Skip to main navigation Skip to search Skip to main content

Common neuropathologic change drivers of hippocampal sclerosis of ageing

  • Davis C. Woodworth
  • , Jerry J. Lou
  • , William H. Yong
  • , Elizabeth Head
  • , María M. Corrada
  • , Peter T. Nelson
  • , S. Ahmad Sajjadi

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Hippocampal sclerosis of ageing (HS-A) - severe cell loss and gliosis in the hippocampal formation - is a neuropathologic change (NC) that affects up to 20% of elderly persons with dementia. The aetiology of HS-A is heterogeneous, but HS-A is strongly associated with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC). Other NCs have also been implicated in relation to HS-A, but these associations have been inconsistent across previous studies. Also, because LATE-NC and HS-A are so strongly associated, it is important to adjust for LATE-NC when examining associations between other NCs and HS-A. The goal of this study was to examine associations of other common NCs with HS-A, both before and after adjusting for LATE-NC. We analysed the National Alzheimer's Coordinating Center (NACC) neuropathology dataset and examined associations of Alzheimer's disease NC (ADNC), Lewy bodies (LB) and cerebrovascular NCs, with HS-A, adjusting for LATE-NC in multiple ways. We used Bayesian multilevel logistic regression models with monotonic modelling for ordinal predictors and report the odds ratios (OR) or average OR across levels (aOR), along with 95% credibility intervals (CI) as well as expected frequencies of HS-A for selected models and predictor levels. Of n = 1933 autopsy participants included (average age at death of 83 years, 51.3% women), HS-A was present in 278 (14.4%). LATE-NC was strongly associated with HS-A (aOR = 3.7, 95% CI = 2.8, 5.0). While ADNC showed a modest association with HS-A in models where LATE-NC was not included as a predictor (aOR = 1.4, CI = 1.1, 1.8), this association was reduced when adjusting for LATE-NC (aOR = 1.11, CI = 0.9, 1.5); results were similar for the ADNC-related A/B/C scores and limbic LBs. However, several cerebrovascular NCs were similarly associated with HS-A both without adjusting for LATE-NC [atherosclerosis aOR = 1.4, arteriolosclerosis aOR = 1.6, white matter rarefaction (WMR) aOR = 1.4] and with adjusting for LATE-NC (atherosclerosis aOR = 1.4, arteriolosclerosis aOR = 1.5, WMR aOR = 1.3). In a combined model, LATE-NC was strongly associated with HS-A, but global cerebrovascular NCs, as well as APOE-ϵ4 (increased odds) and education (decreased odds), were also associated with HS-A. Predicted HS-A frequency for predictor levels of no LATE-NC or global cerebrovascular NCs was 1.5% (CI = 0.6%, 3.1%), while it was 94.5% (CI = 84%, 99.5%) for LATE-NC stage 3 and severe global cerebrovascular NC levels. LATE-NC is likely the most important cause of HS-A. While ADNC seems to be associated with HS-A through its association with LATE-NC, the association of cerebrovascular NCs with HS-A independent of LATE-NC underlines the importance of vascular factors in the aetiology of HS-A. The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.

Original languageEnglish
Pages (from-to)2400-2411
Number of pages12
JournalBrain
Volume148
Issue number7
DOIs
StatePublished - Jul 1 2025

Bibliographical note

Publisher Copyright:
© 2025 Oxford University Press. All rights reserved.

Funding

The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). Funding for this study was provided by National Institutes of Health National Institute on Aging grant R01AG062706. Funding for this study was provided by National Institutes of Health National Institute on Aging grant R01AG062706.

FundersFunder number
National Institute on Aging
National Institutes of Health (NIH)P30 AG062677, P30 AG066514, P30 AG066515, P30 AG066518, P30 AG062715, P30 AG066519, P20 AG068053, P30 AG072975, P30 AG072931, P30 AG066462, P20 AG068077, P30 AG072976, P30 AG072977, P30 AG066444, R01AG062706, P30 AG072972, P30 AG072973, P30 AG066468, P30 AG072978, P30 AG072979, P30 AG072958, P30 AG072959, P30 AG062421, P30 AG079280, P30 AG062422, P30 AG066546, P30 AG066506, P30 AG066507, P30 AG062429, P30 AG066508, P30 AG066509, P30 AG066530, P20 AG068082, P30 AG066511, P30 AG066512, U24 AG072122, P20 AG068024, P30 AG072946, P30 AG072947
National Institutes of Health National Institute on AgingR01AG062706

    Keywords

    • amyloid
    • hippocampus
    • memory
    • neurodegeneration
    • oldest-old
    • tau

    ASJC Scopus subject areas

    • Clinical Neurology

    Access to Document

    Other files and links

    Fingerprint

    Dive into the research topics of 'Common neuropathologic change drivers of hippocampal sclerosis of ageing'. Together they form a unique fingerprint.
    View full fingerprint

    Cite this