Common Infections Linked To Poorer Cognitive Performance In Middle-Aged And Older Adults

The results add to a growing body of evidence suggesting that infections in mid- and late-life can worsen cognitive performance and may increase the risk of Alzheimer's disease and other dementias.

For their analysis, the researchers examined antibody levels to five common pathogens in 575 adults, ages 41 to 97. The adults were recruited from East Baltimore in 1981, as part of the Epidemiologic Catchment Area Study started that year by the National Institute of Mental Health. Baltimore study participants donated blood for testing and took cognitive tests during the same study period. Antibody tests for pathogens were conducted, including four herpes viruses -- herpes simplex virus type 1, cytomegalovirus, varicella zoster virus (chickenpox and shingles viruses), and Epstein-Barr virus -- and the parasite Toxoplasma gondii. The latter often spreads to humans from cat feces or from eating undercooked meat.

The research team compared participants' blood test results to their performance on the Mini-Mental State Examination -- a global cognitive test that assesses things like orientation, attention, verbal comprehension, memory, and visual perception -- and on a word recall task, which tested memory for a list of words after a 20-minute delay. The researchers found that elevated antibodies to either herpes simplex virus type 1 or cytomegalovirus were individually associated with worse performance on the global cognitive test. Further, participants with a higher number of positive antibody tests tended to miss a larger number of items on the global cognition test.

The study was published online April 7 in the journal Alzheimer's & Dementia.

"The idea that common infections could contribute to cognitive decline and perhaps Alzheimer's disease risk was once on the fringe and remains controversial, but due to findings like the ones from this study, it's starting to get more mainstream attention," says senior author Adam Spira, Ph.D., professor in the Bloomberg School's Department of Mental Health and a core faculty member of the Johns Hopkins Center on Aging and Health. "After accounting for participants' age, sex, race, and the largest genetic risk factor for Alzheimer's disease, the data in our study showed that a greater number of positive antibody tests related to five different infections was associated with poorer cognitive performance. To our knowledge, this kind of additive effect of multiple infections on performance on a cognitive test has not been shown before."

The cause of Alzheimer's disease remains unclear. Prior research has made the connection with infections, including studies linking herpes simplex virus type 1 and cytomegalovirus to greater Alzheimer's risk. There is also evidence that the protein fragment amyloid beta, which forms insoluble plaques in the brains of people with Alzheimer's, functions as an antimicrobial peptide, and is secreted at higher levels by brain cells in response to infections.

Since the 2003-2004 wave, ECA study researchers at Johns Hopkins have conducted periodic follow-up interviews in Baltimore, including standard cognitive tests and taking blood samples. The two most recent waves of the study, funded by the National Institute on Aging, have focused on Alzheimer's disease and related outcomes.

The pathogens assessed in the study are often encountered in childhood and are either cleared or turned into suppressed, latent infections. As such, the researchers considered significant levels of antibodies against them in the middle-aged and older study participants as likely indicators of their reactivation due to immune system weakening with age.

The study's first author, Alexandra Wennberg, Ph.D., who completed her doctoral training in Spira's research group, is currently a postdoctoral research associate at Sweden's Karolinska Institutet. The co-authors include faculty in the Johns Hopkins School of Medicine and collaborating scientists at the National Institute on Aging Intramural Research Program.

Co-author Brion Maher, Ph.D., a geneticist and professor in the Bloomberg School's Department of Mental Health, also analyzed the results for participants who had a common Alzheimer's risk factor, the Ɛ4 variant of the apolipoprotein-E (ApoE) gene. The link between positive antibody count and cognitive status was present in both the Ɛ4 and non-Ɛ4 groups, but was stronger in the non-Ɛ4 group.

"That was a surprise, finding a weaker link in the Ɛ4 group," says Maher. "It's something that should be followed up with larger studies."

Spira, Maher, and their team, with funding from the National Institute on Aging, are following up with analyses of the Baltimore ECA data from the 2016 to 2022 wave. The researchers will also be collecting another round of data from this cohort.

"Association of Common Infections with Cognitive Performance in the Baltimore Epidemiologic Catchment Area Study Follow-Up" was co-authored by Alexandra Wennberg, Brion Maher, Jill Rabinowitz, Calliope Holingue, Ross Felder, Jonathan Wells, Cynthia Munro, Constantine Lyketsos, William Eaton, Keenan Walker, Nan-ping Weng, Luigi Ferrucci, Robert Yolken and Adam P. Spira.

Funding was provided by the National Institute on Aging (R01AG075996, U01AG052445), the National Institute of Mental Health (MH 47447), and the Stanley Medical Research Institute.

Author’s Disclosures: Wennberg receives payment from Janssen Pharmaceutica NV for a separate collaboration. Spira received payment for serving as a consultant for Merck and he received honoraria from Springer Nature Switzerland AG for guest editing special issues of Current Sleep Medicine Reports.