Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4
(2025) Alzheimer’s & Dementia — Vol. 21, n° 7, p. e70483 [1-18] (2025)
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Gawor, Klara 
Verrept, Sam Arekatla, Geethika Wouters, David Tomé, Sandra O.
- Abstract
- (en) INTRODUCTION: In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors. METHODS: We analyzed 480 post mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (APOE) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status. RESULTS: Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while APOE ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology. DISCUSSION: Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification. HIGHLIGHTS: In aging individuals, amyloid β peptide (Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration. LATE-NC was the strongest driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration. Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden. Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology. Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.
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Gawor, K., Verrept, S., Arekatla, G., Wouters, D., Ronisz, A., Hecht, M., Laureyssen, C., Donck, H. V., Lahaije, B., Ospitalieri, S., Vandenbulcke, M., Otto, M., von Arnim, C. A. F., Ghebremedhin, E., Hanseeuw, B., Vandenberghe, R., Blaschko, M., Sifrim, A., Sleegers, K., et al. (2025). Alzheimer’s disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4. Alzheimer’s & Dementia, 21(7), e70483 [1-18]. https://doi.org/10.1002/alz.70483 (Original work published 2025)