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Alzheimer's disease polygenic risk in early- and late-onset Alzheimer's disease.

Alzheimer's disease polygenic risk in early- and late-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association Pentchev, J. V., Jackson, T., Khan, N., Rosewood, T. J., Huang, Y., Nho, K., Saykin, A. J., Eloyan, A., Taurone, A., Thangarajah, M., Riddle, M., Salloway, S., Atri, A., Honig, L. S., Johnson, E. C., Turner, R. S., Masdeu, J. C., Foroud, T. M., Clark, D., Hammers, D. B., Dage, J. L., Kirby, K., Ghetti, B., Newell, K., Onyike, C. U., Day, G. S., Graff-Radford, N. R., Murray, M. E., Jones, D. T., Jack, C. R., Vemuri, P., Touroutoglou, A., Duara, R., Grant, I., Sha, S., Wingo, T. S., Beckett, L. A., Rogalski, E., Mendez, M. F., Kramer, J., La Joie, R., Blazhenets, G., Grinberg, L. T., Koeppe, R., Wolk, D. A., Aisen, P., Raman, R., Toga, A., Kukull, W. A., Musiek, E., Womack, K. B., Carrillo, M. C., Rabinovici, G. D., Dickerson, B. C., Apostolova, L. G., Nudelman, K. N., Longitudinal Early-Onset Alzheimer's Disease Study Consortium and the Alzheimer's Disease Neuroimaging Initiative 2026; 22 (1): e71066

Abstract

INTRODUCTION: The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD.METHODS: A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers.RESULTS: Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE epsilon4 carrier status and was not associated with age of EOAD onset (p=0.106) or with cognitive performance (p=0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p=2.3*10-5).DISCUSSION: While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology.HIGHLIGHTS: LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE epsilon4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Abeta42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

View details for DOI 10.1002/alz.71066

View details for PubMedID 41532810