼ cognitive pathologic change when there is an incomplete biomarker
deficit with impact in the daily living activity). Thus, asymp- combination (e.g., A þ T-Nþ). In this context, the presence of
tomatic individuals with positive biomarkers (evidence of other dementias may be uncertain, since biomarkers for
both amyloid and tau biomarkers) are no longer considered other neurodegenerative diseases lack of specificity/
“asymptomatic at risk of AD” but as the earliest form of AD sensitivity.
(preclinical AD). As a result, the IWG/AA criteria considered When no biomarker is available, the 2018 NIA/AA criteria
that the category “asymptomatic at risk for AD” still applies introduced the concept of Alzheimer’s clinical syndrome,
in the case of discrepant amyloidosis and tau biomarker which applies to both mildly impaired and demented indi-
results (evident in cognitively normal individuals of isolated viduals. This refers to the definitions of possible and probable
Aß pathology or of isolated Tau pathology). AD according to the previous NINCDS-ADRDA12 and NIA/
The NIA/AA have recently formalized this new biological AA46 criteria. Nonetheless little is said regarding the precise
definition of AD.39 They propose an A/T(N)(C) classification phenotype except a vague “multi-(or single-) domain amnes-
relying on CSF, PET, and MRI biomarkers (A ¼ amyloid; T ¼ tic syndrome” or a “classic syndromal variant.”
tauopathy; N ¼ neurodegeneration; C ¼ cognitive change),
where A and T positivity define AD while N and C are not Research versus Clinical Criteria
specific to AD and define the severity stage of the disease. More recent clinical criteria allow earlier and more accurate
Hence, in line with the IWG/AA 2016 paper, the focus of these diagnosis of AD, but are very much dependent on the
criteria is no more on the symptoms but on the biological in availability of suitable biomarkers. This is problematic, since
vivo definition of the disease. Besides, in line with the as much as 58% of those suffering from dementia live in low-
conceptual evolution that tauopathy might not only be the and middle-income countries, according to a report of AD
downstream consequence of amyloid pathology but a par- International.47 Sophisticated, high-tech screenings for bio-
allel and independent pathological process,40–45 the hierar- markers are not universally available, even in high-income
chy between amyloid and tau biomarkers has been softened countries, and often limited to tertiary or research centers.
and concomitant tauopathy and amyloidosis now represent This mostly limits the applicability of diagnostic approaches
AD. Amyloid biomarkers validated by these criteria are CSF proposed in recent years to these contexts, i.e., facilities able
Aβ42, or Aβ42/Aβ40 ratio and amyloid-PET. Aggregated tau to screen for a large variety of biomarkers and with access to
(neurofibrillary tangles) validated biomarkers include CSF normative data. These conditions allow for complex diag-
phosphorylated tau and tau-PET. Finally, biomarkers repre- noses such as EOAD, frontal variant AD, or primary

progressive aphasias, where biomarkers are essential for enough for use in clinical practice.59 Therefore, one should be
sufficient accuracy in diagnosis. In less favorable circum- cautious: using the NIA/AA 2018 criteria for AD is more
stances, the clinical syndrome definition of AD as put for- specific and sensitive for neuropathologically diagnosed AD,
ward by NIA/AA may be used for diagnosis. but cannot fully take into account copathologies. This is
Finally, the predictive value of these biomarkers in asymp- important for prognostication of cognitive decline, under-
tomatic populations needs to be confirmed to validate standing of AD pathophysiology in vivo, and for clinical trials.
criteria for the preclinical stages. Indeed, while they have Targeting a single pathophysiological mechanism may
largely proved their ability to predict cognitive decline in explain the lack of success of the past 10 years of antiamyloid
patients with MCI,26 their ability to correctly predict the immunotherapies.60 Therefore, future biomarkers for these
natural clinical course of AD in asymptomatic patients neurodegenerative pathologies, to allow for an in vivo mixed
remains to be established. More data are needed, since pathology diagnosis, will help us diagnose in vivo these
current results are scarce or incomplete.48–50 Moreover, “multiple pathology neurodegenerative diseases” and offer
none of these biomarkers have 100% specificity and sensi- personalized combination therapies.61
tivity for AD pathology (i.e., amyloidosis and tauopathy), so
that every physician should remain extremely cautious when
Alzheimer’s Disease Epidemiology
assigning a diagnosis based on biomarkers only, especially if
there are no therapeutic disease-modifying consequences. Having in mind these definitions of AD and their evolution
across time allows us to make a critical review of relevant
Future Evolution: Mixed Pathology and Mixed epidemiological data. Much of the data rely on the NINCDS-
Diseases in Vivo Diagnoses? ADRDA 1984 clinical criteria (or Diagnostic and Statistical

There is increasing evidence that, when the diagnosis of AD is Manual of Mental Disorders [DSM] dementia definitions)
confirmed by neuropathological examination according to and do not include biomarkers or neuropathology data.
the NIA/AA criteria,5 pure AD pathology is not the rule (30% Therefore, most of what follows relates more closely to
of cases according to age; ►Fig. 2). Instead there is often the “Alzheimer’s clinical syndrome” than to AD, i.e., lacking
co-occurrence of other pathologies such as Lewy body dis- biological mechanism specificity (see above and ►Fig. 1).
ease, vascular pathology, argyrophilic grain disease (AGD), or Nonetheless, according to neuropathological series, AD
TDP43 pathology51–58 that influence both the clinical trajec- remains the most frequent cause of neurodegenerative dis-
tory and the phenotypes (►Fig. 2).54–57 Unfortunately bio- ease and represents about two-thirds of dementias (see
markers for these other pathologies are not currently reliable Nelson et al62 for a review). The incidence of AD increases
exponentially with age, plateauing around 85 years of age.
After 85 years of age, different studies find diverging results—
either a decline in incidence, stable incidence rates, or a
deceleration in the increase in incidence rate.63–67 Interest-
ingly, as the incidence of AD rates decreases with advanced
old age, the incidence of “pure” vascular dementia also
decreases, while mixed pathologies show greater incidence
with extremely old age.68 As a whole, this allows us to have
only a rough estimation of AD prevalence. The World Alzhei-
mer Report 201569 estimated that 46.8 million people have
dementia around the world, with an estimated yearly cost of
880 billion U.S. dollars. Using these numbers, one can
estimate the number of people with AD to be 30 million
(including pure and mixed AD cases) around the world. The
mean duration of survival with AD is estimated to be 5 to
6 years at the time of the dementia stage of the disease, and
longer with earlier age at onset. It therefore reduces life
expectancy.70,71
The frontier between EOAD and LOAD has been somewhat
arbitrarily defined by age at first manifestation of symptoms
(< or >65 years). LOAD represents the vast majority of AD
cases (>95%).72,73 Nonetheless, EOAD remains the most
Fig. 2 Alzheimer’s disease (AD) as a mixed disease. Neuropatholo- common cause of early-onset neurodegenerative dementia.
gical assessments of AD encounter frequent copathologies including In contrast to LOAD, which is a complex disorder with a
vascular pathology, TDP-43 pathology, argyrophilic grain disease, and heterogeneous etiology and a heritability (according to some
α-synucleinopathy (rough estimation of their prevalence in AD brains
models) of 70 to 80%, EOAD is almost entirely genetically
with neuropathogical confirmation is indicated in percentage: note
that figures are highly variable from one study to another). Pure AD is
determined, with a heritability ranging between 92 and
supposed to represent about one-third of all AD cases with neuro- 100%.74,75 Between 35 and 60% of EOAD patients have at
pathogical confirmation.51,53,54,57,58 least one affected first-degree relative, and in 10 to 15% of

those with familial EOAD patients, the mode of inheritance is associated with risk of AD onset, the associations are weak, at
autosomal-dominant.76–78 Rare high-penetrant mutations best, for a majority of factors.
in APP, PSEN1, and PSEN2 genes explain only a small fraction Nonetheless, as stated earlier, the vast majority of these
of EOAD families (5–10%), leaving a large group of autoso- studies have been conducted without biomarkers. For
mal-dominant pedigrees genetically unexplained.74,79 instance, in clinical-autopsy studies, diabetes was associated
Patients with Down syndrome (DS), caused by chromosome with cognitive impairment (and the clinical diagnosis of
21 (partial) trisomy, present with a similar brain pathology of probable AD); however, the pathologic basis for this associa-
amyloidosis and tauopathy as AD patients.80 In fact, AD tion was vascular brain injury and not Aβ plaques and
neuropathology appears in virtually all DS patients above neurofibrillary tangles.85–87 Thus, there is a need to disen-
40 years of age,81 and DS is thus considered a genetic cause of tangle AD from dementia, using the new biological definition
AD. Finally, the APOE ε4 allele also increases the risk for EOAD of the disease, to update well-known established data
in carriers of at least one ε4 allele, and is highest in those with regarding epidemiology and genetic risk factors of the
a positive family history.77 In carriers, homozygosity for the disease.
APOE ε4 allele is sufficient to significantly increase the risk
for EOAD, independent of other genetic factors. In contrast, in
Alzheimer’s Disease Clinical Phenotypes
carriers heterozygous for the APOE ε4 allele, risk is only
significantly increased in the presence of a positive family The recent focus on the biological definition of the disease
history of disease, indicating that the presence of one ε4 should not give us a cause to neglect clinical phenotypes of
allele is insufficient to increase the risk for AD before the age AD in the prodromal or dementia stages of the disease. Given
of 65 years. the lack of an efficient disease-modifying treatment, the

Amongst LOAD, an interesting systematic review has been need in clinical practice for a biological preclinical diagnosis
recently performed by Hersi and colleagues82 regarding remains low. The appearance of such treatments in the
LOAD risk factors. There is an increased risk of AD associated future may change this. Meanwhile, we still need to identify
with head injury in males, depression, MCI, age, diabetes in clinical practice the specific phenotypes and indications
mellitus, conjugated equine estrogen use with medroxypro- for a reasonable and relevant use of MRI, CSF, PET, and blood
gesterone acetate, and exposure to pesticides. With respect tests.
to genetic factors, APOE e4 remains the strongest predictor of
LOAD. The presence of one or two copies of the APOE ε4 allele IWG typical and atypical AD phenotypes
increases the risk to develop LOAD by a factor of 3- or 15-fold, Regarding this specific question, the IWG 2014 criteria are
respectively.83,84 Polymorphisms of IL-1b, IL-1a, IL-10, ACE, the most recent criteria specifying the specific clinical phe-
APOE promoter, TNF-a, OLR1, BIN1, ABCA7, MS4A4E, and notypes of the disease. Typical AD is the progressive amnestic
CD2AP genes are all associated with an increased risk of AD. presentation of the disease, described long before the dis-
Several identified genetic factors appear to confer suscept- covery of AD itself (►Fig. 3).88 The memory disorder of AD is
ibility to AD in specific populations. Polymorphisms of complex and varies with the stage of the disease.88,89 In
MTHFR and VLDLR genes are associated with an increased 1881, Ribot first described progression of memory deficits
risk of AD in Asians. Other associations include ALDH2 gene amongst patients who went on to develop senile dementia:
in East Asian men, PS-1 2/2 gene in Europeans, CR1 gene in “The progressive destruction of memory follows a logical
Caucasians, SORL1 gene in whites and Asians, and the BACE1 progression, a law. It goes from unstable to stable. It starts
gene in APOE e4 noncarriers. Statin use and several genetic with recent memories, weakly settled in the nervous ele-
factors, including APOE e2, polymorphisms of MS4A6A and ments, seldom repeated and consequently weakly associated
CD33 genes, are associated with a reduced risk of AD. Genetic to the others, which represent the weakest level of organiza-
factors that are associated with a protective effect in specific tion. It ends up with this instinctive, sensorial memory,
populations include polymorphisms of PS-1 2/2, CLU, and settled in the organism that has become a part of it, or
PICALM genes in Caucasians, VLDLR gene in non-Asians, even the organism itself, which represents the strongest level
SORL1 gene in whites and Asians (other single nucleotide of organization.”88 We now know that the earlier symptoms
polymorphism than those responsible for a risk factor), and described by Ribot corresponded to episodic memory
BACE1 gene in APOE e4 carriers. Regarding lifestyle factors, impairment. The famous case studies of HM and KC, with
current smoking and lower social engagement are identified lesions of the hippocampus, later localized episodic memory
as factors associated with an increased risk of AD. The to the hippocampus.90,91 To quantify episodic memory def-
available evidence is suggestive of a reduced risk of AD icits, Grober et al92 developed, at the end of the 1980s, a free
associated with light-to-moderate alcohol consumption, and cued selective reminding test (FCSRT), a list-learning test
compliance with a Mediterranean diet, higher educational that controls for successful encoding (achieved by cued
attainment, and regular engagement in physically and cog- recall) and facilitates retrieval processing (with the same
nitively stimulating activities. Physical and cognitive activ- semantic cues) of new words in episodic memory. With this
ities are associated with a beneficial effect on cognitive they highlighted an amnestic pattern specific to AD as
function and other indicators of dementia progression, while opposed to normal aging and other dementias. The test in
higher educational attainment is associated with faster AD patients often showed a low immediate recall score and a
cognitive decline. While several risk factors appear to be low performance despite cueing across successive


Fig. 3 Main clinical phenotypes and differential diagnoses (including only neurodegenerative diseases) of Alzheimer’s disease (AD), included or
not in the IWG2 criteria. 37 See text for details. AGD, argyrophilic grain disease; CARTS, cerebral age-related hippocampal sclerosis with TDP-43;
CBD, cortico-basal degeneration; CTE, chronic traumatic encephalopathy; FTLD, frontotemporal lobar degeneration; FUS, fused in sarcoma;
GGT, globular glial tauopathy; IWG2, International Working Group 2; LBD, Lewy body disease; PART, primary age-related tauopathy; PPA,
primary progressive aphasia; PRNP, PRioN protein; PSP, progressive supranuclear palsy; TDP, TAR DNA-binding protein.
rehearsals/recall trials.19,92,93 Moreover, AD patients also In addition, various neuropsychiatric disturbances can be
produce numerous intrusions, i.e., the patient offers a observed in patients with AD: apathy, dysphoria, and agita-
word which was not in the list of words to be remembered.94 tion are common during the course of the disease.105 In the
This pattern has been confirmed years later using biomarker- early stages of AD, apathy, expressed by profound disinterest
based criteria.95 Impaired FCSRT performance can be corre- in nonroutine and interpersonal activities, can often be
lated with hippocampal atrophy, gray matter loss of the observed, whereas psychosis (delusions or hallucinations)
medial temporal lobe, and the presence of Alzheimer’s CSF is more typical for advanced AD. Deterioration of cognition
biomarkers, even during the prodromal stage.23,24,96–99 It and behavior to a level which interfere with activities of daily
has shown discriminative utility for predicting conversion to living is the basis of a diagnosis of dementia. Ultimately, loss
AD in MCI patients.100 Hence, the FCSRT is specifically of self-care, eating, dressing, ambulation, incontinence, and
recommended in the IWG criteria. Other tests which can motor dysfunction lead to bedridden status and death.106
be useful in identifying the amnestic syndrome of AD focus Epilepsy (generalized convulsive seizures or complex partial
on list learning and delayed recall of information, for exam- seizures) can also occur in AD, but is not among the com-
ple paired-associate learning and the Rey auditory verbal monest manifestations of the disease.107 Younger age and
learning tasks.101 The DMS48 tests visual recognition and increasing dementia severity are the most reliable risk
has shown to correlate with AD patterns in patients with factors for seizures in AD.107
MCI.102 It is one of the several neuropsychological tests Main differential diagnoses for this clinical form encom-
designed to identify amnestic impairment with a pattern pass all neurodegenerative diseases that target the hippo-
which is specific for early pathological involvement of the campus early and preferentially. The long list of differential
entorhinal-perirhinal cortex. The short-term memory bind- diagnoses includes cerebral age-related hippocampal sclero-
ing test might also be a good marker for AD given its high sis with TDP-43 (CARTS),62,108 PART,45,109 AGD,55,110 atypi-
specificity in patients with familial AD and in asymptomatic cal forms of frontotemporal lobar degeneration (FTLD)18,111
carriers with PSEN1 autosomal dominant gene including 17q21.31 duplications,112 MAPT R406W muta-
mutations.103,104 tions,113 GRN mutations,114,115 C9ORF72 hexanucleotide
The natural history of AD is progression of cognitive expansions,116 globular glial tauopathy,117 atypical Lewy
decline and spread to other cognitive domains, for example, body disease,18,118,119 atypical chronic traumatic encepha-
other memory systems than episodic memory, aphasia, lopathy,120,121 and PRNP mutation122,123 (►Fig. 3). Biomar-
apraxia, visuospatial functions, executive functions, etc.89 kers in these cases should help the clinician to address the

correct AD diagnosis. This is complicated by the presence of On the other hand, the dysexecutive-predominant variant
multiple pathologies and the absence of reliable biomarkers AD is also usually an EOAD with a relatively pure dysexecu-
for most other causes (►Fig. 2). Nondegenerative etiologies tive syndrome, while behavior and episodic memory are
for a progressive amnestic syndrome include chronic alcohol usually relatively spared (►Fig. 3).145 AD is a relatively rare
consumption with or without Korsakoff’s syndrome,124 lim- cause of degenerative behavioral frontal dementia (i.e.,
bic encephalitis,125 cerebrovascular disease,18,111,126 and behavioral variant of frontotemporal dementia146): between
medial temporal lobe epilepsy.127 Finally progressive mem- 2 and 20% according to neuropathological series, and etiol-
ory impairment is a common feature in a range of neurolo- ogy is largely dominated by FTLD (►Fig. 3).137,147–150
gical disorders (e.g., Parkinson’s disease, Huntington’s Regarding the dysexecutive-predominant variant AD, the
disease, multiple sclerosis, amyotrophic lateral sclerosis, differential diagnosis is much wider. Indeed, prominent
normal pressure hydrocephalus, etc.), mental disorders impairments in attention and executive functioning prob-
(e.g., depression, posttraumatic stress disorder, schizophre- ably have the widest differential diagnoses and constitute
nia, bipolar disorder), or general medical diseases (e.g., many of the potentially reversible conditions. The neurode-
obstructive sleep apnea, hypothyroidism, vitamin deficiency, generative differentials include FTLD, Lewy body disease, and
amongst other). These alternative diagnoses and mimics may “subcortical neurodegenerative diseases” (Huntington’s dis-
be ruled out by meticulous clinical investigation, neuropsy- ease, Parkinson’s disease, PSP, and CBD; ►Fig. 3). Nonneur-
chological memory impairment profile, blood testing, and odegenerative causes include normal pressure hydrocephalus,
brain imaging.128,129 cerebrovascular disease, alcohol-related cognitive impair-
Beyond this typical amnestic AD profile, several atypical ment, white matter disease (multiple sclerosis, leukodystro-
presentations of AD have been described and account for phies, radiation-induced leukoencephalopathy), chronic

approximately 6 to 14% of AD cases.130–132 These atypical encephalitides (HIV dementia), toxic-metabolic diseases
forms of AD stand out by a relative intactness of memory (e.g., hypothyroidism, medications, obstructive sleep apnea),
function but a recognizable (or characteristic) phenotype fatigue, and psychiatric disorders (e.g., depression, posttrau-
that might be accompanied by topographical evidence of matic stress disorder, schizophrenia, bipolar disorder).151
brain damage (regional atrophy or hypometabolism) in
related regions. Atypical forms of AD generally occur at an Rare AD phenotypes
earlier age at onset than does typical amnestic AD. IWG Corticobasal syndrome is the most frequent atypical form of
criteria thus propose precise definitions for atypical AD AD that was not included in the IWG criteria. It is defined as a
presentations, including a PCA variant of AD, a logopenic progressive asymmetric clinical presentation including limb
variant of AD, and an executive variant of AD. rigidity or akinesia, limb dystonia, limb myoclonus, orobuc-
The visual variant of AD presents as a PCA133 and generally cal or limb apraxia, cortical sensory deficit, and alien limb
results in several signs and symptoms that distinguish two phenomena (►Fig. 3).152 AD represents, according to neu-
subtypes: an occipitotemporal variant130 with a predomi- ropathological series, approximately 24 to 50% of patients
nant impairment in the visual identification of objects, with corticobasal syndromes, confirmed by biomarkers in
symbols, words, or faces, and a more common biparietal clinical series (18%), while other etiologies include CBD,
variant134 with predominant visuospatial dysfunction, as progressive supranuclear palsy, FTLD-TDP, and diffuse Lewy
well as features of Gerstmann’s or Balint’s syndromes, limb body disease (►Fig. 3).137,153–155
apraxia, or neglect (►Fig. 3). AD is the main cause of PCA Other rare focal presentations have also been described
(62–100% according to neuropathological series), while (►Fig. 3). Mesulam and colleagues141 have reported two
other neurodegenerative etiologies include Lewy body dis- cases (12%) of nonfluent variants of primary progressive
ease, corticobasal degeneration (CBD), and prion-associated aphasia due to AD pathology at autopsy. There was also one
diseases (►Fig. 3).135–138 case (33%) of semantic variant of primary progressive apha-
The language variant of AD, which presents as logopenic sia due to AD. This is confirmed by Alladi and colleagues’
variant primary progressive aphasia, is defined by a pro- work,137 where they identified 12 cases (46%) of nonfluent
gressive impairment in single-word retrieval and in repeti- variants of primary progressive aphasia due to AD pathology
tion of sentences in the context of spared semantic, syntactic, and 2 cases (10%) of semantic variant of primary progressive
and motor speech abilities (►Fig. 3).139 AD represents, aphasia (►Fig. 3). Note that the relatively high prevalence of
according to neuropathological series, approximately 55 to AD amongst nonfluent variants of primary progressive
100% of logopenic primary progressive aphasias, while other aphasia in this last study was not reproduced by other
etiologies include FTLD-tau or TDP, CBD, and prion-asso- studies, and may have included logopenic variants of pri-
ciated diseases (►Fig. 3).140–142 mary progressive aphasia (0 AD in 33 cases of nonfluent
The frontal variant of AD presents similarly to the beha- variant of primary progressive aphasia pooled from studies
vioral variant of frontotemporal dementia, with progressive of Harris et al140 and Spinelli et al142).
apathy or behavioral disinhibition, stereotyped behaviors,
and predominant executive dysfunction on testing.143–145 Early-Onset Alzheimer’s disease versus Late-Onset
The behavioral predominant variant of AD is usually an EOAD Alzheimer’s disease
with more severe dysexecutive than behavioral features, Data regarding EOAD have recently been reviewed by Men-
while episodic memory is usually impaired (►Fig. 3).145 dez.156 The EOAD is much more heterogeneous than LOAD

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