A large-scale multi-centre study characterising atrophy heterogeneity in Alzheimer's disease

Previous studies identified atrophy-based Alzheimer's disease(AD) subtypes linked to distinct clinical symptoms, but their consistency across subtyping approaches remains unclear. This large-scale study evaluates subtype concordance using two data-driven approaches. In this work, we analyzed data from n=10,011 patients across 10 AD cohorts spanning Europe, the US, and Australia, extracting regional volumes using Freesurfer. To characterize atrophy heterogeneity in the AD continuum, we developed a two-step approach, Snowphlake (Staging NeurOdegeneration With PHenotype informed progression timeLine of biomarKErs), to identify subtypes and atrophy-event sequences within each subtype. Results were compared with SuStaIn (Subtype and Stage Inference), which jointly estimates subtypes and staging, using similar training and validation. Training included Aβ+ participants (n=1,195) and Aβ- cognitively unimpaired controls (n=1,692). We validated model-staging in a held-out clinical dataset (n=6,362) and an independent dataset (n=762), and assessed clinical significance in Aβ+ subsets(n=1,796 held-out; n=159 external). Concordance analysis evaluated consistency between methods. In the AD dementia(AD-D) training data, both Snowphlake and SuStaIn identified four subtypes. In the validation datasets, staging with both methods correlated with Mini-Mental State Examination(MMSE) scores. The Snowphlake subtypes assigned in Aβ+ validation datasets were associated with alterations in specific cognitive domains(Cohen's f:[0.15-0.33]). Similarly, the SuStaIn subtypes were also associated specific cognitive domains(Cohen's f:[0.17-0.34]). However, we observed low concordance between Snowphlake and SuStaIn, with 39.7% of AD-D patients grouped in concordant subtypes by both methods. In conclusion, Snowphlake and SuStaIn identified four atrophy-based subtypes that linked to distinct symptom profiles. While this highlights that the neuro-anatomically defined subtypes also meaningfully associate with different cognitive impairments at a group level, the low concordance between methods suggests that future research is needed to better understand the biological and methodological factors contributing to the observed variability.