Increasing numbers of positive antibody tests for comorbid infections with cytomegalovirus (CMV), herpes simplex virus (HSV-1), Toxoplasma gondii (TOX), varicella zoster virus (VZV), and Epstein-Barr virus (EBV) are significantly associated with reduced global cognitive functioning in adults. Examined individually, positive antibody tests for HSV-1 and CMV will possibly reduce cognitive functioning. These study findings were published in Alzheimer’s & Dementia.

Current evidence suggests a possible increased risk and causal role of common infections in the development of Alzheimer disease and related dementias (ADRD). Investigators sought to examine the link between positive antibody tests for CMV, HSV-1, TOX, VZV, and EBV with cognitive functioning.

They used data from the population-based cohort Baltimore Epidemiologic Catchment Area Study that included 575 adults (aged 41 to 97 years) and a systematic literature review of the PubMed database to conduct a cross-sectional study exploring the possibility of individual or multiple common infections linking CMV, HSV-1, TOX, VZV, and EBV with cognitive functioning. The Baltimore Epidemiologic Catchment Area Study used the Mini-Mental State Examination (MMSE) and a word list learning and memory task to assess cognitive functioning.

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The Baltimore Epidemiologic Catchment Area Study was conducted in 5 waves spanning 1982 to 2022, and the current investigation used data from the fourth wave conducted from 2003 to 2004 with 1071 participants (63% women; 62% White, 35% Black). Current investigators found complete data for infection, genetic, and cognitive function for 575/1071 participants (aged 58.7±12.5 years). They compared demographic covariates (sex, age, race, years of education) and the apolipoprotein E (APOE) ε4 (carrier vs noncarrier) genotype with the number of antibody tests that were positive (0-5).

Positive antibody tests (EBV, 79.3%; VZV, 70.2%; HSV-1, 68.5%; CMV, 67.5%; TOX, 24.7%) revealed 84.9% of participants had 2, 3, or 4 positive tests. Only 7 participants (1.2%) had 0 and 33 participants (5.7%) had 1 positive test. There were 47 participants (8.2%) with all 5 positive tests. Investigators noted men were slightly more likely to have 0 or 1 infection and women were significantly more likely to have multiple infections as were non-White participants (all P <.001). Older individuals were more likely to have multiple infections vs younger participants as were those with a lower level of education (all P <.001). APOE ε4 carrier status showed no difference according to the number of antibody tests that were positive (P =.1495).

The investigators found that an increasing number of comorbid positive antibody tests for CMV, HSV-1, TOX, VZV, and EBV were significantly associated with reduced MMSE scores (P =.001). The learning and memory test showed a nonstatistically significant trend for this association (P =.079). Lone positive antibody tests for CMV and HSV-1 (P =.011 and P =.018), respectively, showed an individual link with reduced cognitive function (P =.011) in multivariable-adjusted 0-inflated Poisson regression models. These results suggest that positive antibodies to multiple infections with CMV, HSV-1, TOX, VZV, and EBV vs individual infections are associated with reduced cognitive function.

Although sex, age, and race were associated with reduced cognitive function for both tests, there was no statistical evidence of interactions (sex, Pvalue for interaction =.926; age, Pvalue for interaction =.552; race, Pvalue for interaction =.238).

Study limitations include the cross-sectional design of the study, underpowerment for analysis of effect modification and confounding, and cognition only measured at 1 point in time.

In their examination of the association between CMV, HSV-1, TOX, VZV, and EBV with cognitive function, the investigators concluded “After adjusting for potential confounders, a greater number of positive antibody tests for these common infections was significantly associated with poorer global cognitive performance, measured by the MMSE, and we observed a trend toward an association with poorer delayed verbal recall.” They added, “Where individual infectious agents were concerned, positive antibody tests for CMV and HSV-1 were associated with poorer performance on the MMSE.” Investigators believe their findings suggest individual infections have an additive effect on cognitive function. They wrote, “We did not observe evidence of effect modification by sex, age, or race; however, there was a potential interaction by APOE ε4 genotype, with a stronger association between a greater number of infections and worse MMSE performance among ε4 noncarriers than among carriers.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Wennberg AM, Maher BS, Rabinowitz JA, et al. Association of common infections with cognitive performance in the Baltimore Epidemiologic Catchment Area study follow-upAlzheimers Dement. Published online April 7, 2023. doi:10.1002/alz.13070

This article originally appeared on Psychiatry Advisor