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Title | Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Katsumata Y, Shade LM, Hohman TJ, Schneider JA, Bennett DA, Farfel JM, Kukull WA, Fardo DW, Nelson PT |
Corporate Authors | Alzheimer’s Disease Genetics Consortium |
Journal | Neurobiol Dis |
Volume | 174 |
Pagination | 105880 |
Date Published | 11/2022 |
ISSN | 1095-953X |
Keywords | Alzheimer Disease, Genome-Wide Association Study, Humans, LDL-Receptor Related Proteins, Membrane Proteins, Membrane Transport Proteins, Nerve Tissue Proteins, Neurofibrillary Tangles, Plaque, Amyloid |
Abstract | The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with "AD-type" (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans-e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies. |
DOI | 10.1016/j.nbd.2022.105880 |
Alternate Journal | Neurobiol Dis |
PubMed ID | 36191742 |
PubMed Central ID | PMC9641973 |
Grant List | P30 AG066444 / AG / NIA NIH HHS / United States GR066133 / WT_ / Wellcome Trust / United Kingdom R01 AG061111 / AG / NIA NIH HHS / United States U24 AG072122 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States RF1 NS118584 / NS / NINDS NIH HHS / United States / / CIHR / Canada / MRC_ / Medical Research Council / United Kingdom P30 AG066509 / AG / NIA NIH HHS / United States R21 AG061551 / AG / NIA NIH HHS / United States R01 AG057187 / AG / NIA NIH HHS / United States R56 AG057191 / AG / NIA NIH HHS / United States R01 AG054060 / AG / NIA NIH HHS / United States GR080002 / WT_ / Wellcome Trust / United Kingdom P30 AG072946 / AG / NIA NIH HHS / United States RC2 AG036528 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States R01 AG067482 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States |