The concept that
frontotemporal dementia (FTD) is a purely cortical
dementia has largely been refuted by the recognition of its close association with
motor neuron disease, and the identification of transactive response
DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD,
amyotrophic lateral sclerosis (ALS), and FTD-ALS cases and the understanding that repeat-containing
RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential
biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on
chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased
dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between
dementia and
neuromuscular disease, such as
inclusion body myositis with Paget's disease and FTD.