We review the literature on Tau and
TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in
Alzheimer's disease and related
dementias (ADRD), wherein multiple
proteins tend to misfold in a manner that is "reactive," but, subsequently, each
proteinopathy may contribute strongly to the clinical symptoms. Tau
proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions-e.g., developmental, traumatic, and inflammatory/
infectious diseases.
TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although
TDP-43 proteinopathy was first described in the central nervous system of patients with
amyotrophic lateral sclerosis (ALS) and in subtypes of
frontotemporal dementia (FTD/
FTLD),
TDP-43 proteinopathy is also present in
chronic traumatic encephalopathy, cognitively impaired persons in advanced age with
hippocampal sclerosis,
Huntington's disease, and other diseases. We list known Tau and
TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded
proteins, suggesting common pathways or
protein interactions facilitating misfolding in one
protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g.,
APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and
TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and
TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and
TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects.