A prospective study of viral infections and subsequent risk of Alzheimer’s disease

SUMMARY The prevalence of Alzheimer’s disease (AD), the most common form of dementia, is expected to triple and reach 13 million in the United States by the year 2050. Despite the public health burden of dementia on an aging population, the etiology of AD is still not well-understood. The interplay between the human virome—the total collection of viruses in and on the human body—and host immunity is linked to complex diseases, including AD. Evidence suggests that viral infectious pathogens, such as certain herpesviruses, promote the development of AD. However, methodological limitations of the relevant epidemiologic studies include: 1) reverse causality due to cross-sectional or retrospective case-control study design or consideration of viral infections in elderly participants; 2) underdiagnoses of infections due to detection of clinically apparent infections only; 3) confounding due to unmeasured infections; 4) lack of consideration of joint or interacting effects of multiple infections; and 5) lack of consideration of potential intermediate phenotypes, such as changes in brain and cognitive health, AD-related biomarkers, and DNA methylation patterns related to accelerated aging. The limitations of these studies render interpretation of their findings difficult, presenting an important research gap we propose to address. Recently developed high-throughput methods enable detection of immune responses to all human viruses. However, no studies conducted comprehensive analysis of antiviral antibodies in human sera for AD-related outcomes. We propose a prospective study that uses three prospective cohorts to identify viral infections associated with brain health, cognition declines, and the risk of AD later in life. We will use VirScan, a revolutionary new technology that uses bacteriophage immunoprecipitation sequencing (PhIP-Seq) for comprehensive serologic profiling of exposure history to all known human viruses. Our pilot work shows viral signatures are stable over time, supporting one-time measurement for long-term analysis. Our prospective case- control study of AD nested in the NYU Women’s Health Study (NYUWHS), a prospective cohort of 14,273 women (ages 35–65) who were enrolled between 1985–1991 and donated blood samples at baseline, will assess both: 1) responses to viral infections in relation to AD risk, and 2) whether viral infections are associated with epigenetic age acceleration and AD-related biomarkers. We will use the Cognitive Reserve (CR) study and the Reference Ability Neural Network (RANN) study, which share 529 healthy participants recruited since 2011 across the adult lifespan, to assess responses to viral infections in relation to longitudinal averages and changes in AD biomarkers, as well as brain and cognitive health measured using magnetic resonance imaging and neuropsychological tests. Our findings promise to discover emerging risk factors for AD, improve risk stratification, direct earlier intervention, and open new areas for prevention.