Statins may slow dementia in Alzheimer's disease.
Dr. Samuel E. Gandy cautioned against prescribing statins widely to prevent or treat Alzheimer's disease. The findings of Dr. Li and associates "are pathological correlations that support what has been reported in several epidemiologic studies, but they do not substitute for a randomized, placebo-controlled, double-blind clinical trial.
"Such a trial is in progress and results are expected next year," said Dr. Gandy, who is director of the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, and a spokesman for the Alzheimer's Association.
In their report, Dr. Li and her associates noted that myriad processes underlie the development of dementia, and it has also become apparent that clinical diagnosis may be insufficient for the identification of risk and protective factors. In a new study, therefore, the association of statin use and the specific neuropathologic outcomes associated with Alzheimer's disease (AD)--neurofibrillary tangles and neuritic plaques--were evaluated in patients who underwent brain autopsy.
Subjects in the study were drawn from the larger prospective Adult Changes in Thought (ACT) study, which included 3,392 cognitively normal persons aged 65 and older from the Group Health Cooperative of Puget Sound, beginning in 1994.
By July 2006, 608 members of the cohort had died, and 110 had granted consent for neuropathologic examination and brain autopsy. Of these 110 subjects, 36 had received prescriptions for statin drugs and were more often male, smokers, dyslipidemic, and more likely to have cardiovascular disease or diabetes than were statin nonusers. The incidence of all-cause dementia did not differ between the groups (Neurology 2007;69:878-85).
Statin users had more severe vascular pathologic findings overall, including cystic infarcts, microvascular lesions, and more severe atherosclerosis. However, they had a lower burden of the specifically AD-associated neurofibrillary tangles and neuritic plaques.
After researchers controlled for factors such as age at death, gender, and presence of cerebral microinfarcts, statin users had significantly decreased odds of being at a higher stage on the Braak AD staging scale, with a more than twofold reduction in the risk for each one-unit increase on the scale.
In discussing their findings, the investigators noted that increasing epidemiologic evidence links cardiovascular risk factors, including hypercholesterolemia, with AD. One explanation, they said, could be that "comorbid vascular disease reduces the threshold for clinical expression of dementia with a given level of AD-related pathology." But they cautioned that it has not yet been established whether vascular disease "causes, exacerbates, or just coexists with AD pathology."
As to the possible mechanisms by which statins might influence the progression of AD-type neuropathologic changes, they explained that early animal and in vitro findings suggested that high levels of cholesterol in the brain could alter amyloid precursor protein processing. Clinical trials in humans, however, found no reliable evidence of changes in this protein or in the resulting accumulation of [beta]-amyloid (Ann. Neurol. 2002;52:346-50).
Subsequent investigations showed that statins can inhibit tau phosphorylation through mechanisms including blockage of the amyloid cascade and through antiinflammatory effects. Dr. Li and her colleagues have demonstrated that 14 weeks of treatment with simvastatin, which has marked CNS penetration, reduced levels of tau protein phosphorylation at threonine position 181 in the cerebrospinal fluid of hypercholesteremic subjects (J. Alzheimer's Dis. 2006;10:399-406).
The investigators said the fact that some studies have found benefits for statins while others have not, supports the hypothesis "that statins slow the progression of one or more neurodegenerative processes leading to the development of clinical AD but may not be able to reverse neuronal degeneration once it has occurred."
Dr. Li said in an interview that more research must be done before statin therapy can be recommended for either the prevention or treatment of AD.
BY NANCY WALSH
New York Bureau
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|Title Annotation:||Across Specialties|
|Publication:||Clinical Psychiatry News|
|Article Type:||Clinical report|
|Date:||Oct 1, 2007|
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