Fig. 1. Central Alzheimer’s pathologies.

Risk factors for late-onset Alzheimer’s disease (LOAD) are proposed to contribute to at least one of six main pathologies: oxidative stress and oxysterol production, phosphatidylserine (PS)-exposed neurons, pro-inflammatory cytokines, amyloid-beta aggregation and vascular pathology, tau pathology, and glial cell reactivity. Each main pathology likely eventually adds to and increases the burden of other main AD pathologies. These pathologies may ultimately converge to drive improper neuronal support, synaptic loss, and death, resulting in neurodegeneration clinically corresponding to cognitive decline. Centrally, the repeated buildup of these six LOAD pathologies proposedly pushes an aged glial system into senescence induction and accumulation. This burden of senescent glia is predicted to sustain a disease environment that determines local neurodegeneration involved in LOAD progression. Glial senescence is briefly characterized as dysfunctional glial states with impaired endolysosomal function and support for nearby cells. What constitutes glial senescence burden may well vary per an individual’s genetics, physiology, and environmental experiences; nonetheless, it is predicted that the glial senescence burden differentiates a cognitively healthy or resilient individual from one diagnosed with LOAD. Purple color designates associations with senescence and dementia progression. Figure created with BioRender.com.