Abstract: Tar DNA-binding protein 43 (TDP-43, encoded by the gene TARDBP) neuronal and glial inclusions have unified amyotrophic lateral sclerosis (ALS, ~97% of all cases), a fatal adult onset motor neuron disease characterized by the selective loss of upper and lower motor neurons, and frontotemporal dementia (FTD, and sporadic FTD (~45% of all cases), a common form of dementia characterized by progressive deterioration in behavior, personality and/or language, into one disease spectrum. Although the majority of ALS-FTD cases are sporadic, identification of mutations in the TARDBP gene that cause familial ALS, strongly supports the idea that TDP-43 participates in the pathogenesis of ALS-FTD, not merely a secondary phenomenon. That several other genes associated with familial ALS and FTD, including C9ORF72, converge on TDP-43 proteinopathy as a key neuropathological hallmark further strengthens this view. In addition, TDP-43 has been implicated in other major forms of neurodegenerative disorders such as Alzheimer’s disease (AD) (Josephs et al., 2014), chronic traumatic encephalopathy (Chen, 2018) and multiple system atrophy (Koga et al., 2018). Although strong evidence supports an essentially linear progression of disease triggered by β-amyloid (Aβ) in familial AD, the evidence in sporadic AD cases supports a more multifactorial etiology. While extracellular neuritic plaques and intracellular tau neurofibrillary tangles are well-recognized canonical hallmarks for AD, TDP-43-positive inclusions have recently been identified in 30–70% of brains with pathologically diagnosed AD (Josephs et al., 2014). The morphological characteristics of the TDP-43 deposition are similar across different regions of the brain, predominantly neuronal cytoplasmic inclusions; less commonly dystrophic neurites and only rarely intranuclear inclusions. However, the TDP-43 burden in AD appears to follow a stereotypic topographic progression different from that in ALS-FTD. Importantly, greater cognitive impairment and medial temporal atrophy are associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 pathology-positive subjects are 10 times more likely to be cognitively impaired at death compared to TDP-43-pathology negative cases (Josephs et al., 2014).