Midlife circulating autoantibodies and the risk of Alzheimer’s disease in Women - SUMMARY Nearly two-thirds of the 6.9 million Americans age 65 and older with Alzheimer’s disease (AD) are women. Women are more prone to AD than men due to hormonal, reproductive, lifestyle, and other biological factors, even when accounting for their longer life expectancy. Regardless of age, females tend to have more B cells and higher immunoglobulin levels than males, and to develop more intense antibody responses. However, it remains unclear how components of the immune system are related to the risk of AD in women. Autoantibodies (AAbs) are antibodies generated against an individual’s own components (self-antigens), in contrast to those induced by exogenous antigens. Certain AAbs (natural AAbs) mediate first-line defense against pathogens, clearance of apoptotic debris, and suppression of inflammatory responses, and some other AAbs play pathogenic roles in the central nervous system. Animal studies suggest that elevated levels of certain AAbs precede brain plaque and tangle development. Epidemiologic studies link both autoimmune disease-associated AAbs and AAbs unrelated to autoimmune conditions to cognitive impairment and AD. However, limitations of these epidemiological studies include that they: 1) assessed only a few candidate AAbs; 2) included a limited number of cases (n = 10–50); and/or 3) were retrospective studies that collected blood samples after the onset of AD, so levels of AAbs in cases could have been influenced by treatments or presence of disease. Given that the long preclinical phase of AD often starts at midlife, it is crucial to identify midlife AD biomarkers of susceptibility to address the critical need for early risk stratification and to better understand the etiology of AD. However, most blood-based markers are typically measured in late life. There were no prospective studies on AAbs and AD risk, and no study examined the associations of AAbs in midlife with late-onset (after the age of 65) AD. Recent characterizations of AAb profiles identified an abundance of circulating AAbs in apparently healthy individuals by using innovative technologies that allow reproducible omics-scale measurements using low-volume serum samples. We will conduct a prospective case-control study nested in the NYU Women’s Health Study (NYUWHS), a prospective cohort of 14,273 women who provided blood samples at enrollment in 1985–1991 (ages 35–65), with > 2,000 AD cases identified through linkage to the Centers for Medicare & Medicaid Services (CMS) during follow-up. Using the HuProt Human Proteome microarray, which is the most comprehensive array to date (> 21,000 probes), we aim to: 1) discover AAbs associated with AD risk in 300 matched case-control pairs; 2) validate the identified AAbs in an independent set of 600 case-control pairs; and 3) develop and validate a classification model that integrates midlife reproductive factors, lifestyle factors, chronic diseases, sex hormone levels, validated and/or top AAbs, and other AD biomarkers and assess its discriminatory performance. Our findings promise to discover novel blood biomarkers for AD, improve risk stratification in women, and eventually suggest novel therapies.
