Frequency of Variants in Mendelian Alzheimer’s Disease Genes within the Alzheimer’s Disease Sequencing Project (ADSP)

Objective To characterize the consequences of loss-of-function (LoF), predicted damaging missense (DM), and previously-reported clinically-relevant variants in three Mendelian Alzheimer’s disease (AD) genes – presenilin-2 ( PSEN2 ), presenilin-1 ( PSEN1 ), and amyloid precursor protein ( APP ) – within the participants from the Alzheimer’s Disease Sequencing Project (ADSP) whole genome sequence (WGS) and whole exome sequence (WES) data. Methods We identified rare variants (MAF <1%) previously-reported in PSEN2 , PSEN1, and APP in the available ADSP sample of 14,641 individuals with WGS and 16,849 individuals with WES available for research-use (Ntotal = 31,490). We additionally curated variants in these three genes from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as LoF and predicted DM variants in these genes. Results We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in PSEN2 , 25 in PSEN1 , and 2 in APP . Thirty-eight clinical variants with conflicting pathogenicity interpretation within ClinVar or across the databases were identified along with 12 additional LoF and 197 additional DM variants. The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed 78 individuals carrying at least one clinically-relevant variant, 79.5% were cases compared to 3.9% controls. In those with AD, we observed that the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with non-carriers (p-value=7.8×10-57), and the average age of onset of AD is 5 years earlier in carriers of an additional LoF variant (n=5) compared with non-carriers. Conclusion The ADSP data permit further characterization of previously-reported AD clinically-relevant variants. A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to non-carriers. Furthermore, we observed additional LoF variants that potentially contribute to clinical presentation of AD. ### Competing Interest Statement AMG has consulted for Eisai, Biogen, AbbVie, and GSK; she also serves on the Scientific Advisory Boards of Genentech and Muna Therapeutics. All other authors report no disclosures relevant to this manuscript. ### Funding Statement This work was supported in part by NIA grant U01AG058589. ### 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: The Institutional Review Board(IRB) of Boston University gave ethnical approval for this work. 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