Utility of Polygenic Risk Scores in Families with Exceptional Longevity

Introduction Polygenic risk scores (PRS) have been used to assess an individual’s risk for various diseases, including Alzheimer’s disease (AD). This study applied the PRS approach to a cohort of families ascertained for healthy aging, that have shown a reduced risk of AD. Using the SNPs identified as significantly associated with AD in the study by Kunkle and colleagues, we examined the utility of PRS for predicting AD risk in a cohort ascertained for familial healthy aging.

We restricted the study to US LLFS study participants who have been evaluated for AD and have available whole genome sequencing (WGS) data. AD diagnosis was based on consensus diagnosis, and for those without consensus diagnosis, we used the algorithm based on standardized memory scores. PRS were calculated using a published weighted formula. To further examine the predictability of PRS, we assessed the relationship between PRS and AD biomarkers, including Aβ42, Aβ40, NfL, and GFAP. Mixed effects models were used to adjust for confounders as well as relatedness among family members. Given the age at onset of common late onset AD, the present study included those who were at least 65 years of age.

We observed that PRS had limited predictive power for AD in this healthy aging cohort. Yet, allele frequencies for the SNPs used in PRS estimation differed between the two studies in a small number (9.7%) of SNPs, suggesting that the lack of effect of the PRS is likely to be due to the small number of AD associated SNPs (12.3% and 16.1%). Subsequent analysis observed no significant association between PRS and biomarkers. This was explained by the low number of SNPs significantly associated with each of the biomarkers.

This study highlights the importance of ascertainment of study population in interpreting PRS. In LLFS, a population at reduced risk of AD, PRS based on genetic variants identified from the general population may be inadequate to explain the variability in AD risk. Our results suggest that genetic risk variants, the basis of PRS, may need to be adjusted according to the study population of interest. Competing Interest Statement LSH is a consultant for Bioarctic, Biogen, Corium, Eisai, Genentech/Roche, Eli Lilly, Medscape, and New Amsterdam. LSH receives research funding from Acumen, Alector, Alnylam, Biogen, Bristol-Myers Squibb, Cervomed/EIP, Cognition, Eisai, Ferrer, GemVax, Genentech/Roche, GSK, Janssen/Johnson & Johnson, Eli Lilly, Transposon, UCB, Vaccinex, NIH/NIA, NIH/NINDS, and NYS. Funding Statement This work was funded by the National Institute on Aging/National Institutes of Health (grant numbers: U01-AG023746, U01-AG023712, U01-AG023749, U01-AG023755, U01-AG023744, and U19 AG063893) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB at Washington University in St. Louis gave ethical approval for this work. IRB ID #201904204=1025. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data is being uploaded to the ELITE portal and will be available there. If there is immediate need for the data, contact the authors.