Fig. 1.

Pathways of neurodegeneration and cognitive impairment in AD. The human brain is subject to a variety of factors, both genetic and environmental, that either incite (orange) or mitigate (blue) the risk of developing the neuropathologic hallmarks of Alzheimer’s disease (amyloid plaques and neurofibrillary tangles). It is currently unknown whether these factors also influence the development of TDP-43 proteinopathy. While initiation of amyloid, tau, or TDP-43 pathology may occur through independent or overlapping events, the presence of multiple pathologies likely drives synergistic neurotoxicity that leads to cognitive decline and neurodegeneration. Observational data from human autopsy studies, as well as work from model systems, suggest that TDP-43 pathology enhances tau deposition and exacerbates the clinical severity of AD