The mechanisms underlying TDP-43-associated neurodegeneration in Alzheimer's disease and related dementias.

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are among the most prevalent neurodegenerative diseases, characterized by progressive cognitive decline driven by complex and overlapping pathological mechanisms. While amyloid plaques, neurofibrillary tangles, and Lewy bodies are well-established hallmarks, TAR DNA-binding protein 43 (TDP-43) pathology has emerged as a critical contributor to disease progression, particularly in cases exhibiting hippocampal sclerosis and severe brain atrophy. TDP-43 pathology is defined by its cytoplasmic mislocalization, aberrant aggregation, and nuclear depletion, leading to disruptions in RNA metabolism, stress granule dynamics, and mitochondrial function. Increasing evidence suggests that TDP-43 pathology not only exacerbates neuronal degeneration but also interacts with Aβ plaques, tau tangles, and α-synuclein aggregates, compounding neurodegenerative processes and accelerating cognitive decline. Despite its growing recognition, TDP-43 pathology remains underexplored compared to other proteinopathies in AD and ADRDs, highlighting the need for further mechanistic studies and targeted therapeutic development. In this review, we summarize the current understanding of TDP-43 pathology in AD and ADRDs, with a focus on its role in disease progression. We further discuss the molecular mechanisms underlying TDP-43-associated neurodegeneration in AD and ADRDs, emphasizing RNA dysregulation, mitochondrial dysfunction, disrupted protein homeostasis, stress response alternations, and nuclear-cytoplasmic transport impairments. Lastly, given the significant impact on disease pathology, we review ongoing efforts to treat TDP-43-associated neurodegeneration, including antisense oligonucleotides, small-molecule inhibitors, and peptide-based interventions aimed at restoring TDP-43 function or preventing its neurotoxicity and pathological aggregation.