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Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups

  • Mukherjee, Shubhabrata1
  • Mez, Jesse2
  • Trittschuh, Emily H.1, 3
  • Saykin, Andrew J.4
  • Gibbons, Laura E.1
  • Fardo, David W.5
  • Wessels, Madeline1
  • Bauman, Julianna1
  • Moore, Mackenzie1
  • Choi, Seo-Eun1
  • Gross, Alden L.6
  • Rich, Joanne1
  • Louden, Diana K. N.1
  • Sanders, R. Elizabeth1
  • Grabowski, Thomas J.1, 1
  • Bird, Thomas D.3, 1
  • McCurry, Susan M.1
  • Snitz, Beth E.7
  • Kamboh, M. Ilyas7
  • Lopez, Oscar L.7, 7
  • And 5 more
  • 1 University of Washington, Seattle, WA, USA , Seattle (United States)
  • 2 Boston University School of Medicine, Boston, MA, USA , Boston (United States)
  • 3 VA Puget Sound Health Care System, Seattle, WA, USA , Seattle (United States)
  • 4 Indiana University, Indianapolis, IN, USA , Indianapolis (United States)
  • 5 University of Kentucky, Lexington, KY, USA , Lexington (United States)
  • 6 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA , Baltimore (United States)
  • 7 University of Pittsburgh, Pittsburgh, PA, USA , Pittsburgh (United States)
  • 8 Columbia University Medical Center, New York, NY, USA , New York (United States)
  • 9 Rush University Medical Center, Chicago, IL, USA , Chicago (United States)
  • 10 School of Medicine, The University of Washington, Seattle, WA, USA , Seattle (United States)
  • 11 Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA , Seattle (United States)
Published Article
Molecular Psychiatry
Nature Publishing Group UK
Publication Date
Dec 04, 2018
DOI: 10.1038/s41380-018-0298-8
Springer Nature


Categorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10−5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10−27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10−5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

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