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

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.

Keywords: Alzheimer pathophysiology; biomarkers; rates of change.

Figure 1

Individual performance (spaghetti plots) and group mean rates of change (solid lines) over time for cognitive composite and clinical evaluation. (A) The cognitive composite and (B) the CDR-SB. Data from DIAN participants are displayed in red and data from ADNI participants are shown in black. In all parts, 0 represents the time of symptom onset.

Figure 2

Individual performance (spaghetti plots) and group mean rates of change (solid lines) over time for hippocampal volume and precuneus thickness. (A) Hippocampal volume in mm³ and (B) precuneus thickness in mm. In all parts, 0 represents the time of symptom onset.

Figure 3

Individual performance (spaghetti plots) and group mean rates of change (solid lines) over time for amyloid imaging and CSF amyloid ratio. (A) Cerebral amyloid accumulation in CL and (B) the CSF Aβ_42/40 ratio in pg/ml. In all parts, 0 represents the time of symptom onset.

Figure 4

Individual performance (spaghetti plots) and group mean rates of change (solid lines) over time for CSF tau. (A) Concentrations of CSF tau in pg/ml and (B) p-tau₁₈₁ in pg/ml. In all parts, 0 represents the time of symptom onset.