Current research shows that men and women with elevated levels of cholesterol in midlife are at increased risk of developing Alzheimerâ€™s disease (AD) decades later. High cholesterol may promote the development of AD through a variety of mechanisms, including via its negative effects on metabolism of the protein beta amyloid (A-beta) in the brain and on cerebrovascular functioning. Both A-beta deposition in the brain and cerebrovascular dysfunction are associated with preclinical AD and work synergistically to accelerate neuronal degeneration. Thus, therapeutic interventions that both reduce A-beta levels and improve cerebral blood flow (CBF) may interrupt this cascade effect to delay the development of AD pathology. Statins, a group of cholesterol-lowering medications, have been associated with both favorable changes in A-beta levels and improved CBF. Most importantly, investigative treatment with statins has shown up to a 73% reduction in the prevalence of AD, suggesting a potentially promising role for statins in AD prevention. The SHARP study (â€œStatins in Healthy, At Risk Adults: Impact on Amyloid and Regional Perfusionâ€) will examine the effects of a specific statin, simvastatin, on A-beta metabolism and cerebral perfusion in adults at risk for AD. This 18-month randomized, controlled, double-blind pilot clinical trial will enroll 90 subjects with a parental history of AD and high APOE4 allele prevalence who already exhibit neurobiological changes suggestive of possible preclinical disease progression. The study will correlate these biological changes in cerebrospinal fluid (CSF) and MRI biomarkers with changes in cognitive test scores, thereby providing pivotal information concerning possible mechanisms underlying the potential efficacy of statins to reduce the risk for AD. MR imaging will be used to gather structural and perfusion data on all 90 subjects enrolled in the trial. This will provide novel data describing the integrated relationship between cerebral perfusion, A-beta metabolism, and cognition in middle-aged adults at high risk of developing AD and the effects of statin therapy on those integrated relationships.
July 2009 to December 2012
This project led by: Cynthia Carlsson MD