Statin treatment and beta-Amyloid Production in Patients with Alzheimer s Disease

Abstract

Alzheimer s disease (AD) is a progressive neurodegenerative disorder pathologically characterized by neurofibrillary tangles and amyloid plaques. According to the amyloid cascade hypothesis, the increased production of beta-amyloid (Abeta), derived form the amyloid precursor protein (APP), and its aggregation into plaques are key pathological events, driving neurodegeneration in AD. This hypothesis is primarily based on disease causing mutations found in familial forms of AD. The sporadic form of AD represents the vast majority of all AD cases. The cause of overproduction of Abeta in the sporadic form of AD, whether there is any, is not known. Epidemiological, clinical and experimental evidence suggests a link between cholesterol and sporadic AD. The hypothesis for the mechanistic link suggests that cholesterol-lowering treatment using statins reduces cholesterol content of cellular membranes. Thereby the non-amyloidogenic pathway, i.e. decreased Abeta production, is supported. The overall aim of this thesis was to evaluate whether cholesterol lowering treatment using statins has any effect on Abeta production in human beings. Efficacy parameters analyzed were markers for cholesterol homeostasis, including cholesterol, lathosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol, and APP metabolism, including alpha-cleaved soluble APP (alphasAPP), betasAPP and total APP. The thesis includes four open clinical studies where we hypothesize that statin treatment will affect cerebrospinal fluid (CSF) and plasma levels of Abeta, and also a fifth exploratory study trying to advance the cholesterol hypothesis by elucidating whether there are alternative mechanisms underlying the link between statins and reduced prevalence of AD. Despite reduced levels of total cholesterol and LDL cholesterol after 12-36 weeks of statin treatment, no effect on Abeta levels were found. After a prolonged treatment period to 12 months, brain cholesterol synthesis was demonstrated to be reduced, but no effect was seen on levels of Abeta1-40/42 in CSF or plasma. This absence of effect on Abeta was further demonstrated when additional Abeta peptides were analyzed, truncated at the C-terminal Abeta1-37/38 and 39. These findings suggest that the cholesterol dependent mechanism for statins in risk-reduction of AD does not seem to affect Abeta production. However, statins have been reported to have other, pleiotropic, effects which are neuroprotective, in addition to inhibiting cholesterol synthesis. In paper V statin treatment was found to produce a significant change in the CSF levels of 44 proteins. Multivariate analyses revealed eight protein changes which, together, provided the best separation of samples taken at baseline and endpoint. One of these proteins, found to be increased after statin treatment, was identified as C3 anaphylatoxin (C3a), a component of the complement system. In conclusion, this thesis does not support the cholesterol hypothesis demonstrated in experimental studies, as valid in patients. We suggest that the anti-inflammatory effect of statin treatment may be part of the underlying link between statin treatment and reduced prevalence of AD.