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...AD is not a homogeneous


disease and memory impairment
is not always the first symptom
of the disease.
Albert Llad1 & Raquel Snchez-Valle1
Alzheimers Disease & Other Cognitive Disorders Unit, Hospital Clnic Barcelona, C/Villarroel, 170,
08036Barcelona, Spain

Author for correspondence: Tel.: +34 932 275 785 n Fax: +34 932 275 783 n allado@clinic.ub.es
1

Alzheimers disease (AD) is the most frequent


cause of neurodegenerative dementia, and its
prevalence and incidence increases with age. AD
has been divided into two clinical forms according to age at onset: early-onset AD (EOAD) and
late-onset AD (LOAD) [1] . EOAD is arbitrarily
defined by an onset of symptoms below 65years
of age. Few data are available regarding the frequency of EOAD, but incidence is estimated to
be approximately seven new cases per 100,000
individuals at risk per year, with a prevalence of
1535 per 100,000 people at risk [2] . Although
EOAD is a rare disease compared with LOAD,
representing less than 10% of all AD cases,
the interest of EOAD has increased in recent
years, as differences in both clinical features
and individual care needs with LOAD arise.
Nevertheless, the underlying neuropathological changes are similar regardless of the age
at onset. To achieve definite AD diagnosis, a
neuropathological examination is required [3] ,
showing typical extracellular neuritic plaques
with deposits of amyloid-b (Ab) and intraneuronal neurofibrillary tangles composed of
hyperphosphorylatedtau.
Typical & atypical AD

The typical clinical pattern of AD usually starts


with episodic memory alteration and progresses
to affect other cognitive domains. However,
AD is not a homogeneous disease and memory
impairment is not always the first symptom of
the disease [2,4,5] . Different studies have shown
that there are several nonamnestic presentations
of AD, and some of them are well-recognized
syndromes [6] . These cortical focal syndromes
would include posterior cortical atrophy (PCA),
behavioraldysexecutive syndrome or logopenic
aphasia [4,6,7] . Apart from these well-recognized
10.2217/FNL.11.40 2011 Future Medicine Ltd

Editorial

Future Neurology

Focusing on atypical symptoms for


improved diagnosis of early-onset
Alzheimers disease

syndromes, other less-specific cognitive alterations, such as affective disorders, or other


infrequent presentations, such as biparietal syndrome, could also be the first manifestation of
AD [8] . In addition, AD may mimic the typical
clinical presentations of other neurodegenerative diseases, such as corticobasal degeneration
or semantic dementia (SD).

The new recommendations from the


National Institute of Aging and the
Alzheimers Association ... workgroup also
introduce different nonamnestic
presentations as possible core clinical
criteria, including language
presentation, visuospatial presentation
and executive dysfunction.

In this sense, Dubois and collaborators in their


position paper define atypical AD as the less
common and well-characterized clinical phenotypes of the disease that occur with Alzheimers
pathology [9] . These clinical syndromes include
primary progressive nonfluent aphasia, logopenic aphasia, frontal variant of AD and PCA.
They propose that in the case of one of these
clinical presentations, the diagnosis of AD is
supported by invivo evidence of brain amyloidosis (with retention of specific amyloid-labeling
radioligands) or in the cerebrospinal fluid (CSF;
with alterations in Ab42 , total tau and phosphorylated tau concentrations, characteristic of
Alzheimers pathology). The new recommendations from the National Institute of Aging and
the Alzheimers Association (NIAAA) workgroup also introduce different nonamnestic
presentations as possible core clinical criteria,
including language presentation, visuospatial
Future Neurol. (2011) 6(5), 575578

Keywords
Alzheimers disease
symptoms
ndementia n diagnosis
nearly-onset
n

natypical

part of

ISSN 1479-6708

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Llad & Snchez-Valle

presentation and executive dysfunction [10] .


However, NIAAA criteria also state that the
diagnosis of probable AD dementia should not
be applied where there is evidence of prominent
features of behavioral variant frontotemporal
lobar degeneration (bvFTLD), SD or nonfluent/agramatic progressive aphasia. Despite this,
up to 50% of cases with a clinical diagnosis of
corticobasal syndrome (CBS), 71.4% patients
with mixed aphasia, 44.1% of patients with
primary progressive nonfluent aphasia, 7.1%
of patients with bvFTLD and 10% of patients
with SD may present with AD pathology in the
neuropathological examination [6] . Some clinical
clues can suggest AD pathology in some of these
presentations (absence of tremor and presence
of myoclonus in CBS, predominant phrase repetition alteration in progressive aphasia, visuomotor slowness or memory complaints in SD),
but none of these can be used for diagnosis by
themselves [7,11] .
Atypical presentations of AD & EOAD

The atypical presentations of AD are more frequent in patients with EOAD. Koedam etal.
described that a third of patients with EOAD
present with nonmemory impairment compared
with only 6% of patients with LOAD, so atypical
AD could be up to five-times more frequent in
EOAD [1] . Our group also described that a third
of pathologically confirmed EOAD patients presented atypically [4] . The frequency of the different atypical presentations of EOAD varies
between different series. Our group found that
the frontal variant, characterized by behavioral
and/or dysexecutive problems, was the most frequent non-memory presentation in a group of 40
patients with pathologically proven EOAD [4] .
Other atypical presentations described in this
series were visuospatial dysfunction, CBS and
language disturbances. Koedam etal. found that
executive dysfunction was more frequent than
behavioral changes in a minority of 270 patients
studied, and none of them fulfilled the criteria for frontotemporal dementia. In this study,
apraxia/visuospatial dysfunction was the most
frequent nonmemory presentation, followed
by language impairment and aphasicapraxic
agnostic syndrome, whereas PCA was diagnosed
less often [1] .
Atypical presentations of EOAD represent a
problem in everyday clinical practice because
of the higher risk of misdiagnosis. Recently,
our group described that more than half of
patients with pathologically confirmed EOAD
and atypical presentations were misdiagnoses.
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Future Neurol. (2011) 6(5)

For example, half of the EOAD patients with a


dysexecutivebehavioral presentation were diagnosed with bvFTLD during life. Furthermore,
the patients with EOAD and their families can suffer a diagnostic delay longer than
3years [4] , sometimes because of inconclusive
initialdiagnosis.

...a third of patients with EOAD present


with nonmemory impairment compared
with only 6% of patients with LOAD, so
atypical AD could be up to five-times
more frequent in EOAD.
Currently, little is known about why some
patients with AD have an atypical presentation
and why these presentations are more frequent
in EOAD. It has been suggested that differences
in the genetic background or environmental factors could be responsible for the atypical onset
of AD. Thus, the different clinical presentations
of AD could reflect the involvement of different genotypes. AD patients with a nonmemory
phenotype had a lower proportion of APOE e4
alleles in comparison to typical AD, suggesting
that the typical amnesic phenotype is indeed
promoted by the APOE e4 allele [12] . However,
Balasa et al. found no significant difference
between the typical and atypical presentations
in APOE genotypes in EOAD [4] . The presence
of concomitant copathology can be another
cause for an atypical presentation, although it is
improbable in EOAD. Some authors have suggested that the differences found between EOAD
and LOAD could indicate different agerelated
vulnerabilities to amyloid burden[13,14] .
Improving the diagnosis of EOAD

Since 1984, when NINCDSADRDA criteria


for AD were proposed, new diagnostic tools have
appeared, including CSF biochemical markers,
new neuroimaging techniques and genetic studies. These ancillary investigations can be of two
types: biomarkers of neuronal degeneration or
injury and biomarkers of AD pathophysiological process (i.e., markers of the amyloid deposition in the brain). The main markers of neuronal degeneration or dysfunction are MRI and
functional neuroimaging (PET or SPECT). The
structural or functional neuroimaging changes
correlate with the clinical features, and in this
sense, while typical LOAD presents with medial
temporal atrophy and hypometabolism in parietotemporal areas, atypical presentations of AD
do not show these signs. On the contrary, PCA
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Focusing on atypical symptoms for improved diagnosis of early-onset Alzheimers disease

patients present parietooccipital atrophy and


hypometabolism with preserved medial temporal
lobes, for example [15] . In addition, even memory
presentations of EOAD may lack medial temporal atrophy and present predominant atrophy
in neocortical structures, such as the precuneus
[2,14] . Therefore, the interpretation of the neuroimaging findings should take into account
the clinical presentation and characteristics of
the subject. With respect to pathophysiological
markers, multiple studies have demonstrated that
the CSF AD biochemical signature is characterized by a decrease of Ab42 and increase of total
tau and phosphorylated tau, with Ab42 being the
first CSF biomarker to be altered in the course
of the disease [16,17] . The brain amyloid deposition can also be detected by PET with different tracers, such as Pittsburgh compoundB[18] .
Pathophysiological markers are positive in both
LOAD and EOAD and in typical and atypical
presentations. Moreover, the amyloid burden or
the levels of Ab42 are not significantly different
among these different presentations of AD [14,15] .
The main criticism to the use of AD pathophysiological markers for diagnosis is the possible existence of copathology. In EOAD, the presence
of mixed pathology is more unlikely and pathophysiological markers have proven to be even
more specific in EOAD than in LOAD[2,19] .

Editorial

Monogenic AD is infrequent and presents


with early-onset and autosomal-dominant patterns of inheritance. Although rare, the presence of a mutation in one of these genes confirms the diagnosis of AD invivo in patients
with co gnitive decline, even with atypical
features[10,20] .
In conclusion, AD may present with a wide
range of cognitive symptoms, including memory and non-memory presentations (PCA,
progressive aphasia, CBS or frontal variant of
AD). The two new sets of diagnostic criteria
acknowledge, for the first time, the existence
of non-memory presentations of AD, but do
not offer detailed criteria for these presentations [9,10] . Future research in atypical AD will
require consensus criteria for each subtype
and more precise definitions, including data
on cognitive testing and ancillary explorations. EOAD patients need an early and accurate diagnosis and atypical presentations are
more frequent in EOAD. In this sense, the
implementation of AD biomarkers (CSF biomarkers or amyloid brain burden with amyloid
tracers) will be desirable to support diagnosis not only in a research setting, but also in
the everyday clinical practice, particularly in
early-onsetdementias.
Financial & competing interests disclosure

...little is known about why


some patients with AD have
an atypical presentations and
why these presentations are more
frequent in EOAD.

Finally, mutations in the amyloid precursor


protein gene (APP), presenilin1 gene (PSEN1)
or presenilin2 gene (PSEN2) can cause AD.

Department of Health and Human Services


Task Force on Alzheimers disease. Neurology
34, 939944 (1984).

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The authors have no relevant affiliations or financial


involvement with any organization or entity with a
financial interest in or financial conflict with the
subject matter or materials discussed in the
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