%0 Journal Article
%T Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.
%A Joseph-Mathurin N
%A Feldman RL
%A Lu R
%A Shirzadi Z
%A Toomer C
%A Saint Clair JR
%A Ma Y
%A McKay NS
%A Strain JF
%A Kilgore C
%A Friedrichsen KA
%A Chen CD
%A Gordon BA
%A Chen G
%A Hornbeck RC
%A Massoumzadeh P
%A McCullough AA
%A Wang Q
%A Li Y
%A Wang G
%A Keefe SJ
%A Schultz SA
%A Cruchaga C
%A Preboske GM
%A Jack CR
%A Llibre-Guerra JJ
%A Allegri RF
%A Ances BM
%A Berman SB
%A Brooks WS
%A Cash DM
%A Day GS
%A Fox NC
%A Fulham M
%A Ghetti B
%A Johnson KA
%A Jucker M
%A Klunk WE
%A la Fougère C
%A Levin J
%A Niimi Y
%A Oh H
%A Perrin RJ
%A Reischl G
%A Ringman JM
%A Saykin AJ
%A Schofield PR
%A Su Y
%A Supnet-Bell C
%A Vöglein J
%A Yakushev I
%A Brickman AM
%A Morris JC
%A McDade E
%A Xiong C
%A Bateman RJ
%A Chhatwal JP
%A Benzinger TLS
%A  
%J Alzheimers Dement
%V 20
%N 4
%D 2024 04 21
%M 38380882
%F 16.655
%R 10.1002/alz.13729
%X 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.<BR>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.<BR>Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® 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.<BR>We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.<BR>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.