P3‐135: PROTECTIVE GENETIC VARIANTS IN THE MIDWESTERN AMISH

Le résumé fourni par la source

The primary focus of almost all Alzheimer disease (AD) genetic studies has been the identification of variants that increase AD risk. Our goal is to identify functional variants that protect against the development of AD and to find the therapeutic implications of novel pathways currently not associated with AD. We are applying a family-based approach by studying the Amish of Ohio and Indiana. The Amish originate from <1,000 founders and remain culturally and environmentally isolated from the rest of the population. This homogeneous population increases our ability to find rare protective variants for AD that do not exist at a detectable frequency in the general population. Our focus is to identify individuals who are cognitively normal (CN), but at high risk for developing AD (i.e. have an affected sibling). Inclusion criteria are: being of Amish descent, being at least 76 years of age, and currently CN. Each of these individuals is retested every two years to assess their cognition using the CERAD neuropsych assessment. Data on personal medical/family history, environmental risk factors, Geriatric Depression Scale, Functional Assessment (ADLs and IADls) and Performance Testing. DNA from all individuals is currently being genotyped via the GSA (Illumina) SNP chip. Using the extensive genealogical data of families in the Amish population, we have generated a large ∼5,000 person, 13 generation pedigree. As of January 2019, 226 people have completed neuropsychiatric testing: 150 have been adjudicated; 106 (71%) are CN; 44 (29%) are cognitively impaired. The overall mean age is 82.9 years. The power of founder populations can be exploited to identify protective genetic variation in AD. We have specifically targeted individuals who are CN but at high risk of developing AD. This approach is valuable in identifying important rare and hard to detect variation, which will nominate specific genes for further biological and pharmacological study. Our goal is to gain a deeper understanding of the complexity of AD and find new pathways for possible therapeutic targets that may help to slow the progression of AD or even to completely prevent its development.

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