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. 2024 Mar;20(3):2128-2142.
doi: 10.1002/alz.13613. Epub 2024 Jan 22.

Common infections and neuroimaging markers of dementia in three UK cohort studies

Rebecca E Green  1 , Carole H Sudre  1   2   3   4 , Charlotte Warren-Gash  5 , Julia Butt  6 , Tim Waterboer  6 , Alun D Hughes  1 , Jonathan M Schott  2 , Marcus Richards  1 , Nish Chaturvedi  1 , Dylan M Williams  1
Affiliations

Common infections and neuroimaging markers of dementia in three UK cohort studies

Rebecca E Green et al. Alzheimers Dement. 2024 Mar.

Abstract

Introduction: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies.

Methods: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain = 2632; NAPOE-interaction = 1810).

Results: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β = -3.89 mL [-5.81, -1.97], Padjusted < 0.05); these were largely attenuated in fully adjusted models (β = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed.

Discussion: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Keywords: Alzheimer's disease; cerebral small vessel disease; common infections; dementia; multiplex serology; pathogen burden.

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Conflict of interest statement

J.M.S. has received research funding and PET tracers from AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Alliance Medical; has consulted for Roche, Eli Lilly, Biogen, AVID, Merck, and GE; and received royalties from Oxford University Press and Henry Stewart Talks. He is Chief Medical Officer for Alzheimer's Research UK. N.C. receives funds from AstraZeneca for serving on data safety and monitoring committees for clinical trials of glucose lowering agents. R.E.G., C.H.S., C.W.G., J.B., T.W., A.D.H., M.R., D.M.W. report no competing interests. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Study workflow. APOE, apolipoprotein E genotype; BMI, body mass index; MFI, median fluorescence intensity; MRC NSHD, Medical Research Council National Survey of Health and Development; PBI, pathogen burden index; SABRE, Southall and Brent Revisited; UKB, UK Biobank.
FIGURE 2
FIGURE 2
Forest plot indicating meta‐analyzed associations of pathogen serostatus (A) and burden scores (B) with neuroimaging outcomes. Positive estimates indicate larger brain and hippocampal volumes, but more white matter lesions. For pathogen burden analyses, estimates represent the change in outcome per 0.1 unit increase in pathogen burden (proportion of pathogens or neurotropic pathogens seropositive to). Model 1 included adjustments for total intracranial volume and other technical covariates; model 2 additionally for age, sex, and ethnicity; and model 3 additionally for BMI, smoking status, educational attainment, socioeconomic position, and alcohol intake. Statistical models are indicated by color, and significance threshold by shape. Pathogen families are further indicated on the right‐hand side of the figure. BK, BK virus; BMI, body mass index; CI, confidence interval; CMV, cytomegalovirus; EBV, Epstein–Barr virus; HHV, human herpesvirus; HPV, human papillomavirus; HSV, herpes simplex virus; JC, John Cunningham virus; KSHV, Kaposi's sarcoma–associated herpesviruses; MCV, Merkel cell virus; PBI, pathogen burden index; VZV, varicella zoster virus.
FIGURE 3
FIGURE 3
Forest plot indicating meta‐analyzed results between seroreactivity tertiles and neuroimaging outcomes. Positive estimates indicate larger brain and hippocampal volumes, but more white matter lesions. Model 1 included adjustments for total intracranial volume and other technical covariates; model 2 additionally for age, sex, and ethnicity; and model 3 additionally for BMI, smoking status, educational attainment, socioeconomic position, and alcohol intake. Statistical models are indicated by color, and significance threshold by shape. Pathogens and specific antigens (in brackets) are indicated on the y‐axis, with pathogen families further indicated on the right‐hand side of the figure. Antigens selected at random from a larger pool of recommended antigens for the pathogen are indicated by an asterisk. BK, BK virus; BMI, body mass index; CI, confidence interval; CMV, cytomegalovirus; EBV, Epstein–Barr virus; HHV, human herpesvirus; HPV, human papillomavirus; HSV, herpes simplex virus; JC, John Cunningham virus; MCV, Merkel cell virus; VZV, varicella zoster virus.
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