In this sample of 2,956 nationally representative older adults in the US, positive toxoplasma gondii infection is independently associated with worse immediate and delayed verbal learning, language proficiency, executive functioning, processing speed, sustained attention, working memory, as well as global cognition. This relationship is independent of age, race/ethnicity, education, depressive symptoms, smoking status, BMI, prevalent CHD, stroke, and systolic blood pressure. Although our findings should be validated using longitudinal studies, they suggest that serum toxoplasma gondii seropositivity may be used as a biomarker of cognitive decline and preventing toxoplasma gondii infection a target of public health intervention to protect cognitive functioning in older adults. This is very important given the prevalence of toxoplasma gondii infection and the increasing population aging in the US.
A limited number of studies have examined the associations of toxoplasma gondii seropositivity with cognitive outcomes in humans. Two studies utilized the NHANES 1988–1994 cycle data and thus could not reflect the current epidemic of toxoplasma gondii infection (14, 15). In addition, one of them only included school-aged children (15). To the best of our knowledge, only two relevant studies exclusively targeted older adults (26, 27). In one study of 84 older adults aged 65 years and above in Germany, toxoplasmosis-positive participants showed impaired working memory, attention, and word fluency, but not processing speed measured by DSST, compared with those who were toxoplasmosis negative (26). It is important to note that the sample size of that study is very small. Then, in another study including older adults in the US, while no statistically significant association was found between toxoplasma gondii IgG levels and memory performance or attention, toxoplasma gondii IgG levels were inversely associated with global cognition measured by Mini-Mental State Examination (MMSE) (27). However, in that study, researchers did not adjust BMI, exercise, or depressive symptoms. In another longitudinal study targeting adults aged > 30 years with eleven years’ follow-up, researchers found no associations of toxoplasma gondii infections with verbal fluency and verbal learning assessed by CERAD (3). However, their study population was middle-aged, which was different from our participants. Overall, the findings of existing cross-sectional or longitudinal studies on this topic are inconsistent. Most of these studies were based on relatively small sample sizes, had methodological limitations, or targeted a different age group. However, in our study, we took advantage of a nationally representative, relatively large, and latest sample and calculated global cognition, adding stronger evidence on the negative relationship between toxoplasma gondii infection and cognitive functioning.
The possible mechanisms that account for the association between toxoplasmosis gondii infection and worse cognitive functioning are complicated. T gondii infection has been shown to increase dopamine release in vitro and animal trials (28–31). Excess dopamine turnover has been associated with worse cognitive decline (32–34). Dysregulated dopamine may influence neuronal plasticity in the hippocampus in humans, a brain region important for memory and spatial orientation (35, 36). In addition, as a defense mechanism against toxoplasma gondii infection, the host may rapidly catabolize tryptophan and produce more kynurenine and quinolinic acid (37). It is reported that higher levels of dopamine, kynurenine, and quinolinic acid were associated with increased neurotoxic effects and impulsive behavior incidence (38). Furthermore, toxoplasma gondii infection was associated with the dysbiosis of gut microbiota in mice, which may increase gut-blood-barrier permeability and induce mental disturbances and behavioral changes (39–41). Future studies are expected to explore the underlying mechanism.
The major strength of this study is the relatively large, nationally representative sample of older adults in the US. Stringent quality control and assurance measures were implemented throughout the NHANES study, including the rigorous assessment of toxoplasma gondii IgG and the adoption of validated cognitive tests to assess multiple cognitive functioning domains, therefore guaranteeing the quality of data used in this study. Moreover, a comprehensive list of sociodemographic, lifestyle, mental, and physical health covariates was adjusted, minimizing residual confounding. Thus, the findings of our study are generalizable to U.S. older adults. Importantly, the cognitive effects of toxoplasma gondii infection in humans are understudied in the literature. Thus, our study fills in a research gap. Last but not least, the findings of lower DSST score associated with toxoplasma gondii infection is important as previous studies have shown that lower DSST scores were independently associated with a higher risk of dementia (42, 43).
The major limitation of this study is the cross-sectional design which prevented us from examining whether participants had long-term exposure to toxoplasma gondii or a recent exposure where the IgG immune response to toxoplasma gondii had just started (4). Reverse causation is also possible. Additionally, research has revealed that specific genes affect susceptibility and immune response to toxoplasma gondii infection (44). However, our study did not assess any genetic factors. Finally, with three cognitive tests, we may not assess all domains of participants’ cognitive functioning. In addition, the excluded people (n = 516) were different from the included participants (n = 2,956) in many aspects; thus, selection bias is possible (45).
Future students are expected to 1) use more advanced methods for identifying specific strains and stages of toxoplasma gondii infection (46), 2) explore the pathophysiological mechanisms on the cognitive effects of toxoplasma gondii infection, 3) include non-western populations, and 4) utilize longitudinal designs to assess the temporal relationship between toxoplasma gondii infection and cognitive functioning. These studies may enable the identification of new biomarkers for cognitive decline and enlighten the development of toxoplasma gondii medications and vaccinations to protect people from the adverse effects of toxoplasma gondii infection.
In conclusion, toxoplasma gondii seropositivity is prevalent in U.S. older adults and is independently associated with worse immediate and delayed verbal learning, language proficiency, executive functioning, processing speed, sustained attention, working memory, as well as global cognition in this population. Future studies are expected to examine the longitudinal relationship and pathophysiological mechanism between toxoplasma gondii infection and cognitive functioning. Public health measures are needed to prevent toxoplasma gondii infection, which may help preserve cognitive functioning in older adults.