Abstract

AbstractBackgroundThe heterogeneous nature of Alzheimer’s disease and uncertainty of determining disease severity and subtype can confound treatment effects in clinical trials. Computational methods for subtyping can assist in trial enrichment. This study investigates the latent heterogeneity and severity (including absence) of neurodegeneration in the cognitively unimpaired A4 cohort enriched for elevated amyloid.MethodBaseline 3T T1‐weighted MRI data from ADNI (N=687) and A4 pre‐randomization (N=1240, all Aβ+ [Sperling et al. 2020, DOI:10.1001/jamaneurol.2020.0387]) studies were included. FreeSurfer was used to estimate regional brain volumes, of which 13 features were input to SuStaIn (Young et al., 2018, DOI:10.1038/s41467‐018‐05892‐0) to train two cohort‐specific models of neurodegeneration subtypes. Volumes were first adjusted for age, sex, education, and intracranial volume, and z‐scored relative to controls (Aβ– in A4; cognitively normal in ADNI). For each feature, z‐score events of z=1 (subtle abnormality) and z=2 (atrophy) were used. The number of subtypes was determined using cross‐validation.ResultFigure 1 shows our SuStaIn model for ADNI, replicating the three‐subtype finding of Young et al. (2018). Figure 2 shows our SuStaIn model for A4, which estimated a similar three‐subtype model: typical, cortical, subcortical (named for the earliest atrophy events). Notable differences between the models are in the subtle abnormality (z=1) events in A4 that might, or might not, develop into more prominent atrophy (z=2), such as with the caudate which stalls at z=1 (Figure 2, top‐left). Our results indicate the presence of AD‐like heterogeneity in the A4 cohort. Figure 3 shows boxplots of amyloid PET SUVr — there are no statistically significant differences between subtypes (Mann‐Whitney U test), suggesting amyloid PET screening is insufficient to detect neurodegeneration heterogeneity. There were no statistically significant subtype differences in cognitive measures nor demographics (Table 1).ConclusionOur results show that neurodegeneration heterogeneity exists in the A4 cohort, despite amyloid PET screening. This heterogeneity could have ramifications on the potential success of the A4 trial, particularly if it correlates with different rates of cognitive decline and confounds anti‐amyloid therapeutic effects on trial endpoints. Our results support the use of more holistic, multimodal, data‐driven screening for clinical trials in Alzheimer’s disease to reduce cohort heterogeneity.

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