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Basic Science and Pathogenesis.

Abhijit Satpati1, Felipe Luiz Pereira2, Alexander V Soloviev2

  • 1Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
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Summary
This summary is machine-generated.

Orexinergic neurons are the first to degenerate in Alzheimer's disease (AD), beginning at Braak stage I. Early tau pathology triggers inflammation and cellular stress, highlighting these neurons as a key target for early AD intervention.

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Area of Science:

  • Neuroscience
  • Neuropathology
  • Molecular Biology

Background:

  • The neuromodulatory subcortical system (NSS) and its orexinergic neurons (OrxN) are crucial for homeostasis and are early sites of tau pathology in Alzheimer's disease (AD).
  • Orexin pathway dysfunction is implicated in AD progression, with recent trials showing biomarker improvements.
  • The precise timing and molecular drivers of OrxN loss in human AD remain poorly understood, hindering targeted therapies.

Purpose of the Study:

  • To determine the extent and timing of orexinergic neuron loss in human Alzheimer's disease brains.
  • To investigate the molecular mechanisms underlying early orexinergic neuron degeneration in AD.
  • To establish orexinergic neurons as a potential therapeutic target for early AD intervention.

Main Methods:

  • Utilized unbiased stereology on postmortem human brains (Braak stages 0-VI, n=38) to quantify orexin-A positive neurons.
  • Performed immunohistochemistry for phosphorylated tau (CP13) and counterstained with Nissl.
  • Conducted RNA sequencing on lateral hypothalamic area (LHA) samples (n=38) using NanoString nCounter® for gene expression analysis.

Main Results:

  • Orexinergic neuron loss begins at Braak stage I (43% reduction) and progresses significantly by Braak stage V-VI (70% reduction vs. Braak 0).
  • A 50% drop in orexinergic neurons at Braak II correlated with altered gene expression in lysosomal function, glial reactivity, oxidative stress, and phosphorylation pathways.
  • Despite neuronal loss, orexin-related genes (HCRT, HCRTR1) were upregulated in later Braak stages (III-IV).

Conclusions:

  • Orexinergic neurons represent the earliest neuronal population to degenerate in Alzheimer's disease, initiating at Braak stage I.
  • Early p-tau accumulation in the LHA, independent of significant β-amyloid, drives T-cell inflammation, lysosomal dysfunction, and oxidative stress, leading to OrxN loss.
  • Targeting orexinergic neurons offers a promising strategy for early AD intervention, potentially providing both symptomatic and disease-modifying benefits.