Hemispheric Asymmetry of Neuroimaging Biomarkers in Early Onset Alzheimer's Disease: Clinical and Cognitive Outcomes

OBJECTIVE: Individuals diagnosed with Alzheimer's disease (AD) often exhibit amyloid, tau, and atrophy predominantly in the left or right hemisphere, but group-level analyses typically ignore inter-individual variability and changing asymmetry patterns when averaging data across participants in phenotypically diverse cohorts. METHODS: We examined left/right hemispheric asymmetry in amyloid positron emission tomography (PET), tau PET, and cortical atrophy in sporadic early-onset AD from 585 deeply phenotyped individuals across 2 cohorts to investigate its clinical correlates. For each imaging biomarker, we computed a global asymmetry index reflecting left/right hemisphere signal difference, and an analogous asymmetry value for PET/magnetic resonance imaging (MRI) voxels. We examined clinical and cognitive correlates of this asymmetry across phenotypes cross-sectionally and longitudinally in a subset of 218 participants. RESULTS: Both left and right asymmetry were common for all clinical phenotypes and was correlated between imaging biomarkers. Asymmetry patterns varied spatially within phenotypes, and asymmetry in tau PET and MRI volumes was related to hemisphere-dependent cognitive deficits and neuropsychiatric symptoms. Longitudinal analyses revealed stable amyloid PET asymmetry, decreasing tau PET asymmetry, and increasing MRI volume asymmetry. INTERPRETATION: Hemispheric asymmetry is common in early onset AD and correlates with clinical outcomes. Our longitudinal findings suggest a time-lagged asymmetry peak in amyloid, then tau, then atrophy. Taken together, our results position asymmetry as an important feature of AD heterogeneity, as it provides insight into disease mechanisms and trajectories. ANN NEUROL 2026.