The influence of Aβ-dependent and independent pathways on TDP-43 proteinopathy in Alzheimer's disease: a possible connection to LATE-NC.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results from the accumulation of plaques by cleaved Aβ42 peptides as well as neurofibrillary tangles of tau proteins. This accumulation triggers a complex cascade of cytotoxic, neuroinflammatory, and oxidative stresses that lead to neuronal death throughout the progression of the disease. Much of research in AD focused on the 2 pathologic proteins. Interestingly, another form of dementia with similar clinical manifestations of AD, but preferentially affected much older individuals, was termed as limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) and involved the cytotoxic intraneuronal deposition of phosphorylated TDP-43. TDP-43 proteinopathy was also found to be involved in AD pathology leading to the possibility that AD and LATE may share a common upstream etiology. This paper discusses the roles molecular pathways known in AD may have on influencing TDP-43 proteinopathy and the development of AD, LATE, or the 2 being comorbid with each other.