# Modulation of TNFα as a Treatment for Alzheimer's Disease and Related Dementia > **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $469,306 ## Abstract TITLE: Modulation of TNFα as a Treatment for Alzheimer’s Disease and Related Dementia ABSTRACT Growing evidence suggest a major determinant of age-related cognitive impairment, and associated dementia, is cerebral insulin dependent diabetes and vascular health. While Alzheimer’s disease (AD) is the most common form of dementia, and is characterized by amyloid plaques and TAU pathology, clinical trials targeting these pathologies have not been successful. Studies show AD cases are comorbid with diabetes and cerebrovascular pathology. Under normal physiology, insulin mediates glucose transport into the cell via the glucose transporter; however, in pathophysiological conditions, the insulin receptor signal becomes desensitized, resulting in metabolic dysfunction. Comorbid with these changes are cerebrovascular pathologies, which manifest as reduced blood flow, strokes, and micro-infarcts. Despite these observations, few clinical trials have studied brain insulin dependent hypometabolism and associated vascular dysfunction. We, and others, believe that metabolic and vascular dysregulation can be considered initiators of a spectrum of dementias that share common pathways of activation. Improving or preserving metabolism and cerebrovascular health through aging may reduce risk or prevent cognitive impairment and dementia. We hypothesize that modulating the Tumor Necrosis Factor alpha (TNFα) pathway will preserve cerebral metabolism and maintain vascular and health. The TNFα pathway is a key regulator in immune signaling, which has been shown to increase with age. Moreover, recent studies have shown that TNFα mediated action via the TNFα receptors (TNFR1 and TNFR2) is implicated in the glycolytic and vascular dysregulation observed with advancing age and dementia. Previous work in our lab has identified that mice carrying APOEE4/E4 show uncoupling of perfusion and glucose metabolism with age, similar to the phenotype also reported in the human patient population. Therefore, this grant will use mice carrying APOEE4/E4, and we will modulate TNFα signaling through two different approaches. In Aim 1, we will determine whether the APOEE3/E4 variant show similar neurovascular dysfunction as APOEE4/E4, as this is more common in the human population. If so, we will utilize this for all subsequent aims. We will then use timed ablation of TNFα through the use of a newly developed B6.TNFαflox/flox mouse paired with a tamoxifen inducible cre, CAGGCre- ER (JAX stock #004682) to determine if global genetic TNFα ablation leads to preservation of cerebrovascular function. This will be assessed using highly translational clinical measure such as PET/CT. Blood and tissue will be collected for biochemical and molecular analyses. In Aim 2, we will take a complementary interventional approach using R-7050 as a tool compound to elucidate the role of TNFR1 signaling in metabolic and vascular dysfunction by disrupting TNFR1-TRADD-RIP1 signal transduction. Combined these data w... ## Key facts - **NIH application ID:** 10511026 - **Project number:** 1R21AG078575-01 - **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS - **Principal Investigator:** Gareth R Howell - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $469,306 - **Award type:** 1 - **Project period:** 2022-08-20 → 2025-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10511026 ## Citation > US National Institutes of Health, RePORTER application 10511026, Modulation of TNFα as a Treatment for Alzheimer's Disease and Related Dementia (1R21AG078575-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10511026. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*