Presenilin‐1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage

• DOI: 10.1002/alz.13729
• Publication Date: 2024-02-21T13:25:41Z
• Authors: Nelly Joseph‐Math...; 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 A. McCullough; Qing Wang; Yan Li; Guoqiao Wang; Sarah J. Keefe; Stephanie A. Schultz; Carlos Cruchaga; Gregory M. Preboske; Clifford R. Jack; Jorge J. Llibre‐G...; Ricardo F. Allegri; Beau M. Ances; Sarah B. 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‐Bell; Jonathan Vöglein; Igor Yakushev; Adam M. Brickman; John C. Morris; Eric McDade; Chengjie Xiong; Randall J. Bateman; Jasmeer P. Chhatwal; Tammie L. S. Benz...
• Keywords: Physiology; small vessel disease (SVD); genetics [Alzheimer Disease]; Vascular dementia; Peak width of skeletonized mean diffusivity (PSMD); pathology [Alzheimer Disease]; Autosomal dominant Alzheimer's disease (ADAD); Mechanisms of Alzheimer's Disease; Pathology; Psychology; Disease; autosomal dominant Alzheimer's disease (ADAD); Internal medicine; Research Articles; PSEN1; White matter hyperintensity (WMH); Familial Amyloid Polyneuropathy; White matter; Life Sciences; genetics [Presenilin-1]; Amyloidosis; Diagnosis and Management of Alzheimer's Disease; Alzheimer's disease; Magnetic Resonance Imaging; FOS: Psychology; Psychiatry and Mental health; white matter hyperintensity (WMH); Diffusion Tensor Imaging; complications [Cerebral Small Vessel Diseases]; Microbleeds; Medicine; diagnostic imaging [Cerebral Small Vessel Diseases]; PiB-PET; Hyperintensity; Radiology; codon 200; genetics [Mutation]; Neuroimaging; Cerebral amyloid angiopathy (CAA); Presenilin; Diffusion MRI; PSEN1 protein, human; Magnetic resonance imaging; Alzheimer Disease; Codon 200; Microhemorrhages; Biochemistry, Genetics and Molecular Biology; Presenilin‐1; Health Sciences; Presenilin-1; Humans; ddc:610; dominantly inherited Alzheimer's disease (DIAD); Cerebral amyloid angiopathy; Molecular Biology; presenilin-1; PiB‐PET; microhemorrhages; Small vessel disease (SVD); peak width of skeletonized mean diffusivity (PSMD); cerebral amyloid angiopathy (CAA); Cerebral Small Vessel Diseases; FOS: Biological sciences; microbleeds; Mutation; genetics [Cerebral Small Vessel Diseases]; presenilin‐1; Dementia; Molecular Mechanisms of Amyloidosis; diagnostic imaging [Alzheimer Disease]; Dominantly inherited Alzheimer's disease (DIAD); Neuroscience

AbstractINTRODUCTIONAmyloidosis, 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.METHODSIndividuals 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.RESULTSPostcodon 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.DISCUSSIONWe 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.