Alzheimer’s disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4
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INTRODUCTION
In neurodegenerative dementias, the co-occurrence and interaction of Aβ, tau, 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, LATE-NC, α-synuclein, other age-related lesions, and 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 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 α-synuclein, while APOE ε4 was mainly associated with extracellular and capillary Aβ.
DISCUSSION
Although Alzheimer’s 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.
