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

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.

Fig. 1

Proportions of people in each study and overall in each cognitively defined subgroup

Fig. 2

Novel SNPs associated with cognitively defined subdomains with p < 10^–5 and OR < 0.77 or > 1.33. CAF=coded allele frequency. SNPs further than 50 kB from a gene do not have a gene name reported here. Gray shading in the odds ratios column of the figure delineates ORs > 0.77 and < 1.30, which is the range of ORs outside APOE from the International Genomics of Alzheimer’s Project (IGAP) [6]