Clinician Article

Pharmacologic Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.

  • Fink HA
  • Jutkowitz E
  • McCarten JR
  • Hemmy LS
  • Butler M
  • Davila H, et al.
Ann Intern Med. 2018 Jan 2;168(1):39-51. doi: 10.7326/M17-1529. Epub 2017 Dec 19. (Review)
PMID: 29255847
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  • Public Health
    Relevance - 7/7
    Newsworthiness - 6/7
  • Neurology
    Relevance - 7/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Geriatrics
    Relevance - 6/7
    Newsworthiness - 4/7


BACKGROUND: Optimal treatment to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia is uncertain.

PURPOSE: To summarize current evidence on the efficacy and harms of pharmacologic interventions to prevent or delay cognitive decline, MCI, or dementia in adults with normal cognition or MCI.

DATA SOURCES: Several electronic databases from January 2009 to July 2017, bibliographies, and expert recommendations.

STUDY SELECTION: English-language trials of at least 6 months' duration enrolling adults without dementia and comparing pharmacologic interventions with placebo, usual care, or active control on cognitive outcomes.

DATA EXTRACTION: Two reviewers independently rated risk of bias and strength of evidence; 1 extracted data, and a second checked accuracy.

DATA SYNTHESIS: Fifty-one unique trials were rated as having low to moderate risk of bias (including 3 that studied dementia medications, 16 antihypertensives, 4 diabetes medications, 2 nonsteroidal anti-inflammatory drugs [NSAIDs] or aspirin, 17 hormones, and 7 lipid-lowering agents). In persons with normal cognition, estrogen and estrogen-progestin increased risk for dementia or a combined outcome of MCI or dementia (1 trial, low strength of evidence); high-dose raloxifene decreased risk for MCI but not for dementia (1 trial, low strength of evidence); and antihypertensives (4 trials), NSAIDs (1 trial), and statins (1 trial) did not alter dementia risk (low to insufficient strength of evidence). In persons with MCI, cholinesterase inhibitors did not reduce dementia risk (1 trial, low strength of evidence). In persons with normal cognition and those with MCI, these pharmacologic treatments neither improved nor slowed decline in cognitive test performance (low to insufficient strength of evidence). Adverse events were inconsistently reported but were increased for estrogen (stroke), estrogen-progestin (stroke, coronary heart disease, invasive breast cancer, and pulmonary embolism), and raloxifene (venous thromboembolism).

LIMITATION: High attrition, short follow-up, inconsistent cognitive outcomes, and possible selective reporting and publication.

CONCLUSION: Evidence does not support use of the studied pharmacologic treatments for cognitive protection in persons with normal cognition or MCI.

PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Clinical Comments


Meds with side effects that are not efficacious should not be used.


The findings from this meta-analysis confirm what is now becoming widely apparent and known: pharmacologic interventions do not significantly prevent or treat cognitive decline/impairment among individuals in their 60s and 70s. What is not known is whether such treatments at earlier ages would prevent the later development of cognitive decline or dementia.


This is likely to be a very influential comprehensive meta-analysis that demonstrates the failure of pharmacologic intervention to prevent cognitive decline, and, in the case of oral conjugated equine estrogen, the potential to increase the risk of dementia. Only raloxifen, a SERM, has demonstrated the potential to reduce the risk for MCI (but, paradoxically, not dementia) when taken at high dose, but at the expense of a substantially increased risk for thromboembolism. The article briefly discusses potential reasons for the disparity between the favorable results of aggressively managing hypertension and DM on the incidence of cognitive decline in observational studies versus the null effect in RCTs. Another area deserving mention is the paradox that cognitive enhancers (cholinesterase inhibitors, memantine) don't have any statistical benefit in MCI but can produce statistically significant (albeit small and transient) improvement once the MCI becomes syndromal dementia, even though it is generally believed that MCI and dementia represent a single continuum of cognitive decline.


Good quality systematic review that shows us that there is some clinical trial evidence to show no evidence of benefit with most drug treatments for MCI/prevention of dementia. Lifestyle interventions, e.g. exercise, diet, seem to have stronger evidence of benefit.


There are medications that I believe some practitioners use in MCI, and there are things that patients take to prevent cognitive decline. I think it is good to review that we haven't found the Holy Grail for preventing cognitive impairment.


Goes against recent UK study with metformin in mice.

Public Health

This article is very important. The prevention of cognitive decline is very important issue. This systematic review found that no pharmacological interventions are proven beneficial for preventing dementia. The strength of this review are in searching and appraising the evidence. The systematic process of searching and appraising the studies are well described. Further trials and review are warranted.

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