Developing Topics.

Background: Early-onset Alzheimer's disease (EOAD) occurs before age 65 and has more diverse disease presentations than late-onset AD. To improve our understanding of phenotypic heterogeneity among EOAD individuals, we analyzed cognitive scores using data-driven statistical analysis.

Method: Baseline cognitive data from 286 sporadic EOAD individuals from the Longitudinal EOAD study (LEADS) were transformed to z-scores using data from 95 cognitively normal (CN) individuals. Cognitive composites were generated for domains of memory, language, speed/attention, visuospatial, and executive function. Residuals from linear regression models on Z-scores adjusted for age, sex, and education were obtained. Cluster analysis using the Ward method on the cognitive domain residuals was performed and scree plot using the pseudo T-squared determined the optimal number of clusters for the EOAD sample. We also compared gray matter density (GMD) of each EOAD cluster to CN participants using voxel-wise multiple linear regressions.

Results: Three clusters of cognitive performance were identified from the EOAD sample. Disease duration was not significantly different across clusters. Using a z-score of -1.5 SD as the impairment threshold, all clusters were impaired across most domains (Table 1). Cluster-3 was more impaired than cluster-2 in all domains (Table 2; all p<.0001), and in all domains except episodic memory compared to cluster-1 (all p<.01). Cluster-1 (n = 71; 85.9% amnestic) was most impaired in executive function, visuospatial, and speed/attention. Cluster-2 (n = 133; 88.7% amnestic) was most impaired in episodic memory. Cluster-3 (n = 82; 69.5% amnestic) was most impaired in executive function, visuospatial, and speed/attention (Table 1). 3D-comparisons showed all EOAD clusters had reduced GMD compared to CN. Cluster-1 and cluster-3 both showed widespread atrophy, with cluster-3 being more severe. Cluster-2 showed the most atrophy in the temporal and parietal lobes (Figure 1).

Conclusion: We identified heterogeneity in cognitive patterns among sporadic EOAD individuals. Cluster-3 appeared to reflect widespread impairment, and cluster-2 represented an amnestic-only presentation. Despite comparable disease duration, some EOAD patients progress faster, while some are more resilient. 3D-comparisons showed neurodegenerative changes affecting brain regions responsible for respective impaired cognitive functions in each cluster (e.g., cluster-2 is primarily amnestic-impaired and has temporoparietal atrophy). Future work should explore amyloid-PET and tau-PET burden.