Clinical, genetic, and neuropathologic correlates of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC): A systematic review and meta-analysis.

Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) has emerged as a major contributor to cognitive decline in older adults; however, the constellation of factors associated with its presence remains poorly defined. To date, no analysis has comprehensively evaluated correlates of LATE-NC. This analysis was conducted to quantify associations between LATE-NC and an array of potential links, including neurocognitive disorders, neurodegenerative neuropathologic change (NC), cerebrovascular NC, demographic factors, clinical comorbidities, and genetic factors. A comprehensive literature search through December 2025 identified 40 eligible studies. Meta-analyses demonstrated significant associations between LATE-NC and neurocognitive disorders including all-cause dementia, Alzheimer disease (AD), and mild cognitive impairment. Significant neurodegenerative NC associations included ADNC, higher amyloid-β and tau burden, hippocampal sclerosis, and aging-related tau astrogliopathy. Significant cerebrovascular NC associations included cerebral amyloid angiopathy and arteriosclerosis. Increasing age at death was the only significant demographic correlate. Most clinical comorbidities were not significantly associated. Significant genetic associations included APOE ε4 and GRN. This first-of-its-kind meta-analysis outlines a distinct pattern of correlates associated with LATE-NC, emphasizing its strong linkage to AD-related and multimorbid neuropathologic processes, and underscoring the need for refined diagnostic frameworks and future mechanistic studies to differentiate LATE-NC from coexisting neuropathologies.