Infections drive brain volume loss and dementia risk by altering key immune proteins, study reveals

Study: Proteomics identifies potential immunological causes of brain atrophy and cognitive decline after infection. Image credits: Kateryna Kon / Shutterstock

This is evident from a recent study published in the journal Nature agingresearchers examined how past infections are linked to changes in brain volume and the risk of dementia.

Earlier diagnoses of serious infections are associated with a higher risk of neurodegenerative diseases and dementia. However, some of these associations did not remain statistically significant after adjusting for multiple comparisons, indicating that further research is needed to confirm these findings. Studies suggest that acute bacterial and viral infections may be associated with brain volume loss. Decreases in total brain volume and gray matter thickness have been observed following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, accelerated white matter atrophy has been observed after symptomatic herpes infections.

Systemic infections can influence the risk of dementia and neurodegeneration. Changes in circulating inflammatory proteins in response to immune challenges can impact brain health. Although selected immunological markers have been associated with preceding inflammatory events and subsequent cognitive performance, it is unclear how infections relate to various immunological proteins and which proteins predict atrophy-prone brain areas.

The research and findings

In the current study, researchers focused on identifying specific immunological proteins that predict changes in brain regions vulnerable to infection-related atrophy. Using data from the Baltimore Longitudinal Study of Aging, they examined changes in brain volume between people with and without a history of one of fifteen selected infections. A total of 982 cognitively normal individuals aged 65.4 years were included on average.

ABLSA participants were classified based on the presence or absence of infection diagnoses using ICD-9 codes collected during study visits as early as 1958. Repeated 3T MRI scans were initiated in 2009-2010. Blood samples were collected during the initial 3T MRI scan and, for a subset of participants, during an initial PET scan as part of a separate study. bAnalyzes examined how infection diagnoses are associated with changes in brain volume over time and an immunological plasma proteome in the BLSA, as well as the risk of all-cause dementia, AD dementia and VaD in the UK Biobank and a Finnish multicohort sample (the FPS study, the HeSSup study and the STW study). cCandidate proteins were selected if they were associated with infection and related to changes in brain regions vulnerable to infection-specific atrophy, and were defined as protective or pathogenic depending on whether they predicted preserved or reduced longitudinal brain volumes, respectively. DCandidate proteins were related to longitudinal performance in five cognitive domains (the BLSA), cross-sectional performance in five cognitive domains (the GenS study), dementia risk (the ARIC study), and ADRD biomarkers (Aβ_42/40GFAP, NfL, pTau-181; the BLSA and the ARIC study). eGenetic variants affecting the levels of candidate proteins were associated with changes in brain volumes in the BLSA and an external cohort (the ENIGMA consortium). FThe biological implications and functional relevance of candidate proteins were assessed using a variety of complementary analytical tools and open source databases. All panels were created with BioRender.

Of these, 67% were white and 55.2% were female. Approximately 43% of participants had no history of infection and more than 10% had at least two infection diagnoses. The regions of interest (ROIs) were the volumes of the lobar, white matter, gray matter, total brain, and characteristic regions of Alzheimer’s disease (AD). If a significant association was found between infection and ROI, follow-up analyzes on lobar gray/white matter were performed.

Six infections were associated with greater brain volume loss, especially in the temporal gray and white matter areas. These were influenza, infections with the human herpes virus (HHVs), infections of the lower (LRTIs) and upper (URTIs) respiratory tract, skin and subcutaneous infections and various viral infections. However, it should be noted that these associations were not statistically significant after applying a false discovery rate (FDR) correction, suggesting that these findings should be interpreted with caution. Furthermore, follow-up analyzes indicated that influenza-related brain volume loss was specific to the gray matter of the occipital and temporal lobe.

Herpetic infection-related reductions in white matter volumes were specific to the temporal lobe. Accelerated atrophy related to various viral infections occurred exclusively in the gray matter. URTIs were associated with accelerated loss in the temporal lobe, but were not specific to gray or white matter. LRTI-related volume loss in the temporal lobe was specific to the white matter, while in the occipital lobe loss was observed in the gray and white matter.

Gray matter atrophy associated with cutaneous and subcutaneous infections was specific to the occipital and temporal lobes. However, overall history of infections or number of infections did not show a statistically significant association with changes in brain volume after corrections. The number of infections or history of any infections was not associated with volume changes. The team then examined links between brain loss-related infections and the risk of all-cause dementia, AD and vascular (VaD) dementia using data from the United Kingdom Biobank. They found that the six infections were associated with a higher risk of all-cause dementia.

Five and four infections were associated with VaD and AD dementia, respectively. Notably, the risk was greatest for VaD, consistent with previous findings that immune changes following infection may contribute more strongly to cerebrovascular pathology.

The team then assessed the plasma immune-proteomic signature of brain atrophy-related infections. Influenza was found to be associated with the highest number of differentially expressed proteins (141), while various viral infections were associated with the fewest (21).

A total of 260 proteins were associated with at least one infection, and 38 with multiple infections. Of the 260 proteins, 35 were associated with changes in brain volume and were termed candidate proteins.

The (candidate) proteins were further defined as pathogenic or protective based on whether they reduced or preserved brain volume, respectively. Protective proteins were reduced in individuals with a history of infection, while pathogenic proteins were increased. Furthermore, the researchers examined whether candidate proteins were associated with cognitive performance.

Ten protective proteins were associated with preserved verbal memory performance, and some were associated with preserved verbal fluency or visuospatial performance. Four pathogenic proteins were associated with rapid performance declines. Interestingly, one pathogenic protein (CD27) was unexpectedly linked to preserved visuospatial abilities, highlighting the complexity of these associations.

The team then evaluated whether candidate proteins are related to AD and neurodegeneration plasma biomarkers.

Twelve protective proteins that decreased after infection were associated with significantly increased amyloid beta (Aβ)_42/40 ratio, and 11 were associated with phosphorylated Tau (pTau)-181. One pathogenic protein was associated with increased neurofilament light chain (NfL) and lower Aβ_42/40 ratio, and several others had negative associations with pTau-181 and NfL.

Finally, the team investigated whether genetic variants that affect the levels of candidate proteins are associated with changes in brain volume. They found that genetic variants linked to lower pathogenic protein levels were associated with preserved brain volumes, even in areas prone to atrophy. However, not all genetic variants were protective; some that reduced pathogenic protein levels were paradoxically associated with accelerated volume loss, indicating a complex relationship.

Conclusions

The study revealed how infections, such as LRTIs, URTIs, influenza, HHVs, skin and subcutaneous infections and various viral infections, are associated with increased brain atrophy and future risk of dementia. Although some associations did not hold after multiple testing corrections, the overall pattern suggests a link between infections and neurodegeneration. Thirty-five immunologically relevant plasma proteins were identified as differentially expressed after infection.

These proteins were related to changes in brain areas vulnerable to infection-specific atrophy. Some proteins were associated with cognitive decline and plasma biomarkers of neurodegeneration and AD pathology. Together, the findings support the role of infection in dementia risk and reveal the molecular mediators through which infections contribute to neurodegeneration. Further research is needed to fully understand these complex relationships and their implications for dementia risk.