The road ahead to cure Alzheimer’s disease: development of biological markers and neuroimaging methods for prevention trials across all stages and target populations
Résumé
Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which
pathophysiological abnormalities, detectable in vivo by biological markers, precede overt
clinical symptoms by many years to decades. Use of these biomarkers for the detection of
early and preclinical AD has become of central importance following publication of two
international expert working group's revised criteria for the diagnosis of AD dementia, mild
cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence
of matured research evidence six AD biomarkers are sufficiently validated and partly
qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary
and secondary prevention trials. These biomarkers fall into two molecular categories:
biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein
related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core
feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF)
analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1-40 ratio, T-tau, and P-tau Thr181 &
Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and
AD dementia. Conversely, having all three biomarkers in the normal range rules out AD.
Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI)
at increasing field strength and resolution allows detecting the evolution of distinct types of
structural and functional abnormality pattern throughout early to late AD stages. Anatomical
or volumetric MRI is the most widely used technique and provides local and global measures
of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive
impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker),
which is considered an indicator of regional neuronal injury. Advanced image analysis
techniques generate automatic and reproducible measures both in regions of interest, such as
the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and
advanced tractography as well as resting-state functional MRI provide useful additionally
useful measures indicating the degree of fiber tract and neural network disintegration
(structural, effective and functional connectivity) that may substantially contribute to early
detection and the mapping of progression. These modalities require further standardization
and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated
biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as
fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of
early AD pathological processes and associated neurodegeneration. How to use, interpret, and
disclose biomarker results drives the need for optimized standardization. Multimodal AD
biomarkers do not evolve in an identical manner but rather in a sequential but temporally
overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of
plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be
combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in
secondary prevention trials to stratify and select individuals at genetic risk of AD. Although
most of these biomarker candidates are not yet qualified and approved by regulatory
authorities for their intended use in drug trials, they are nonetheless applied in ongoing
clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient
stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety.
Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic,
electrophysiological, and neuroimaging markers for use in clinical trials are being developed.
The current state-of-the-art and future perspectives on both biological and neuroimaging
derived biomarker discovery and development as well as the intended application in
prevention trials is outlined in the present publication.
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