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Normal aging and Alzheimer's Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD. Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD. ### Competing Interest Statement The authors have declared no competing interest.

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