Clarifying the interplay between herpesvirus infection and reactivation, immune responses, APOE genotype, and development of tau-pathology
openNIA - National Institute on Aging
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.
Up to $3.3M
health research