%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.
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.
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.
We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.
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.