Enrichment and stratification for predementia Alzheimer disease clinical trials

Abstract

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.

Figure 1. Annual atrophy rates for MCI participants, with 95% confidence intervals, for AD-relevant cortical and subcortical ROIs, grouped with respect to baseline Aβ, ptau, and volumetric MRI status (top row).

In the bottom row, all participants are Aβ-positive. N is the number of participants. Numerical values are in File S1, Tables S1A–F.

Figure 2. Annual atrophy rates for (A) Aβ⁺ HC participants, 4 of whom converted to MCI, and (B) Aβ⁺Ptau⁺ HCs participants (i.e., the HCs most likely to be preclinical-AD), 3 of whom converted to MCI, compared with the control group of stable Aβ^– HCs.

N is the number of participants. Numerical values, including p-values, are in File S1, Tables S2A and S2B.

Figure 3. Estimated sample sizes, per arm, to detect a 25% reduction in annual rate of change in MCI participants under several enrichment strategies, relative to the annual rate of change in amyloid-negative stable HCs, at the p<0.05 level with 80% power assuming a 24 month trial with scans every six months.

Sample sizes are estimated using a linear mixed effects model with fixed intercepts (no relative change at baseline) and random slopes applied to all data available up through 36 months. Error bars show the 95% confidence intervals. N is the number of participants. All numerical values are shown Table 3; p-values for comparisons are in Tables 4 and 5.