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Clinical Manifestations.

Tyler R Bell1,2, Carol E Franz1,2, Christine Fennema-Notestine1,2

  • 1Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 26, 2025
PubMed
Summary
This summary is machine-generated.

Moderate-to-severe chronic pain accelerates cognitive decline and neurodegeneration, mainly through amyloid-beta (Aβ) pathways. This highlights the importance of addressing significant pain in Alzheimer's disease (AD) risk assessments and interventions.

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Area of Science:

  • Neuroscience
  • Gerontology
  • Biomarkers

Background:

  • Chronic pain affects 20% of older adults, increasing Alzheimer's disease (AD) dementia risk.
  • Limited research exists on chronic pain's association with AD biomarkers, particularly moderate-to-severe pain.

Purpose of the Study:

  • To investigate the association between moderate-to-severe chronic pain and cognitive decline and AD biomarkers.
  • To explore the mediating role of amyloid-beta (Aβ) and neurodegeneration in this relationship.

Main Methods:

  • Utilized data from 2487 participants without baseline dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
  • Categorized participants based on moderate-to-severe chronic pain (onset >3 months prior) and analyzed cognitive outcomes (CDR-SB, memory, executive function).
  • Assessed AD biomarkers (CSF Aβ42, tau, p-tau) and structural MRI (brain signature, hippocampal volume, cortical thickness, whole brain volume) using mixed-effects and mediation models.

Main Results:

  • Moderate-to-severe chronic pain correlated with accelerated global cognitive decline, memory, executive function decline, and whole brain volume loss.
  • Faster Aβ pathology accumulation was observed in individuals with moderate-to-severe chronic pain.
  • Aβ pathology and whole brain volume loss mediated the link between pain and cognitive decline; Aβ also mediated the pain-brain volume loss association. Mild pain showed no significant associations.

Conclusions:

  • Moderate-to-severe chronic pain significantly contributes to accelerated cognitive decline and neurodegeneration, primarily mediated by Aβ.
  • Findings underscore the need to incorporate moderate-to-severe chronic pain into AD risk assessments and intervention strategies.