Elsevier

NeuroImage: Clinical

Volume 2, 2013, Pages 827-835
NeuroImage: Clinical

Multilocus genetic profiling to empower drug trials and predict brain atrophy

https://doi.org/10.1016/j.nicl.2013.05.007Get rights and content
Under a Creative Commons license
open access

Highlights

  • ApoE genotype status helps enrich MCI trials, using a structural MRI outcome measure.

  • CLU, PICALM and CR1 risk genes boost potential MCI trial power beyond ApoE alone.

  • CLU, PICALM and CR1 show significant, aggregate effects on TBM maps of brain atrophy.

Abstract

Designers of clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are actively considering structural and functional neuroimaging, cerebrospinal fluid and genetic biomarkers to reduce the sample sizes needed to detect therapeutic effects. Genetic pre-selection, however, has been limited to Apolipoprotein E (ApoE). Recently discovered polymorphisms in the CLU, CR1 and PICALM genes are also moderate risk factors for AD; each affects lifetime AD risk by ~ 10–20%. Here, we tested the hypothesis that pre-selecting subjects based on these variants along with ApoE genotype would further boost clinical trial power, relative to considering ApoE alone, using an MRI-derived 2-year atrophy rate as our outcome measure. We ranked subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on their cumulative risk from these four genes. We obtained sample size estimates in cohorts enriched in subjects with greater aggregate genetic risk. Enriching for additional genetic biomarkers reduced the required sample sizes by up to 50%, for MCI trials. Thus, AD drug trial enrichment with multiple genotypes may have potential implications for the timeliness, cost, and power of trials.

Keywords

Alzheimer's disease
Neuroimaging
Brain atrophy
Genetics
Genetic risk score
Clinical trial enrichment

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1

Data used in preparing this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators include those listed at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.