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 sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients self-reported white, non-Hispanic ethnicity and six 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 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 polygenic risk scores than patients with late onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Early‐onset Alzheimer's disease explained by polygenic risk of late‐onset disease?

“…A recent report supports this hypothesis; participants with a strong family history of dementia had a higher likelihood of harboring rare pathogenic variants with large effect sizes. 23 A second methodological difference is that the age of onset of the two studies’ early‐onset AD groups are different; the present study's mean age of AD symptom onset was 5 years younger than the prior report. Furthermore, for inclusion as an early‐onset AD participant, we used an age of diagnosis < 65 whereas the Cruchaga et al.…”

“…study and this study is that polygenic modes of inheritance may underlie sporadic early‐onset AD, whereas highly penetrant oligogenic or recessive inheritance may underlie early‐onset AD with positive family histories. A recent report supports this hypothesis; participants with a strong family history of dementia had a higher likelihood of harboring rare pathogenic variants with large effect sizes 23 . A second methodological difference is that the age of onset of the two studies’ early‐onset AD groups are different; the present study's mean age of AD symptom onset was 5 years younger than the prior report.…”

“…A recent report supports this hypothesis; participants with a strong family history of dementia had a higher likelihood of harboring rare pathogenic variants with large effect sizes. 23 homozygotes. 26,28 Elsewhere, a recent study observed no effect of APOE ε4 on age of onset in men with early-onset AD, but a decreased age of onset for females with early-onset AD lacking an APOE ε4 allele.…”