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Background and Objective <p>Gabapentinoids, particularly gabapentin and pregabalin, are widely prescribed for neuropathic pain and other chronic conditions, including in populations at risk for cognitive decline. Their long-term cognitive safety and potential association with Alzheimer’s disease and related dementias (ADRD) remain uncertain. We examined whether gabapentinoid use is associated with ADRD risk and assessed between-study heterogeneity and potential study-level modifiers.</p> Methods <p>PubMed, Embase, and the Cochrane Library were searched from inception through November 2025. We included observational studies comparing gabapentinoid users with non-users or non-gabapentinoid comparators and reporting incident ADRD. Risk of bias was assessed using ROBINS-E. A random-effects meta-analysis was performed using odds ratios. Subgroup and meta-regression analyses explored study-level modifiers. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). The protocol was registered in PROSPERO (CRD420251240055).</p> Results <p>Five observational studies (325,245 participants) were included. Gabapentinoid use was associated with modestly higher estimated odds of ADRD (odds ratio, 1.28; 95% confidence interval 1.10–1.50; <i>P</i> = 0.002), with high heterogeneity (<i>I</i><sup>2</sup> = 90.3%). This association was attenuated when restricted to studies with a low risk of bias (odds ratio, 1.23; 95% confidence interval 0.83–1.84). Studies enrolling younger populations yielded larger estimates than those with older cohorts, though the subgroup difference was not statistically significant. Meta-regression identified mean age as a study-level moderator, accounting for 60.2% of between-study variance. Certainty of evidence was low overall.</p> Conclusions <p>Gabapentinoid use was associated with modestly higher estimated odds of ADRD in pooled observational data. High heterogeneity, residual confounding, and confounding by indication preclude causal inference. These findings support cautious prescribing, particularly for off-label and long-term use, and underscore the need for prospective studies.</p> Clinical Trial Registration <p>PROSPERO protocol number: CRD420251240055.</p>

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Gabapentinoid Use and Risk of Alzheimer’s Disease-Related Dementias: A Systematic Review and Meta-analysis of Observational Studies

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Anderson Matheus Pereira da Silva,
  • Marianna Leite,
  • Giovana Menegucci,
  • Maria Fernanda Liphaus Almeida Negreli,
  • Maria Eduarda Scheffer Valverde,
  • Isabelle Rodrigues Menezes,
  • Ocilio Ribeiro Gonçalves,
  • Jorge Dornellys da Silva Lapa,
  • Gustavo Noleto,
  • Diogo Haddad Santos,
  • Filipe Silveira Duarte,
  • George Perry,
  • Eryvelton de Souza Franco,
  • Maria Bernadete de Sousa Maia

摘要

Background and Objective

Gabapentinoids, particularly gabapentin and pregabalin, are widely prescribed for neuropathic pain and other chronic conditions, including in populations at risk for cognitive decline. Their long-term cognitive safety and potential association with Alzheimer’s disease and related dementias (ADRD) remain uncertain. We examined whether gabapentinoid use is associated with ADRD risk and assessed between-study heterogeneity and potential study-level modifiers.

Methods

PubMed, Embase, and the Cochrane Library were searched from inception through November 2025. We included observational studies comparing gabapentinoid users with non-users or non-gabapentinoid comparators and reporting incident ADRD. Risk of bias was assessed using ROBINS-E. A random-effects meta-analysis was performed using odds ratios. Subgroup and meta-regression analyses explored study-level modifiers. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). The protocol was registered in PROSPERO (CRD420251240055).

Results

Five observational studies (325,245 participants) were included. Gabapentinoid use was associated with modestly higher estimated odds of ADRD (odds ratio, 1.28; 95% confidence interval 1.10–1.50; P = 0.002), with high heterogeneity (I2 = 90.3%). This association was attenuated when restricted to studies with a low risk of bias (odds ratio, 1.23; 95% confidence interval 0.83–1.84). Studies enrolling younger populations yielded larger estimates than those with older cohorts, though the subgroup difference was not statistically significant. Meta-regression identified mean age as a study-level moderator, accounting for 60.2% of between-study variance. Certainty of evidence was low overall.

Conclusions

Gabapentinoid use was associated with modestly higher estimated odds of ADRD in pooled observational data. High heterogeneity, residual confounding, and confounding by indication preclude causal inference. These findings support cautious prescribing, particularly for off-label and long-term use, and underscore the need for prospective studies.

Clinical Trial Registration

PROSPERO protocol number: CRD420251240055.