Alzheimer's disease polygenic risk in early- and late-onset Alzheimer's disease.
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Pentchev Julian V, Jackson Trever, Khan Naazneen, Rosewood Thea J, Huang Yen-Ning, Nho Kwangsik, Saykin Andrew J, Eloyan Ani, Taurone Alexander, Thangarajah Maryanne, Riddle Meghan, Salloway Steven, Atri Alireza, Honig Lawrence S, Johnson Erik C B, Turner Raymond Scott, Masdeu Joseph C, Foroud Tatiana M, Clark David, Hammers Dustin B, Dage Jeffrey L, Kirby Kala, Ghetti Bernardino, Newell Kathy, Onyike Chiadi U, Day Gregory S, Graff-Radford Neill R, Murray Melissa E, Jones David T, Jack Clifford R, Vemuri Prashanthi, Touroutoglou Alexandra, Duara Ranjan, Grant Ian, Sha Sharon, Wingo Thomas S, Beckett Laurel A, Rogalski Emily, Mendez Mario F, Kramer Joel, La Joie Renaud, Blazhenets Ganna, Grinberg Lea T, Koeppe Robert, Wolk David A, Aisen Paul, Raman Rema, Toga Arthur, Kukull Walter A, Musiek Erik, Womack Kyle B, Carrillo Maria C, Rabinovici Gil D, Dickerson Bradford C, Apostolova Liana G, Nudelman Kelly N H, Longitudinal Early‐Onset Alzheimer's Disease Study Consortium and the Alzheimer's Disease Neuroimaging Initiative
Аннотация
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 ε4 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 ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 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.