Pilot Trial of Carvedilol in Alzheimer's Disease
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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and the cause of major burden for AD patients, caregivers, and the health care system. Current FDA-approved AD treatments have modest symptomatic effects at best and do not significantly modify disease course. In a population-based sample of incident AD, we observed that use of ¿-adrenergic antagonists was associated with slower functional decline. Our data combined with other epidemiologic data point to the potential therapeutic effect of ¿-adrenergic antagonists in patients with AD. This observation prompted us to screen ¿-adrenergic antagonists for effects on amyloid-¿ (A¿) synthesis in cell culture. One agent that passed the screen was carvedilol, a ¿-adrenergic antagonist FDA-approved for several cardiac indications. In two different transgenic mouse models of AD chronic oral administration of carvedilol decreased brain monomeric and oligomeric A¿ content, attenuated cognitive deterioration, and improved basal neuronal transmission in the brain. The effect on lowering A¿ oligomers is especially relevant, since there is growing evidence that these soluble oligomers (rather than the insoluble A¿ fibrils in plaques) disrupt synaptic transmission early in AD prior to neuronal loss. Thus, a treatment that lowers brain A¿ oligomer levels may be of particular benefit in early AD. Additionally, carvedilol may have a beneficial effect on vascular risk factors for AD by stabilizing blood pressure and improving brain perfusion, since it is an approved treatment for hypertension and congestive heart failure and has been shown to be neuroprotective in brain ischemia models. These preliminary data suggests that carvedilol may have a dual mechanism of action, by decreasing brain A¿ oligomer levels and by having a beneficial effect on cerebrovascular conditions. Since carvedilol is a generic drug, already FDA approved, with a well understood, generally well tolerated safety profile and if carvedilol has a beneficial effect in AD it offers the advantages of being relatively safe and inexpensive. For these reasons, we propose to administer a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6-month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Significance: The results of this proof-of-concept trial will underlie a "Go-No-Go" decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well tolerated safety profile and is available as a generic drug.
