APOE3 Christchurch mutation carriers from the Colombian kindred with autosomal dominant Alzheimer’s disease due to PSEN1 E280A

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AbstractBackgroundOur understanding of the mechanisms of protection mediated by APOE has advanced significantly in the past years. Our group previously showed that APOE3 Christchurch (APOE3ch) homozygosity was associated with the protection against Alzheimer’s disease dementia in an individual who carried the Presenilin‐1 (PSEN1)‐E280A variant for autosomal dominant AD (ADAD) (Arboleda‐Velasquez et al., 2019). Here we present the initial characterization of individuals from the PSEN1‐E280A kindred with the APOE3ch variant.Methods1,000 PSEN1‐E280A variant carriers and 1,000 non‐carriers from the Colombian ADAD kindred were characterized in terms of their common APOE variants and the rare APOEch variant. Participants had previously completed a comprehensive neurological and neuropsychological evaluation. Those who were alive were re‐contacted in 2021 to undergo comprehensive clinical assessments, including the CERAD‐Colombia neuropsychological battery, and MRI and FDG PET imaging as part of the Resist Alzheimer’s Project.ResultsWe discovered 97 ADAD kindred members with the APOE3ch variant (95 heterozygotes), including 84 who are living and 13 who are deceased (7 who were brain donors). 29 of the APOE3ch carriers also had the PSEN1‐E280A variant, including 18 who are living and 11 who are deceased. The age range for all APOE3ch variant carriers was from 17 to 72 years, including 11 APOE3ch + PSEN1‐E280A carriers who were 50‐72 years old (i.e., older than the PSEN1‐E280A variant carriers’ median age at dementia onset). Overall, global cognition and memory performances of the first three APOE3ch + PSEN1‐E280A carriers (older than 50 years of age) assessed fell within the normal range, compared to age‐matched individuals from this kindred.ConclusionsThe prevalence rate of APOE3 Christchurch heterozygosity in the Colombian kindred with ADAD (4.85%) is very high compared to the general population (e.g., gnomAD database reports an allele frequency of 0.00001283; Karczewski et al., 2019). Preliminary clinical and cognitive data from APOE3ch variant carriers are consistent with the hypothesis that heterozygosity may have a mild‐to‐moderate protective effect against cognitive decline. We plan to compare longitudinal clinical, cognitive, biomarker, and post‐mortem neuropathological changes in PSEN1‐E280A carriers with and without the APOE3ch variant to clarify the role of APOE3ch heterozygosity in the protection from ADAD.