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Alzheimers disease
Philip Scheltens, Kaj Blennow, Monique M B Breteler, Bart de Strooper, Giovanni B Frisoni, Stephen Salloway, Wiesje Maria Van der Flier

Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have Lancet 2016; 388: 50517
decreased as a result of better vascular care and improved brain health. Alzheimers disease, the most prevalent cause Published Online
of dementia, is still dened by the combined presence of amyloid and tau, but researchers are gradually moving away February 23, 2016
from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective,
and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid 42, and tau
Department of Neurology &
proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid oligomers and Alzheimer Center
synaptic markers. MRI and uorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimers (Prof P Scheltens MD), and
disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-eectiveness remain to be Department of Epidemiology
and Biostatistics
established. Tau PET might oer new insights and be of great help in dierential diagnosis and selection of patients
(Prof W M Van der Flier PhD),
for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving VU University Medical Center,
increasingly into the earliest phase of disease. Preclinical Alzheimers disease is dened as biomarker evidence of Amsterdam, Netherlands;
Alzheimers pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have Clinical Neurochemistry Lab,
Institute of Neuroscience and
been identied as a useful population in whom to look for preclinical Alzheimers disease. Moderately positive results
Physiology, Sahlgrenska
for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim Academy, University of
results for lowering amyloid in pre-dementia Alzheimers disease suggest that, ultimately, there will be a future in Gothenburg, Gothenburg,
which specic anti-Alzheimers therapy will be combined with lifestyle interventions targeting general brain health to Sweden (Prof K Blennow MD);
German Center for
jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimers research.
Neurodegenerative diseases
(DZNE), and Institute for
Introduction dementia (memory impairment and executive dys- Medical Biometry, Informatics
Alzheimers disease is the main cause of dementia and function interfering with daily life activities)elderly and Epidemiology, University
of Bonn, Bonn, Germany
one of the great health-care challenges of the 21st century. individuals, who are often on their own and increasingly
(Prof M M B Breteler MD); VIB
In December, 2013, the G8 stated that dementia should dependent on others for care. The second is an atypical Center for the Biology of
be made a global priority and their ambition that a cure presentation, and all too often such clinical manifestations Disease, VIB-Leuven, Leuven,
or a disease-modifying therapy should be available by are not recognised by primary care doctors and others. Belgium (Prof B de Strooper MD);
KU Leuven Center for Human
2025. Research since the discoveries of amyloid (A) Atypical presentations include language, visual, practic, Genetics, LIND en Universitaire
and tau, the main components of plaques and tangles or executive problems beforeand more pronounced ziekenhuizen, Leuven, Belgium
respectively, has provided detailed information about thanmemory decits. Fortunately, increasing attention (Prof B de Strooper); Institute of
molecular pathogenetic events, yet little is known about is being paid to early-onset Alzheimers disease and its Neurology, University College
London, London, UK
the cause of Alzheimers disease and no curative often-atypical presentations.25 In early-onset disease with (Prof B de Strooper); University
treatments are available. Furthermore, although the atypical presentation, diagnostic biomarkers can make Hospitals and University of
presence of Alzheimers pathological changes are a sine all the dierence and can guide management and Geneva, Geneva, Switzerland
qua non for diagnosis and sucient to cause symptoms decision making. (Prof G B Frisoni MD); IRCCS
Fatebenefratelli, Brescia, Italy
in some patients, several causes are implicated in Clinical diagnosis of any dementia syndrome depends (Prof G B Frisoni); and Warren
patients who become symptomatic aged older than on taking a history from the patient and their carers, Alpert Medical School, Brown
75 years. neuropsychological testing, and assessment of symptoms University, Providence, RI, USA
With the advent of modern techniques to image and with time. The rst set of criteria proposed for diagnosis (Prof S Salloway MD)

measure brain processes and analyse big data (including of Alzheimers disease was launched in 1984 and focused Correspondence to:
Prof Philip Scheltens,
genetic and genomic data), and with governments across Department of Neurology &
the world increasingly prioritising dementia in national Alzheimer Center, Neuroscience
health-care agendas, there is hope that the rate of scientic Search strategy and selection criteria Campus Amsterdam,
progress will increase. In this Seminar, we present novel, VU University Medical Center,
Between March 1, and Sept 15, 2015, we searched the Cochrane De Boelelaan 1117, 1081HV
promising ndings from the rapidly evolving eld of Library, PubMed, and Embase with the search term Alzheimers Amsterdam, Netherlands
Alzheimers research, which seem to provide a glimpse Disease in combination with the terms pathology,
into a future when Alzheimers disease might be cured imaging, diagnosis, therapy, trials, epidemiology,
orperhaps even more likelyprevented. We describe CSF, and biomarkers for articles published in any language
the clinical context of the disease and novel developments since Jan 1, 2010. We also searched the reference lists of articles
in epidemiology, molecular genetics and pathophysiology, identied by this search strategy and selected those we judged
uid biomarkers, imaging biomarkers, and treatment. relevant. We largely selected publications from the past 5 years,
but did not exclude commonly referenced and highly regarded
Clinical signs and symptoms older publications. Review articles and book chapters are cited
In panel 1, we describe two cases, which show the range to provide readers with more details and more references than
of Alzheimers disease in terms of age and clinical this Seminar permits.
presentation. The rst case is a typical presentation of Vol 388 July 30, 2016 505


critieria, presence of memory impairment is no longer

Panel 1: Case vignettes required for diagnosis, as long as biomarker evidence is
Mrs A, a 79-year-old woman, is brought to see a geriatric psychiatrist by her brother available. Preclinical Alzheimers disease (NIAAA)8 and
because of progressive complaints of memory loss and occasional word-nding at risk for Alzheimers disease (IWG)9 have been accepted
diculties. She has managed the household independently since her husband died 5 years and are dened as evidence of Alzheimers pathological
ago, but can no longer do so. She sometimes forgets to cook, skips meals, and pays less changes in cognitively healthy individuals (panel 2).
attention to her appearance than she used to. She has three children and seven
grandchildren, whose names she sometimes mixes up. Her Mini-Mental State Epidemiology
Examination (MMSE) score is 23 out of 30, her Cambridge Cognition (CAMCOG) score is An estimated 40 million people, mostly older than
78 out of 104, both below the cuto for dementia. Because she has a 7 year history of 60 years, have dementia worldwide, and this gure is
mild hypertension and mild diabetes (both well controlled), the specialist orders an MRI, projected to double every 20 years, until at least 2050.18
which shows grade 2 bilateral hippocampal atrophy on the Scheltens scale and grade 1 Within these estimates, both the number of people who
white matter hyperintensities on the Fazekas scale. The geriatric psychiatrist diagnoses develop the disease at a specic age and the survival
mild Alzheimers disease, starts Mrs A on an acetylcholinesterase inhibitor, and time of those with the disease are assumed to remain
recommends a daily visit from a home-care nurse. stable for a given region. Projected increases in the
prevalence of dementia are proportionally much higher
Mrs B is a highly educated 52-year-old university professor, who presents to the
for developing countries with young populations than
neurologist with gradual progressive loss of sight and problems with identication of
for western Europe and the USA, which already have a
objects, which prompted several visits to the ophthalmologist and changing glasses,
much older population. Reliable estimates of the
without success. Her wife and two teenage children are worried: she has been o work for
prevalence of early-onset dementia and Alzheimers
8 months already with a diagnosis of mild depression, but drugs provided no relief. On
disease (before age 65 years) are scarce. The prevalence
examination, her MMSE score is 28 and his CAMCOG score is 93, both within normal
of dementia before age 50 years is less than 1 per 4000,
range, and routine neurological and laboratory investigations show no abnormal
with roughly 30% of cases being attributed to
ndings. Neuropsychological examination reveals visuoperceptive disturbances and
Alzheimers disease.19
executive dysfunction. MRI shows bilateral parietal atrophy, no hippocampal atrophy, and
In the past 5 years, several European population-based
no vascular changes. Because of her young age, a family history of dementia (her mother,
cohort studies have provided evidence that the age-
who received her diagnosis at age 76 years), and progressive dysfunction in her job, the
specic incidence of dementia has decreased in the past
neurologist suspects dementia and performs a lumbar puncture. Analysis of cerebrospinal
20 years, thereby raising expectations for preventive
uid shows an abnormal pattern of low amyloid 142 together with increased total tau
interventions. In a study20 in which incidence was directly
and phosphorylated tau. A diagnosis of probable Alzheimers disease with high likelihood
compared between sub-cohorts, age-specic incidence
of Alzheimers pathophysiology was made according to the National Institute of
was 24% lower in the 2000 cohort than in the 1990 cohort.
AgingAlzheimers Association criteria,1 and Mrs B is included in a clinical trial. An amyloid
Risk factor proles and brain imaging scans were also
PET, done as part of the trial, shows abnormal deposition of amyloid in the parietal and
compared: the 2000 cohort had less evidence of
posterior cingulate regions. Her university puts her on sick leave.
generalised brain atrophy and cerebral small vessel
disease and their vascular risk factors were better
on clinical symptoms only. At the time, Alzheimers controlled, notwithstanding an overall increase in
pathological changes could not be measured in vivo, so vascular risk factors (ie, hypertension, diabetes, obesity).
disease could be denitively diagnosed only after death. In several other European studies9 in which prevalence
With the advent of MRI and the discovery of cerebrospinal in the same areas was compared, with similar methods
uid (CSF) biomarkers and amyloid PET, the and diagnostic criteria but years or decades apart, similar
International Working Group (IWG) proposed new conclusions were reached. Long-term monitoring of
criteria,6 which formed the inspiration for a subsequent health-care records and other health survey data suggest
set of criteria by the National Institute of Aging and similar trends in the USA.21
Alzheimers Association (NIAAA) working groups.1,7,8 Data for time trends in other regions are limited.
Several important developments are included in these Results of a 2013 systematic review22 suggested that the
new criteria. A long pre-dementia stage is acknowledged. prevalence of dementia has increased in China, but this
Mild cognitive impairment is recognised as prodromal notion was challenged by another review in which
Alzheimers disease in the IWG criteria and in the variation in methods and changing diagnostic criteria
NIAAA criteria when supported by biomarkers were taken into account.23 A common observation across
suggesting the presence of amyloid and neuro- Asian studies is an apparent shift from vascular
degeneration. Biomarker evidence can be used to dementia, which used to be more common, to
attribute the clinical syndrome of dementia or mild Alzheimers disease, with a resulting disease ratio akin to
cognitive impairment to underlying Alzheimers that in western countries.24 Demographic and lifestyle
pathological changes with high, intermediate, or low changes; changes in vascular background risk, diagnostic
likelihood (ie, the likelihood that the diagnosis is methods, and criteria; and adaptation to the more
Alzheimers disease) in the NIAAA criteria. Atypical Alzheimers-focused international research community
presentations are acknowledged, such that in the IWG could all have contributed to this shift.25

506 Vol 388 July 30, 2016


Lifestyle and vascular risk factors Genome-wide association studies have been used to
For the declaration on
Alzheimers disease develops over a long preclinical identify more than 20 genetic loci associated with the
dementia risk reduction see
period of several decades, which raises the question of risk of Alzheimers disease. The newly identied genes http://dementiachallenge.dh.
the extent to which risk factors assessed in late life or point at pathways implicated in the immune system and
shortly before onset of clinical symptoms are a result of
developing pathological changes rather than a causal
relation. Two dierent approaches have been taken to Panel 2: A shift in diagnostic framework
address this issue. Studies that were started decades ago The eld of dementia has changed substantially since the conceptual shift towards the
and included people in early life or midlife allowed idea that Alzheimers disease exists before dementia is present. This game-changing
assessment of the relations between early-life or midlife notion was needed to boost drug development and advance-care planning. However, the
risk factors and cognitive decline and dementia risk later diagnostic criteria of the International Working Group and the National Institute of
in life. Whereas the results of most studies2629 conrmed AgingAlzheimers Association still rely on a clinical phenotype combined with biomarker
the relation between vascular health status and risk of information, mainly driven by amyloid and tau.
later cognitive decline and dementia, an important caveat
when interpreting such longitudinal studies is the The next step that can be envisaged is the development of clinical-label-free protein
potential for selective dropout. An alternative, and more characterisation for each patients protein abnormalitiessuch as amyloid, tau, TDP43,
specic, approach has focused therefore on intermediate progranulin, -synuclein, tau speciesin combination with appreciation of aggravating
or endophenotypesparticularly brain imaging markers. risk factors (eg, genetics, vascular risk factors, vascular disease) and protective factors
The challenge of these studies is to avoid potential biases (eg, genetics, healthy lifestyle). Essentially, clinical nosology would be replaced with labels
during sampling, particularly for convenience or clinic- describing pathophysiological processes. This approach has the potential to revolutionise
based sampling.30,31 In light of the falling age-specic diagnosis by acknowledging that treatment ultimately needs to be directed against the
incidence of dementia, the World Dementia Council causative proteinopathies and other pathological changes, irrespective of the clinical
declared that dementia risk reduction is crucial to the phenotype. That most patients dementia has mixed causes is also acknowledged: these
global dementia agenda, with strong evidence that patients could thus receive treatment targeted at dierent aspects of their disease. This
interventions for cardiovascular risk could improve approach will fuel and speed up therapeutic development for any neurodegenerative
cognitive health at the population level. dementia. It will necessitate even closer collaboration between molecular biologists,
Increasing evidence suggests that many other lifestyle- chemists, engineers, and clinicians. Clinical diagnosis will still be necessary to establish the
related factors, including diabetes, obesity, physical and syndrome diagnosis (ie, severity). Also, better prognostic biomarkers will be needed to
mental inactivity, depression, smoking, low educational determine which patient needs to be treated when (eg, an amyloid-positive individual
attainment, and diet have a role in dementia, and the that will never become symptomatic does not need treatment).
potential for primary prevention related to such Thus, a focus on preclinical Alzheimers disease is pivotal. Studies in which cerebrospinal
modiable risk factors is huge but yet to be fully uid biomarkers and amyloid PET are analysed have shown that roughly a third of elderly
explored.32 On the basis of the Rotterdam study, it has people are amyloid positive, and that this amyloid positivity is associated with an
been modelled that elimination of the seven most increased risk of clinical progression.10,11 Several important questions will hopefully be
important modiable risk factors would lead to a 30% answered in the next 5 years. Which factors determine that an individual becomes
reduction in dementia incidence.33 This nding shows amyloid positive? Will every amyloid-positive patient develop a dementia syndrome if
both the huge potential of risk-factor reduction, and the they live for long enough? If so, which factors determine when a patient will develop
need for other therapeutic strategies for the remaining dementia? If not, can protective factors be identied? Even if all amyloid-positive
70% of cases. individuals were to ultimately develop dementia, there is a dierence between hearing at
85 years old that you will be demented in 20 years, or hearing at age 65 years that onset
Genetic susceptibility of dementia will happen within the next 2 years. Biomarkers providing this information
APOE4 is the major genetic risk factor for Alzheimers are absent. A follow-on question would be, do all amyloid-positive patients follow the
disease. Lifetime risk for Alzheimers disease is more same route to Alzheimers disease? The existence of individuals with suspected
than 50% for APOE4 homozygotes and 2030% for non-amyloid pathology who progress to Alzheimers disease already suggests that the
APOE3 and APOE4 heterozygotes, compared with 11% order in which events occur (eg, amyloid followed by tau or the other way around) might
for men and 14% for women overall irrespective of dier among patients.12,13
APOE genotype.34 APOE4 has several eects on In addition to the well studied syndrome of mild cognitive impairment or prodromal
Alzheimers disease. It interferes with A clearance Alzheimers disease, the focus of research is now shifting even earlier. Individuals with
from the brain,35 and is also processed into neurotoxic subjective cognitive decline, which is dened as personal sensation of cognitive decline
fragments.36 Furthermore, mice that express APOE4 despite results within healthy limits on cognitive tests might be an excellent population
show disinhibition of a cyclophilin A signalling in which to study preclinical Alzheimers disease.14 Subjective cognitive decline is
mechanism in the pericytes of the brain blood vessels, associated with an increased risk of progression to dementia, especially when the patient
resulting in degeneration of these vessels, leakage of the is worried about the decline.15 Compared with healthy controls, patients with subjective
bloodbrain barrier, and neurodegeneration independent cognitive decline have more brain abnormalities, including hippocampal volume loss and
of A.37 The pleomorphic eects of APOE4 show the hypometabolism.16 Furthermore, in patients with subjective cognitive decline,
complex interplay of mechanisms contributing to cerebrospinal amyloid is strongly predictive of subsequent clinical progression.17
sporadic Alzheimers disease. Vol 388 July 30, 2016 507


inammatory responses, cholesterol and lipid metab- Pathophysiology

olism, and endosomal-vesicle recycling.38 Some factors The past 30 years of Alzheimers disease research have
could be age related, whereas others could have protective produced substantial evidence that accumulation of
eects; all these factors probably interact with the core abnormally folded A and tau proteins in amyloid
mechanisms of the disease. These polymorphisms are plaques and neuronal tangles are causally related to
frequent in the population but contribute little to the neurodegenerative processes in patients brains.47 Yet
individual risk for disease (gure).39 observational and pathological studies have generated
Patients with Alzheimers disease do not induce overwhelming evidence for the complexity and
expression of REST,40 which exerts cell survival eects multicausality of dementia.48 This complexity is
and is normally upregulated in the ageing brain.40 increasingly recognised in basic and clinical studies too,
Alterations in other genes and in non-coding RNA, such and research is moving away from the simple assumption
as microRNA, might also have important roles in disease of linear causality as proposed in the original amyloid
susceptibility.41,42 Novel genome-sequencing technologies hypothesis.49
have been used to identify rare mutations, which convey The strongest evidence for A and tau as causative
substantial increases in risk to carriers.43,44 The best comes from studies of familial Alzheimers diseasecases
validated are mutations in TREM2, a microglia receptor with mutations in APP, PSEN1, or PSEN2.39 APP is the
involved in A clearance.45 Genome-wide proling of precursor of the A peptides and APP mutations aect A
gene expression in the brains of patients with late-onset cleavage and aggregation. PSEN1 and PSEN2 provide the
Alzheimers disease supports the hypothesis of an catalytic subunit to the secretases, which cleave APP.
upregulated immune-specic and microglia-specic Originally thought to result in an increase in A42,50
module with TYROBP as a key regulator.45,46 studies51 show that PSEN mutations cause less ecient

APP metabolism
Tau metabolism
Causes Immune response
Alzheimers APP Endocytosis
disease Cytoskeleton/axon development

High risk
Risk of Alzheimers disease


Medium risk

ADAM10 (heterozygous)



Low risk


3 4 5 6 7 8 9 10 11 12 13 14 20 30 40 50
Rare Common
Population frequency (%)

Figure: Schematic overview of genes linked to Alzheimers disease

The colours in the key show the pathways in which these genes are implicated. Genes that are known to aect APP metabolism are circled in red, whereas those that aect
the tau pathway are circled in yellow. The interior colours provide further information on what functions the genes have. When there are two colours, the gene might have
functional roles in two dierent biological pathways. Many of the genes have been related to APP processing or tracking (red or red border), suggesting the central
importance of APP metabolism in Alzheimers disease. The gure was adapted with permission from Karch et al, 2015.39

508 Vol 388 July 30, 2016


processing of APP and the generation of longer and more -secretase complex,68 which will probably revolutionise
hydrophobic A peptides. A is thought to be the trigger, drug discovery research for this aspect of disease. Better
or even the driver, of the disease process, at least in familial three-dimensional cell culture models that generate
cases.47 Tau is also a prerequisite for diagnosis of plaques and tangle-like pathological changes in vitro will
Alzheimers disease, but mutations in the tau gene cause probably speed up drug discovery further.69
frontotemporal dementia without amyloid plaquesie,
tau can act independently of A to cause neuro- Fluid biomarkers
degeneration. Although in the amyloid hypothesis, Core CSF biomarkers
pathological alterations of tau were thought to be Core CSF biomarkers for Alzheimers disease are A42,
downstream events of A deposition, it is equally plausible which shows cortical amyloid deposition; total tau (t-tau),
that tau and A act in parallel pathways causing which reects the intensity of neurodegeneration; and
Alzheimers disease and enhancing each others toxic phosphorylated tau (p-tau), which correlates with
eects.49 neurobrillary pathological changes.70 These core CSF
Analogous with prion disorders, toxic conformations of biomarkers have high diagnostic accuracy, with
A or tau, or both, are generated during the disease. sensitivity and specicity of 8590%, to identify
These so-called seeds can induce pathological confor- prodromal Alzheimers disease in the mild cognitive
mations of normal peptides, which can cause spreading impairment stage.71,72 When assessing the diagnostic
of the disease across the brain.52 Evidence for this idea performance of Alzheimers disease biomarkers, it is
comes from a pathological study53 in which pathological essential to consider that a continuum of pathological
changes were noted in four of eight young (<55 years) changes (eg, plaque counts) exists without any clear
patients who died from iatrogenic Creutzfeldt-Jakob distinction between patients with Alzheimers disease
disease caused by injections from human-pituitary- and cognitively healthy elderly people who died from
derived growth hormone. Mutations in APP, PSEN1, and other causes,73 that clinical diagnosesoften used as a
PSEN2 probably accelerate the generation of such seeds, gold standardare an imperfect criterion,74 and that
whereas in sporadic Alzheimers disease, decreased elderly patients with Alzheimers disease often show
clearance of A54 or oxidative stress55 might have roles in several pathological changes, including -synuclein,
the accumulation of toxic A species. However, the nature TDP43, and vascular changes.75 This pathobiological
of the pathological conformations (oligomeric or brillic, variance precludes any biomarker from having 100%
specic post-translational modications, dierent diagnostic accuracy. Nonetheless, CSF biomarkers can
strains)56,57 and the associated mechanisms of toxic eects help with diagnostic decision making at memory clinics
need to be further elucidated.58 A oligomers, for instance, (panel 1),76 and have especially good negative predictive
seem to bind to various membrane receptors,59 including valueie, healthy concentrations of all three biomarkers
the prion protein,60 but the relative importance of these in a patient with mild memory disturbances almost
dierent interactions to the disease process is unclear. excludes Alzheimers disease.
Because A has such a crucial role, a rational way to treat Variability in measurements between clinical labora-
or prevent Alzheimers disease would be to block the tories has hampered the identication of uniform cutos
proteases that generate A. The rst cleavage step in the for CSF biomarkers. This problem stems from
generation of A is mediated by the -secretase BACE1, dierences in analytic procedures for manual ELISA
which is highly expressed in neurons and cleaves many methods between laboratories and variability in reagent
physiologically important substrates.61 Mice decient in quality and manufacturing procedures that results in
BACE1 show complex phenotypes,62 and BACE1 is involved batch-to-batch variations,77 and is most pronounced for
in synaptic plasticity.63 Furthermore, inhibition of BACE1 A42. Standardisation eorts have resulted in fully
induces alternative processing of APP and generation of validated mass-spectrometry-based reference measure-
synaptically active peptides that are dierent from A.64 ment procedures for CSF A42,78 and certied reference
Inhibitors of secretase are being tested in clinical trials,65 materials to serve as gold standards for standardisation
and side-eects so far seem surprisingly limited. Inhibitors of CSF biomarker measurements. Additionally, novel
of the secretases, which are implicated in the second assays have been developed on fully automated
cleavage step, were unsuccessful in clinical trials because of laboratory analysers, resulting in very stable
side-eects,66 but to rule out secretases as drug targets for measurements between laboratories. Taken together,
Alzheimers disease would be premature. In the future, these standardisation eorts provide the basis for the
their activity could be modulated by compounds called introduction of uniform cutos and more general use of
-secretase modulators such that shorter, less toxic versions CSF biomarkers for routine clinical diagnosis of
of A are generated. Such modulators, given in combination Alzheimers disease.
with a -secretase inhibitor, could be particularly ecient The frequency of misdiagnosis in clinical trials in
in reduction of potential side-eects.67 Structural work with which diagnosis is made on clinical grounds alone79
powerful new cryo-electron microscopy techniques has underscores the need for biomarker-based inclusion
provided the rst atomic resolution of the structure of the criteria. Large clinical studies show high concordance Vol 388 July 30, 2016 509


with identical diagnostic performance for CSF A142 ultra-sensitive techniques could provide the analytic
and amyloid PET,80,81 suggesting that these techniques sensitivity needed to allow accurate measurement of
can be used interchangeably for trial enrolment. CNS-specic proteins such as tau,93 but large clinical
studies are needed to assess diagnostic performance of
Novel CSF biomarkers this type of blood biomarker.
Additional objective measures of pathogenetic processes
implicated in Alzheimers disease would help to provide Imaging
insight into the full range of molecular pathogenesis. Towards an inclusionary approach
Investigation of dierent biomarkers is at dierent stages Imaging has a key role in the clinical assessment of
of development. One such biomarker is A oligomers, patients with suspected Alzheimers disease. The
which are thought to be a toxic form of A that cause traditional view that at least one structural scan (either
synaptic dysfunction.82 In most studies, an increase in CT or MRI) should be done at least once in every patient
CSF A oligomers is reported in Alzheimers disease,83 with cognitive impairment to rule out intracranial causes
but overlap with control groups is large. A oligomers are (eg, meningioma, subdural haematoma) has been
rarely detected in CSF, which limits quantication by complemented by the notion that the demonstration of
ELISA, thus making it unreliable.84 Encouragingly, novel regional atrophy in the medial temporal region can
ultra-sensitive techniques hold the promise of clinically provide positive diagnostic information (panel 1).94 A
useful tests for A oligomers.85 Another novel candidate visual scale rating of medial temporal atrophy is
is synaptic biomarkers, such as the dendritic protein commonly used in the diagnostic work-up of patients
neurogranin, which is involved in long-term potentiation with cognitive impairment.95,96 Hippocampal volumetry
and memory consolidation.86 High CSF concentrations of might be more accurate,97 and a protocol for the manual
neurogranin predict progression to Alzheimers disease segmentation of the hippocampus has been standardised
in patients with mild cognitive impairment and correlate globally98,99 but is not easily applicable in routine clinical
with rapid cognitive deterioration during clinical follow- settings because sophisticated hardware and software
up.87 Concentrations of the presynaptic protein SNAP25 are needed. Automated hippocampal segmentation
increase substantially during the prodromal stage.88 algorithms have been developed and need to be validated
Synaptic biomarkers could be a link to both cognitive against the manual segmentation gold standard.100 For
symptoms and therapeutic response. patients with atypical Alzheimers disease, such as
posterior cortical atrophy, appreciation of atrophy in the
Blood biomarkers parietal region is of the utmost importance. A visual
Blood is more accessible than CSF, which makes blood rating scale for this purpose has been developed, helping
biomarkers desirable for use in both primary care and implementation in clinical practice.101 Additionally, MRI
multiple sampling in clinical trials (and perhaps even remains the modality of choice for the assessment of
future population screening). In many studies, vascular brain changes, such as white matter hyper-
combinations of proteins, lipids, metabolites, or other intensities, lacunes, and microbleeds (which have gained
molecules have been used to discriminate patients with increasing attention because they are frequent side-
Alzheimers disease from healthy controls, and such eects in anti-amyloid trials).102,103 Novel developments
panels could represent novel Alzheimers blood show the need for, and potential of, automated image
biomarkers.89,90 These studies are often based on screening analysis, multimodal analysis, and computer-aided
of many unselected molecules followed by identication diagnostics.
of a combination that shows diagnostic separation when
multivariate statistics are used, but overlap for individual PET
molecules is often substantial. Besides patient and control- The diagnostic work-up of patients with cognitive
cohort dierences and diculties with pre-analytic and impairment can be dicult during the early stage, when
analytic standardisation,91 statistical over-tting of data on the dierential diagnosis is still wide and includes normal
the basis of the presence of a combination of molecules ageing.7 F-uorodeoxyglucose (FDG) PET measures
unrelated to Alzheimers disease pathogenesis to a panel glucose uptake of neurons and glial cells and is sensitive
in a specic cohort could introduce bias. Thus, the results to synaptic dysfunction. A normal FDG PET virtually
from these panels often fail to be replicated in independent excludes a diagnosis of neurodegenerative disease.104 A
clinical cohorts,92 or dissimilar protein biomarker panels positive scan, conversely, suggests Alzheimers disease if
are suggested in dierent studies.90 the pattern is temporoparietal and posterior cingulate,
Another approach is to measure CNS-specic proteins; and frontotemporal dementia if the pattern is anterior or
however, it is notoriously dicult because of low asymmetric, or both. Ultimately, accurate interpretation
concentrations in blood, because these proteins undergo of FDG PET in patients with dementia does not rest on
degradation by plasma proteases, and because of the the presence or absence of a single region of
huge amount of matrix proteins in blood that can cause hypometabolism but rather should take into account the
assay interference. Nonetheless, application of novel pattern of hypometabolism across the whole cortex.105

510 Vol 388 July 30, 2016


Consensus is consolidating that visual analysis should Alzheimers disease and show a better correlation with
be complemented by quantitative operator-independent hypometabolism and atrophy than does amyloid PET.116
readouts, such as Statistical Parametric Mapping, Tau imaging is being used in clinical trials of drugs aiming
Stereotactic Surface Projections, or other commercial to delay progression of Alzheimers disease, but its
products. The resulting maps provide detailed anatomical usefulness for clinical diagnosis remains to be conrmed.
localisation of dysfunctional brain regions but still need
to be interpreted by an expert reader. Pattern recognition Imaging markers in clinical trials
classication software, which is based on neural networks In clinical trials of drugs that are designed to delay onset
or other sophisticated statistical programs (those that of dementia or progression of cognitive impairment in
analyse dierences in grey matter structures on MRI, for patients with Alzheimers pathology, imaging is
instance),106 might help in the classication. Synaptic frequently used for inclusion and as a secondary outcome
dysfunction in the posterior regions (the so-called default measure. Hippocampal atrophy and amyloid PET have
mode network) is captured also by network analysis of been qualied by the European Medicines Agency to
functional blood-oxygen-level-dependent MRI. However, enrich clinical trials at the pre-dementia stage of
standardisation and reproducibility issues mean that this Alzheimers disease.117,118
technique is not yet useful on an individual level.107 Repeated MRI scans sensitive to microbleeds are
The most innovative imaging marker for Alzheimers mandatory in clinical trials of anti-amyloid drugs to
disease that is used clinically is PET with ligands for A. monitor amyloid-related imaging abnormalities.119
Three ligands have been approved for clinical use by the These include signal hyperintensities on uid
European Medicines Agency and the US Food and Drug attenuation inversion recovery sequences, which are
Administration: orbetapir, orbetaben, and utemet- thought to represent vasogenic oedema or sulcal
amol.108 These ligands have very high accuracy for cortical eusion, and signal hypointensities on gradient-
amyloidosis, as shown by verication studies of recalled echo/T2*, which are thought to represent
pathological changes in elderly patients scanned just haemosiderin deposits, including microhaemorrhage
before death.109 However, because brain amyloidosis is a and supercial siderosis. Amyloid-related imaging
necessary but not sucient condition for diagnosis of abnormalities develop after removal of amyloid from
Alzheimers disease, the diagnostic value of amyloid PET cerebral microvessels, which leads to endothelial
is more exclusionary (ie, a high negative predictive value) damage, increased vascular permeability, and leakage
than inclusionary (ie, it has a moderate positive predictive of water or blood in the brain parenchyma.
value). A patient with cognitive impairment and negative The road towards full exploitation of imaging biomarkers
amyloid PET is unlikely to have Alzheimers disease, is still long both in the clinic and in clinical trials.
whereas up to 35% of cognitively healthy people older Standardisation of collection and measurement of all
than 60 years have positive amyloid PET scans.110 Brain biomarkers is mandatory. The added diagnostic value of
amyloidosis was strongly associated with age in a large one biomarker over another should be elucidated to devise
meta-analysis,111,112 which also showed that the curve parsimonious and cost-eective diagnostic protocols. The
representing the increase of amyloid with age highly individual and societal benets of an expensive biomarker-
resembles that representing the increase in dementia based diagnosis should be demonstratedespecially until
prevalence with age, although the former precedes the eective drugs are available. Imaging-based surrogate
latter by at least 20 years. outcomes of ecacyanalogous to white-matter changes
Increasing evidence suggests that the combination of in multiple sclerosisshould be developed to allow
several markersie, hippocampal volumetry, FDG PET, clinical trials with small group sizes and in the
amyloid PET, CSF A42, t-tau, and p-tau, as suggested in presymptomatic stage.
the NIAAA criteriahas good positive and negative
predictive value to dierentiate Alzheimers disease from Treatment
normal ageing in patients with mild cognitive The mainstay of treatment for Alzheimers disease is
impairment. In a multicentre memory clinic study, supportive care from family and other caregivers.
patients with mild cognitive impairment with positive Patients with dementia have better quality of life in a
results for hippocampal atrophy, temporoparietal predictable home environment that meets their daily
hypometabolism on FDG PET, and CSF A42, invariably needs. Familial caregivers need help to learn how to
developed dementia at follow-up, whereas those with manage the progressive nature of the illness and
negative results for all three parameters almost never guidance on how to mobilise the resources needed to
did.113 This nding has been supported by the results of maintain care for their loved one while preserving their
larger independent samples.114 own wellbeing.
Fluorinated ligands for tau have been developed, and Four drugs are used for the treatment of the dementia
bind to brillary tau aggregates with remarkable phase: the cholinesterase inhibitors donepezil, rivastig-
accuracy.115 Tau ligands have shown binding topography mine, and galantamine, and the glutamate antagonist
that correlates well with the clinical syndrome in memantine. Acetylcholinesterase inhibitors tend to Vol 388 July 30, 2016 511


stabilise cognitive performance and daily functioning for aggregated forms of A (ie, soluble oligomers and
during the rst year of treatment. Further decline ensues, insoluble brils), in patients with early Alzheimers
but continued treatment might produce some benets. disease (ie, mild cognitive impairment and mild
Memantine might provide some benet for patients with dementia) was associated with a dose-dependent
moderate-to-severe dementia, either as monotherapy or decrease in amyloid uptake and a slower decline in
in combination with a cholinesterase inhibitor. cognition and global functioning. These results have
New treatments that will prevent, delay, or treat the prompted a direct move to a pivotal phase 3 trial in
symptoms of Alzheimers disease are urgently needed. patients with early Alzheimers disease (table). Blocking
Researchers have focused on anti-amyloid approaches, the proteases that generate A is another important
including active and passive immunisation strategies, approach to treat or prevent Alzheimers disease, and
-secretase and -secretase inhibitors, and anti- -secretase inhibitors are in clinical development in
aggregation drugs. Several large phase 3 trials of phase 2 and 3 clinical trials for early Alzheimers disease
anti-amyloid approaches in patients with mild-to- and secondary prevention.
moderate Alzheimers disease have been published, with
disappointing results.66,79,120123 In an 18-month trial,79 Secondary prevention, risk reduction, and other
bapineuzumab, a monoclonal antibody that targets the approaches
N-terminus of A, was not associated with any clinical Several major trials investigating how to delay the onset
benet despite a slight decrease in amyloid accumulation of cognitive decline in individuals at high risk for
and lowering of CSF p-tau in APOE 4 carriers. Dosing Alzheimers disease are underway. The Anti-Amyloid in
was limited because of the development of transient Asymptomatic Alzheimers disease (A4) study is testing
amyloid-related imaging abnormalities.79,119,124 An 18 month whether solanezumab given monthly for 3 years could
trial120 of solanezumab, a monoclonal antibody that binds delay cognitive decline in cognitively healthy elderly
to soluble A, showed no benet in the primary cognitive patients with a positive amyloid PET scan.127 Four
clinical outcomes. A secondary analysis of the trial studies aiming to delay cognitive decline in individuals
showed a possible slight decrease in the rate of cognitive with high genetic risk are underway, two in families
decline in patients with mild dementia and a new study of with a deterministic Alzheimers mutation (the
solanezumab in patients with mild Alzheimers disease is Dominantly Inherited Alzheimers NetworkTreatment
ongoing (NCT01900665). As many as 30% of patients Unit and Alzheimers Prevention InitiativeColombia
who underwent amyloid PET in the bapineuzumab and trials), one in APOE 4 homozygotes, and one in
solanezumab trials had amyloid concentrations below the individuals at risk according to an algorithm based on
cuto for Alzheimers disease, and this proportion was TOMM40 and APOE (the TOMMORROW study).128130
higher in APOE 4 non-carriers. Disease progressed more These early intervention trials face challenges of
slowly in amyloid-negative participants, which raises widespread screening, a high screening-failure rate,
questions about the validity of the diagnosis. ethical issues in disclosure of genetic and biomarker
Anti-amyloid trials have incorporated screening with results, and the need for sensitive outcome measures.
amyloid biomarkers to ensure that participants have The US Food and Drug Administration has issued
amyloid pathological changes. The unsuccessful trials guidance providing provisional approval for compounds
show the huge need for more basic research in tested in preclinical Alzheimers disease based on a
Alzheimers disease. For instance, passive vaccination positive response on a composite cognitive measure,
strategies against A or tau assume that the antibodies with ongoing monitoring to demonstrate benets in
will block or clear various A species, but whether the terms of functional outcomes.131
antibodies bind disease-relevant conformations is Tau neurobrillary tangles are closely associated with
unknown. Such knowledge might provide clues as to synaptic loss and cognitive decline, and tau-based
why the trials with A antibodies failed.125 Other possible immunotherapy and other tau-modulating strategies are
reasons for the disappointing results of anti-amyloid in active clinical development. The selective 5-HT6
trials include treating too late, poor diagnostic regimens receptor antagonist idalopirdine was associated with
(without amyloid biomarkers) focusing on the wrong signicant cognitive benet compared with placebo in
target or drug, and insucient target engagement. mild-to-moderate Alzheimers disease in combination
There is a growing consensus that anti-amyloid drugs with donepezil, and phase 3 trials are in progress.132
will probably be most eective early in the disease Insulin signalling might have a role in pathogenesis of
process. However, results of trials of the monoclonal Alzheimers disease, and a trial of long-acting intranasal
antibody gantenerumab126 and the -secretase inhibitor insulin is underway in patients with mild cognitive
avagacestat in patients with prodromal Alzheimers impairment and mild dementia.133 Deep brain
disease, in which a low concentration of A42 in the CSF stimulation, which is approved for the treatment of
was an inclusion criterion, were discouraging. On the Parkinsons disease, is now being tested in a double-
For the interim trial analysis see positive side, an interim analysis of a phase 1b trial of blind trial targeting the limbic memory circuit in patients aducanumab, a human monoclonal antibody selective with mild Alzheimers disease.134 The medical food

512 Vol 388 July 30, 2016


Manufacturer Epitope Origin Isotype Target Possible Outcomes in latest Amyloid Trials planned Rate of
mechanism of stage trial biomarker or in progress amyloid-
action inclusion related
criteria in imaging
trials abnormalities
Solanezumab Eli Lilly Mid-domain Humanised IgG1 Soluble, Sequestration Negative clinical None Phase 3 trials Low
(NCT0760005, monomeric, of soluble outcomes in two phase 3 underway in
NCT01900665) non-brillar monomeric A trials in mild-to-moderate mild, preclinical,
A Alzheimers disease; and autosomal-
possible slowing of dominant
cognitive decline in mild Alzheimers
disease disease
Bapineuzumab Pzer/Johnson N-terminus Humanised IgG1 All forms of A Microglia- Negative clinical None Related to dose
(NCT00575055, & Johnson (brillar, mediated outcomes in two phase 3 and APOE 4
NCT00574132) oligomeric, clearance trials despite signicant carrier status
monomeric) decrease in amyloid PET
and phosphorylated tau
concentrations in
cerebrospinal uid
Crenezumab Roche/ Mid-domain Humanised IgG4 All forms of A Microglia- Negative clinical None in ABBY Phase 3 trial in Low
(NCT 01397378, Genentech (brillar, mediated outcomes in phase 2 trials trial; amyloid autosomal-
NCT01723826, oligomeric, clearance in mild-to-moderate PET in BLAZE dominant
NCT01998891) monomeric) Alzheimers disease; trial Alzheimers
possible cognitive disease underway
slowing in mild disease in
patients given high doses
BAN2401 Eisai/Biogen N-terminus Humanised IgG1 Fibrillar and Microglia- No phase 2 trials yet Amyloid PET Phase 2 trial
(NCT01767311) oligomeric A mediated completed underway in mild
clearance cognitive
Gantenerumab Roche/ N-terminus Human (phage IgG1 Fibrillar and Microglia- Negative clinical Cerebrospinal New phase 3 trial Related to dose
(NCT01224106, Genentech and mid- display library oligomeric A mediated outcomes in phase 3 trial uid A in planning phase and APOE 4
NCT02051608) domain and anity clearance for prodromal Alzheimers carrier status
maturation) disease
Aducanumab Biogen/ N-terminus Human (RTM) IgG1 Fibrillar and Microglia- Dose-dependent decrease Amyloid PET Phase 1 trial in Related to dose
(NCT02484547, Neurimmune oligomeric A mediated in amyloid PET and prodromal or and APOE 4
NCT02477800) clearance cognitive decline in early mild Alzheimers carrier status
Alzheimers disease (mild disease and
cognitive impairment and phase 3 trial of
mild disease) in interim early disease
analysis of phase 1b trial underway

A=amyloid . =not applicable. RTM=reverse translational medicine.

Table: Anti-amyloid monoclonal antibodies in clinical development

Axona,135 a formulation of fractionated coconut oil inhibitor, reduced symptoms of agitation in a controlled
(caprylictrigyceride) that is thought to improve energy trial138 but were also associated with an average decline of
supply to the brain, is approved for the treatment of 1 point on the Mini-Mental State Examination.
Alzheimers disease in the USA, and the nutritional In view of the multifactorial nature of Alzheimers
formulation Souvenaid,136 a combination of 11 vitamins disease, multidomain, long-term interventions targeting
and supplements, is approved for early Alzheimers several risk factors simultaneously might be needed. In
disease in some European countries, Australia, and the Finnish Geriatric Intervention Study to Prevent
China. Cognitive Impairment and Disability (FINGER) trial,139
Although psychotropic drugs are often prescribed, no elderly patients at risk of dementia were randomly
treatments are approved for management of behavioural assigned to either a combined regimen of exercise, diet,
symptoms in dementia. In a trial, the combination of cognitive training, and close management of cardiovascular
quinidine and dextromethorphan, which is approved for risk factors or to standard care; patients in the intervention
treatment of pseudobulbar aect, decreased agitation in group did better in tests of executive function and
patients with dementia compared with placebo, and the processing speed and had higher total neuropsychological
combination is being tested in two phase 3 randomised, battery scores (but not on memory). In the European
placebo-controlled trials for treatment of agitation in PREVENT trial, a similar intervention strategy will be
Alzheimers disease (NCT02442765 and NCT02442778).137 compared with usual care in middle-aged individuals with
High doses of citalopram, a selective serotonin reuptake a parental history of Alzheimers disease.140 Vol 388 July 30, 2016 513


Panel 3: Diagnosis and management of early Alzheimers disease in 2025 PS designed the Seminar outline and invited the other authors to provide
parts of the text according to their expertise. PS and WMYdF combined
To make the postulated changes to the diagnosis and management of Alzheimers disease and edited these texts, and did additional searches for references.
a reality by 2025, lots of work is needed. The validity and cost-eectiveness of amyloid
Declaration of interests
and tau imaging need to be shown. Ideally, less invasive and expensive methods will have PS has received research support from Merck, GE Healthcare, Piramal,
been developed and become available, such as retinal amyloid imaging or a blood test. Alzheimer Nederland, Dioraphte, Stichting VUmc Fonds and Stichting
Hopefully, more and eective personalised lifestyle recommendations can be provided, Alzheimer & Neuropsychiatrie; served as a consultant for AbbVie,
Avraham, ARC, Janssen Research Foundation, MD Start, Nutricia,
perhaps on the basis of individual genetic and environmental characteristics (ie, a
Takeda, Probiodrug, and EIP Pharma; and received speaker fees from
personalised risk prole). Eective treatments to reduce Alzheimers disease burden are Piramal and GE Healthcare. He is co-editor-in-chief of Alzheimers
urgently needed. An era of discovery is underway to identify drugs targeting the key Research & Therapy and associate editor of Alzheimers Disease and
components of pathogenesis, neuritic plaques, neurobrillary tangles, inammation, and Associated Disorders. KB has served as a consultant for Eli Lilly, Novartis,
Roche Diagnostics, Sano-Aventis, Amgen, and IBL International; has
neurodegeneration. Open science and a broad alliance of scientic, clinical, public, and received speaker fees from Fujirebio Europe and Lundbeck; and is
private sectors will be needed for treatment breakthroughs. Future treatment will cofounder of Brain Biomarker Solutions. BdS has received research
probably involve a combination of two or more drugs with lifestyle and risk-reduction support from Janssen and served as a consultant for Janssen, Remynd,
strategies. The development of combination treatments will necessitate adaptive trial and Forum. SS has received research support from NIAADNI, DIAN,
A4, Alz AssocDIAN; been involved in clinical trials sponsored by Lilly,
designs with early readouts and important safety, dosing, regulatory, and intellectual Biogen, Genentech, Bayer, Avid, Roche, Merck, and Functional
property challenges will need to be overcome.141 In 2025, treatment of Alzheimers disease Neuromodulation; served as a consultant for Avid-Lilly, GE, Baxter,
might have progressed to where some cancer treatments are nowie, with diagnosis and Biogen, Roche, Genentech, Forum, Piramal, and Merck; and been on the
management based on multimodal information that enables personalised treatment. editorial boards of the Journal of Neuropsychiatry and Clinical
Neurosciences, Journal of Prevention of Alzheimers Disease, and Alzheimers
Research is at a crucial tipping point, and a world in which Alzheimers disease is a and Dementia: Diagnosis, Assessment and Disease Monitoring. WMYdF has
preventable and treatable condition could soon be a possibility. received research support from ZonMW, NWO, EU-FP7, Alzheimer
Nederland, CardioVascular Onderzoek Nederland, Stichting Dioraphte,
Gieskes-Strijbis fonds, Boehringer Ingelheim, Piramal Neuroimaging,
Conclusions Roche, Janssen Stellar, Stichting VUmc Fonds, and Stichting Alzheimer
& Neuropsychiatrie, and speaker fees from Boehringer Ingelheim.
Alzheimers research is rapidly progressing. Advances MMBB and GBF declare no competing interests.
in basic science and molecular diagnostics have
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