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 A. McCullough, Qing Wang, Yan Li, Guoqiao WangSarah J. Keefe, Stephanie A. Schultz, Carlos Cruchaga, Gregory M. Preboske, Clifford R. Jack, Jorge J. Llibre-Guerra, 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. Benzinger

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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: 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. 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.

Original languageEnglish
Pages (from-to)2680-2697
Number of pages18
JournalAlzheimer's and Dementia
Issue number4
StatePublished - Apr 2024


  • PSEN1
  • PiB-PET
  • autosomal dominant Alzheimer's disease (ADAD)
  • cerebral amyloid angiopathy (CAA)
  • codon 200
  • dominantly inherited Alzheimer's disease (DIAD)
  • microbleeds
  • microhemorrhages
  • peak width of skeletonized mean diffusivity (PSMD)
  • presenilin-1
  • small vessel disease (SVD)
  • white matter hyperintensity (WMH)


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