Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?

Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35.6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops.

Effects of a high-fat, high-cholesterol diet on brain lipid profiles in apolipoprotein E ε3 and ε4 knock-in mice.

Apolipoprotein E (ApoE) is important in facilitating the transport of lipids (cholesterol, phospholipids, and sulfatides) and plays a fundamental role in normal lipid metabolism. High cholesterol levels increases the risk of developing Alzheimer's disease. In this study, we investigated the effects of a high-fat high cholesterol (HFHC) diet on brain lipid profiles in 95 young and aged APOE ε3 and ε4 knock-in mice to determine whether diet leads to altered brain levels of a number of glycerophospholipids, sphingolipids, cholesterol precursors, cholesterol, cholesterol oxidation products, and cholesterol esters. The results in this study revealed significant changes in lipid levels. The HFHC-enriched diet influenced the levels of cholesterol esters. A sharp increase in cholesterol ester levels, particularly in the aged APOE ε4 diet-enriched group, might be suggestive of abnormal acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT) activity and/or levels. Age exerts appreciable effects on the brain lipidome, especially with regard to polar lipid species.

Associations of a novel IL4RA polymorphism, Ala57Thr, in Greenlander Inuit.

BACKGROUND: A novel IL4RA polymorphism, Ala57Thr, was identified in Greenlander Inuit. OBJECTIVE: We sought to determine whether the novel Thr57 allele is population specific and to assess the associations of Ala57Thr and Ile50Val with atopy in 2 Inuit populations. METHODS: Ala57Thr and Ile50Val were genotyped in 651 Inuit living in Denmark, 1295 Inuit living in Greenland, and 1329 individuals from 7 populations from widely differing global locations. In Inuit the polymorphisms were evaluated for associations with atopy, rhinitis, asthma, and pulmonary function. RESULTS: Thr57 was in linkage disequilibrium with Ile50 (D' = 1, r(2) = 0.13) and was common (33%) in the Inuit but rare (<0.6%) in all other populations. In Inuit living in Denmark, the Thr57 allele (in a dose-dependent manner) and the Ile50/Thr57 haplotype were associated with lower risk of atopy (P(linear) = .003 and P = .034, respectively), with similar trends observed for atopic rhinitis and atopic asthma. In Inuit living in Greenland, Thr57 was not associated with atopy or atopic diseases, but Ile50 was weakly associated with lower risk of atopy. CONCLUSION: The novel IL4RA Ala57Thr was common in and population specific to Greenlander Inuit, with Thr57 associated with a lower risk of atopy in those living in Denmark. Hence a full investigation of genotype-phenotype relationships in a given population can only be achieved if each gene is screened for novel polymorphisms in that population. CLINICAL IMPLICATIONS: Clinical risk attributable to variations in a gene in an ethnic group requires that all variations of the gene are known for that group.

Deletion Mutations in an Australian Series of HNPCC Patients.

Hereditary non polyposis colorectal cancer (HNPCC) is characterized by the presence of early onset colorectal cancer and other epithelial malignancies. The genetic basis of HNPCC is a deficiency in DNA mismatch repair, which manifests itself as DNA microsatellite instability in tumours. There are four genes involved in DNA mismatch repair that have been linked to HNPCC; these include hMSH2, hMLH1, hMSH6 and hPMS2. Of these four genes hMLH1 and hMSH2 account for the majority of families diagnosed with the disease. Notwithstanding, up to 40 percent of families do not appear to harbour a change in either hMSH2 or hMLH1 that can be detected using standard screening procedures such as direct DNA sequencing or a variety of methods all based on a heteroduplex analysis.In this report we have screened a series of 118 probands that all have the clinical diagnosis of HNPCC for medium to large deletions by the Multiplex Ligation-Dependent Probe Amplification assay (MLPA) to determine the frequency of this type of mutation. The results indicate that a significant proportion of Australian HNPCC patients harbour deletion or duplication mutations primarily in hMSH2 but also in hMLH1.