Autosomal dominant and sporadic late onset Alzheimer disease share a common in vivo pathophysiology.
Brain. 2022 May 17:awac181. doi: 10.1093/brain/awac181. Epub ahead of print. PMID: 35580594.
|Authors/Editors:||Morris JC, Weiner M, Xiong C, Beckett L, Coble D, Saito N, Aisen PS, Allegri R, Benzinger TLS, Berman SB, Cairns NJ, Carrillo MC, Chui HC, Chhatwal JP, Cruchaga C, Fagan AM, Farlow M, Fox NC, Ghetti B, Goate AM, Gordon BA, Graff-Radford N, Day GS, Hassenstab J, Ikeuchi T, Jack CR, Jagust WJ, Jucker M, Levin J, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S; PREPARE Consortium, Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J.|
The extent to which the pathophysiology of autosomal dominant Alzheimer disease corresponds to the pathophysiology of “sporadic” late onset Alzheimer disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer disease to late onset Alzheimer disease.
We compared brain magnetic resonance imaging and amyloid positron emission tomography data, as well as cerebrospinal fluid concentrations of amyloid-beta-42, amyloid-beta-40, tau, and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer disease from the Dominantly Inherited Alzheimer Network with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and cerebrospinal fluid samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer 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 disease and late onset Alzheimer 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 positron emission tomography was greater after symptomatic onset in autosomal dominant Alzheimer disease than in late onset Alzheimer disease participants, cerebrospinal fluid assays of amyloid-beta-42, amyloid-beta-40, 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 disease participants.
These findings suggest a similar pathophysiology of autosomal dominant Alzheimer disease and late onset Alzheimer disease, supporting a shared pathobiological construct.