APOE and cholesterol homeostasis in Alzheimer’s disease Vale ´ rie Leduc 1 , Ste ´ phanie Jasmin-Be ´ langer 1 and Judes Poirier 1, 2 1 Douglas Mental Health University Institute, 6875 Lasalle, Montreal (Verdun), Quebec, H4H 1R3, Canada 2 Center for Studies in Aging, McGill University, Verdun, Quebec, H4H 1R3, Canada Converging evidence from clinical and pathological stu- dies indicate the presence of important relationships between the ongoing deterioration of brain lipid homeo- stasis, vascular changes and the pathophysiology of sporadic Alzheimer’s disease (AD). These associations include the recognition of cholesterol transporters apo- lipoprotein E (APOE), APOC1 and APOJ as major genetic risk factors for common AD and observations associat- ing risk factors for cardiovascular disease such as high midlife plasma cholesterol, diabetes, stroke, obesity and hypertension to dementia. Moreover, recent clinical find- ings lend support to the notion that progressive deterioration of cholesterol homeostasis in AD is a central player in the disease pathophysiology and is, therefore, a potential therapeutic target for disease prevention. Alzheimer’s disease and cholesterol homeostasis Dementias are progressive neurodegenerative disorders characterized by a decline in cognitive functions beyond what might be expected from normal aging. Of these dementias, Alzheimer’s disease (AD) is the most common type among the elderly accounting for approximately 60% of all dementia cases diagnosed [1]. Pathologically, AD is characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (Box 1) as well as extensive neuronal and synaptic losses [2]. Although gradual atrophy of the brain is observed, degeneration occurs preferentially in neuronal populations of cholinergic phenotype [3]. There are several reasons why these particular neurons might be more vulnerable to AD, notably their high-energy requirement, their reliance on axonal transport for sustained function and trophic sup- port, and their large and poorly protected (sparsely mye- linated) cell surface area that increases their exposure to toxic environmental conditions and oxidative stresses [3,4]. Accordingly, neuronal loss usually starts in brain structures rich in long cholinergic fibers, that is the entorh- inal cortex and hippocampus of the limbic system, spreads to the temporal lobe, then to the frontal cortex and ulti- mately to primary sensory and visual areas [3,4]. Etiologically, AD is considered a multifactorial disease with a strong genetic component. The disease can be sub- divided into two distinct categories, the so-called familial and sporadic forms of the disease. The identification of specific gene mutations has provided new insight into the molecular changes responsible for the pathophysiological processes of AD. Mutations in the genes encoding the amyloid precursor protein (APP), presenilin 1 and prese- nilin 2 associate with rare early-onset forms of familial AD [5]. However, coding mutations in these genes do not increase the risk of the more prevalent late-onset disease, which accounts for more than 95% of all AD cases world- wide [1]. APOE is the only known locus that affects the risk of the late-onset form of the disease, with the e4 allele (encoding apolipoprotein 4, APOE4) and the e2 allele (encoding APOE2) increasing and decreasing the risk level, respectively [6,7]. Recently, several independent genome- wide association studies (GWAS) in homogeneous and heterogeneous populations of AD with age-matched control cases in North America, Europe and Asia associated the e4 allele with AD [8–12]. Surprisingly, the remaining genetic associations uncovered in these GWAS failed to replicate across studies, except for the gene encoding APOJ, which is an accessory protein to APOE in the maintenance of cho- lesterol homeostasis. APOE coordinates the mobilization and redistribution of cholesterol in repair, growth and maintenance of myelin and neuronal membranes during development or after injury in the peripheral nervous system [13,14]. In the central nervous system (CNS), APOE in partnership with APOJ and APOC1 plays a pivotal role in cholesterol deliv- ery during the membrane remodeling associated with synaptic turnover and dendritic reorganization [15,16]. The near complete absence of other key plasma apolipo- proteins such as APOA1 and APOB in the brain further emphasizes the critical and unique role of APOE for cho- lesterol transport in the normal or injured CNS. Cardiovascular contributions to AD pathology The prevalence and incidence of degenerative and vascular dementias increase almost exponentially with age, from 70 years onward. In view of the increasing longevity of humans, both types of dementia have progressively evolved into major public health problems worldwide [17]. The integrity of the cerebral vasculature is crucial for the maintenance of cognitive function; vascular factors, such as hypertension, myocardial infarction, diabetes, obesity, hyper- or dyslipidemia, ischemic white matter lesions and generalized atherosclerosis, associate with dementia and cognitive decline [18]. The connection be- tween vascular factors and cognition remain largely unknown, although recent evidence associates the e4 allele with regional cerebral blood flow (rCBF) disturbances in regions of the brain affected by AD [19]. Indeed, apparently Review Corresponding author: Poirier, J. (judes.poirier@mcgill.ca) 1471-4914/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2010.07.008 Trends in Molecular Medicine, October 2010, Vol. 16, No. 10 469