Moving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer’s disease

Alzheimer’s disease (AD) is heterogeneous as regards the age of onset, rates of progression, and the order in which cognitive domains are affected. Furthermore, a diverse combination of cognition-relevant neuropathological phenotypes occurs among patients with AD.Over 70 genetic loci have been associated with AD, and genes at these loci point to different biological processes and pathways in a variety of cell types that contribute to risk and resilience in AD.Improved experimental systems that capture biological diversity are necessary to disentangle subtype-specific drivers of AD. Systems such as human induced pluripotent stem cells (iPSCs) and new rodent models will be critical tools for elucidating molecular mechanisms leading to dementia, testing new therapeutic strategies, and determining subtype-specific responsiveness to interventions.Matching the right treatment or combinations of treatments to the appropriate population is a key challenge for the next wave of therapeutic development for AD.