Multilocus genetic profiling to empower drug trials and predict brain atrophy

Omid Kohannim, Xue Hua, Priya Rajagopalan, Derrek P. Hibar, Neda Jahanshad, Joshua D. Grill, Liana G. Apostolova, Arthur W. Toga, Clifford R. Jack, Michael W. Weiner, Paul M. Thompson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)827-835
Number of pages9
JournalNeuroImage: Clinical
Volume2
Issue number1
DOIs
StatePublished - Jul 23 2013
Externally publishedYes

Fingerprint

Atrophy
Alzheimer Disease
Apolipoproteins E
Sample Size
Brain
Pharmaceutical Preparations
Biomarkers
Genotype
Clinical Trials
Functional Neuroimaging
Therapeutic Uses
Neuroimaging
Genes
Cerebrospinal Fluid
Outcome Assessment (Health Care)
Costs and Cost Analysis
Cognitive Dysfunction
Power (Psychology)

Keywords

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

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Kohannim, O., Hua, X., Rajagopalan, P., Hibar, D. P., Jahanshad, N., Grill, J. D., ... Thompson, P. M. (2013). Multilocus genetic profiling to empower drug trials and predict brain atrophy. NeuroImage: Clinical, 2(1), 827-835. https://doi.org/10.1016/j.nicl.2013.05.007

Multilocus genetic profiling to empower drug trials and predict brain atrophy. / Kohannim, Omid; Hua, Xue; Rajagopalan, Priya; Hibar, Derrek P.; Jahanshad, Neda; Grill, Joshua D.; Apostolova, Liana G.; Toga, Arthur W.; Jack, Clifford R.; Weiner, Michael W.; Thompson, Paul M.

In: NeuroImage: Clinical, Vol. 2, No. 1, 23.07.2013, p. 827-835.

Research output: Contribution to journalArticle

Kohannim, O, Hua, X, Rajagopalan, P, Hibar, DP, Jahanshad, N, Grill, JD, Apostolova, LG, Toga, AW, Jack, CR, Weiner, MW & Thompson, PM 2013, 'Multilocus genetic profiling to empower drug trials and predict brain atrophy', NeuroImage: Clinical, vol. 2, no. 1, pp. 827-835. https://doi.org/10.1016/j.nicl.2013.05.007
Kohannim O, Hua X, Rajagopalan P, Hibar DP, Jahanshad N, Grill JD et al. Multilocus genetic profiling to empower drug trials and predict brain atrophy. NeuroImage: Clinical. 2013 Jul 23;2(1):827-835. https://doi.org/10.1016/j.nicl.2013.05.007
Kohannim, Omid ; Hua, Xue ; Rajagopalan, Priya ; Hibar, Derrek P. ; Jahanshad, Neda ; Grill, Joshua D. ; Apostolova, Liana G. ; Toga, Arthur W. ; Jack, Clifford R. ; Weiner, Michael W. ; Thompson, Paul M. / Multilocus genetic profiling to empower drug trials and predict brain atrophy. In: NeuroImage: Clinical. 2013 ; Vol. 2, No. 1. pp. 827-835.
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