Contributions of rare and common variation to early-onset and atypical dementia risk

Abstract

We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with 68 newly described in this report. Of those 68, 62 patients self-reported white, non-Hispanic ethnicity and 6 reported as African-American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score (PRS) was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non-APOE PRSs than patients with late-onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Keywords: Alzheimer disease; frontotemporal dementia.

Figure 1.

Summary of genomic sequencing findings for the (A) 68-proband cohort and (B) all 100 enrolled probands including the 32 described in Cochran et al. Patients carrying one APOE ε4 allele are noted as APOE ε4 Het. and those carrying two alleles are noted as APOE ε4 Hom. Patients carrying a risk allele in addition to one or two APOE ε4 allele are listed as APOE ε4 Het. or Hom. + risk. (VUS) Variant of uncertain significance.

Figure 2.

Evaluation of five probands with a MAPT R406W variant. (A) Pedigrees for the five probands with the MAPT variant. Probands are marked with arrow. Affected family members are solid pink. Patients 1–3 were identified in our previous study (Cochran et al. 2019). (B) Diagram showing the KING kinship coefficients between probands. Values in red denote third-degree relatives. Figure was generated at biorender.com. (EOAD) Early-onset Alzheimer's disease, (FTD) frontotemporal dementia.

Figure 3.

Violin plot comparing PRS of the University of Alabama at Birmingham (UAB) early-onset dementia (UAB EOAD) cohort to patients with a late-onset dementia (LOAD) cohort, and the control (Control) cohort. This PRS excludes APOE status. Only individuals with a self-reported ancestry of self-reported white, non-Hispanic were included in this analysis. ANOVA with Kruskal–Wallis test was used to calculate adjusted P-values.