Hippocampal Neuronal Loss and Cognitive Decline in LATE-NC and ADNC Among Community-dwelling Older Persons

Overview

Journal Alzheimers Dement

Date 2025 Jan 31

PMID 39888320

Authors

Sonal Agrawal

Lei Yu

Sue E Leurgans

Sukriti Nag

Lisa L Barnes

David A Bennett

Julie A Schneider

Affiliations

Soon will be listed here.

Abstract

Introduction: This study investigates the inter-related roles of hippocampal neuronal loss (HNL), limbic-predominant age-related TAR-DNA binding protein of 43 kDa (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline.

Methods: Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE-NC, and other age-related pathologies were evaluated. Regression and mixed-effects models examined the association of HNL with ADNC and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which associations of LATE-NC and ADNC with cognitive decline were attributable to HNL.

Results: LATE-NC was associated with more severe HNL, but ADNC was associated only after excluding subjects with hippocampal sclerosis (HS). HNL was associated with faster decline in global cognition and episodic, semantic, and working memory. In path analyses, about 61% of the association of LATE-NC with cognitive decline was attributable to HNL, whereas for ADNC it was mostly independent of HNL.

Discussion: HNL has an independent contribution to cognitive decline and acts as a major step in LATE-NC-related cognitive decline.

Highlights: Hippocampal neuronal loss (HNL) is associated with cognitive decline. HNL is a prominent feature of limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) and less so with Alzheimer's disease neuropathologic changes (ADNC). HNL acts as a major pathway in cognitive decline for LATE-NC. Differential mechanisms in hippocampal degeneration are associated with LATE-NC versus ADNC.

Citing Articles

Hippocampal neuronal loss and cognitive decline in LATE-NC and ADNC among community-dwelling older persons.

Agrawal S, Yu L, Leurgans S, Nag S, Barnes L, Bennett D Alzheimers Dement. 2025; 21(2):e14500.

PMID: 39888320 PMC: 11851160. DOI: 10.1002/alz.14500.

References

Schneider J, Wilson R, Cochran E, Bienias J, Arnold S, Evans D . Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology. 2003; 60(7):1082-8. DOI: 10.1212/01.wnl.0000055863.87435.b2. View

Nag S, Barnes L, Yu L, Wilson R, Bennett D, Schneider J . Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents. Neurology. 2020; 95(15):e2056-e2064. PMC: 7713750. DOI: 10.1212/WNL.0000000000010602. View

Yushkevich P, Lopez M, Iniguez de Onzono Martin M, Ittyerah R, Lim S, Ravikumar S . Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe. Brain. 2021; 144(9):2784-2797. PMC: 8783607. DOI: 10.1093/brain/awab262. View

Gosche K, Mortimer J, Smith C, Markesbery W, Snowdon D . Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology. 2002; 58(10):1476-82. DOI: 10.1212/wnl.58.10.1476. View

Fukutani Y, Cairns N, Shiozawa M, Sasaki K, Sudo S, Isaki K . Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late-onset sporadic Alzheimer's disease. Psychiatry Clin Neurosci. 2000; 54(5):523-9. DOI: 10.1046/j.1440-1819.2000.00747.x. View

Boyle P, Wang T, Yu L, Wilson R, Dawe R, Arfanakis K . To what degree is late life cognitive decline driven by age-related neuropathologies?. Brain. 2021; 144(7):2166-2175. PMC: 8370442. DOI: 10.1093/brain/awab092. View

Nelson P, Schmitt F, Lin Y, Abner E, Jicha G, Patel E . Hippocampal sclerosis in advanced age: clinical and pathological features. Brain. 2011; 134(Pt 5):1506-18. PMC: 3097889. DOI: 10.1093/brain/awr053. View

Nelson P, Smith C, Abner E, Wilfred B, Wang W, Neltner J . Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease. Acta Neuropathol. 2013; 126(2):161-77. PMC: 3889169. DOI: 10.1007/s00401-013-1154-1. View

Ala T, Beh G, Frey 2nd W . Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer's disease. Neurology. 2000; 54(4):843-8. DOI: 10.1212/wnl.54.4.843. View

10.

McInnes J, Wierda K, Snellinx A, Bounti L, Wang Y, Stancu I . Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau. Neuron. 2018; 97(4):823-835.e8. DOI: 10.1016/j.neuron.2018.01.022. View

11.

Zarow C, Weiner M, Ellis W, Chang Chui H . Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample. Brain Behav. 2012; 2(4):435-42. PMC: 3432966. DOI: 10.1002/brb3.66. View

12.

Wegiel J, Tarnawski M, Bobinski M, Reisberg B, de Leon M, Miller D . Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease. J Neuropathol Exp Neurol. 1997; 56(4):414-20. DOI: 10.1097/00005072-199704000-00010. View

13.

Nelson P, Trojanowski J, Abner E, Al-Janabi O, Jicha G, Schmitt F . "New Old Pathologies": AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS). J Neuropathol Exp Neurol. 2016; 75(6):482-98. PMC: 6366658. DOI: 10.1093/jnen/nlw033. View

14.

Uylings H, De Brabander J . Neuronal changes in normal human aging and Alzheimer's disease. Brain Cogn. 2002; 49(3):268-76. DOI: 10.1006/brcg.2001.1500. View

15.

Gomez-Isla T, HOLLISTER R, West H, Mui S, Growdon J, Petersen R . Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997; 41(1):17-24. DOI: 10.1002/ana.410410106. View

16.

Selkoe D . Alzheimer's disease is a synaptic failure. Science. 2002; 298(5594):789-91. DOI: 10.1126/science.1074069. View

17.

Polvikoski T, van Straaten E, Barkhof F, Sulkava R, Aronen H, Niinisto L . Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old. Neurology. 2010; 75(23):2071-8. PMC: 2995533. DOI: 10.1212/WNL.0b013e318200d6f9. View

18.

Arvanitakis Z, Capuano A, Leurgans S, Bennett D, Schneider J . Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol. 2016; 15(9):934-943. PMC: 4969105. DOI: 10.1016/S1474-4422(16)30029-1. View

19.

Sordo L, Qian T, Bukhari S, Nguyen K, Woodworth D, Head E . Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old. Acta Neuropathol. 2023; 146(3):415-432. PMC: 10412485. DOI: 10.1007/s00401-023-02606-9. View

20.

Rhein V, Song X, Wiesner A, Ittner L, Baysang G, Meier F . Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl Acad Sci U S A. 2009; 106(47):20057-62. PMC: 2774257. DOI: 10.1073/pnas.0905529106. View