Presenilin‐1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage
Nelly Joseph‐Mathurin, Rebecca L. Feldman, Ruijin Lu, Zahra Shirzadi, Carmen Toomer, Junie R. Saint Clair, Yinjiao Ma, Nicole S. McKay, Jeremy F. Strain, Collin Kilgore, Karl A. Friedrichsen, Charles D. Chen, Brian A. Gordon, Gengsheng Chen, Russ C. Hornbeck, Parinaz Massoumzadeh, Austin McCullough, Qing Wang, Yan Li, Guoqiao Wang, Sarah Keefe, Stephanie A. Schultz, Carlos Cruchaga, Gregory M. Preboske, Clifford R. Jack, Jorge J. Llibre‐Guerra, Ricardo Allegri, Beau M. Ances, Sarah Berman, William S. Brooks, David M. Cash, Gregory S. Day, Nick C. Fox, Michael Fulham, Bernardino Ghetti, Keith A. Johnson, Mathias Jucker, William E. Klunk, Christian la Fougère, Johannes Levin, Yoshiki Niimi, Hwamee Oh, Richard J. Perrin, Gerald Reischl, John M. Ringman, Andrew J. Saykin, Peter R. Schofield, Yi Su, Charlene Supnet, Jonathan Vöglein, Igor Yakushev, Adam M. Brickman, John C. Morris, Eric McDade, Chengjie Xiong, Randall J. Bateman, Jasmeer P. Chhatwal, Tammie L.S. Benzinger, for the Dominantly Inherited Alzheimer Network
Abstract
INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.