Proteomics identifies immunological drivers of post‐infection brain atrophy and cognitive decline

Abstract

AbstractBackgroundPrior infections can modify the risk for dementia and neurodegenerative disease, yet the mechanisms by which infections contribute to neurodegeneration remain unclear.MethodWe examined how infection diagnoses documented in the Baltimore Longitudinal Study of Aging (BLSA) are associated with rates of change in brain volumes over time, and how these same infections relate to dementia risk using hospital records from UK Biobank and a Finnish multicohort sample (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study). After determining how infections differentially relate to an immunological plasma proteome (942 proteins) in BLSA participants, we then identified a subset of infection‐related proteins that also predict changes in brain regions vulnerable to infection‐specific atrophy (candidate proteins). In addition to evaluating their associations with longitudinal cognitive performance as well as Alzheimer’s disease and related dementias (ADRD) plasma biomarkers (Aβ42/40, GFAP, NfL, pTau‐181), we also investigated the causal link between candidate proteins and longitudinal brain volume loss using Mendelian randomization. Study design is illustrated in Figure 1.ResultA total of 982 cognitively normal participants (age: 65.4 [SD 14.9]); 55.2% female; 66.9% white) were included in the primary MRI analysis. Of the 15 infections examined, we identified six diagnoses related to accelerated brain volume loss, including influenza, viral, respiratory, and skin/subcutaneous infections, with atrophy commonly observed in the temporal lobe. Each infection linked to brain volume loss in the BLSA was associated with increased risk of dementia in the UK Biobank (n = 495,896), with many also associated with increased risk in the Finnish multicohort sample (n = 273,132). From a set of 260 infection‐related proteins, we identified 35 candidate proteins that also predicted changes in brain regions vulnerable to infection‐specific atrophy (Figure 2A‐F). Many candidate proteins were related to cognitive decline, plasma ADRD biomarkers or mechanistically implicated in longitudinal brain volume loss in Mendelian randomization analyses (Figure 2G‐H; Figure 3A).ConclusionWe demonstrate that infections are linked to accelerated regional brain atrophy and dementia risk. Additionally, we identify molecular mediators by which infections may contribute to neurodegeneration (Figure 3B).