Oxysterols and Alzheimer’s disease There is a clear link between cholesterol turnover and neurodegenerative diseases. Hypercholeste- rolemia is thus a risk factor for Alzheimer’s disease (AD) and there is a strong genetic link between this disease and one of the allelic forms of the choles- terol transporter apoE [for general reviews – see (1, 2)]. Generation of b-amyloid is regarded to be of key importance in the pathophysiology of the disease, and this generation is dependent upon the balance between cleavage of the amyloid precursor protein by the a- and the b-secretase, respectively. The latter cleavage, resulting in insoluble b-amyloid as an end product, is favoured in cholesterol-rich membranes. In contrast, the enzymes of the a-secretase pathway, leading to soluble products only, dominate in phospholipid rich areas and are inhibited by cholesterol. The relation between cholesterol turnover and development of AD suggests that pharmacological interventions which aim to decrease cholesterol levels in critical membranes of the central nervous system may be of value. Statin treatment appears to have a beneficial effect in a transgenic mouse model, and positive effects of such treatment have been reported in some but not all clinical studies (1–3). To which extent the statin-induced effects are direct or mediated by e.g. effects on cerebral endothelial cells is not yet clear. In the present review, we have focussed on the possible role of oxysterols in the development of AD. In contrast to unmetabolized cholesterol, these metabolites are able to pass the blood-brain barrier and we have shown that there is a continuous flux of such steroids in both directions. We speculate that these fluxes correspond to a Ôcross-talkÕ between cerebral and extracerebral cholesterol pools and the possibility is discussed that they may be of importance in the pathogenesis of AD. Review of literature Oxysterols – general properties Oxysterols are oxygenated derivatives of choles- terol that are important as intermediates or end Bjo¨rkhem I, Heverin M, Leoni V, Meaney S, Diczfalusy U. Oxysterols and Alzheimer’s disease. Acta Neurol Scand 2006: 114 (Suppl. 185): 43–49. Ó Blackwell Munksgaard 2006. There is a clear link between cholesterol turnover and neurodegenerative diseases and hypercholesterolemia is an established risk factor for Alzheimer’s disease (AD). The failure to demonstrate a transfer of cholesterol from the circulation into the brain in humans and experimental animals makes it difficult to explain the link between hypercholesterolemia and AD. In contrast to cholesterol itself, side- chain oxidized cholesterol metabolites such as 24S-hydroxycholesterol and 27-hydroxycholesterol are able to pass the blood–brain barrier (BBB). Formation of 24S-hydroxycholesterol is the quantitatively most important mechanism for elimination of cholesterol from the brain and we recently demonstrated a significant net uptake of 27- hydroxycholesterol by the brain from the circulation. We have also shown that patients with AD have increased brain levels of 27- hydroxycholesterol, which may affect the production of b-amyloid in the brain. The levels of 27-hydroxycholesterol in the circulation are correlated with the levels of cholesterol and the possibility must be considered that the flux of 27-hydroxycholesterol into the brain is the missing link between hypercholesterolemia and Alzheimer’s disease. Current knowledge about the role of the two oxysterols for cholesterol homeostasis in the brain as well as their diagnostic potential are reviewed. I. Bjçrkhem, M. Heverin, V. Leoni, S. Meaney, U. Diczfalusy Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Key words: Alzheimer's disease; blood–brain barrier; cholesterol; 27-hydroxycholesterol; oxysterols I. Bjçrkhem, Department of Laboratory Medicine, Divi- sion of Clinical Chemistry, Karolinska University Hospital – Huddinge, S-141 86 Huddinge, Sweden Tel.: 46 8 58581235 Fax: 46 8 58581260 e-mail: ingemar.bjçrkhem@karolinska.se Accepted for publication 16 April, 2006 Acta Neurol Scand 2006: 114 (Suppl. 185): 43–49 Copyright Ó Blackwell Munksgaard 2006 ACTA NEUROLOGICA SCANDINAVICA 43