Spatial-Temporal Patterns of β-Amyloid Accumulation: A Subtype and Stage Inference Model Analysis

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.

Figure 1. Representation of the 3 Subtypes

(A) Representation of the final 3 subtypes as identified by Subtype and Stage Inference (SuStaIn), referred to as frontal (top row), parietal (middle row), and occipital (bottom row), in accordance with the earliest regions to become abnormal. (B) The same representation for a 1-trajectory model across the dataset, which was not preferred against the 3-subtype model.

Figure 2. Subtype Assignment Probability Against Assigned Stage

Boxplots show the relationship between stage assignment on the x-axis against the probability of subtype assignment on the y-axis for the whole baseline dataset. The solid line represents the cutoff for high probability, i.e., >50%. It can be appreciated that subtype assignment probability is lowest for those participants in stage 0 or 17, who present little least spatiotemporal information. Also, the highest probability assignment is observed for those participants around 7, where the subtypes are most different from each other.

Figure 3. Cross-sectional Relationships

For the 788 participants with a strong subtype assignment (>50% probability) at baseline, differences in subtypes are shown for (A) cohort and tracer representation, (B) diagnostic groups, (C) APOE ε4 carriership, (D) amyloid burden expressed in Centiloid units, (E) amyloid burden in CSF Aβ₄₂, and (F) CSF p-tau. Demographics and risk factors (A–C) were significantly different between the 3 subtypes. (D, F) The frontal subtype was associated with higher Centiloid and CSF p-tau values, although (E) no differences were observed for CSF Aβ₄₂ between subtypes. ABIDE = Alzheimer's biomarkers in daily practice project; ADNI = Alzheimer's Disease Neuroimaging Initiative; ALFA = Alzheimer's and Family cohort of the Barcelonaβeta Brain Research Center; EMIF-AD = European Medical Information Framework for AD; FBB = [¹⁸F]florbetaben; FBP = [¹⁸F]florbetapir; FMM = [¹⁸F]flutemetamol; OASIS = Open Access Series of Imaging Studies; PiB = Pittsburgh compound B.

Figure 4. Longitudinal Validation

(A) Subtype assignment at baseline vs at follow-up. Spaghetti plots illustrate the change in (B) stage and (C) Centiloid units per subtype as assigned at baseline. Lines are color coded to show changes in subtype assignment at follow-up. Overall, changes in stage are associated with changes in Centiloid and yearly rates of change were lowest for the frontal subtype.