Alzheimer's Disease: Genes, pathogenesis and risk prediction

With the aging of western society the contribution to morbidity of diseases of the elderly, such as dementia, will increase exponentially. Thorough preventative and curative strategies are needed to constrain the increasing prevalence of these disabling diseases. Better understanding of the pathogenesis of disease will enable development of therapy, prevention and the identification of high-risk groups in the population. Here, we review the genetic epidemiology of Alzheimer's disease, the most common cause of dementia in the western world. The search for genetic risk factors, though far from completed, has been of major importance for understanding the pathogenesis of Alzheimer's disease. Although effective therapy is still awaited, these findings have led to new avenues for the development of drugs

Risk factors for Alzheimer's disease : a genetic-epidemiologic study

The work presented in this thesis has been motivated by the Jack of knowledge of risk factors for Alzheimer's disease. It has been long recognised that genetic factors are implicated, in particular in early-onset Alzheimer's disease.4 But to what extent are genetic factors involved? Are all cases with Alzheimer's disease of genetic origin or is the disease in some cases primarily of envîronmental origin? If the latter is true, which envîronmental factors may lead to Alzheimer's disease and how do these factors interact with the genetic component? The research described in this thesis aimed at resolvîng these questions. The studies of Alzheimt;;r's disease presented bere have started very much from an epidemiologie point of view. Yet, the issues addressed in this thesis required methodologie and analytic techniques of the field of genetics. The schools of thought of bath epidemiology and genetics are also reflected in the design of the various studies on which this thesis is based. Same studies follow the traditional epidemiologie design as they deal with camparisans of cases and controls. Other are more compatible with genetic studies as relatives of cases and controls are the subject of investigation

Serum levels of interleukin-6 are not elevated in patients with Alzheimer's disease

Serum levels of interleukin-6 (IL-6) were determined in 97 patients with clinically diagnosed Alzheimer's disease and 79 age- and sex-matched control subject. Median serum levels of IL-6 did not differ significantly between Alzheimer patients (8.6 U/ml) and controls (8.2 U/ml). Median levels of serum IL-6 were similar for sporadic and familial patients. The concentration of IL-6 was not associated with the severity of the dementia or the duration of the disease since first symptoms. According to these observations there is no evidence for a significant elevation in serum IL-6 in Alzheimer's disease

Infiltration in porous media with dynamic capillary pressure : travelling waves

We consider a model for non-static groundwater flow where the saturation-pressure relation is extended by a dynamic term. This approach together with a convective term due to gravity, results in a pseudo-parabolic Burgers type equation. We give a rigorous study of global travelling wave solutions, with emphasis on the role played by the dynamic term and the appearance of fronts

Infiltration in porous media with dynamic capillary pressure: travelling waves

We consider a model for non-static groundwater flow where the saturation-pressure relation is extended by a dynamic term. This approach together with a convective term due to gravity, results in a pseudo-parabolic Burgers type equation. We give a rigorous study of global travelling wave solutions, with emphasis on the role played by the dynamic term and the appearance of fronts

A polymorphic CA repeat in the promoter region of the insulin-like growth factor-I (IGF-I) gene

Commentar

Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study

BACKGROUND AND PURPOSE: Microangiopathy-related cerebral damage (MARCD) is a common finding in the elderly. It may lead to cognitive impairment and gait disturbances. Arterial hypertension and age are the most important risk factors. We assessed the association between MARCD and sequence alterations in the promoter region of the angiotensinogen (AGT) gene. METHODS: We studied 410 randomly selected community-dwelling individuals aged 50 to 75 years. MARCD was defined as early confluent or confluent white matter hyperintensities or lacunes on a 1.5-T MRI. The AGT promoter was analyzed by temporal temperature gradient gel electrophoresis and automated sequencing. RESULTS: We detected 4 polymorphic sites, at positions -6, -20, -153, and -218. They created 5 haplotypes, which we coded as A (-6:g, -20:a, -153:g, -218g), B (-6:a, -20:c, -153:g, -218:g), C (-6:a, -20:c, -153:a, -218:g), D (-6:a, -20:a, -153:g, -218:g), and E (-6:a, -20:a, -153:g, -218:a). MARCD was seen in 7 subjects (63.6%) carrying 2 copies of the B haplotype (B/B), in 12 subjects (38.7%) carrying 1 copy of the B haplotype in the absence of the A haplotype (B+/A-), but in only 70 subjects (19.0%) in the remaining cohort (P:<0.001). The odds ratios for the B/B and the B+/A- genotypes were 8.0 (95% CI, 2.1 to 31.1; P:=0.003) and 1.8 (95% CI, 0.8 to 4.2; P:=0.14) after adjustment for possible confounders. CONCLUSIONS: The B haplotype of the AGT promoter in the absence of the wild-type A haplotype might represent a genetic susceptibility factor for MARCD

Variance heterogeneity analysis for detection of potentially interacting genetic loci: Method and its limitations

Background: Presence of interaction between a genotype and certain factor in determination of a trait's value, it is expected that the trait's variance is increased in the group of subjects having this genotype. Thus, test of heterogeneity of variances can be used as a test to screen for potentially interacting single-nucleotide polymorphisms (SNPs). In this work, we evaluated statistical properties of variance heterogeneity analysis in respect to the detection of potentially interacting SNPs in a case when an interaction variable is unknown.Results: Through simulations, we investigated type I error for Bartlett's test, Bartlett's test with prior rank transformation of a tr

Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family

Background: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. Objective: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations. Methods: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls. Results: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8–2.4), p = 0.31). Conclusion: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk