Abstract：
: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.
journal_name
Mol Psychiatryjournal_title
Molecular psychiatryauthors
Mukherjee S,Mez J,Trittschuh EH,Saykin AJ,Gibbons LE,Fardo DW,Wessels M,Bauman J,Moore M,Choi SE,Gross AL,Rich J,Louden DKN,Sanders RE,Grabowski TJ,Bird TD,McCurry SM,Snitz BE,Kamboh MI,Lopez OL,De Jager PL,Benndoi
10.1038/s41380-018-0298-8subject
Has Abstractpub_date
2020-11-01 00:00:00pages
2942-2951issue
11eissn
1359-4184issn
1476-5578pii
10.1038/s41380-018-0298-8journal_volume
25pub_type
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