HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease and why it would be ill-advise to use one that crosses the blood-brain barrier

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Increased circulating cholesterol has been long linked to an increased risk of coronary artery disease (CAD), and is now linked to an increased risk of developing Alzheimer's disease (AD). We first showed the neuropathologic link between CAD and AD as increased incidence of cerebral senile plaques in both disorders. We then showed that AD-like neuropathology occurred in the brains of cholesterol-fed rabbits; including increased β-amyloid (Ab). Currently there are a number of transgenic mouse models of AD that exhibit enhanced Ab pathology if cholesterol diet is administered. Culture studies clearly show that excess cholesterol enhances beta-metabolism of amyloid precursor protein (APP) and production of β-amyloidogenic peptides, and that sufficiently reducing cholesterol levels by inhibition of synthesis completely inhibits all beta-metabolism of APP. Our finding that the elevated levels of Ab in rabbits fed cholesterol diet could be cleared from the brain by resuming a control diet prompted the hypothesis that lowering cholesterol levels in the blood of AD patients may be of some clinical benefit. Pilot data suggests that therapeutically lowering circulating cholesterol may attenuate Ab production in the cholesterol-fed rabbit brain, may stabilize cognitive performance in mildly impaired AD patients, and may reduce the risk of developing AD. Accordingly, we have initiated a double-blind treatment trial evaluating Atorvastatin Na+ among 120 mild-to-moderately impaired AD subjects randomized to one of two groups receiving placebo or active drug once a day. Atorvastatin is one of a general class of HMG-CoA reductase inhibitor drugs called statins that lower cholesterol by inhibition of synthesis. We chose to use Atorvastatin in this AD Treatment Trial because it does not cross the blood-brain-barrier, and believe it would be ill-advised to use a statin that does. This position stems from the observations that excess cholesterol inhibits cholesterol synthesis and increases Ab production, that Ab kills cells in part by inhibiting cholesterol synthesis, and that statins acting at the neuronal level could further exacerbate degeneration in AD by further inhibition of necessary cholesterol synthesis.

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Journal of Nutrition, Health and Aging







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