Alzheimer's disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ϵ4

Gawor, K.; Verrept, S.; Arekatla, G.; Wouters, D.; Ronisz, A.; Hecht, M.; Laureyssen, C.; Ver Donck, H.; 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.; Thal, D. R.; Tome, S. O.

doi:10.1101/2025.04.11.648343

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bioRxiv · 10.1101/2025.04.11.648343

Alzheimer's disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ϵ4

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Abstract

INTRODUCTIONIn neurodegenerative dementias, the co-occurrence and interaction of A{beta}, tau, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors. METHODSWe analyzed 480 post-mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among A{beta}, tau, LATE-NC, -synuclein, other age-related lesions, and APOE {varepsilon}4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status. RESULTSA{beta}, tau, LATE-NC, and amygdala-predominant -synuclein pathology were highly interconnected. 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 -synuclein, while APOE {varepsilon}4 was mainly associated with extracellular and capillary A{beta}. DISCUSSIONAlthough Alzheimers 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.

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Gawor, K., Verrept, S., Arekatla, G., Wouters, D., Ronisz, A., Hecht, M., Laureyssen, C., Ver Donck, H., 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., Thal, D. R., Tome, S. O.. 2025-04-17. Alzheimer's disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ϵ4. https://doi.org/10.1101/2025.04.11.648343

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