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Cover of Interventions to Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s-Type Dementia

Interventions to Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s-Type Dementia

Comparative Effectiveness Reviews, No. 188

Investigators: , MD, , PhD, MBA, , MD, MPH, , PhD, MLIS, , MPA, , MHP, , BA, , PhD, , MSc, , MD, , BA, , MD, , PhD, and , PhD, LP.

Author Information and Affiliations
Rockville (MD): Agency for Healthcare Research and Quality (US); .
Report No.: 17-EHC008-EF

Structured Abstract


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®, Ovid PsycINFO®, Ovid Embase®, 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.


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.


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.


Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract No. 290-2015-00008-I. Prepared by: Minnesota Evidence-based Practice Center, Minneapolis, MN

Suggested citation:

Kane RL, Butler M, Fink HA, Brasure M, Davila H, Desai P, Jutkowitz E, McCreedy E, Nelson VA, McCarten JR, Calvert C, Ratner E, Hemmy LS, Barclay T. Interventions To Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s-Type Dementia. Comparative Effectiveness Review No. 188. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2015-00008-I.) AHRQ Publication No. 17-EHC008-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2017. www.effectivehealthcare.ahrq.gov/reports/final.cfm. doi: https://doi.org/10.23970/AHRQEPCCER188.

This report is based on research conducted by the Minnesota Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2015-00008-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.

The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.

AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.

This report may periodically be assessed for the currency of conclusions. If an assessment is done, the resulting surveillance report describing the methodology and findings will be found on the Effective Health Care Program Web site at www.effectivehealthcare.ahrq.gov. Search on the title of the report.


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Bookshelf ID: NBK442425PMID: 28759193


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