Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology

John C. Morris, Michael Weiner, Chengjie Xiong, Laurel Beckett, Dean Coble, Naomi Saito, Paul S. Aisen, Ricardo Allegri, Tammie L.S. Benzinger, Sarah B. Berman, Nigel J. Cairns, Maria C. Carrillo, Helena C. Chui, Jasmeer P. Chhatwal, Carlos Cruchaga, Anne M. Fagan, Martin Farlow, Nick C. Fox, Bernardino Ghetti, Alison M. GoateBrian A. Gordon, Neill Graff-Radford, Gregory S. Day, Jason Hassenstab, Takeshi Ikeuchi, Clifford R. Jack, William J. Jagust, Mathias Jucker, Johannes Levin, Parinaz Massoumzadeh, Colin L. Masters, Ralph Martins, Eric McDade, Hiroshi Mori, James M. Noble, Ronald C. Petersen, John M. Ringman, Stephen Salloway, Andrew J. Saykin, Peter R. Schofield, Leslie M. Shaw, Arthur W. Toga, John Q. Trojanowski, Jonathan Vöglein, Stacie Weninger, Randall J. Bateman, Virginia D. Buckles

Research output: Contribution to journalArticlepeer-review

Abstract

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

Original languageEnglish (US)
Pages (from-to)3594-3607
Number of pages14
JournalBrain : a journal of neurology
Volume145
Issue number10
DOIs
StatePublished - Oct 21 2022

Keywords

  • Alzheimer pathophysiology
  • biomarkers
  • rates of change

ASJC Scopus subject areas

  • Medicine(all)

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