Evaluating the updated LATE-NC staging criteria using data from NACC

Abstract

Introduction: Limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathologic change (LATE-NC) staging criteria were updated in 2023. We evaluated this updated staging using National Alzheimer's Coordinating Center data.

Methods: We examined associations of LATE-NC stages with cognition and other neuropathologic changes (NCs), and with cognition while accounting for other NCs, using multilevel regression models.

Results: Of 1352 participants, 502 (37%) had LATE-NC (23% stage 1a, 6% stage 1b, 58% stage 2, 13% stage 3). LATE-NC stages were associated with cognition, hippocampal sclerosis of aging (HS-A), Alzheimer's disease NC (ADNC), Lewy bodies (LBs), and hippocampal atrophy. While stage 1b was associated with cognition and HS-A consistent with other stages, it was not associated with ADNC or LBs. All LATE-NC stages remained significantly associated with worse cognition when accounting for other NCs.

Discussion: The updated LATE-NC staging criteria capture variations in early TDP-43 pathology spread which are consequential for cognition and associations with other NCs.

Highlights: We applied the updated limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathologic change (LATE-NC) staging criteria to data from the National Alzheimer's Coordinating Center. LATE-NC stage 1b was identified in 22% of participants with stage 1. In contrast to other LATE-NC stages, stage 1b was not associated with Alzheimer's disease neuropathologic change (ADNC) or Lewy bodies. Stages 1a and 1b were significantly associated with dementia and memory impairment. Stages 1b+ were more strongly tied to dementia than all other neuropathologic changes except high likelihood ADNC.

Keywords: Alzheimer's disease; National Alzheimer's Coordinating Center; amygdala; dementia; hippocampal sclerosis of aging; hippocampus; limbic predominant age‐related TAR DNA‐binding protein of 43 kDa encephalopathy neuropathologic change; neuropathology.

FIGURE 1

Illustration of updated LATE‐NC staging system as applied to NACC neuropathology data in this study. Presence of TDP‐43 neuronal cytoplasmic inclusions for different brain regions by LATE‐NC stage, including stage 1 subtypes (1a and 1b). Stage 1a denotes TDP‐43 inclusions found only in the amygdala but not the hippocampus or middle frontal gyrus, while stage 1b denotes TDP‐43 inclusions found only in the hippocampus but not the amygdala or the middle frontal gyrus. Stage 2 denotes TDP‐43 inclusions found in the amygdala and hippocampus but not the middle frontal gyrus, while stage 3 denotes TDP‐43 inclusions found in all three regions. LATE‐NC, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change; NACC, National Alzheimer's Coordinating Center; TDP‐43, TAR DNA‐binding protein of 43 kDa.

FIGURE 2

Results from logistic regressions for clinical diagnosis and other NCs by LATE‐NC stages. Logistic regressions were adjusted for age at death, sex, education, the interval between the last visit and death, and varying intercepts for center. Dots represent odds ratios and error bars represent 95% confidence intervals. Open circles denote p > 0.05. The thick vertical dashed line represents odds ratio = 1. ADNC, Alzheimer's disease neuropathologic change; CAA, cerebral amyloid angiopathy; HS‐A, hippocampal sclerosis of aging; LATE‐NC, limbic‐predominant age‐related TAR DNA‐binding protein of 43 kDa encephalopathy neuropathologic change; NC, neuropathologic changes.

FIGURE 3

Results from logistic regressions of dementia and memory impairment for LATE‐NC stages and related NCs. Logistic regressions were adjusted for age at death, sex, education, the interval between the last visit and death, and varying intercepts for center. Dots represent odds ratios and error bars represent 95% confidence intervals. Open circles denote p > 0.05. The thick vertical solid line represents odds ratio = 1. ADNC, Alzheimer's disease neuropathologic change; CAA, cerebral amyloid angiopathy; LATE‐NC, limbic‐predominant age‐related TAR DNA‐binding protein of 43 kDa encephalopathy neuropathologic change; NCs, neuropathologic changes; OB/B‐stem, olfactory bulb or brainstem; OR, odds ratio.