Fig. 1: Study design.
a, BLSA participants were classified according to the presence or absence of infection diagnoses using ICD-9 codes collected at study visits as early as 1958. Repeated 3T MRI scans were initiated in 2009–2010. Blood samples were collected at the initial 3T MRI scan and, for a subset of participants, at the time of a first PET scan as part of a separate study. b, Analyses examined how infection diagnoses are associated with brain volume changes over time and an immunological plasma proteome in the BLSA, as well as 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). c, Candidate proteins were selected if they were associated with an 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. d, Candidate proteins were related to longitudinal performance across five cognitive domains (the BLSA), cross-sectional performance across five cognitive domains (the GenS study), dementia risk (the ARIC study), and ADRD biomarkers (Aβ42/40, GFAP, NfL, pTau-181; the BLSA and the ARIC study). e, Genetic variants that influenced candidate protein levels were associated with changes in brain volumes in the BLSA and an external cohort (the ENIGMA consortium). f, The 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.
