Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer's disease

Alzheimer's disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-beta (A beta) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed A beta, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

Automated summary

Alzheimer's disease is characterized by two main types of protein aggregates in the brain, but a significant proportion of patients also have TDP-43 aggregates, which may worsen outcomes. Research suggests that TDP-43 interacts with neurodegenerative processes in AD, highlighting the need for mechanistic studies and therapeutic interventions to target neurotoxic synergies between tau and TDP-43.