Clarifying the interplay between herpesvirus infection and reactivation, immune responses, APOE genotype, and development of tau-pathology

PROJECT SUMMARY/ABSTRACT The role of microbial infections in triggering Alzheimer's disease (AD) has gained increasing support. In several studies, specific viruses and bacteria capable of infecting the central nervous system (CNS) were found more frequently in AD patients, and recent discoveries link infections to key aspects of AD pathology. Recent findings suggest that antiviral drugs for herpes simplex virus 1 and vaccines for herpes zoster (shingles) may reduce the risk of AD, with studies showing up to 20% risk reduction. While these findings are intriguing, they have important limitations. Most notably, they are prone to reverse causation, as behavioral and pathological changes related to AD may increase susceptibility to CNS infections. Furthermore, most studies used traditional case-control designs, which are prone to bias due to convenience sampling of controls, and had insufficient follow-up to account for the long preclinical phase of AD. Most studies also used laboratory assays that cannot distinguish between important viruses or measure immune responses against these viruses. We will use a unique resource, the Nurses’ Health Study, a longitudinal cohort following over 100,000 women since 1976. It features detailed information on dietary and behavioral habits collected biennially during follow-up, critical for assessing and controlling potential sources of confounding. In our proposed study, we will analyze archived samples from 1,800 women, enriched for those with high-risk APOE genotypes and low cognitive scores, for tau-pathology using phosphorylated tau 217 (pTau-217), a biomarker whose abnormal results are now deemed sufficient to establish an AD diagnosis. In 300 women with the highest and 300 with the lowest levels of tau-pathology, we will analyze immune responses in samples collected 10 years earlier using the luciferase immunoprecipitation system (LIPS) and Nucleic Acid Programmable Protein Array (NAPPA). This will enable a longitudinal assessment of humoral immunity against 1,800 proteins mapping to 158 viruses and bacteria, including all herpesviruses, and subsequent development of tau-pathology. We will also assess the interplay between infections, APOE genotype, aging, and AD risk factors, which may inform underlying mechanisms. With our proposed project, we seek to transform our understanding of AD and contribute to the development of new treatment and prevention strategies. Our study represents the first comprehensive longitudinal investigation combining state-of-the-art biomarkers of infection exposure and AD pathology to determine whether and how infections trigger AD pathology before symptom onset. With our proposed project, we seek to transform our understanding of AD and contribute to the development of new treatment and prevention strategies.