Spatial-temporal patterns of β-amyloid accumulation: a subtype and stage inference model analysis

Collij, Lyduine E.; Salvadó, Gemma; Wottschel, Viktor; Mastenbroek, Sophie E.; Schoenmakers, Pierre; Heeman, Fiona; Aksman, Leon; Wink, Alle Meije; Berckel, Bart N.M.; van de Flier, Wiesje M.; Scheltens, Philip; Visser, Pieter Jelle; Barkhof, Frederik; Haller, Sven; Gispert, Juan Domingo; Lopes Alves, Isadora; Alzheimer’s Disease Neuroimaging Initiative; ALFA Study

doi:http://dx.doi.org/10.1212/WNL.0000000000200148

Spatial-temporal patterns of β-amyloid accumulation: a subtype and stage inference model analysis

Citation

Collij LE, Salvadó G, Wottschel V, Mastenbroek SE, Schoenmakers P, Heeman F, et al. Spatial-temporal patterns of β-amyloid accumulation: a subtype and stage inference model analysis. Neurology. 2022 Apr 26; 98(17): e1692-703. DOI: 10.1212/WNL.0000000000200148

Abstract

Background and objectives: β-amyloid (Aβ) staging models assume a single spatial-temporal progression of amyloid accumulation. We assessed evidence for Aβ accumulation subtypes by applying the data-driven Subtype and Stage Inference (SuStaIn) model to amyloid-PET data. Methods: amyloid-PET data of 3,010 participants were pooled from 6 cohorts (ALFA+, EMIF-AD, ABIDE, OASIS, and ADNI). Standardized uptake value ratios were calculated for 17 regions. We applied the SuStaIn algorithm to identify consistent subtypes in the pooled dataset based on the cross-validation information criterion and the most probable subtype/stage classification per scan. The effects of demographics and risk factors on subtype assignment were assessed using multinomial logistic regression. Results: participants were mostly cognitively unimpaired (n = 1890 [62.8%]), had a mean age of 68.72 (SD 9.1) years, 42.1% were APOE ε4 carriers, and 51.8% were female. A 1-subtype model recovered the traditional amyloid accumulation trajectory, but SuStaIn identified 3 optimal subtypes, referred to as frontal, parietal, and occipital based on the first regions to show abnormality. Of the 788 (26.2%) with strong subtype assignment (>50% probability), the majority was assigned to frontal (n = 415 [52.5%]), followed by parietal (n = 199 [25.3%]) and occipital subtypes (n = 175 [22.2%]). Significant differences across subtypes included distinct proportions of APOE ε4 carriers (frontal 61.8%, parietal 57.1%, occipital 49.4%), participants with dementia (frontal 19.7%, parietal 19.1%, occipital 31.0%), and lower age for the parietal subtype (frontal/occipital 72.1 years, parietal 69.3 years). Higher amyloid (Centiloid) and CSF p-tau burden was observed for the frontal subtype; parietal and occipital subtypes did not differ. At follow-up, most participants (81.1%) maintained baseline subtype assignment and 25.6% progressed to a later stage. Discussion: whereas a 1-trajectory model recovers the established pattern of amyloid accumulation, SuStaIn determined that 3 subtypes were optimal, showing distinct associations with Alzheimer disease risk factors. Further analyses to determine clinical utility are warranted.