Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Biochemistry
• Systems Biology

Background:

• Lipid biology is significantly disrupted in Alzheimer's disease (AD), with genetic studies implicating lipid metabolism, cellular trafficking, and bioenergetics.
• Current hypotheses do not fully reconcile lipid disruption with neuronal loss in AD etiology.

Purpose of the Study:

• To develop a unified hypothesis for AD etiology that integrates lipid disruption and neuronal loss.
• To build a model of brain homeostasis using systems engineering and quantitative systems pharmacology (QSP) approaches.

Main Methods:

• Utilized baseline measurements from ADNI plasma lipidomics and CSF proteomics.
• Reconciled extensive literature data with systems engineering and QSP methods.
• Validated the developed model against large multiomic datasets (ADNI, GNPC).

Main Results:

• Identified two convergent feedback loops driving AD pathophysiology: impaired microglial processing of debris and disrupted astrocyte signaling due to elevated cholesterol.
• Evidence suggests elevated cholesterol disrupts astrocyte membrane function, impairing astrocyte-neuronal lactate shuttle (ANLS) signaling and neuronal metabolic support.
• Microglia become overwhelmed by neuronal and myelin debris, leading to impaired processing capacity.

Conclusions:

• Neurodegeneration in AD is driven by the brain's failure to process excess cholesterol from neuronal debris, causing widespread lipidomic, metabolic, and proteomic disruptions.
• Lipid homeostasis disruption precedes amyloid and tau pathology, accelerating amyloid production and impairing neuronal metabolic support.
• This cholesterol homeostasis breakdown offers a comprehensive explanation for AD's multi-omic alterations, positioning lipid dysregulation as a primary disease driver and enabling identification of novel therapeutic targets.