References for our review were identified by conducting a systematic PubMed search with the term “Alzheimer's disease” in combination with “apoE”, “cholesterol”, “statins”, “ABCA1”, “CYP46”, “LRP”, and “low density lipoprotein receptor-related protein” from January 1966 to March 2005. The initial search was done in March 2005, with further update in August 2005 during the revision of the review. We also searched references from selected publications, and referred to textbooks for basic
ReviewCholesterol in Alzheimer's disease
Introduction
Affecting up to 15 million individuals worldwide, Alzheimer's disease (AD) is the most common form of dementia. Prevalence doubles every 5 years in people over age 60 years, increasing from 1% among people age 60–64 years to 40% in those age 85 years and older;1 within ageing populations, prevalence may triple by 2050.2 In AD, there are characteristic abnormal protein aggregates in the brain with regional accumulation of hyperphosphorylated tau in neurofibrillary tangles and amyloid-β peptides (Aβ) in senile plaques, there is also progressive brain atrophy.
Community, clinic-based, and experimental studies have provided converging evidence for a link between AD and vascular injury in the brain. AD and vascular dementia, once seen as mutually exclusive disorders, are now recognised as coexisting processes that contribute to the expression of dementia.3 Recent evidence indicates a great overlap between the two disorders on the basis of risk factors, pathological hallmarks, and clinical symptoms.4, 5 Hypertension, history of stroke, diabetes mellitus, and hypercholesterolaemia are all associated with a high risk of AD.3, 6, 7, 8, 9, 10, 11 There is also a growing amount of evidence suggesting a connection between cholesterol metabolism and susceptibility to AD, as well as increased cholesterol release through synaptic degeneration.12, 13, 14, 15, 16, 17, 18, 19 The use of statins, a class of cholesterol-lowering drugs, has been variably reported to be associated with a low risk of AD.20, 21, 22, 23, 24, 25, 26, 27
In this review we provide a translational overview—from the bench to the clinic—on the role of cholesterol in the pathogenesis of AD and assess the potential of statins as a therapy to prevent and treat the disease.
Section snippets
Cholesterol metabolism in the brain
The brain is the most cholesterol-rich human organ. Cholesterol forms an essential component of cell membranes, and has a crucial role in development and maintenance of neuronal plasticity and function.28 The homoeostasis of cholesterol in the brain is maintained by a series of interdependent processes that include synthesis, storage, transport, and removal. Glial cells and neurons can synthesise cholesterol de novo, while cholesterol can also be recycled from extracellular locations within the
Aβ production
Cholesterol influences the activity of the enzymes involved in the metabolism of the amyloid precursor protein and in the production of Aβ. The post-translational cleavage of amyloid precursor protein by β and γ secretases, membrane associated proteins, results in amyloidogenic products that aggregate as extracellular plaques, whereas cleavage by α secretase results in non-amyloidogenic or soluble amyloid precursor protein. In animal studies, dietary cholesterol accelerates Aβ deposition in the
Diet
Over the past 15 years, several epidemiological studies have shown an association between high serum concentrations of cholesterol and an increased susceptibility to AD.13, 91, 92, 93 Furthermore, high plasma concentrations of cholesterol in midlife, as opposed to later life, may determine the risk of developing late onset AD.91, 93, 94 Consumption of unsaturated fatty acids, omega-3 polyunsaturated fatty acids from fish or vegetable sources, and low intake of hydrogenated fats might reduce the
Biochemistry and pharmacology
Statins are competitive inhibitors of HMG-CoAR, the key enzyme that regulates the synthesis of cholesterol in the step between HMG-CoA to mevalonate. The general chemical structure of statins includes three major components (figure 3). The variable side chain determines the solubility across the blood–brain barrier. Atorvastatin, lovastatin and simvastatin are lipophilic and cross into the brain readily, while cerivastatin, fluvastatin and pravastatin are hydrophilic and do not cross. An
Towards an integrated view
There is considerable converging evidence that cholesterol plays an important part in AD. In animal models, there are consistent data that high cholesterol diets are associated with a pathological accumulation of Aβ in the cortex. In cell culture studies the activities of β and γ secretases are modulated by cholesterol. Epidemiological studies and neuropathological investigations emphasise the shared risk factors and pathological overlap between cerebrovascular injury and AD. There is emerging
Search strategy and selection criteria
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