Cognitive symptoms progress with limbic-predominant age-related TDP-43 encephalopathy stage and co-occurrence with Alzheimer disease

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a neuropathologic entity characterized by transactive response DNA-binding protein of 43-kDa (TDP-43)-immunoreactive inclusions that originate in the amygdala and then progress to the hippocampi and middle frontal gyrus. LATE-NC may mimic Alzheimer disease clinically and often co-occurs with Alzheimer disease neuropathologic change (ADNC). This report focuses on the cognitive effects of isolated and concomitant LATE-NC and ADNC. Cognitive/neuropsychological, neuropathologic, genetic, and demographic variables were analyzed in 28 control, 31 isolated LATE-NC, 244 isolated ADNC, and 172 concurrent LATE-NC/ADNC subjects from the National Alzheimer's Coordinating Center. Cases with LATE-NC and ADNC were significantly older than controls; cases with ADNC had a significantly higher proportion of cases with at least one APOE epsilon 4 allele. Both LATE-NC and ADNC exhibited deleterious effects on overall cognition proportional to their neuropathological stages; concurrent LATE-NC/ADNC exhibited the worst overall cognitive effect. Multivariate logistic regression analysis determined an independent risk of cognitive impairment for progressive LATE-NC stages (OR 1.66; p = 0.0256) and ADNC levels (OR 3.41; p < 0.0001). These data add to the existing knowledge on the clinical consequences of LATE-NC pathology and the growing literature on the effects of multiple concurrent neurodegenerative pathologies.