Co-pathologies and Biological Processes Beyond Amyloid-Beta and Tau in People with Alzheimer's Disease: Evidence from Clinical Cohort Studies

Alzheimer's disease (AD) is neuropathologically defined by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. However, co-pathologies and other pathobiological processes are involved in the pathogenesis of AD, contributing to neurodegeneration and clinical symptoms. The most common co-pathologies in people with AD are alpha-synucleinopathy, vascular brain injury and transactive response DNA-binding protein of 43 kDa-related pathology. Neuroinflammation, iron accumulation, cholinergic dysfunction and cellular senescence are recognized pathobiological processes beyond Aβ- and tau-related pathology. However, the exact mechanisms by which these co-pathologies and pathobiological processes contribute to the neurodegeneration and clinical symptoms in people with AD remain unclear. The individual combination of these co-pathologies and pathobiological processes increases phenotypical heterogeneity in people with AD. This highlights the unmet need to advance their current understanding, and the field strives to develop accurate biomarkers for personalized assessment and investigation. Elucidating this biologic-clinical complexity and heterogeneity is crucial for increasing our current understanding of AD, with implications for diagnosis, prognosis and therapeutics.