Too early for LATE? Age at onset is associated with the clinical and neuroimaging expression of limbic-predominant age- related TDP-43 pathology in Alzheimer’s disease

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) frequently co-occurs with Alzheimer’s disease (AD) pathology and has been studied mainly in older populations. We examined its frequency and expression in 196 individuals with autopsy-confirmed intermediate-to-high AD neuropathologic change, enriched for younger-onset cases, integrating neuropathology with antemortem clinical, cognitive and neuroimaging data. LATE-NC occurred in 31% overall and 19% of individuals with symptom onset ≤65 years. Its frequency increased with older age at symptom onset, and its presence was associated with greater episodic memory impairment and smaller amygdala and hippocampal volumes. Among individuals with LATE-NC, older age at symptom onset was associated with memory-first presentation and greater medial temporal involvement, including higher inferior-to-medial temporal metabolism ratios on FDG PET. Despite its lower frequency, LATE-NC co-pathology should still be considered in early-onset AD, where selected clinical features and neuroimaging markers described in older populations may be less applicable.