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

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.