OBJECTIVE: This review assessed evidence for interventions aimed at preventing or delaying the onset of age-related cognitive decline, mild cognitive impairment (MCI), or clinical Alzheimer's-type dementia (CATD). DATA SOURCES: Ovid Medline((R)), Ovid PsycINFO((R)), Ovid Embase((R)), and Cochrane Central Register of Controlled Trials (CENTRAL) bibliographic databases; hand searches of references of prior reviews, eligible studies, gray literature; expert recommendations. REVIEW METHODS: Two investigators screened abstracts and full-text articles of identified references. Eligible studies included randomized and nonrandomized controlled trials and quasi-experimental observational studies published to September 2016 that enrolled people with normal cognition and/or MCI. We extracted data, assessed risk of bias, summarized results for studies without high risk of bias, and evaluated strength of evidence for studies with sufficient sample size. Cognitive outcomes were grouped into domains to facilitate analysis; strength of evidence was assessed by MCI or CATD incidence and cognitive outcome domain. RESULTS: We identified 263 eligible studies addressing 13 classes of interventions: cognitive training, physical activity, nutraceuticals, diet, multimodal interventions, hormone therapy, vitamins, antihypertensive treatment, lipid lowering treatment, nonsteroidal anti-inflammatory drugs (NSAIDs), antidementia drugs, diabetes treatment, and "other interventions." We found no high-strength evidence for the effectiveness of any intervention to delay or prevent age-related cognitive decline, MCI, and/or CATD. Moderate-strength evidence shows cognitive training in adults with presumed normal cognition improves performance in the cognitive domain trained (memory, reasoning, or processing speed), but not transfer of benefits to other cognitive areas and little evidence for benefit beyond 2 years; evidence for effect on CATD is weak. Interventions with moderate-strength evidence for having no benefit in cognitive performance included: vitamin E in women; B12 plus folic acid for executive/attention/processing speed; and angiotensin-converting enzyme plus thiazide versus placebo and angiotensin receptor blockers versus placebo on brief cognitive screening tests. We found low-strength evidence that the selective estrogen receptor modulator raloxifene reduced risk of probable MCI, but also that estrogen replacement with or without progesterone therapy increased risk of MCI and CATD. Physical activity interventions show no consistent benefit in preventing cognitive decline, but the percent of results showing benefit was unlikely to be explained solely by chance, providing a signal of a possible relationship. A few other interventions (vitamin B12 plus folic acid; nutraceuticals; one multimodal intervention using diet, physical activity, and cognitive training; antihypertensives; and NSAIDs) showed at least one positive finding for a specific outcome, some reaching low strength of evidence, but these were more than offset by findings of no effect for other outcomes. Many interventions (e.g., nutraceuticals; one multimodal intervention using lifestyle advice and drug treatment; hormone therapy; antihypertensives; NSAIDs; acetylcholinesterase inhibitors; diabetes management) showed low-strength evidence for no benefit for some cognitive performance tests. We found no eligible studies for the following interventions: depression treatment, smoking cessation, and community-level interventions. CONCLUSIONS: We found mostly low-strength evidence that a wide variety of interventions had little to no benefit for preventing or delaying age-related cognitive decline, MCI, or CATD. There was moderate-strength evidence that cognitive training improved performance in the trained cognitive domains, but not in domains not trained. Evidence of an effect on CATD incidence was weak. There was a mix of positive and negative findings for different outcomes, all of low strength, for physical activity, antihypertensives, NSAIDs, B vitamins, nutraceuticals, and multimodal interventions. Signals seem more promising for physical activity and vitamin B12 plus folic acid. Testing interventions that address modifiable risk factors can help to establish their causative role in MCI and CATD. Methodological problems in the available literature were widespread and should be addressed in future studies, including use of consistent cognitive outcome measures, longer followups, and recognizing that attrition is a major problem in longer studies. More work is needed to understand the relationship between intermediate outcomes such as cognitive test results and the onset of mild cognitive impairment and dementia.