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BackgroundVariants in the presenilin‐1 gene (PSEN1) are known to be pathogenic for Alzheimer disease (AD). The change of glycine at amino acid 206 to alanine (G206A) in PSEN1 has been identified in AD Caribbean Hispanic families from Puerto Rico with variable ages of onset and incomplete segregation (Athan et.al., 2001). Here we set out to confirm the role of G206A in the genetic etiology of AD in Puerto Rico while investigating its ancestral history and founding haplotype.MethodWe performed genotyping and whole genome sequencing (WGS) of 43 AD families (N = 182: 87 AD, 41 MCI, and 44 cognitively unimpaired) and 272 AD, 145 MCI, and 297 cognitively unimpaired unrelated individuals of Puerto Rican background and identified carriers of G206A. Genotyping data were phased using SHAPEIT to identify local ancestry of the PSEN1 haplotype followed by RFMix to estimate the genetic ancestral background (African, European, or Amerindian). Haplotype modeling was performed using MERLIN software.ResultWe identified 19 carriers of G206A among individuals with sequencing data in eight of the 43 families (14 AD, two MCI, one neuropsychiatric disorder, and two cognitively unimpaired individuals under 65 years old). G206A did not completely explain AD in these eight families as six other AD cases in the families did not carry the variant. In the unrelated cohort, we identified 13 carriers (nine AD, one MCI, one Pick’s disease, and two cognitively unimpaired under 65 years old). Local ancestry indicated that the mutation arose on an African ancestral haplotype. However, in screening WGS of individuals of primarily African ancestry from Ibadan, Nigeria (63 AD and 648 controls) and African Americans part of the Alzheimer Disease Sequencing Project (1347 AD, 2290 controls) no other carriers were identified.ConclusionOur results support that G206A contributes to AD in the Puerto Rican population, but in AD families does not completely explain the genetic risk. We also show that this variant occurs on a common haplotype across carriers representing a founder event on an African haplotype background in Puerto Rico.

BackgroundDepression (DEP) is a known risk factor for . However, DEP symptoms vary by race‐ethnicity (e.g. greater somatization among African Americans). The relationship between DEP and AD progression in underrepresented groups is not well‐understood. We hypothesize that certain DEP symptoms will be associated with earlier AAO, and that this relationship is moderated by race‐ethnicityMethodSelf‐declared Non‐Hispanic White (NWH), African American (AA), and Hispanic (HI) participants with AD and CDR data were identified from a larger genetic study. Our dataset consisted of 549 persons with a self‐completed GDS (mean CDR = 0.6; 15% NWH, 43% AA, 42% HI), 334 persons with informant completed CSDD (CDR = 1.7; 41% NWH, 20% AA, 39% HI), and 266 persons with self‐reported DEP and anxiety in a medical history exam (CDR = 0.7; 26% NWH, 23% AA, 51% HI). All measures were completed after the onset of AD. Univariate linear regressions examined the relationship between AAO and DEP (total scores and individual items), and race‐ethnicity x DEP interactions after controlling for sex, race‐ethnicity, disease duration, and APOE‐e4.ResultSelf‐reported (p = 0.04), informant‐reported anxiety (CSDD) (p = 0.02), and self‐reports of feeling empty (GDS) (p = 0.02) were associated with an earlier AAO across all groups. Informant‐reports of poor self‐esteem (CSDD) was associated with an earlier AAO overall (p < 0.01), but an interaction showed that this was not significant in HI (p = 0.). Unique items associated with an earlier AAO in NHW included higher GDS total scores (p = 0.01), feeling bored (GDS) (p < 0.01), and perceived problems with memory (GDS) (p < 0.01). In AA self‐reported DEP was associated with an earlier AAO (p = 0.02). No items were uniquely associated with AAO in HI.ConclusionSelf‐ and informant‐reported anxiety and self‐reported feelings of emptiness were associated with an earlier AAO in all groups. However, several DEP symptoms associated with earlier AAO differed as a function of race‐ethnicity. We believe our findings suggest that the occurrence of DEP may be culturally or ancestrally influenced, which in turn has a differential impact on AAO in underrepresented groups.