Executive Prominent Alzheimer’s Disease: Genetics and Risk Factors
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Item type: Item , Item type: Item , Genetic data and cognitively defined late-onset Alzheimer's disease subgroups(Nature, 2018-12-04) Mukherjee, Shubhabrata; Mez, Jesse; Trittschuh, Emily H.; Saykin, Andrew J.; Gibbons, Laura E.; Fardo, David W.; Wessels, Madeline; Bauman, Julianna; Moore, Mackenzie; Choi, Seo-Eun; Gross, Alden L.; Rich, Joanne; Louden, Diana Nelson; Sanders, R. Elizabeth; Grabowski, Thomas J.; Bird, Thomas D.; McCurry, Susan M.; Snitz, Beth E.; Kamboh, Ilyas; Lopez, Oscar L.; De Jager, Philip L.; Bennett, David A.; Keene, C. Dirk; Larson, Eric B.; EPAD Study Group; Investigators from ACT; Investigators from ROS; Investigators from MAP; Investigators from ADNI; Investigators from the University of Pittsburgh ADRC; Crane, Paul K.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.Item type: Item , Genome-wide summary statistics for cognitively defined late-onset Alzheimer’s disease subgroups(NIAGADS, 2018-12-19)GWAS meta-analysis summary statistics for case-control analyses of five cognitively defined Alzheimer’s disease subgroups. 1. Controls vs. memory predominant AD 2. Controls vs. visuospatial predominant AD 3. Controls vs. language predominant AD 4. Controls vs. no domain with substantial relative impairment AD group 5. Controls vs. multiple substantial relative impairment AD group The subgroups were assigned on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. The executive functioning prominent AD subgroup was too small to analyze and was left out. The individual GWAS sets were based on 1000G imputed data (March 2012 build) and were adjusted for age, sex, and principal components and finally meta-analyzed using METAL. The studies used for meta-analysis were the Adult Changes in Thought (ACT) study, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Religious Orders Study (ROS), the Memory and Aging Project (MAP), and the University Of Pittsburgh (PITT) study. The GWAS summary statistics files were quality controlled to exclude SNPs with minor allele frequency < 3%, monomorphic SNPs. The p-value data is generally available to all users using the link below; however, gaining access to the complete dataset requires a formal data request.Item type: Item , Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups(Nature, 2018-12-04) Mukherjee, Shubhabrata; Mez, Jesse; Trittschuh, Emily H.; Saykin, Andrew J.; Gibbons, Laura E.; Fardo, David W.; Wessels, Madeline; Bauman, Julianna; Moore, Mackenzie; Choi, Seo-Eun; Gross, Alden L.; Rich, Joanne; Louden, Diana Nelson; Sanders, R. Elizabeth; Grabowski, Thomas J.; Bird, Thomas D.; McCurry, Susan M.; Snitz, Beth E.; Kamboh, Ilyas; Lopez, Oscar L.; De Jager, Philip L.; Bennett, David A.; Keene, C. Dirk; Larson, Eric B.; EPAD Study Group; Investigators from ACT; Investigators from ROS; Investigators from MAP; Investigators from ADNI; Investigators from the University of Pittsburgh ADRC; Crane, Paul K.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.