Intersecting Pathways to Hippocampal Sclerosis in the Elderly: LATE-NC and Vascular Links

Overview

Hippocampal sclerosis of ageing (HS-A) is strongly associated with limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), with a dose-dependent relationship observed between LATE-NC stage and HS-A prevalence. Additionally, cerebrovascular disease independently contributes to HS-A, while associations with Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease (LBD) are largely mediated through LATE-NC.

Background

HS-A is a neuropathological condition characterized by neuronal loss and gliosis in the hippocampal CA1 region and subiculum, predominantly affecting the oldest-old. Initially linked to hypoxic injury or epilepsy, HS-A is now recognized as part of broader age-related neurodegenerative processes, especially associated with LATE-NC, a TDP-43 proteinopathy. LATE-NC mimics Alzheimer’s disease clinically due to its impact on episodic memory and progresses through defined pathological stages. Understanding the interplay between HS-A, LATE-NC, and vascular pathology is critical for accurate diagnosis and potential therapeutic strategies.

Data Highlights

Key Findings

• HS-A prevalence increases dose-dependently with advancing LATE-NC stage, reaching 55.9% at stage 3.
• LATE-NC is a primary driver of HS-A, with a high adjusted odds ratio (aOR 3.72 overall; 57.2 at stage 3).
• Associations of HS-A with ADNC and limbic LBD are largely mediated by co-occurring LATE-NC pathology.
• Global cerebrovascular disease independently associates with HS-A, highlighting vascular contributions beyond LATE-NC.
• Microinfarctions show a paradoxical negative association with HS-A in the absence of LATE-NC, indicating complex pathogenesis.
• Neuropathologic assessments limited to one hemisphere may underestimate HS-A prevalence and distribution.

Clinical Implications

Recognition of LATE-NC as a key driver of HS-A underscores the importance of considering TDP-43 pathology in elderly patients presenting with dementia and hippocampal atrophy disproportionate to global brain atrophy. The independent role of cerebrovascular disease suggests that maintaining vascular health could be a potential therapeutic target to mitigate HS-A progression. Although in vivo biomarkers for LATE-NC are not yet established, emerging diagnostic criteria and biomarker research may soon enable earlier and more accurate diagnosis.

Conclusion

Woodworth et al. provide compelling evidence that LATE-NC is the predominant neuropathologic driver of hippocampal sclerosis of ageing, with cerebrovascular disease also contributing independently. These insights refine our understanding of HS-A pathogenesis and highlight the need for improved diagnostic tools and vascular health interventions.

References

1. Woodworth et al. 2021 -- Common neuropathologic change drivers of hippocampal sclerosis of ageing