Fig. 2: Annual changes in brain volumes and dementia risk associated with infections.

a–f, Forest plots showing the associations of brain volume loss over time with influenza (a), HHVs (b), miscellaneous viral infections (c), URTIs (d), LRTIs, (e) and skin and subcutaneous infections (f) in the BLSA. Adjusted differences in annual changes of standardized brain volumes associated with a history of a given infection (β) were derived from linear mixed-effect models (n = 982) adjusted for intracranial volume, baseline age, sex, race, education, APOEε4, a comorbidity index (that is, obesity, hypertension, diabetes, cancer, ischemic heart disease, chronic heart failure, chronic kidney disease and chronic obstructive pulmonary disease) and two-way interactions of covariates with time. Pink squares reflect statistically significant associations. The AD signature region was the combined volume of the hippocampus, parahippocampal gyrus, entorhinal cortex, posterior cingulate gyrus, precuneus and cuneus. g,h, Additional forest plots showing the associations of infections with risk of all-cause dementia, AD dementia and VaD in the UK Biobank (g) and the Finnish multicohort sample (h; the FPS study, the HeSSup study and the STW study) after excluding dementia cases documented within 1 year postinfection. Columns report frequencies of the total sample, individuals exposed to a given infection and individuals diagnosed with dementia. Filled-in shapes reflect statistically significant associations. Data are presented as hazard ratios (HRs) and 95% confidence intervals (CIs). N/A indicates insufficient sample size to assess dementia risk. Adjusted differences in dementia risk associated with history of a given infection were derived from Cox proportional hazards regression models adjusted for age, sex and socioeconomic status. All-cause dementia included participants with a diagnosis of AD dementia, VaD, Parkinson’s disease dementia, frontotemporal dementia and other, less common dementia diagnoses (for example, unspecified dementia). Statistical significance was defined at a two-sided P < 0.05 without adjustment for multiple comparisons. The exact P values are presented in the source data files of Supplementary Tables 4, 7 and 9. AD sig, AD signature; exp., exposed; dem, dementia.