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Does Midlife Antibiotic Use Increase Risk for Future Cognitive Decline?

  • Authors: News Author: Marta Zaraska; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 5/13/2022
  • Valid for credit through: 5/13/2023, 11:59 PM EST
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This activity is intended for primary care physicians, neurologists, nurses, pharmacists, physician assistants, and other members of the healthcare team who treat and manage adults on antibiotic therapy.

The goal of this activity is that learners will be better able to assess the possible effect of antibiotic use on cognitive function among adults.

Upon completion of this activity, participants will:

  • Evaluate a possible link between antibiotic use and the risk for cancer
  • Analyze the risk for cognitive decline associated with the use of antibiotics among middle-aged women
  • Outline implications for the healthcare team


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News Author

  • Marta Zaraska

    Freelance writer, Medscape


    Disclosure: Marta Zaraska has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine
    Irvine, California


    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: GlaxoSmithKline; Johnson & Johnson

Editor/Nurse Planner

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC


    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.

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  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance
    Medscape, LLC


    Disclosure: Amanda Jett, PharmD, BCACP, has disclosed no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Does Midlife Antibiotic Use Increase Risk for Future Cognitive Decline?

Authors: News Author: Marta Zaraska; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 5/13/2022

Valid for credit through: 5/13/2023, 11:59 PM EST


Clinical Context

Healthcare professionals have experience in describing the potential negative consequences of inappropriate antibiotic use, including adverse events and a higher risk for incident resistant bacteria. However, many clinicians do not consider the potential long-term health effects of antibiotic prescriptions, which might be related to changes in the microbiome. A previous study by Petrelli and colleagues provides a systematic review of the relationship between antibiotic use and incident cancer. Their results were published in the August 2019 issue of Cancers.[1]

The researchers found 25 observational studies of the risk for cancer after antibiotic prescriptions, which included a total of nearly 8 million people. Overall, the odds ratio (OR) for incident cancer in comparing individuals who received antibiotics vs those who did not was 1.18 (95% confidence interval [CI], 1.12-1.24). The researchers found that antibiotic use was associated with higher risks for lung cancer, lymphomas, pancreatic cancer, renal cell carcinoma, and multiple myeloma. Beta lactams, cephalosporins, macrolides, and quinolones were all associated with a higher risk for cancer.

Previous research has found a link between antibiotic use and the risk for neuropsychiatric illness, but data on antibiotic use and cognitive decline are lacking. The current study addresses this issue.

Study Synopsis and Perspective

A new study, published online March 23 in PLOS ONE, suggests that prolonged use of antibiotics in midlife is related to cognitive decline several years down the road.[2]

For the study, scientists paired self-reported antibiotic use of more than 14,000 middle-aged nurses with outcomes on neuropsychological tests conducted 7 years later. The results revealed that those nurses who received antibiotics for at least 2 months during a period of 4 years had lower scores on tasks involving memory, learning, attention, and psychomotor speed. Overall, the negative effects of antibiotics on cognition were comparable to those caused by 3 to 4 years of aging.

Although Andrew Chan, MD, MPH, a gastroenterologist at Harvard Medical School who co-led the study, does not preclude the possibility that the antibiotics might have acted directly on the brain, he told Medscape Medical News that his leading hypothesis is that the drugs had disruptive effects on the gut microbiota. Indeed, research on mice shows that antibiotics such as ampicillin, although undetectable in the brain, are linked to gut dysbiosis and cognitive impairment.[3]

A previous study on humans showed that those afflicted with Alzheimer's dementia had altered gut microbiome compared with healthy volunteers.[4] They had, for instance, more bacteria from the genus Bacteroides and less of those from the genus Bifidobacterium. Other research has revealed changes in diversity and decreased richness of gut microbes in several other conditions, from Crohn's disease and autism spectrum disorder to multiple sclerosis and Parkinson's disease.

"Numerous animal studies, and some human studies as well, have shown that gut dysbiosis is linked to cognitive impairment as well as brain alterations," Viktoriya Nikolova, MRes, MSc, a PhD student and researcher at King's College London, told Medscape Medical News when asked for independent comment. Antibiotics can cause changes in the microbiome that may last months or even years.[5,6]

There are many ways in which the trillions of microbes that reside in the human gut may affect the mind. They can hack into the vagus nerve, release neurotransmitters into the blood that crosses into the brain and interact with immune cells.

According to Dr Chan, "antibiotics and the disruption of the gut microbiome may trigger a chronic state of inflammation that predisposes people to develop cognitive decline." Such inflammation could be caused, for instance, by bacterial endotoxins, which are potentially toxic compounds released by gram-negative bacteria, such as Bacteroides, which are found in abundance in the guts of patients with Alzheimer's disease.

Experiments show that injecting mice with endotoxins can lead to greater formation of amyloid plaques, which are insoluble clumps of misfolded proteins that form between nerve cells in the brain, potentially blocking cell-to-cell signaling.[7] Rodent research suggests that antibiotics can indeed affect the formation of amyloid plaques.[8]

Although the new study in PLOS ONE adds to our knowledge of the potential negative effects of antibiotics on brain health, Dr Chan believes that it is too early to make any recommendations about whether people should avoid antibiotics specifically out of concern regarding dementia.

He does believe, however, that the study "does provide some additional rationale for being careful about how one uses antibiotics." Considering that the Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions in the US are unnecessary, that is certainly a cause for concern.[9]

The study was independently supported. Dr Chan and Dr Nikolova have disclosed no relevant financial relationships.

PLoS One. Published online March 23, 2022.

Study Highlights

  • Study data were drawn from the Nurses' Health Study 2, which enrolled 116,430 female nurses between the ages of 25 and 42 years in 1989. Study participants provide health updates every 2 years as part of the research protocol.
  • In 2009, participants were asked about their history of antibiotic use. At a mean of 7 years later, participants completed a self-administered online battery of cognitive tests that measured psychomotor speed, attention, learning, and working memory.
  • The main study outcome was the effect of antibiotic use on the cognitive test scores. This result was adjusted to account for demographic and disease factors, as well as health habits, medication use, and body mass index.
  • 14,542 women provided data for study analysis. The mean age of participants at the time of antibiotic assessment was 54.7 years, and the mean age at the time of cognitive testing was 61.7 years.
  • Most baseline characteristics were similar regardless of antibiotic use, but women who reported antibiotic use had higher rates of myocardial infarction, stroke, and emphysema, and they were more likely to use antidepressant medications.
  • Overall, antibiotic use was associated with globally lower scores in cognitive testing. The difference between scores in the antibiotic and no-antibiotic groups was similar to what could be expected with the antibiotic group being 3 to 4 years older, on average, vs the no-antibiotic group.
  • Examined individually as outcomes, antibiotic use was associated with significant reductions in psychomotor speed, attention, learning, and working memory.
  • The indications for most antibiotic prescriptions, in order, were respiratory infections, "other" (including acne), urinary tract infection, and dental indications. Antibiotics for respiratory infection and urinary tract infection had the strongest associations for subsequent cognitive decline.
  • Secondary analyses based on comorbid illness and the use of antidepressants failed to alter the main study outcome.

Clinical Implications

  • In a previous systematic review of observational studies, antibiotic use was associated with a significant 18% increase in the risk for subsequent cancer, including lymphoma, lung cancer, pancreatic cancer, and multiple myeloma. Multiple classes of antibiotics were associated with a higher risk for cancer.
  • The current study suggests that antibiotic use during middle age among women can advance the rate of cognitive decline by the equivalent of 3 to 4 years of age.
  • Implications for the healthcare team: Antibiotic use may be associated with significant negative long-term health outcomes, including cognitive decline among women. Members of the healthcare team should use antibiotic stewardship to ensure unnecessary antibiotic prescribing.


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