Hyperlipidemias: Blennow K

Höglund K, Blennow K. · Department of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry at the Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. · CNS Drugs. · Pubmed #17521225 No free full text.

Abstract: To date, a number of hypotheses of the cause of Alzheimer's disease, the most common form of dementia, have been postulated. The beta-amyloid peptide (Abeta) is the major constituent of senile plaques, which together with atrophy and neurofibrillary tangles, is the main neuropathological finding in Alzheimer's disease. It is a widely accepted theory that aggregation of Abeta into plaques is an initial event in the pathogenesis of Alzheimer's disease, driving neurodegeneration. The cholesterol hypothesis, primarily based on in vitro and animal studies, states that increased levels of cholesterol promote the production of Abeta. Furthermore, treating animals with HMG-CoA reductase inhibitors ('statins'; cholesterol-lowering agents), or adding these agents to cell culture, results in decreased production of Abeta. This 'positive' effect of statin treatment has further been verified by some, but not all, longitudinal studies where a reduced prevalence of Alzheimer's disease is seen among patients taking statins. These findings have together been interpreted to indicate that statins act via a cholesterol-dependent mechanism, reducing the production of Abeta and, hence, the risk of developing Alzheimer's disease.This review focuses on the cholesterol hypothesis of Alzheimer's disease and investigations into its validity in the clinical setting, i.e. the outcome of clinical trials where the effect of statin treatment on Abeta production has been studied. To date, the cholesterol hypothesis has not been shown to be valid in clinical trials. We hypothesise that the vascular contributions in Alzheimer's disease may be one possible mechanism for statins to interfere with the disease process and reduce the prevalence of Alzheimer's disease. We also suggest that statins may act through the inflammatory pathway. Both of these mechanistic suggestions are good candidates, supported by the literature, for the underlying mechanistic link between statin treatment and a reduced prevalence for Alzheimer's disease.

Sjögren M, Blennow K. · Section of Experimental Geriatrics, Neurotec, Karolinska Institute KFC, Novum Plan 4, SE-14186 Huddinge, Sweden. · World J Biol Psychiatry. · Pubmed #16156481 No free full text.

Abstract: A leading hypothesis on the pathophysiology of Alzheimer's disease (AD) is the mis-metabolism of amyloid precursor protein. This mis-metabolism causes the 42-amino acid form of A beta(Abeta42) to form oligomers that in turn start a chain of events leading to the accumulation of amyloid plaques. Vascular factors such as hypertension, hypercholesterolemia and diabetes as well as the inheritance of the epsilon4 allele of the ApoE gene are risk factors for AD. These risks are thought to promote the production of beta-amyloid (Abeta). An association between cholesterol and the development of AD was suggested in 1994 and since then, research has confirmed a link between cholesterol and the development of AD. A high cholesterol level in mid-life is a risk for AD and statins i.e. cholesterol-lowering drugs, reduce this risk. Statins inhibit enzymes involved in the endogenous synthesis of cholesterol and evidence is mounting that they also affect enzymes in Abeta metabolism i.e. beta-secretase. This normalises the breakdown of the precursor of Abeta, amyloid precursor protein, thereby promoting the nonamyloidogenic pathway. This review focusses on the link between cholesterol and Alzheimer's disease.

Höglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K. · Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg, Sweden. · Arch Neurol. · Pubmed #15023808 links to  free full text

Abstract: BACKGROUND: Epidemiological studies suggest that statins reduce the risk of developing Alzheimer disease. Cell and animal experiments have revealed a connection between cholesterol metabolism and the processing of amyloid precursor protein. To our knowledge, the mechanism for statins in risk reduction of Alzheimer disease is unknown. OBJECTIVE: To test the effect of statin treatment on beta-amyloid (A beta) metabolism in humans. DESIGN: A prospective, randomized, dose-finding 36-week treatment trial with statins. Plasma samples were taken at baseline (week 0) and at weeks 6, 12, and 36. SETTING: Outpatient clinical study at a university hospital. PATIENTS: Thirty-nine patients who met the criteria for hypercholesterolemia. INTERVENTIONS: Patients were randomized to oral treatment with either simvastatin or atorvastatin calcium according to the following regimen: simvastatin, 40 mg/d, or atorvastatin, 20 mg/d, for 6 weeks; followed by simvastatin, 80 mg/d, or atorvastatin, 40 mg/d, for 6 weeks; and finally, simvastatin, 80 mg/d, or atorvastatin, 80 mg/d, for 24 weeks. MAIN OUTCOME MEASURES: Plasma levels of A beta(1-40) and A beta(1-42) were measured using 2 enzyme-linked immunosorbent assays, and total A beta was quantified by Western blotting. RESULTS: Treatment with both statins reduced total plasma cholesterol levels by 56% (P =.00). The plasma levels of A beta(1-40), A beta(1-42), and total A beta were stable in individual patients during the treatment period. No significant change in the level of A beta(1-40), A beta(1-42), or total A beta was found. CONCLUSION: This study questions the effect of statins on the processing of amyloid precursor protein in humans.