Alzheimer’s disease (AD) is a devastating disease for which current therapeutics are only marginally successful. Clinical studies estimate that 12% of United States citizens 65 yrs. and older suffer from Alzheimer’s dementia and 34% of those over age 85 have the disease. Collateral consequences of the disease include approximately 15 billion hours of annual non-professional caregiving — a tremendous societal stress — and a fiscal burden estimated in 2022 at 0.6 trillion dollars in the United States alone. Without mitigation, AD prevalence will rise substantially as the majority of the baby-boom generation enters the over-65 age category.

     Our group has discovered a target protein that simultaneously controls several major molecular AD determinants and has developed novel drugs that bind and regulate the target. This proposal will test the efficacy of the target and drugs in mice that exhibit humanized forms of the disease.

     The molecular etiology of AD is complex and not fully understood. It is generally agreed that dysregulated cholesterol metabolism and chronic neuroinflammation are fundamental contributors to the initiation and progression of the disease. In the brain, cholesterol metabolism is regulated by the Liver-X-Receptor (LXR). Drugs that bind and activate LXR substantially slow disease progression and recover short-term memory in AD-mice. Unfortunately, they cause severe fatty liver and cannot be used therapeutically. Our strategy circumvents the liver and should thus allow LXR to re-emerge as a viable AD target. In cell-based assays our compounds potently suppress the inflammation response, substantially reduce major molecular AD determinants, Ab-plaque and tau-fibrils, and stimulate Ab-plaque consumption.

     Current FDA-approved AD drugs are mono-therapeutics that solely target Ab-plaques. The multifaceted metabolic approach outlined herein promises a single small-molecule therapeutic that will slow and potentially reverse the symptoms of this pernicious disease.