Background <p>Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has become a cornerstone therapy for heart failure (HF) since its approval over a decade ago. However, concerns have emerged about potential cognitive risks, as neprilysin inhibition may contribute to the accumulation of amyloid-beta (Aβ) in the brain—a hallmark of Alzheimer’s disease, the most common form of dementia.</p> Objective <p>Given the already elevated risk of dementia in patients with HF and the widespread use of sacubitril/valsartan, this meta-analysis aimed to evaluate whether its use is associated with an increased risk of all-cause dementia in HF populations.</p> Methods <p>A systematic literature search was conducted on 23 March 2025, to identify eligible studies comparing the risk of dementia in patients receiving sacubitril/valsartan versus those receiving placebo, no treatment, or other HF medications. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model.</p> Results <p>Six studies, comprising 101,074 participants and published between 2017 and 2024, were included in the meta-analysis. Treatment with sacubitril/valsartan was associated with a significant 15% reduction in the risk of all-cause dementia (RR = 0.85; 95% CI: 0.74–0.98; <i>p</i> = 0.02). Leave-one-out sensitivity and subgroup analyses confirmed the robustness of the findings.</p> Conclusions <p>This meta-analysis suggests that sacubitril/valsartan is associated with a reduced risk of dementia in patients with HF, helping to alleviate previous concerns about potential cognitive adverse effects. These findings support the continued use of sacubitril/valsartan as a foundational therapy in this high-risk population.</p>