Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort. Alzheimer's & dementia : the journal of the Alzheimer's Association Nudelman, K. N., Jackson, T., Rumbaugh, M., Eloyan, A., Abreu, M., Dage, J. L., Snoddy, C., Faber, K. M., Foroud, T., Hammers, D. B., DIAN/DIAN-TU Clinical/Genetics Committee, Taurone, A., Thangarajah, M., Aisen, P., Beckett, L., Kramer, J., Koeppe, R., Kukull, W. A., Murray, M. E., Toga, A. W., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J. C., Mendez, M., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Wingo, T. S., Wolk, D. A., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G., LEADS Consortium 2023

Abstract

INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N=299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

View details for DOI 10.1002/alz.13482

View details for PubMedID 37801072