Figure 1.

Schematic depiction of a standard model of Alzheimer’s disease. The Model is based conceptually on the Aβ cascade and the NIA-AA Research Framework, and mechanistically on the misfolding, structural corruption and seeded self-assembly of Aβ (A) and abnormally phosphorylated (P) tau (T). This molecular process instigates numerous neurodegenerative (N) and clinical sequelae that fully comprise the disease phenotype, but which also occur in other brain disorders, and thus are not specific to Alzheimer’s disease [1]. Risk factors (orange) increase the likelihood that the Aβ cascade will ensue, and in many cases these overlap with the set of sequelae (blue). Neurodegeneration involves the dysfunction and loss of neurons and accompanying changes in various brain compartments. The influence of risk factors and the expression of sequelae increase over time, and some sequelae may feed back into the cascade (blue arrows). Of the risk factors that do not overlap with the sequelae, advancing age and genetic anomalies are well established; there is also strong evidence that infectious agents, head trauma, and certain environmental toxins increase risk. Proposed biochemical and physiological factors that may confer risk and/or result from the cascade include inflammation, oxidative/nitrative stress, DNA damage, epigenetic changes, excitotoxicity, endosomal/lysosomal failure, dysproteostasis, autophagy failure, lipid dysmetabolism, calcium ion (Ca²⁺) dyshomeostasis, post-translational protein modifications, neuronal cell cycle re-entry, mitochondrial failure, cytoskeletal disruption, glucose dysmetabolism, vascular or lymphatic impairments, biometal dyshomeostasis, hypertension, insomnia, depression, and stress. In some cases, putative risk factors can promote dementia by means independent of the Aβ cascade, i.e., by a non-Alzheimer mechanism.