The role of chronic migraine as an early biomarker of Alzheimer's Disease

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

Project Summary / Abstract Alzheimer’s Disease (AD) is a devastating neurodegenerative disease characterized behaviorally by memory loss typically later in life and is ultimately fatal. Early detection of potential AD biomarkers in asymptomatic patients will promote disease prevention strategies. Migraine disorder is a disabling chronic disease condition that affects over 15% of the general population. Clinical reports show that AD is prevalent in individuals with a history of migraine, and that the incidence of AD is significantly higher in those that suffer from migraine at a younger age. There is a lot of overlap in the CNS neuroinflammatory pathways involved in the pathogenesis of both migraine disorders and AD, however, a mechanistic and behavioral understanding of the molecular contributors to migraine-induced AD remains unknown. A major barrier to progress is that the AD field has not reverse translated this increased AD incidence in migraine patients to preclinical animal models. Here, we show that transgenic AD mice exposed to chronic migraine via a series of injections with the migraine-causing drug, Nitroglycerin, don’t learn as well as non-migraine AD mice during a cognitive task. Additionally, we show increased amyloid accumulation in the brains of AD mice treated with Nitroglycerin. The central hypothesis of this proposal is that chronic migraine accelerates the development of AD pathology and associated cognitive decline in preclinical AD mouse models. In Aim 1, we will determine how chronic migraine affects multiple domains of cognition in a preclinical mouse model of AD. We will utilize an identical test that is currently used in the clinic to diagnose AD. In Aim 2, we will work with the IUSM Biomarkers Core to run spatial transcriptomics and proteomics in order to determine whether migraine progresses the activation of particular gene and protein expression patterns known to be altered in AD transgenic mice. We will measure key pathological features of both AD and migraine including amyloid plaques, multiple forms of tau, and CNS inflammatory markers in hippocampus, an area of the brain known for its role in spatial learning and memory processes. In both Aims, we will assess for potential sex differences. Indeed, female patients with a history of migraine have a much higher risk of developing AD compared to age-matched males. This area of research is highly novel to the AD field in that we are the first to reverse translate the increased human AD incidence in chronic migraine sufferers to preclinical animal models and the first to identify overlapping transcriptome and proteome targets associated with both diseases. Based on the spatial-omics data collected here, we will have the necessary rationale in our future R01 application to determine whether targeting various proteome biomarkers restores cellular function in various regions of the brain including hippocampus, frontal cortex, and in areas of the brain that greatly contribute to the onset of migraine and AD pathology including the locus coeruleus. A large percentage of the human population suffer from migraine disorders and will greatly benefit from this area of work that will allow for us to identify early biomarkers of AD in chronic migraine sufferers.