Alzheimer's Disease and Its Possible Evolutionary Origin: Hypothesis

Area of Science:

• Neuroscience
• Evolutionary Biology
• Pathology

Background:

• Human neocortex expansion occurred without compensatory growth of the entorhinal cortical (EC) gateway to the hippocampus.
• This evolutionary imbalance may explain the emergence of Alzheimer's disease (AD) in long-lived populations.
• Age-dependent processing strain on the lateral entorhinal cortex (LEC) may trigger amyloid-beta (Aβ) pathology.

Purpose of the Study:

• To investigate the evolutionary origins of Alzheimer's disease (AD).
• To elucidate the role of the entorhinal cortex (EC) and cellular prion protein (PrPC) in AD pathogenesis.
• To propose a potential therapeutic strategy for arresting AD.

Main Methods:

• Analysis of evolutionary pressures on hominin brain development.
• Examination of the molecular interactions between amyloid-beta oligomers (AβOs), cellular prion protein (PrPC), and tau.
• Investigation of the role of Ca2+-sensing receptors (CaSRs) in Aβ propagation.

Main Results:

• The EC's limited capacity struggles with increasing neocortical data, leading to neuronal strain and Aβ release.
• Amyloid-beta oligomers (AβOs) bind to cellular prion protein (PrPC), inducing tau hyperphosphorylation and synaptic damage.
• Amyloid-beta (Aβ) production, mediated by Ca2+-sensing receptors (CaSRs), facilitates AβOs spread.

Conclusions:

• Alzheimer's disease (AD) may be a connectopathic glitch resulting from an evolutionary mismatch.
• Cellular prion protein (PrPC) is central to AβOs-induced neurodegeneration.
• Combined therapeutic targeting of AβOs and CaSRs may offer an effective AD intervention.