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
Abstract
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) frequently co-occurs with Alzheimers 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.
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BibTeX
@misc{zhu2026early,
title = {{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}},
author = {Nuole Zhu and Renaud La Joie and Isabel Elaine Allen and Marlene Lin and D. Luke Fischer and David N. Soleimani-Meigooni and Howard J. Rosen and Maria Luisa Gorno-Tempini and Zachary Miller and David C. Perry and Joel Kramer and Katherine L. Possin and Yann Cobigo and Lyzzette Melgoza and Argentina Lario Lago and Jennifer Yokoyama and Claire Yballa and Ganna Blazhenets and Bruce L. Miller and Lea T. Grinberg and William W. Seeley and Salvatore Spina and Gil D. Rabinovici},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.26365384},
url = {https://www.medrxiv.org/content/10.64898/2026.10.15.26365384v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - 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
AU - Nuole Zhu
AU - Renaud La Joie
AU - Isabel Elaine Allen
AU - Marlene Lin
AU - D. Luke Fischer
AU - David N. Soleimani-Meigooni
AU - Howard J. Rosen
AU - Maria Luisa Gorno-Tempini
AU - Zachary Miller
AU - David C. Perry
AU - Joel Kramer
AU - Katherine L. Possin
AU - Yann Cobigo
AU - Lyzzette Melgoza
AU - Argentina Lario Lago
AU - Jennifer Yokoyama
AU - Claire Yballa
AU - Ganna Blazhenets
AU - Bruce L. Miller
AU - Lea T. Grinberg
AU - William W. Seeley
AU - Salvatore Spina
AU - Gil D. Rabinovici
PY - 2026
DA - 2026/10/15
PB - medRxiv
DO - 10.64898/2026.10.15.26365384
UR - https://www.medrxiv.org/content/10.64898/2026.10.15.26365384v1
AB - Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) frequently co-occurs with Alzheimers 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.
ER -