Midlife obesity and prediabetes trigger later life cognitive decline through central nervous system inflammaging and innate immune dysregulation of cGAS/STING

The size of the aging population is reaching record levels worldwide, causing a parallel increase in the number of individuals with cognitive impairment and dementia, including Alzheimer’s Disease and Alzheimer’s Disease- Related Dementias (AD/ADRD).

Multiple factors predispose individuals to the development of cognitive impairment and dementia, including obesity, the metabolic syndrome, prediabetes, and diabetes, whose rates are also growing worldwide.

With few to no available treatments, research is critical to understand the mechanisms by which these metabolic dysfunctions promote cognitive impairment and AD/ADRD with aging, especially during early phases of metabolic imbalance, such as in midlife obesity and in prediabetes before progression to frank diabetes.

Inflammation is a common denominator across aging, obesity, prediabetes, diabetes, and cognitive impairment, including in AD/ADRD.

Inflammatory mechanisms may play a particularly important role by promoting early or increased inflammaging, a chronic low-grade inflammation.

One particular innate inflammatory mechanism that may be contributing to inflammaging is the double-stranded DNA (dsDNA) sensing cGAS/STING pathway. cGAS/STING is dysregulated in peripheral tissues in obesity, the metabolic syndrome, prediabetes, and diabetes.

This pathway responds to cytosolic dsDNA from bacteria or viruses or released as a result of nuclear or mitochondrial stress and upregulates pro-inflammatory cytokines.

We hypothesize that dyslipidemia and insulin resistance during the progression of obesity and prediabetes trigger inflammatory pathways, including cGAS/STING, that exacerbate and transmit inflammatory signals within the central nervous system (CNS).

We also anticipate that as the primary immune cells of the CNS, microglia mediate this inflammatory transmission, in part via extracellular vesicle inflammatory crosstalk, further worsening neurologic and cognitive outcomes.

We will test our hypothesis by: 1) establish the role of cGAS/STING and the inflammatory milieu during the progression of midlife to later life obesity- and prediabetes-induced cognitive impairment, 2) determine the role of microglial cGAS/STING in HFD-induced cognitive impairment in mid and later life, and 3) investigate extracellular vesicle mediated cGAS/STING inflammatory crosstalk mechanisms in the CNS in obesity- and prediabetes-induced cognitive impairment during aging.

This study will establish how inflammation and the cGAS/STING pathway fluctuate during aging as obesity and prediabetes progress, and how they contribute to cognitive impairment that overtime leads to AD/ADRD.

Additionally, the study will identify disease-modifying targets and, perhaps more importantly, ideal therapeutic windows for these potential therapies for early intervention and the prevention of AD/ADRD.