Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers.
Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-beta (Abeta) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Abeta and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment.
Serrano-Pozo
Alberto
A
Memory Disorders Unit, Department of Neurology and Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston , MA 02114, USA.
Vega
Gloria L
GL
Lütjohann
Dieter
D
Locascio
Joseph J
JJ
Tennis
Marsha K
MK
Deng
Amy
A
Atri
Alireza
A
Hyman
Bradley T
BT
Irizarry
Michael C
MC
Growdon
John H
JH
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood* / Q000134:cerebrospinal fluid*; D001921:Brain / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood; D006937:Hypercholesterolemia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage* / Q000009:adverse effects
D016229:Amyloid beta-Peptides; D000924:Anticholesteremic Agents; D015415:Biomarkers; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D002784:Cholesterol; D019821:Simvastatin
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