Fitting TDP-43 into the APOE ε4 and neurodegeneration story

Abstract

Some researchers have placed the transactive response DNA-binding protein of 43 kDa (TDP-43) onto the neurodegenerative centre court, next to the other key neurodegenerative proteins including amyloid-β, paired helical filament tau, and α-synuclein. TDP-43 was first reported to be a key biological component of frontotemporal lobar degeneration and amyotrophic lateral sclerosis in 2006. 1 Neumann M Sampathu DM Kwong LK et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314: 130-133 Crossref PubMed Scopus (4505) Google Scholar Subsequently, findings suggested that TDP-43 immunoreactive lesions were also frequently present in the brains of patients with pathologically confirmed Alzheimer's disease. 2 Amador-Ortiz C Lin WL Ahmed Z et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol. 2007; 61: 435-445 Crossref PubMed Scopus (661) Google Scholar More recently, TDP-43 has been implicated in memory loss, hippocampal volume loss, and rate of hippocampal atrophy in people with Alzheimer's disease 3 Josephs KA Dickson DW Tosakulwong N et al. Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study. Lancet Neurol. 2017; 16: 917-924 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar , 4 Josephs KA Whitwell JL Weigand SD et al. TDP-43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol. 2014; 127: 811-824 Crossref PubMed Scopus (266) Google Scholar and in broader cohorts of community-based older adults. 5 Wilson RS Yu L Trojanowski JQ et al. TDP-43 pathology, cognitive decline, and dementia in old age. JAMA Neurol. 2013; 70: 1418-1424 Crossref PubMed Scopus (158) Google Scholar These findings have catapulted TDP-43 into the limelight. Unfortunately, even with strong evidence supporting TDP-43 being an integral part of late-life neurodegeneration, many investigators continue to focus only, or predominantly, on amyloid-β and paired helical filament tau, with the suggestion that TDP-43 is not an Alzheimer's disease spectrum proteinopathy or that TDP-43 pathology is only an age-associated occurrence. One of the reasons for these opinions is that TDP-43 has not been strongly linked with key genetic mechanisms underlying Alzheimer's disease, such as the APOE ε4 allele, which is undoubtedly the principal genetic risk factor for Alzheimer's disease. 6 Liu CC Liu CC Kanekiyo T Xu H Bu G Apolipoprotein ɛ and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013; 9: 106-118 Crossref PubMed Scopus (1904) Google Scholar Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort studyAPOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration. Full-Text PDF