Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common cause of dementia in older age. LATE-NC was first coined in 2019 with proposed staging criteria of TDP-43 progressing from amygdala (stage 1), to hippocampus (stage 2), to middle frontal gyrus (stage 3). Criteria were updated in 2023 to further categorize stage 1 to either TDP-43 inclusions in amygdala alone (stage 1a) or hippocampus alone (stage 1b). We applied this updated LATE-NC staging criteria to data from participants in the National Alzheimer's Coordinating Center (NACC) and examined associations with clinical diagnosis and other neuropathologic changes (NCs).

Method: We selected participants in NACC with regional TDP-43 assessments, excluding those with frontotemporal dementia-related and rare NCs, or with a non-Alzheimer's disease (AD) etiologic clinical diagnosis. LATE-NC stages were assigned according to updated criteria. We performed logistic regressions with LATE-NC stages as predictors and clinical diagnosis (dementia, cognitive impairment, memory impairment), other neuropathologic changes (ADNC, Lewy bodies, hippocampal sclerosis of aging (HS-A), and vascular NCs), or gross atrophy at autopsy (cortical, hippocampal, frontal/temporal lobar) as outcomes. We also examined the association of LATE-NC stages with dementia and memory impairment while accounting for other NCs.

Result: Of N = 1365 participants, LATE-NC was present in 519 (37%): 31% stage 1 (78% 1a, 22% 1b), 56% stage 2, 13% stage 3 (Table-1). Participants with stage 1a were younger at death compared to higher stages. Stage 1a and 1b had similar associations with cognitive problems (Figure-1). However, while other stages were associated with ADNC and Lewy bodies, stage 1b was not. Meanwhile stage 1b was associated with HS-A more strongly than stage 1a and to a similar degree as stage 2. We observed expected associations of higher LATE-NC stages with dementia and other NCs (Figure-1). Lastly, LATE-NC stage 1b was significant (and stage 1a trended) for associations with dementia and memory impairment, while higher LATE-NC stages had associations eclipsed in strength only by highest level ADNC (Figure-2).

Conclusion: These findings highlight the utility of the updated LATE-NC staging criteria in general, and stage 1 subtypes in particular, in capturing broad associations with cognitive impairment and specific associations with other neuropathologic changes.