Atherosclerosis Supplements 9 (2008) 19–25 Chylomicron amyloid-beta in the aetiology of Alzheimer’s disease R. Takechi, S. Galloway, M.M.S. Pallebage-Gamarallage, J.C.L. Mamo ∗ Faculty of Health Sciences, Curtin University of Technology, ATN Centre for Metabolic Health and Fitness, Building 400, Bentley Campus, Perth, Western Australia 6102, Australia Received 31 January 2008; received in revised form 12 March 2008; accepted 13 May 2008 Abstract Alzheimer’s disease is characterized by inflammatory proteinaceous deposits comprised principally of the protein amyloid-beta (A). Presently, the origins of cerebral amyloid deposits are controversial, though pivotal for the prevention of Alzheimer’s disease. Recent evidence suggests that in blood, A may serve as a regulating apoprotein of the triglyceride-rich-lipoproteins and we have found that the synthesis of A in enterocytes and thereafter secretion as part of the chylomicron cascade is regulated by dietary fats. It is our contention that chronically elevated plasma levels of A in response to diets rich in saturated fats may lead to disturbances within the cerebrovasculature and exaggerated blood-to-brain delivery of circulating A, thereby exacerbating amyloidosis. Consistent with this hypothesis we show that enterocytic A is increased concomitant with apolipoprotein B48. Furthermore, cerebral extravasation of immunoglobulin G, a surrogate marker of plasma proteins is observed in a murine model of Alzheimer’s disease maintained on a saturated-fat diet and there is diminished expression of occludin within the cerebrovasculature, an endothelial tight junction protein. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Chylomicrons; Amyloid-beta; Alzheimer’s disease; Blood–brain barrier 1. Cerebrovascular integrity in Alzheimer’s disease Based on epidemiologic studies, there are statistically sig- nificant correlations between the prevalence of Alzheimer’s disease (AD) and diabetes, hypercholesterolemia, hyper- tension, hyperhomocysteinemia, dietary saturated fats, cholesterol, antioxidants, alcohol consumption, smoking, physical activity, atherosclerotic disease, and the plasma con- centration of some hemostatic factors. Most of the risk factors found to be associated with AD are age-dependent, and the prevalence of AD increases with age. Therefore, the associ- ation could simply be attributed to aging. On the other hand, common pathogenetic mechanisms for diseases such as AD and atherosclerosis, such as inflammation and the generation of free radicals, suggest a causal link. If this is the case, the identification of modifiable risk factors for dementia becomes a research priority and early intervention aimed at reducing those risk factors by therapeutic imperative. An accumulating body of evidence is consistent with the concept that the onset and progression of sporadic ∗ Corresponding author. Tel.: +61 8 92667232; fax: +61 8 92662258. E-mail address: J.Mamo@Curtin.edu.au (J.C.L. Mamo). and late-onset AD is significantly influenced by lifestyle factors including nutrition. Several population studies in humans have found that high-fat diets are a positive risk factor [1,2], and high-fat feeding markedly exacerbates Alzheimer’s-like cerebral pathology in animal models of AD [3,4]. The mechanisms for the high-fat diet/AD link are presently unclear, but we will present in this article a novel hypothesis that may explain this effect. We contend that further studies are urgently needed to delineate the rela- tionship between diet and AD. Indeed, by 2030 the expected global health burden for dementia will exceed treatment of cancers by 30% and will be equivalent to the combined costs for the prevention and treatment of cardiovascular dis- ease. The cerebrovasculature in subjects with AD shows patho- logical alterations including vascular endothelial and smooth muscle cell proliferation [5]. Blood plasma proteins have been detected in the parenchyma of AD brains [6,7] and inflammatory sequelae are commonly reported [8,9], obser- vations that are consistent with breakdown of the blood–brain barrier (BBB). Despite the increasing evidence supportive of AD having an underlying vascular component, most research focuses on damage of neurons [10]. 1567-5688/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosissup.2008.05.010