Free neuropathology · 2 authors, 2 centres
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This is a hypothesis paper proposing that the entrapment of lipoprotein particles in the brain's extracellular space during ageing is the primary cause of Alzheimer's disease pathology. The authors argue this mechanism unifies known features like amyloid-β accumulation and tau aggregation, but direct evidence for the core hypothesis is lacking.
The authors propose a unifying hypothesis for Alzheimer's disease (AD) pathogenesis centered on the impaired movement of lipoprotein particles in the brain's extracellular space. They reason that age-related trapping of these particles disrupts cholesterol delivery to neurons, leading to synaptic dysfunction. This primary abnormality is proposed to secondarily cause extracellular amyloid-β accumulation, which triggers a neurotoxic microglial response, and intraneuronal tau aggregation. The hypothesis aims to explain why clinical trials targeting amyloid-β or tau have failed. The authors acknowledge significant limitations, including the lack of direct evidence for lipoprotein particle entrapment in the human brain and for the solubilization of amyloid-β within the particles' core.
