Deep brain stimulation of the fornix for Alzheimer's disease: A systematic review and meta-analysis of cognitive outcomes.

Deep brain stimulation of the fornix (fornix-DBS) has been proposed as a potential neuromodulatory strategy for Alzheimer’s disease (AD), based on its role within the Papez memory circuit and reported effects on hippocampal metabolism and network connectivity. However, clinical studies vary substantially in design, disease stage, stimulation parameters, and outcome assessment, and the consistency of cognitive benefit remains uncertain. To systematically evaluate the clinical cognitive effects of fornix-targeted DBS in Alzheimer’s disease and to quantitatively synthesize available evidence from controlled and observational studies. This systematic review was conducted in accordance with PRISMA-2020 guidelines and registered in PROSPERO (CRD420251175724). PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials and observational studies investigating fornix-targeted DBS in patients with Alzheimer’s disease. Meta-analyses were performed for ADAS-Cog and MMSE outcomes using random-effects models. Subgroup analyses by study design (RCT vs. observational) and sensitivity analyses were conducted to assess robustness. Structural and metabolic issues were narratively synthesis. Ten studies encompassing mild, moderate, and severe AD populations met inclusion criteria. Individual studies reported heterogeneous and predominantly short-term cognitive responses, with transient improvements mainly observed in small severe-AD cohorts. In contrast, randomized trials in mild AD consistently demonstrated no clinically meaningful benefit.