Infection Plus Pollution Equals Increased Alzheimer’s Risk

The combination of a history of infections and exposure to traffic-related air pollution increased the risk for Alzheimer’s disease (AD) by 177% in adults aged 60-75 years, based on data from approximately 100,000 individuals.

A growing evidence base suggests that vulnerability to infections plays a role in the development of AD, but the mechanism of action remains unclear, said Svetlana V. Ukraintseva, PhD, a professor of research on the biodemography of aging at Duke University, Durham, North Carolina, and colleagues in a poster presented at the Gerontological Society of America annual meeting. 

“My view on Alzheimer’s disease is that it is a ‘multi-hit’ disorder that requires not one but several risk factors to ‘hit’ an individual for AD to develop to clinical stage,” Ukraintseva said in an interview. 

The AD risk factors/hits include high exposure to traffic-related air pollution (TRAP) and infections, as well as factors such as hypertension, depression, sleep disorders, brain trauma, and also genes and their components, including APOE4 and the single nucleotide polymorphism rs6859, she said.

In a previous study, the researchers found a significant synergistic effect of TRAP and APOE4 on hippocampal volume, a biomarker for neurodegeneration, Ukraintseva told Medscape Medical News. “We decided, as the next step, to evaluate the joint effect of high exposure to TRAP and infections (another AD risk factor) on AD,” she said.

In the current study, the researchers examined risk factors that could synergistically increase AD risk and predict AD clinical onset with more than 80% probability, Ukraintseva said. Identifying combinations of risk factors is important for AD prevention, because targeting multiple risk factors at once in the same individual at the preclinical stage may potentially prevent clinical onset of AD in most cases, she explained. 

The researchers used data from the UK Biobank for 51,079 women and 48,983 men, aged 60-75 years, for whom data on infectious diseases, AD, and other dementias were available. High exposure to TRAP was defined as having a primary residence 50 meters or less from a major road. 

Overall, the presence of both a history of infections and exposure to TRAP was associated with 164% higher risk for AD onset after age 75 years, compared with individuals with neither infection history nor TRAP exposure (risk ratio, 2.64). 

Potential mechanisms driving the association include compromised integrity of the blood-brain barrier as a result of TRAP, which might make the brain more vulnerable to infections and related damage, the researchers noted in their poster.

Given their previous data on the multi-hit concept of AD risk, the current findings were not unexpected, Ukraintseva told Medscape Medical News.

“Targeting several AD risk factors simultaneously in the same individual may potentially prevent most cases of AD clinical onset, especially if these factors synergistically increase AD risk,” Ukraintseva said. “More research is needed in this direction, which is currently underexplored,” she said, and she and her team plan to explore the impact of other combinations of risk factors on clinical onset of AD, she added. 

Focus on Prevention Strategies and Stronger Studies

AD prevention remains a key strategy, given the limited treatment options and absence of cures, said Ryan T. Demmer, PhD, MPH, professor of epidemiology at the Mayo Clinic, Rochester, Minnesota, in an interview. 

“There is strong evidence implicating severe infections in the etiology of AD,” said Demmer. “The premise for air pollution to have adverse effects on multiple organ systems is also strong, and there is substantial evidence linking TRAP to cardiovascular disease and diabetes, both of which are linked to increased risk of dementias,” he said. 

Demmer was “somewhat surprised” by the strength of the associations in the current study, given the high degree of measurement error in measuring air pollution and infection, which often reduces the findings toward weaker or no association. 

Limitations of the current study include the use of ICD codes alone to define infections, which can contribute to measurement error, Demmer said. If doctors suspect infection, patients may be classified that way even if further examination showed that no infection was present, he noted. “There is also a potential for measurement error that occurs differentially among people at higher vs lower risk for AD development,” Demmer said. “Older individuals with more risk factors for AD might be more likely to seek medical attention for mild infections and have the ICD code documented in their medical record, while younger, healthier people may be less likely to seek care,” he said. 

In addition, “the air pollution information is based on address, but people spend different amounts of time at the home address, which creates a lot of bias in terms of how much exposure they have to air pollution in their community,” Demmer noted. “Confounding is also a concern in this study; common causes of infections and AD, such as health behaviors or comorbidities, might explain the association, and it doesn’t appear that these factors were accounted for,” he said. 

Additional research is needed to determine causality of the relationships among air pollution, infections, and AD, Demmer told Medscape Medical News. “A few examples include studies that can more robustly measure potential confounders, more carefully measure infectious disease and air pollution history, and/or directly investigate underlying biological mechanisms,” he said.

Although the lack of causality limits the impact of the study findings on clinical practice at present, “there is little downside in recommending that patients take precautions to prevent severe infections and minimize exposure to air pollution,” Demmer added.

The study was supported by the National Institute on Aging of the National Institutes of Health. The researchers had no financial conflicts to disclose. Demmer had no financial conflicts to disclose.