Systemic medications and dementia risk: a systematic umbrella review

BACKGROUND: Previous meta-analyses have found that systemic medications may modulate dementia risk. We aimed to provide an overview of this evidence to guide clinical practice and future research. METHODS: We conducted an umbrella review of meta-analyses (PROSPERO CRD42021226307), searching databases from inception to 15th April 2024. Only peer-reviewed meta-analyses examining dementia risk and systemic medications in humans were included. Two authors independently screened studies for inclusion, extracted study data and assessed quality of meta-analyses using the AMSTAR-2 tool. Three authors independently rated the certainty of evidence for each drug using the GRADE framework. RESULTS: 68 meta-analyses were included, across 11 drug categories. Across meta-analyses, available data were primarily observational. Confounding by indication and potential reverse causality were important limitations. Randomised-controlled data were rare but supported an association between treatment of hypertension and reduced dementia incidence. Overall, we found moderate certainty evidence of reduced risk of dementia associated with anti-hypertensives, statins, sodium-glucose transport protein 2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and moderate certainty of increased risk with anticholinergics. DISCUSSION: Currently, there is insufficient evidence to advise repurposing any systemic drugs with the primary aim of reducing dementia risk. On the basis of our findings, we recommend proactive treatment of hypertension to reduce risk of all-cause dementia. Our findings did not find a difference between antihypertensive drug classes, but dementia risk was associated with blood pressure reading. In addition, we advise avoidance of anticholinergic drugs in cognitive impairment, with assessment of anticholinergic burden and consideration of alternatives during routine clinical contacts.