Abstract
This report gives a comprehensive and up-to-date review of Alzheimer' s disease
biomarkers. Recent years have seen significant advances in this field. Whilst
considerable effort has focused on Aβ and tau related markers, a
substantial number of other molecules have been identified, that may offer new
opportunities.
This Report : Identifies 60 candidate Alzheimer' s (AD) biomarkers and their
associated studies. Of these, 49 are single species or single parameters, 7
are combinations or panels and 4 involve the measurement of two species or
parameters or their ratios. These include proteins (n=34), genes (n=11),
image-based parameters (n=7), small molecules (n=3), proteins + genes (n=2)
and others (n=3). Of these, 30 (50%) relate to species identified in CSF and
19 (32%) were found in the blood. These candidate may be classified on the
basis of their diagnostic utility, namely those which i) may allow AD to be
detected when the disease has developed (48 of 75†= 64%), ii) may allow
early detection of AD (18 of 75† = 24%) and iii) may allow AD to be
predicted before the disease has begun to develop (9 of 75†= 12%).
† Note: Of these, 11 were linked to two or more of these capabilities
(e.g. allowed both early-stage detection as well as diagnosis after the
disease has developed).
Biomarkers: AD biomarkers identified in this report show significant
diversity, however of the 60 described, 18 (30%) are associated with amyloid
beta (Aβ) and 9 (15%) relate to Tau. The remainder of the biomarkers
(just over half) fall into a number of different groups. Of these, some are
associated with other hypotheses on the pathogenesis of AD however the vast
majority are individually unique and not obviously linked with other markers.
Analysis and discussion presented in this report includes summaries of the
studies and clinical trials that have lead to the identification of these
markers. Where it has been calculated, diagnostic sensitivity, specificity and
the capacity of these markers to differentiate patients with suspected AD from
healthy controls and individuals believed to be suffering from other
neurodegenerative conditions, have been indicated. These findings are
discussed in relation to existing hypotheses on the pathogenesis of the AD and
the current drug development pipeline. Many uncertainties remain in relation
to the pathogenesis of AD, in diagnosing and treating the disease and many of
the studies carried out to identify disease markers are at an early stage and
will require confirmation through larger and longer investigations.
Nevertheless, significant advances in the identification of AD biomarkers have
now been made. Moreover, whilst much of the research on AD biomarkers has
focused on amyloid and tau related species, it is evident that a substantial
number of other species may provide important opportunities.
Purpose of Report: To provide a comprehensive review of important and recently
discovered candidate biomarkers of AD, in particular those with potential to
reliably detect the disease or with utility in clinical development, drug
repurposing, in studies of the pathogenesis and in monitoring drug response
and the course of the disease. Other key goals were to identify markers that
support current pipeline developments, indicate new potential drug targets or
which advance understanding of the pathogenesis of this disease.
Drug Repurposing: Studies of the pathogenesis of AD have identified aberrant
changes in a number of other disease areas including inflammation, diabetes,
oxidative stress, lipid metabolism and others. These findings have prompted
studies to evaluate some existing approved drugs to treat AD. This report
identifies studies of 9 established drug classes currently being investigated
for potential repurposing.
Alzheimer' s Disease: In 2005, the global prevalence of dementia was estimated
at 25 million, with more than 4 million new cases occurring each year. It is
also calculated that the number of people affected will double every 20 years,
to 80 million by 2040, if a cure is not found. More than 50% of dementia cases
are due to AD. Today, approximately 5 million individuals in the US suffer
from AD, representing one in eight people over the age of 65. Direct and
indirect costs of AD and other forms of dementia in the US are around $150
billion annually. Worldwide, costs for dementia care are estimated at $315
billion annually. Despite significant research into this debilitating and
ultimately fatal disease, advances in the development of diagnostic tests for
AD and moreover, effective treatments, remain elusive.
Background: Alzheimer' s disease is the most common cause of dementia, yet its
clinical diagnosis remains uncertain until an eventual post-mortem
histopathology examination is carried out. Currently, therapy for patients
with Alzheimer disease only treats the symptoms; however, it is anticipated
that new disease-modifying drugs will soon become available. The urgency for
new and effective treatments for AD is matched by the need for new tests to
detect and diagnose the condition. Uncertainties in the diagnosis of AD mean
that the disease is often undiagnosed and under treated. Moreover, it is clear
that clinical confirmation of AD, using cognitive tests, can only be made
after substantial neuronal cell loss has occurred; a process that may have
taken place over many years. Poor response to current therapies may therefore,
in part, reflect the fact that such treatments are generally commenced only
after neuronal damage has occurred. The absence of tests to detect or diagnose
presymptomatic AD also means that there is no standard that can be applied to
validate experimental findings (e.g. in drug discovery) without performing
lengthy studies, and eventual confirmation by autopsy.
These limitations are focusing considerable effort on the identification of
biomarkers that advance understanding of the pathogenesis of AD and how the
disease can be diagnosed in its early stages and treated. It is hoped that
developments in these areas will help physicians to detect AD and guide
therapy before the first signs of neuronal damage appears. The last 5-10 years
have seen substantial research into the pathogenesis of AD and this has lead
to the identification of a substantial number of AD biomarkers, which offer
important insights into this disease. This report brings together the latest
advances in the identification of AD biomarkers and analyses the opportunities
they offer in drug R&D and diagnostics.
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