Infections and immune-specific proteins may increase dementia risk and brain atrophy

Infections and varying levels of immune-specific proteins may contribute to increased dementia risk and brain volume loss in older adults, according to a team led by NIA scientists. While other researchers have found a link between infections and cognitive decline, this study identified the proteins involved and used a genetics tool to support the protein connection between infection, dementia risk, and neurodegeneration. The findings, published in Nature Aging, suggest that a range of infections are associated with an elevated risk of dementia and increased brain atrophy.

Infections can promote the development of dementia and other negative neurocognitive outcomes (lower arrow) and can directly lead to brain atrophy and neurodegeneration (upper arrows). Illustration courtesy of Michael Duggan.

Several earlier studies have described an association between infections and a negative impact on brain health. One of those studies was the result of research conducted by NIH Center for Alzheimer's and Related Dementias (CARD) scientists. The CARD team used data from European biobanks and found links between viral exposures and neurodegeneration.

This new study takes that work one step further, looking at infections from influenza, herpes, and other viruses, as well as bacterial and fungal infections in the upper respiratory and urinary tracts and skin. After separating plasma from approximately 1,200 blood samples obtained via the Baltimore Longitudinal Study of Aging (BLSA), the researchers measured more than 7,000 proteins in plasma. They then used magnetic resonance imaging to conduct brain scans on nearly 1,000 of those BLSA participants. The team processed the data using a new technique called Mendelian randomization, an analysis that uses statistical genetics to estimate a cause for a particular outcome.

The scientists identified 35 immune-specific proteins that correlated with infection history and predicted patterns of brain atrophy that were specific to infections. Further investigation revealed that individuals who'd had infections on average 16 years earlier still had higher levels of damaging proteins and lower levels of protective proteins circulating in their bodies.

The authors note this research seems to challenge current thinking about the origins of dementia. Rather than infections leading to the production of detrimental proteins and increased dementia risk, the research suggests that infections are more associated with lower levels of protective proteins. Additional research is necessary to determine how low levels of these beneficial proteins may make some people more susceptible to dementia and cognitive decline.

The scientists theorize that genetic variability could provide the backdrop for infection susceptibility and altered protein regulation, both of which can contribute to dementia risk and brain atrophy. They suggest that older adults obtain and stay current with recommended vaccinations, which can prevent some individuals from developing certain diseases, and may help promote optimal brain health.

This research was supported in part by NIA grants RF1AG054409, ZIAAG000935, ZIAAG000949, R01AG059716, R00AG070109, R01AG056477, and R00AG052830.

NIA leads NIH's systematic planning, development, and implementation of research milestones to achieve the goal of effectively treating and preventing Alzheimer's and related dementias. This research relates to NIH's AD+ADRD Research Implementation Milestone 2.L, "Advance basic research on the common and interacting risk factors and mechanisms of multiple etiology cognitive impairment and dementia in diverse populations."

Reference: Duggan MR, et al. Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline. Nature Aging. 2024;4(9):1263-1278. doi: 10.1038/s43587-024-00682-4.

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