Chronic Back Pain Increases Alzheimer’s Disease Risk Independent of Gross Brain Structural Alterations: Genetic Evidence from Two Populations

Background: Observational studies suggest chronic musculoskeletal pain (CMP) may be a risk factor for dementia, but confounding factors or reverse causation could obscure these findings. Additionally, whether brain structure imaging measurements mediate this relationship remains unclear. We aimed to investigate their causal association using Mendelian randomization (MR). Methods: Genetic instruments derived from genome-wide association studies were employed in a two-sample MR framework. Forward MR analysis examined the genetic effect of CMP on dementia, while reverse MR analysis evaluated the genetic effect of dementia on CMP to assess reverse causation. Primary causal estimates were obtained using the inverse-variance weighted method. Mediation analyses tested brain structural markers as potential mediators. Sensitivity analyses evaluated robustness and horizontal pleiotropy. Results: Primary inverse-variance weighted analysis suggested genetically predicted chronic back pain (CBP) is associated with an increased risk of Alzheimer’s disease (AD) (Odds Ratio 2.287, 95% confidence interval: 1.338 to 3.909, P = 0.002). However, this estimate was characterized by wide confidence intervals, conservative SNP heritability estimates, and null results in MR-Egger sensitivity analyses, indicating potential directional pleiotropy cannot be fully ruled out. No significant causal associations were detected for all-cause, frontotemporal, or vascular dementia. Other CMP subtypes showed no significant genetic effect on any dementia type. There was no evidence of reverse causation. While CBP influenced nine brain structures, these did not mediate the CBP-AD link. Conclusion: Primary MR analyses support a directional association between genetically predicted CBP and increased AD risk. However, due to methodological constraints and wide confidence intervals, the large point estimate of the odds ratio should be interpreted with caution. Structural brain alterations do not appear to mediate this relationship. These findings highlight a potential causal pathway between CBP and AD, but require rigorous validation in independent, adequately powered cohorts before clinical inferences can be drawn. Keywords: chronic musculoskeletal pain, chronic back pain, dementia, brain structure imaging measurements, epidemiology, genome-wide association studies, Mendelian randomization