The
tau and amyloid pathobiological processes underlying Alzheimer disease
(AD) progresses slowly over periods of decades before clinical
manifestation as mild cognitive impairment (MCI), then more rapidly to
dementia, and eventually to end-stage organ failure. The failure of
clinical trials of candidate disease modifying therapies to slow disease
progression in patients already diagnosed with early AD has led to
increased interest in exploring the possibility of early intervention
and prevention trials, targeting MCI and cognitively healthy (HC)
populations. Here, we stratify MCI individuals based on cerebrospinal
fluid (CSF) biomarkers and structural atrophy risk factors for the
disease. We also stratify HC individuals into risk groups on the basis
of CSF biomarkers for the two hallmark AD pathologies. Results show that
the broad category of MCI can be decomposed into subsets of individuals
with significantly different average regional atrophy rates. By thus
selectively identifying individuals, combinations of these biomarkers
and risk factors could enable significant reductions in sample size
requirements for clinical trials of investigational AD-modifying
therapies, and provide stratification mechanisms to more finely assess
response to therapy. Power is sufficiently high that detecting efficacy
in MCI cohorts should not be a limiting factor in AD therapeutics
research. In contrast, we show that sample size estimates for clinical
trials aimed at the preclinical stage of the disorder (HCs with evidence
of AD pathology) are prohibitively large. Longer natural history
studies are needed to inform design of trials aimed at the
presymptomatic stage.
Citation: Holland D, McEvoy LK, Desikan RS, Dale AM,
for the Alzheimer’s Disease Neuroimaging Initiative
(2012) Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials. PLoS ONE 7(10):
e47739.
doi:10.1371/journal.pone.0047739
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