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Basic Science and Pathogenesis.

Tom Paterson1, Jennifer Rohrs1, Timothy J Hohman2

  • 1Fulcrum Neuroscience, Palo Alto, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
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Alzheimer's disease (AD) neurodegeneration stems from the brain's inability to process excess cholesterol, leading to lipid disruptions upstream of amyloid and tau pathology. This lipid dysregulation is a primary driver of AD progression.

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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.