Chronic pain as a risk factor for Alzheimer’s disease pathology: a longitudinal ADNI study

AI Summary

Chronic pain combined with APOE-ε4 carriership predicts greater longitudinal increases in CSF p-tau181 and decreases in CSF Aβ42/Aβ40, precuneus thinning, and memory decline.
Neither chronic pain nor APOE-ε4 independently predicted baseline CSF or PET amyloid or CSF p-tau181.
Associations persisted excluding MCI and among Aβ-negative participants; chronic pain may be a dementia prevention target though causality requires further study.

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BACKGROUND: Growing evidence supports chronic pain (CP) as a risk factor for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD).

Linear mixed-effects models tested longitudinal change in cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid-β (Aβ) and phosphorylated tau (p-tau181), structural MRI indices (AD-related cortical signature, hippocampal and entorhinal volumes, precuneus thickness), and cognitive outcomes (episodic memory, executive function, Mini-Mental State Examination [MMSE]).

Models included fixed effects of CP status, APOE-ε4 status, time (years since baseline), and their two-way and three-way interactions, adjusting for age, sex, education, baseline Aβ positivity status, and time-varying depressive symptoms.

Basic summary

Alzheimers Res Ther. 2026 Jul 3. doi: 10.1186/s13195-026-02137-x. Online ahead of print.

ABSTRACT

BACKGROUND: Growing evidence supports chronic pain (CP) as a risk factor for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). We examined whether CP is associated with longitudinal worsening of AD-related biomarkers, brain structure, and cognition, and whether effects differ by APOE-ε4 status.

METHODS: Data were drawn from 1,493 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) without baseline dementia (mean age = 72.4 ± 7.19 years; 48% female). Linear mixed-effects models tested longitudinal change in cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid-β (Aβ) and phosphorylated tau (p-tau181), structural MRI indices (AD-related cortical signature, hippocampal and entorhinal volumes, precuneus thickness), and cognitive outcomes (episodic memory, executive function, Mini-Mental State Examination [MMSE]). Models included fixed effects of CP status, APOE-ε4 status, time (years since baseline), and their two-way and three-way interactions, adjusting for age, sex, education, baseline Aβ positivity status, and time-varying depressive symptoms.

RESULTS: At baseline, 30% of participants (n = 452) reported CP and 45% (n = 666) were APOE-ε4 carriers. CP and APOE-ε4 status did not independently predict baseline CSF Aβ42/Aβ40, PET Aβ burden, or CSF p-tau181. Longitudinally, the CP+/ε4 + group showed greater AD-like changes in CSF Aβ42/Aβ40 and CSF p-tau181, thinning of the precuneus (β=-0.09, p<.001) and faster decline in episodic memory (β=-0.08, p<.001), compared to all other groups. Many of these associations remained when excluding participants with MCI or restricting to Aβ-negative participants.

CONCLUSIONS: The combination of CP and APOE-ε4 carriership was associated with greater longitudinal worsening of brain structure and cognitive function, even among individuals who were Aβ-negative at baseline. These findings provide in vivo evidence that CP is associated with greater AD-related worsening over time in the context of genetic susceptibility. As evidence accumulates, CP may warrant recognition as a risk factor in dementia prevention frameworks, though causal inferences require further study.

PMID:42399965 | DOI:10.1186/s13195-026-02137-x

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