Hort et al 2010 European Journal of Neurology.pdf

European Journal of Neurology 2010, 17: 1236–1248
doi:10.1111/j.1468-1331.2010.03040.x
E F N S G U I D E L I N E S / C M E A R T I C L E
EFNS guidelines for the diagnosis and management of AlzheimerÕs
disease
J. Horta, J. T. OÕBrienb, G. Gainottic, T. Pirttilad, , B. O. Popescue, I. Rektorovaf, S. Sorbig
and P. Scheltensh on behalf of the EFNS Scientist Panel on Dementia
aMemory Disorders Clinic, Deartment of Neurology, Charles University in Prague, Second Faculty of Medicine and Motol Hospital, Prague,
Czech Republic; bInstitute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK; cNeuropsychology Service, Policlinico
Gemelli/Catholic University, Rome, Italy; dDepartment of Neurology, Kuopio University Hospital, Kuopio, Finland; eDepartment of
Neurology, University Hospital, ÔCarol DavilaÕ University of Medicine and Pharmacy, Bucharest, Romania; fFirst Department of Neurology,
Masaryk University and St. AnneÕs Hospital, Brno, Czech Republic; gDepartment of Neurological and Psychiatric Sciences University of
Florence, Italy; and hDepartment of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands
Keywords:
Background and objectives: In 2008 a task force was set up to develop a revision of the
AlzheimerÕs disease,
European Federation of the Neurological Societies (EFNS) guideline for the diagnosis
dementia, diagnosis,
and management of AlzheimerÕs disease (AD) and other disorders associated with
guideline, management,
dementia, published in early 2007. The aim of this revised international guideline was
review, treatment
to present a peer-reviewed evidence-based statement for the guidance of practice for
clinical neurologists, geriatricians, psychiatrists, and other specialist physicians
Received 21 January 2010
responsible for the care of patients with AD. Mild cognitive impairment and non-
Accepted 11 March 2010
Alzheimer dementias are not included in this guideline.
Methods: The task force working group reviewed evidence from original research
articles, meta-analysis, and systematic reviews, published before May 2009. The evi-
dence was classiﬁed and consensus recommendations graded (A, B, or C) according to
the EFNS guidance. Where there was a lack of evidence, but clear consensus, good
practice points were provided.
Results: The recommendations for clinical diagnosis, blood tests, neuropsychology,
neuroimaging, electroencephalography, cerebrospinal ﬂuid (CSF) analysis, genetic
testing, disclosure of diagnosis, treatment of AD, behavioural and psychological
symptoms in dementia, legal issues, counselling and support for caregivers were all
revised as compared with the previous EFNS guideline.
Conclusion: A number of new recommendations and good practice points are made,
namely in CSF, neuropsychology, neuroimaging and reviewing non-evidence based
therapies. The assessment, interpretation, and treatment of symptoms, disability,
needs, and caregiver stress during the course of AD require the contribution of many
diﬀerent professionals. These professionals should adhere to these guideline to
improve the diagnosis and management of AD.
Societies (EFNS) recommendation on the diagnosis and
Objectives
management of Alzheimer disease (AD) [1]. The pre-
The objective of the Task Force set up in 2008 was to
vious guideline reﬂected Diagnostic and Statistical
revise previous European Federation of Neurological
Manual, 4th edition (DSM IV) and National Institute
of Neurological, Communicative Disorders and Stroke
Correspondence: J. Hort, MD, PhD, Associated Professor, Memory
– AlzheimerÕs Disease and Related Disorders Associa-
Disorders Clinic, Department of Neurology, Charles University,
tion (NINCDS-ADRDA) criteria for dementia syn-
Second Faculty of Medicine and Motol University Hospital, V u´valu
drome and AD. In the revised guideline special
84, 150 18 Praha 5, Czech Republic (tel.: +420 22443 6801;
attention was given to whether further evidence had
fax: +420 22443 6875; e-mail: [email protected]).

become available for biomarkers of disease like mag-
Deceased.
netic resonance imaging (MRI), positron emission
This is a Continuing Medical Education article, and can be found with
tomography (PET) and cerebrospinal ﬂuid (CSF) that
corresponding questions on the Internet at http://www.efns.org/
have been proposed to increase the conﬁdence of the
EFNSContinuing-Medical-Education-online.301.0.html. Certiﬁcates
for correctly answering the questions will be issued by the EFNS.
clinical diagnosis [2]. Special attention was given to
Ó 2010 The Author(s)
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European Journal of Neurology Ó 2010 EFNS

EFNS guidelines for AlzheimerÕs disease
1237
results of recent clinical trials in AD, both for cognitive
evaluated according to pre-speciﬁed levels of certainty
and behavioral aspects of the disease. Because AD is the
(classes of evidence I, II, III, and IV) by the expert
focus of this guideline, non-Alzheimer dementias such
group members, and the recommendations were graded
as vascular (VaD), frontotemporal (FTLD), Parkinson
according to the strength of evidence (grade A, B, or C),
disease dementia, dementia with Lewy bodies (DLB),
using the deﬁnitions given in the EFNS guidance [6]. In
corticobasal degeneration (CBD), progressive supra-
addressing important clinical questions, for which no
nuclear palsy (PSP), Creutzfeldt–Jacob (CJD) and
evidence was available, Ôgood practice pointsÕ were
others will be dealt with separately. This guideline
recommended based on the experience and consensus of
represents desirable standards to guide practice, but
the expert task force group.
may not be appropriate in all circumstances as clinical
presentation of the individual patient and available
Reaching of the consensus
resources should be taken into account. Cost-eﬀective-
ness is not discussed, as heterogeneity across Europe
A proposed guideline with speciﬁc recommendation
will result in diﬀerent, country speciﬁc, conclusions.
was drafted for circulation to task force members and
displayed on EFNS web pages for comments from all
panel members. Consensus was reached at three task
Background
force meetings during 2009.
Dementia aﬀects 5.4% of the over 65s and its prevalence
further increases with age [3]. AD is responsible for the
Results
majority of cases. The European Collaboration on
Dementia, co-ordinated by Alzheimer Europe, found
Clinical diagnosis: medical history, laboratory,
there were currently 8.45 million people in Europe with
neurological and physical examination
AD. Dementia causes a signiﬁcant ﬁnancial burden to
society, estimated at 141 billion Euros of annual cost for
The history, from the patient and a close informant,
the whole of Europe, of which 56% are the costs of
should focus on the aﬀected cognitive domains, the
informal care. The costs per person with dementia was
course of the illness, and the impact on ADL and any
about 21 000 Euros per year, while disability caused by
associated non-cognitive symptoms. Past medical his-
the illness is estimated at 350 disability adjusted life
tory, co-morbidities, family and educational history are
years per 100 000 persons, compared to 247 caused by
important. The neurological and general physical
diabetes [4]. With increasing longevity, numbers of
examination is particularly important in distinguishing
people with dementia are set to double in the next
AD from other primary degenerative and secondary
30 years [3]. AD with early onset (< 65 years) merits
dementias and co-morbidities [1]. There exist no evi-
special consideration because of its greater genetic pre-
dence-based data to support the usefulness of speciﬁc
disposition, diﬀering clinical and cognitive proﬁle and
routine blood tests for evaluation of those with dementia
course, which is characteristically more aggressive than
but these are useful in excluding co-morbidities. Most
in late onset cases. In addition subjects may still be
expert opinion advises to screen for vitamin B12, folate,
working and of childbearing age. Early onset AD,
thyroid stimulating hormone, calcium, glucose, com-
therefore, poses particular management issues.
plete blood cell count, renal and liver function abnor-
Clinical AD is often preceded by a phase called Mild
malities. Serological tests for syphilis, Borrelia and HIV
Cognitive Impairment (MCI) in which there are com-
should be considered in individual cases at high risk or
plaints and objective impairments in one or more cog-
where there are suggestive clinical features.
nitive domains, but with preserved activities of daily
living (ADL) [5]. The panel decided not to review MCI
Assessment of cognitive functions
syndrome extensively since discussions around the
nosological status of MCI and its relationship to AD
There are two main reasons for neuropsychological
are ongoing.
assessment in AD: (i) the diagnosis of dementia requires
evidence of multiple cognitive defects; and (ii) initial
stages of all principal forms of dementia have a selective
Search strategy
anatomical localisation reﬂected by typical patterns of
The evidence for this guideline was collected from
neuropsychological impairment. Screening tests are
Cochrane Library reviews, meta-analyses and system-
used to assess cognitive functions globally to identify
atic reviews and original scientiﬁc papers published in
patients who require more detailed investigation. This
peer-reviewed journals before May 2009 accessed using
is then undertaken with a battery of neuropsycho-
the MEDLINE database. The scientiﬁc evidence were
logical tests which should evaluate memory, executive
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1238
J. Hort et al.
functions, language, praxis and visual-spatial abilities.
mesial temporal lobe atrophy (entorhinal cortex, hip-
The most widely used screening test (I) is the Mini-
pocampus) which disables consolidation. Retrieval,
Mental State Examination (MMSE), which standard
which depends on frontal lobe and subcortical struc-
cut-oﬀ score (24) should be increased to 27 in highly
tures, is less aﬀected. This can be clariﬁed by cuing as
educated individuals [7] and lowered in patients whose
applied in California Verbal Learning Test [9] or Bus-
native tongue is another language or with low educa-
chke Free and Cued Selective Reminding test, to dis-
tion. Patients with early AD fail mainly in orientation
tinguish patients at an early stage of AD from other
and memory tasks, whereas fronto-temporal dementia
subjects [10]. The Rey Auditory Verbal Learning Test
(FTD) individuals exhibit early impairment in speech
(RAVLT) can distinguish between patients with AD
and DLB patients may be aﬀected in visuospatial
and those without dementia or between AD and other
components (pentagons) [8]. Other neuropsychological
forms of dementia with a diagnostic accuracy of
or clinical screening instruments reported in Table 1
83–86% [11]. In particular, a very severe impairment
provide an equal or greater accuracy in the diagnosis of
(0 score) on RAVLT delayed free recall has a very high
AD (III).
(97%) speciﬁcity for AD (I) [11]. A less severe score can
raise diagnostic problems, since it can be due to defec-
Memory functions
tive encoding resulting from depression, anxiety or
Memory, especially episodic memory, should be sys-
attentional deﬁcit. A comparison between free recall
tematically assessed (I), because it is the function most
and cued recall revealed diﬀerent results in mild AD
commonly impaired early in AD as consequence of
patients. Vogel et al. [12] found that cued and free recall
Table 1 Assessment of cognitive functions in AD
Screening tests
Sensitivity
Speciﬁcity
References
Neuropsychological instruments
MMSE
80–85% (Demented
76–80%
[94]
versus non-demented
very old patients)
7 min
93%
93% (AD versus various forms of depression and dementia)
[95]
ACE
94%
89% (AD versus NC and other forms of dementia)
[96]
MOCA
90%
90% (Mild AD versus MCI and NC)
[97]
Mattis D.R.S.
85%
85% (AD versus FTD)
[98]
Clock drawing 67%
97%
(very mild AD versus NC)
[99]
CERAD battery 80%
81%
(Mild AD versus MCI and NC)
[100]
5 words test
91%
87% (AD versus functional memory disorders)
[15]
Assessment of speciﬁc cognitive domain
Episodic memory
Logical memory
89% (free recall)
87% (very mild AD versus NC)
[14]
FCSRT
80% (free and cued recall)
90% (MCI converters versus non-converters)
[10]
CVLT
50% (free and cued recall)
98% (Mild AD versus MCI and NC)
[9]
Category cued recall
88%
89% (very mild AD versus NC)
[12]
RAVLT
50% (0 score) (free recall
97% (AD versus other forms of dementia)
[11]
and recognition)
Semantic memory (category ﬂuency)
[16]
Language (naming)
Graded naming
[21]
Boston naming
Overall accuracy: 77%
[20]
(AD versus NC)
Visual-spatial abilities
BVRT
[22]
Executive functions
Verbal ﬂuency tests
[16]
WCST
[17]
TMT
[18]
Stroop test
[19]
MMSE, Mini-Mental State Examination; ACE, AddenbrookeÕs cognitive examination; MOCA, Montreal Cognitive Assessment; FCSRT, Free
and Cued Selective Reminding test; CVLT, California Verbal Learning Test; RAVLT, Rey Auditory Verbal Learning Test; BVRT, Benton Visual
Retention Test; CST, Wisconsin Card Sorting test; TMT, Trail Making Test; AD, AlzheimerÕs disease; MCI, mild cognitive impairment; FTD,
fronto-temporal dementia; NC, normal controls.
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EFNS guidelines for AlzheimerÕs disease
1239
had the same values of sensitivity and speciﬁcity
Roth Dementia Scale and the Informant Questionnaire
whereas Ivanoiu et al. [13] found that cued recall test
on Cognitive Decline in the Elderly are also helpful in
was the best predictor of mild AD. High values of
detection of dementia [1]. The AD8 is a brief, sensi-
sensitivity and speciﬁcity have also been obtained by
tive informant-based questionnaire that reliably diﬀer-
Salmon et al. [14] with the delayed recall from the
entiates
between
non-demented
and
demented
ÔLogical MemoryÕ test or in the Ô5 wordÕ test [15].
individuals. The respondent rates change (yes versus
Semantic memory (category ﬂuency test, pictures
no) in memory, problem-solving abilities, orientation,
naming task, word and picture deﬁnition) testing may
and ADL [25].
conﬁrm deﬁcits in AD or more prominently in Semantic
Dementia [16].
Assessment of behavioural and psychological
symptoms
Executive functions
A predominance of executive dysfunction over episodic
The term Ôbehavioral and psychological symptoms of
memory impairment is typical for FTLD and VaD (III)
dementiaÕ (BPSD) is used to describe the spectrum
and is more frequent in early onset AD. Decreased
of non-cognitive symptoms of dementia (apathy, psy-
ﬂuency on verbal ﬂuency tests, perseverations on the
chosis, aﬀective and hyperactive behaviors) [26] Iden-
Wisconsin card sorting test (WCST) [17]; reduced speed
tiﬁcation of neuropsychiatric symptoms is essential
of processing on the Trail Making test [18] and defects
since BPSD occur in the majority of persons with
in inhibiting automatic responses on the Stroop test
dementia over the course of the disease, and in 35–
[19], may be caused by subcortical or frontal lesions
75% of MCI patients [27] (I). BPSD are associated
[18,19].
with declining cognitive and functional ability [27],
Language (speech comprehension and production,
decreased quality of life and increased institutionali-
reading and writing) praxis and visual-spatial abilities
zation. Somatic co-morbidity and environmental trig-
can be variably aﬀected according to type and stage of
gers should be ruled out as a possible cause. Several
dementia suggesting for prominent cortical involve-
global reliable and validated scales are used to assess
ment. Boston Naming test [20] or the Graded Naming
BPSD and their change as a result of treatment [28].
test [21] are frequently impaired in the earliest stages of
They rely upon the report of an informant and include
AD. High number of errors on the Benton visual
the neuropsychiatric inventory, and the behavior rating
retention test can predict the development of AD more
scale for dementia of the CERAD (CERAD-BRSD)
than a decade before diagnosis [22].
[29]. For assessing treatment eﬀects the change in
Studies of apraxia are remarkably few in AD, but a
scales representing a clinically meaningful improve-
signiﬁcant relationship has been found between apraxia
ment has not been established. More focused scales
severity and dependency in ADL [23].
evaluating agitation or depression in dementia are also
The ADAS cog is a 11-item cognitive test battery that
available [29]. The Cornell scale for depression in
has been particularly useful to detect changes in severity
dementia (CSDD) is based on combined caregiver and
of AD, mainly in clinical trials, but it is not useful for
patient interviews. The 15-item geriatric depression
diagnostic purposes.
scale has also been validated for use in AD but the
CSDD appears to be a more sensitive and speciﬁc tool
for detecting depression independently of the severity
Assessment of ADL
of dementia [30].
Functional decline is required for the diagnosis of
dementia. It also allows evaluation of the need for
Assessment of co-morbidity
personal and institutional care. ADLÕs are divided into
Basic (e.g. bathing, toileting) and Instrumental (e.g.
AD patients commonly have co-morbid medical con-
shopping, handling ﬁnances), the latter being more
ditions such as depression, cardiovascular and pulmo-
vulnerable to cognitive decline early in the course of the
nary diseases, infections, arthritis, other neurological
disease. There is no Ôgold standardÕ available for ADL
disorders, sleep disturbances, falls and incontinence,
assessment. Out of 12 systematically reviewed scales the
and drug-related adverse eﬀects, especially in older
informant-based questionnaires the Disability Assess-
patients. There is a strong association between medical
ment for Dementia and the Bristol ADL are among the
conditions and impaired cognitive status in AD and the
most useful, though their overall psychometric prop-
prompt identiﬁcation and treatment of the associated
erties were still only of moderate quality [24]. ADL are
medical illnesses at the time of diagnosis and through-
reﬂected in the clinical dementia rating scale which is
out the disease evolution may improve cognition in AD
widely used for rating of dementia severity. The Blessed
patients [31].
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J. Hort et al.
Neuroimaging
standardized acquisition and analysis methods are used
since results and interpretation of DATScans may
Structural imaging in the diagnostic work up of AD
otherwise vary [39]. FDG-PET has become a practically
serves two purposes: exclude other, potentially surgically
applicable tool since the wide distribution of PET CT
treatable diseases and include speciﬁc ﬁndings for AD.
machines. It may reveal speciﬁc abnormalities in AD
For the former CT and MRI perform as well and
by showing reduced glucose metabolism in the parietal
most current guidelines agree that such an imaging
and superior/posterior temporal regions, posterior
procedure should be carried out once in every patient.
cingulate cortex, and precuneus. In advanced stages of
However, MRI is more sensitive to subtle vascular
AD, frontal lobe defects are also seen. 18FDG-PET has
changes (strategic infarcts for instance) and to changes
been reported to have a sensitivity of 93% and a
that may indicate speciﬁc conditions such as multiple
speciﬁcity of 63% in predicting a pathological diagnosis
sclerosis, PSP, multiple-system atrophy, CBD, prion
of AD (II) [40]. FDG-PET is particularly useful in the
disease, FTLD (for review see [32]). For practice
diﬀerential diagnosis of AD towards other dementias
purposes a standard MR protocol involving at least
with speciﬁcity higher than 95% in early onset cases
coronal T1 and axial T2 or ﬂuid-attenuated inversion
[41]. Based on the study by Foster et al. [42] FDG-PET
recovery sequences should be used. Contrast is not
is reimbursed in the USA for the distinction between
indicated. Of note, vascular changes seen on CT or
AD and FTD only. A very promising development is
MRI need not preclude a diagnosis of AD, especially in
the possibility of imaging amyloid with new PET
older age, but should prompt adequate evaluation and
ligands. As of yet these are not available for routine use.
treatment of cardiovascular risk factors.
Hippocampal atrophy is best seen on MRI but may
also be visualized on the more modern type CT scanner
Electroencephalography (EEG)
[33] and yields sensitivity and speciﬁcity values between
The EEG may help to diﬀerentiate between AD, sub-
80 and 90% in most studies [32–34] (II). Since the
jective complains and psychiatric diagnoses. EEG is
previous guideline only one prospective study has been
recommended in diﬀerential diagnosis of atypical clin-
performed examining the added value of hippocampal
ical presentations of AD. It can also provide early
atrophy on MRI in the diagnosis of AD with post-
evidence for CJD or suggest the possibility of a toxic-
mortem veriﬁcation [35]. However, being a single cen-
metabolic disorder, transient epileptic amnesia or other
ter, small study, in a selected population, it just fails
previously unrecognized seizure disorder. Even though
class I evidence.
reduced alpha power, increased theta power and lower
AD patients with early age of onset often present with
mean frequency are characteristic for AD patients,
complaints and cognitive deﬁcits other than memory
EEG can be normal early in the course of the disease in
impairment [36]. Several structural MRI studies localize
up to 14% of cases. In diﬀerent studies, the diagnosis
the pattern of the atrophy in early-onset AD to more
accuracy of EEG for AD patients versus healthy con-
posterior regions with prominent involvement of the
trol subjects with similar demographic characteristics
precuneus and posterior cingulate cortex [37].
varied widely, with diagnosis odds ratios between 7 and
In addition, MRI may also be useful to monitor
219 [43]. EEG with only diﬀuse abnormalities argues
changes over time and may aid the clinician in following
for AD, EEG with both diﬀuse and focal changes
the disease process and explaining it to the patient
suggests AD or other forms of dementia [44].
(good practice point).
Functional neuroimaging [i.e., ﬂuorodeoxy-glucose-
(FDG-) PET and single photon emission computed
CSF analysis
tomography (SPECT)] may increase diagnostic conﬁ-
Routine CSF cell count, protein, glucose and protein
dence in the evaluation of dementia. In a clinical-
electrophoresis assessment is mandatory when vasculi-
pathological study, a positive perfusion SPECT scan
tis, inﬂammatory, hematologic or demyelinating disease
raised the likelihood of AD to 92%, whereas a negative
is suspected and in cases of suspected CJD in diﬀeren-
SPECT scan lowered the likelihood to 70%. SPECT
tiation with AD.
was more useful when the clinical diagnosis was
The elevation of the 14-3-3 protein reﬂects acute
ÔpossibleÕ AD, with the likelihood of 84% with a
neuronal loss and supports diagnosis of CJD [45] (II)
positive SPECT, and 52% with a negative SPECT
while high to very high levels of total tau yield high
[38]. Dopaminergic SPECT imaging (FP-CIT or
speciﬁcity for CJD [46,47]. In AD decreased levels of
DATScanä; GE Healthcare, Amersham, UK) is useful
beta-amyloid 42 (Ab42) and increased total-tau or
to diﬀerentiate AD from DLB with sensitivity and
phospho-tau in CSF are frequently found. The pooled
speciﬁcity around 85% (I). Care should be taken that
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EFNS guidelines for AlzheimerÕs disease
1241
sensitivity and speciﬁcity for Ab42 in AD versus controls
diagnosis. Brain biopsy may have a role in the diagnosis
from 13 studies involving 600 patients and 450 controls
of dementia where a treatable disease cannot be
were 86% and 90% [48]. For total-tau, the sensitivity
excluded by other means. However, it has been shown
was 81% and the speciﬁcity 90%, pooled from 36 studies
that information obtained at biopsy aﬀected treatment
with 2500 patients and 1400 controls. Across 11 studies
in only 11% of cases biopsied for the suspicion of an
with a total of 800 patients and 370 controls, phospho-
infectious or inﬂammatory etiology, though the role
tau had a mean sensitivity of 80% and speciﬁcity was set
of brain biopsy may increase as disease-modifying
at 92% but sensitivities varied widely among studies
therapies become available [56].
using diﬀerent methods. Combined assessment of Ab42
and total-tau revealed sensitivities (85–94%) and speci-
Recommendations for diagnosis
ﬁcities (83–100%) in AD versus controls [48] (I).
Speciﬁcity of these markers for AD has been lower
Clinical history should be supplemented by an infor-
(39–90%) in diﬀerential to the other dementias in clinic-
mant (Level A). A neurological and physical examina-
based series [49] which may relate to the presence of
tion should be performed in all patients with dementia
co-morbid AD pathology [50] (III).
(good practice point). ADL impairment due to cogni-
There are considerable diﬀerences in absolute con-
tive decline is an essential part of the diagnostic criteria
centrations of these markers between laboratories, even
for dementia and should be assessed in the diagnostic
when the same kit is used [51,52]. Before CSF can be
evaluation (Level A).
widely accepted as a reliable tool a consensus for pro-
Several informant based questionnaires are available
cessing and handling of the samples is needed [51].
and should be used where possible (good practice point).
Cognitive assessment should be performed in all
patients (Level A). Quantitative neuropsychological
Genetic testing
testing should be made in patients with questionable or
The genetics of dementia is complex and genetic testing
very early AD (Level B). The assessment of cognitive
is associated with many ethical concerns. APP, PS1 and
functions should include a general cognitive measure
PS2 gene mutations explain 50% of the familial form of
and more detailed testing of the main cognitive
early-onset AD [53]. The ApoE 4 allele is the only
domains, and in particular an assessment of delayed
genetic factor consistently implicated in late-onset AD,
recall (Level A). In patients with moderate memory
but it is neither necessary nor suﬃcient for development
impairment cued recall could be more appropriate than
of the disease [54]. Hence, there is no evidence to suggest
free recall (Level B).
ApoE testing is useful in a diagnostic setting. Autopsy
Assessment of BPSD should be performed in each
diagnosis in familial dementias can be valuable for
patient (Level A). Information should be gathered from
subsequent diagnosis and counselling. Testing of
an informant using an appropriate rating scale (good
patients with familial dementia and of unaﬀected
practice point).
at-risk-relatives should be accompanied by neurogenetic
Assessment of co-morbidity is important in AD
counselling and undertaken only after full consent and
patients, both at the time of diagnosis and throughout
by specialist centres. Pre-symptomatic testing may be
the course of the illness (good practice point) and should
performed in at risk member of family-carrying muta-
always be considered as a possible cause of BPSD (Level
tion. It is recommended that the HuntingtonÕs disease
C). Blood levels of folate, vitamin B12, thyroid stimu-
protocol is followed for pre-symptomatic testing [55].
lating hormone, calcium, glucose, complete blood cell
count, renal and liver function tests should be evaluated
at the time of diagnosis and serological tests for syphilis,
Other investigations
Borelia and HIV might also be needed in cases with
A number of non-nervous tissue specimens (mostly
atypical presentation or clinical features suggestive of
ﬁbroblasts, platelets, olfactory and vascular epithelium)
these disorders (good practice point).
have been investigated in AD, including analysis
CT and MRI may be used to exclude treatable causes
of DNA damage and repair, autophagy, proteomic
of dementia. Multislice CT and coronal MRI may be
analysis, oxidative processes, ionic channels and
used to assess hippocampal atrophy to support a clin-
transduction, APP levels and intracellular calcium
ical diagnosis of AD (Level B). FDG PET and perfu-
regulation. However these studies, while potentially
sion SPECT are useful adjuncts when diagnosis remains
informative about the disease process, are presently
in doubt (level B). Dopaminergic SPECT is useful to
not of clinical use. Skin and muscle biopsy are
diﬀerentiate AD from DLB (level A). Follow up with
used in cerebral autosomal dominant arteriopathy
serial MRI is useful in a clinical setting to document
with subcortical infarcts and leukoencephalopathy
disease progression (good practice point).
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1242
J. Hort et al.
EEG is recommended in diﬀerential diagnosis of
trials (RCT) to decrease psychiatric symptoms in care-
atypical clinical presentations of AD (good practice
givers and lead to delays in institutionalisation for
point) and when CJD or transient epileptic amnesia is
patient [60,61] (I). Management should include clear
suspected (Level B).
arrangements for follow-up, as regular monitoring of
Routine CSF analysis is recommended in diﬀerential
medication response and adverse eﬀects as well as
diagnosis for atypical clinical presentations of AD
changes in the severity of dementia (using scales like the
(good practice point). CSF 14-3-3 or total tau mea-
MMSE) should be undertaken. Reassessment for
surement are recommended for the identiﬁcation of
development of co-morbidity (including carer stress)
CJD in patients with rapidly progressive dementia
should be an integral part of management.
(Level B). Alterations in CSF total tau, phospho-tau
and Ab42 support diagnosis of AD (Level B).
Primary prevention of AD
Screening for known pathogenic mutations can be
undertaken in patients with appropriate phenotype or a
This refers to the prevention of subsequent dementia in
family history of an autosomal dominant dementia.
cognitively normal subjects and is the ultimate goal for
Routine Apo E genotyping is not recommended.
AD management. Several risk factors have been well
established for AD, though some (such as age, sex and
genotype) are not modiﬁable. Potentially modiﬁable
Management of AlzheimerÕs disease
risk factors which have been established through several
The ﬁrst step in AD management is accurate recogni-
epidemiological studies include vascular risk factors
tion and diagnosis of the disorder, and then disclosing
(hypertension, smoking, diabetes, atrial ﬁbrillation and
that diagnosis in a sensitive and timely way to the
obesity) and head injury while protective factors
patient and others as appropriate. Disclosure of diag-
described include use of antihypertensives, non-steroi-
nosis is not harmful, and actually decreases depression
dal anti-inﬂammatories, statins and hormone replace-
and anxiety in patients and their care-givers [57] (II).
ment therapy, high education, diet, physical activity
The vast majority of patients with mild dementia wish
and engagement in social and intellectual activities.
to be fully informed and 75% of caregivers wish their
However, whether modifying these factors will reduce
relative to be informed [58]. Diﬀerences among ethnic,
risk of dementia is not yet known. A meta-analysis
cultural, and religious groups may inﬂuence how and
concluded that there is no good evidence to recommend
what disclosure occurs. It oﬀers the patient opportunity
statins for reducing the risk of AD [62] while results of
to pursue desired activities and maximizes individual
the large, prospective, placebo-controlled ÔWomenÕs
autonomy and choice by providing information neces-
Health Initiative Memory StudyÕ showed that the use of
sary for decision making and advance planning,
estrogen plus progestin in post-menopausal women was
including the decision to give informed consent to
actually associated with a signiﬁcantly increased risk of
research projects and autopsy. At time of diagnosis
dementia [63] (I).
several issues need to be addressed, including the pro-
Treatment
of
hypertension
for
prevention
of
vision of high quality understandable information
dementia, including AD, has been the best studied risk
about the illness and its course to patient and care-
factor to date. However, most RCTs have been stopped
giver, a careful assessment for any co-morbidities and
early because cardiovascular endpoints were reached,
consideration given to other services that may be
meaning they were underpowered to detect diﬀerences
required including social services, mental stimulation,
in rates of dementia. A study of treating hypertension in
occupational therapy, physiotherapy, speech and lan-
the very old reached similar conclusions, and contained
guage therapy (IV). Occupational therapy can beneﬁt
a meta-analysis of all studies supporting a signiﬁcant
patientsÕ daily functioning and reduce the need for
risk reduction [64] (I). However, the period over which
informal care [59] (II). Medico-legal issues need to be
treatment needs to be given is not known, nor has it
addressed, with driving often needing prompt attention
been established whether treating vascular risk factors,
and action taken according to the legal framework
including hypertension, in those with established AD
operating in that particular country. Care-giver support
aﬀects disease progression. Currently, no clear recom-
should consist of education about AD, and attending
mendations about dementia prevention can be made.
peer support groups may be helpful. Care-giver stress
and depression are common and, if present, more
Secondary prevention of AD
intensive care-giver support and counselling and/or
speciﬁc treatment for depression may be needed. The
This refers to the prevention of development of AD in
provision of a standard education and support package
non-demented subjects with some evidence of cognitive
to caregivers has been shown in randomized controlled
impairment. The groups most often studied in this
Ó 2010 The Author(s)
European Journal of Neurology Ó 2010 EFNS European Journal of Neurology 17, 1236–1248

EFNS guidelines for AlzheimerÕs disease
1243
regard are those with MCI and several RCTs of cho-
between ChEIs, and those which have been under-
linesterase inhibitors (ChEIs) have been undertaken in
taken have been small in size and not produced con-
MCI, most using ÔconversionÕ to dementia as the pri-
sistent evidence of better eﬃcacy of one drug over
mary outcome. A meta-analysis included eight studies
another (II). There is some evidence from open-label
involving all three ChEIs, with duration of treatment
studies that patients who do not tolerate or do not
ranging from 16 weeks to 3 years [65]. There were no
seem to beneﬁt from one ChEI may tolerate or draw
diﬀerences in rate of conversion to AD between active
beneﬁt from the other (III). One of the ChEIs, riv-
and placebo groups, and most secondary outcomes
astigmine, is now available in a transdermal (patch)
were also negative (I). There have also been negative
formulation which appears to have lower incidence of
studies of aspirin in primary prevention of cognitive
side eﬀects than oral administration but equal eﬃcacy
decline and of anti-inﬂammatories and vitamin E in
[71] (I).
MCI (I). A large study showed no eﬀect of Gingko on
A disease modifying eﬀect of ChEIs has been pro-
preventing AD [66] (I). Therefore, no treatments have
posed, and has some basic scientiﬁc support, but no
demonstrated eﬃcacy for preventing or delaying
convincing clinical data, either from trials of clinical
development of AD in MCI subjects until now, while
endpoints or of those using biomarkers, has yet been
evidence exists that ChEIs, Vitamin E, Gingko Biloba
forthcoming to support these claims (IV).
and anti-inﬂammatories are not substantively helpful.
Eﬀects on non-cognitive BPSD have also been
shown, though as with cognition eﬀect sizes are modest
(I). There remains uncertainty as to which particular
Treatment of established AD
non-cognitive symptoms may respond best, though
Cholinesterase inhibitors
eﬀects on psychosis and apathy are consistently
There have been several well conducted placebo-con-
reported (II). Eﬀects on agitation are less clear, and a
trolled, large scale RCTs with the three ChEIs,
large placebo-controlled RCT in moderate to severe
donepezil, rivastigmine and galantamine, which have
AD failed to show an eﬀect of donepezil on patients
shown eﬃcacy on cognitive function, global outcome
with clinically signiﬁcant agitation [72] (I).
and ADL in patients with mild to moderate AD(I),
usually deﬁned as MMSE between 16 and 26. Mean
Memantine
global improvement over placebo is 3–4 points on the
Memantine, a non-competitive N-methyl-D-aspartate
ADAS-Cog, a level of improvement roughly equivalent
receptor antagonist, also has been subject to several
to the naturalistic decline expected over a 6 month
RCTs in AD. Studies in moderate to severe AD have
period. Most studies have been over relatively short
been more consistently positive than those in mild to
duration (6 months), though 1 and 3 year studies have
moderate AD, previous reviews of the literature have
been reported with donepezil which suggest the beneﬁts
concluded that while there is a signiﬁcant eﬀect in
of ChEIs continue in the longer long (I). Retrospective
cognition at all severities, but eﬀects on global outcome,
analysis and some long term open studies suggest a
ADL and behaviour were only apparent in the mod-
possible eﬀect of ChEI on disease modiﬁcation, but
erate to severe studies [73] (I). Once daily dosing has
more data are needed before this can be conﬁrmed [67].
been shown to be as eﬀective as the original recom-
RCTs of ChEIs in more severe AD (MMSE < 10)
mendation of administration twice daily (I) [74]. Mod-
have also shown positive results [68,69] and a Coch-
est eﬀects on behaviour were also found in a pooled
rane review concluded that trials supported evidence of
analysis of six studies which included all those with
beneﬁt in mild, moderate and severe AD [70]. In light
MMSE < 20, with delusions, agitation/aggression and
of current evidence, limiting prescribing of ChEIs to
irritability being the most responsive symptoms [75]
only some AD subjects according to certain cut-oﬀs on
(II), though studies of subjects primarily selected for the
a measure such as the MMSE, as operated in many
presence of these behavioural features have not yet been
countries, does not seem justiﬁed. Although a point
reported.
will be reached in severe AD when ChEI are unlikely
The beneﬁts of adding memantine to ChEIs are not
to continue to have beneﬁt, it is currently unclear at
clear, an early study of adding memantine to donepezil
what point in the disease process ChEI should be
was positive, but a recent study of over 400 subjects
withdrawn.
which added the drug or placebo to those stable on any
Cholinesterase inhibitors (ChEIs) are generally well
of the three ChEIs showed no evidence of beneﬁt in
tolerated, although common gastrointestinal adverse
either cognitive or non-cognitive symptoms [76] (I).
eﬀects such as nausea, diarrhea, and vomiting may
Further studies are needed before clear recommenda-
sometimes lead to discontinuation of treatment in
tions can be made about the beneﬁts of adding
some patients. There have been few direct comparisons
memantine to ChEIs.
Ó 2010 The Author(s)
European Journal of Neurology Ó 2010 EFNS European Journal of Neurology 17, 1236–1248

1244
J. Hort et al.
Other drugs and interventions
immunisation [84] and of the drug Dimebon [85].
Several other treatments have been suggested as poten-
However, recommendations about the usefulness of
tially beneﬁcial for AD, including non-steroidal anti-
these and other agents must await ﬁnal results from
inﬂammatory drugs, oestrogens and statins. A large,
rigorous Phase III studies.
placebo-controlled RCT of vitamin E (1000 IU, twice a
day over 2 years) in moderate AD, was found to sig-
Treatment of behavioural and psychological symptoms
niﬁcantly delay the time to a composite outcome of
primary outcome measures, but a study in MCI has been
Management of BPSD begins with careful search for
negative and the conclusion of a Cochrane review is that
trigger and/or exacerbating factors including environ-
there is insuﬃcient evidence for the eﬃcacy of vitamin E
mental cues, physical problems (infections, constipa-
in the treatment of AD or MCI [77] (I). Studies of ste-
tion), medication and depression or psychosis. As
roidal, non-steroidal and cyclo-oxygenase-2 inhibitors
studies of BPSD indicate a high placebo response, safe
in AD and MCI have been negative yet have had
non-pharmacological management (education, exer-
potentially serious side eﬀects (I). Evidence – based data
cise, aromatherapy, sensory stimulation, personalised
report studies of Ginkgo biloba extract (explicitly EGb
music) should be tried wherever possible in the ﬁrst
761), but there remains controversy about the role of the
instance as symptoms may naturally resolve within a
EGb 761 as studies to date have included mixed popu-
short time. The beneﬁcial eﬀects of ChEIs and
lations and have not been consistent in results. A meta-
memantine for mild BPSD have been described above,
analysis concluded that the evidence that Ginkgo Biloba
but a recent RCT found donepezil did not help clini-
has predictable and clinically signiﬁcant beneﬁt for
cally signiﬁcant agitation in those with moderate to
people with dementia or cognitive impairment is
severe AD [72]. Both conventional and atypical anti-
inconsistent and unreliable [78] (I). However two class I
psychotics reduce BPSD, with particular eﬀects dem-
studies [79,80] demonstrating positive eﬀects were
onstrated for risperidone for agitation/aggression and
omitted because of signiﬁcant heterogeneity between the
psychosis [86,87] (I). However, antipsychotics have
trials. Further evidence is needed before eﬃcacy for
important and potentially serious side eﬀects, most
Gingko can be clearly established.
especially increased stroke risk, increased mortality,
Many other compounds, such as piracetam, nicerg-
parkinsonism and cognitive impairment [88]. They
oline,
selegiline,
vinpocetine,
pentoxyphylins
and
should be used with caution, at low dose, and for the
Cerebrolysin are prescribed in some countries as treat-
shortest period needed only for those with moderate to
ments for AD. For example, a recent Cochrane review
severe symptoms causing distress and after careful
of piracetam, one of the most widely studied drugs to
assessment of risk and beneﬁt and after discussion
date, found poor study design, possible publication bias
with care-giver and, where possible, patient. There is
and that overall the evidence from trials did not support
no evidence that conventional agents are any safer in
the use of piracetam in people with dementia or cog-
regard to risk of stroke or mortality than atypical
nitive impairment [81]. A review of 6 Cerebrolysin trials
agents [89] and they have a less established evidence
[82] found an eﬀect on global outcome but no consis-
base and greater side eﬀects. Low doses of antipsy-
tent eﬀect on other scales. Further evidence is therefore
chotics should be used with careful monitoring, and
required before its use can be recommended. Similarly,
drugs prescribed for the minimum period required.
a Cochrane review of selegiline found no evidence for
When BPSD have settled, antipsychotics can be
its eﬃcacy in AD [83]. At present, therefore, there is no
withdrawn in most cases without re-emergence of
convincing evidence for eﬃcacy of any of these drugs
BPSD, unless behavioural disturbance is still present
for AD.
[90]. Evidence for other drugs is limited, carbamaze-
There is much interest in the use of cognitive thera-
pine may help aggression [91] (II), though most studies
pies in AD. Preliminary studies seem to suggest a ben-
of valproate have been negative [92] (II). Antidepres-
eﬁcial eﬀect of cognitive stimulation, also known as
sants, especially Selective serotonin reuptake inhibitors
Reality
Orientation
(see
http://www.nice.org.uk,
(SSRIs), may be useful for depression in dementia and
dementia guideline (no 42) for comprehensive review).
do not have the adverse anticholinergic eﬀects of older
More studies are needed before it can be classiﬁed as
tricyclics [93] (II).
class I evidence, but in individual cases the clinician
may decide to try this form of therapy (good practice
Recommendations on management
point).
There are many ongoing clinical studies aimed at
Diagnosis of AD should be disclosed to patient (and
modifying the underlying disease process, including
caregivers as appropriate) (Level B). Disclosure of
international trials of passive and active amyloid
diagnosis should be individually tailored. It should be
Ó 2010 The Author(s)
European Journal of Neurology Ó 2010 EFNS European Journal of Neurology 17, 1236–1248

EFNS guidelines for AlzheimerÕs disease
1245
accompanied by information and counseling, as well as
Management of BPSD should begin with a careful
useful contacts such as AlzheimerÕs patient organiza-
search for triggers and causative factors (i.e. physical
tions. Patients and caregivers should be provided with
illness). Where possible, initial treatment should be
education and support (Level A). Driving, medico-legal
non-pharmacological (Level C).
issues and the need for other support services should be
Antipsychotics should only be used for moderate or
considered (good practice point). If possible physicians
severe BPSD symptoms causing signiﬁcant distress
may encourage patients to draw up advance directives
which have either not responded to other treatments
containing future treatment and care preferences (good
(like non-pharmacological measures or ChEIs) or when
practice point).
other treatments are not appropriate (Level A). Low
There is insuﬃcient evidence to support the use of
dose of atypical agents should be used only after
any drugs purely for the primary prevention of
assessment of risk beneﬁt and full discussion with
dementia. ChEIs, vitamin E, gingko and oestrogens
patient (when capacity allows) and caregiver (good
should not be used as treatments for those with MCI
practice point).
(Level A).
Atypical agents have fewer side eﬀects and do not
In
patients
with
AD,
treatment
with
ChEIs
confer a greater risk of stroke or mortality than con-
(donepezil, galantamine, or rivastigmine) should be
ventional drugs (Level B).
considered at the time of diagnosis, taking into account
Selective serotonin reuptake inhibitors rather than
expected therapeutic beneﬁts and potential safety issues
tricyclic antidepressants should be used to treat
(Level A). Beneﬁts on cognitive and non-cognitive
depression in AD (Level B).
symptoms have been demonstrated in those with mild,
moderate and severe disease (Level A). Realistic
Scheduled update
expectations for treatment eﬀects and potential side
eﬀects should be discussed with the patient and care-
2012.
givers (good practice point).
In patients with moderate to severe AD, treatment
Acknowledgements
with memantine should be considered taking into
account expected therapeutic beneﬁts and potential
The co-authors remember Tuula Pirttila who passed
safety issues (Level A). Beneﬁts on cognitive and non-
away in March 2010.
cognitive symptoms are apparent, some non-cognitive
symptoms (agitation, delusions) may respond better
Conflicts of interest
than others (Level B). Realistic expectations for treat-
ment eﬀects and potential side eﬀects should be dis-
Authors have received speakerÕs and/or consultancy
cussed with the patient and caregivers (good practice
honoraria from Eisai, GE Healthcare, Janssen-Cilag,
point).
Lundbeck, Mertz, Shire, Novartis, Elan, Zentiva, Pﬁz-
Regular patient follow-up, which should include
er, Wyeth and Elan. For the conception and writing of
scales like the MMSE to monitor response to treatment
this guideline no honoraria or any other compensation
and disease progression, should be an integral part of
were received by any of the authors.
management (good practice point).
Aspirin should not be used as a treatment for AD
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