Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease

Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE ε4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD

Ubiquitin Carboxyl-Terminal Esterase LI (UCHLI) SI8Y Polymorphism in Patients with Cataracts

Background: Cataract is characterized by light-scattering protein aggregates. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a de-ubiquitinating enzyme wit

Alzheimer’s Disease: effect of Tau-related genes on the pathology, neurochemistry and risk of disease

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. The predominant sporadic form of AD is a genetically complex disorder probably involving a combination of genetic factors together with environmental influences. To date, the best established genetic risk factor identified is the APOE ε4 allele. However not all AD cases have the APOE ε4 allele, thus several susceptibility genes remain to be found. One of the characteristics of AD is the intraneuronal accumulation of neurofibrillary tangles (NFTs). NFTs are composed of a hyperphosphorylated form of the tau protein. Since tau pathology is a central and an important event in AD this thesis has focused on studying genes that are directly or indirectly related to tau and examine their effect on pathology, neurochemistry and risk of disease. In the first paper, we identified a single nucleotide polymorphism (SNP) in the cell division cycle (CDC2) gene. In AD brain, cdc2 is expressed in neurons and is involved in hyperphosphorylation of tau. The SNP was tested for association with sporadic AD. A significant association between both genotype and allele frequencies and AD was found. In next paper, we examined a SNP in the Saitohin (STH) gene, a gene located in on of the introns of the human TAU gene. Numerous SNPs span the human tau gene and are in complete linkage disequilibrium (LD) with each other yielding two separate haplotypes, H1 and H2. Patients with AD, FTD and PD and controls were genotyped for the STH SNP and/or the TAU haplotype. Genotype data were tested for their association to AD biomarkers in the cerebrospinal fluid (CSF) and to neuropathological scores of senile plaques. The STH SNP and the TAU haplotype were in complete LD in all patients (AD and FTD) and controls investigated for both genes. There were no significant differences in genotype or allele distributions in AD, FTD or PD patients compared to controls. Neither TAU haplotype nor STH influenced CSF biomarkers or neuropathological scores significantly. In next study, we followed up the findings from paper I and examined possible effects of the CDC2 SNP on CSF biomarkers and neuropathological scores in AD patients. The CDC2 I allele was associated with a gene dose-dependent increase of CSF total-tau levels. In conclusion, the results from paper I suggest a link between the CDC2 gene and AD. This is further supported by the findings from paper III, where we could provide evidence for an involvement of CDC2 in the pathogenesis of AD. We found no evidence that could support a major pathogenic role of STH and TAU haplotype in AD, FTD or PD in paper II

Primary Non-Adherence to Preventive Drugs and Associations with Beliefs About Medicines in Stroke Survivors

Background: Medication non-adherence is a common problem in clinical practice. Little is known about stroke survivors’ primary non-adherence to preventive drugs, and we hypothesised that their beliefs about medicines are associated with primary non-adherence. The objective was to describe primary non-adherence among stroke survivors and to assess associations between primary non-adherence to preventive drugs and beliefs about medicines. Methods: Questionnaires were sent to 797 individuals 3 months after stroke to assess beliefs about medicines through the Beliefs about Medicines Questionnaire (BMQ). All participants were registered in the Swedish Stroke Register (Riksstroke), and prescriptions for new preventive drugs during the hospital stay were identified through data from Riksstroke. Primary non-adherers were those who failed to fill one or more new prescriptions within 1 month of hospital discharge based on data from the Swedish Prescribed Drug Register. Differences between primary non-adherers and adherers were assessed by X2 tests and associations between the BMQ subscales and primary non-adherence were analysed using independent two-sample t-tests and multivariable logistic regression models. Results: A total of 594 individuals responded to the survey, of which 452 received new prescriptions of preventive drugs. Overall, 53 (12%) participants were classified as primary non-adherent. Primary non-adherers were more often dependent on help or support from next of kin (p=0.032) and had difficulties with memory more often (p=0.002) than the primary adherent individuals. No statistically significant differences in BMQ subscale-scores were found between the two groups (p>0.05). Conclusion: Primary non-adherence to preventive drugs was low, and no associations were found between primary non-adherence and beliefs about medicines. Associations with cognitive impairments such as difficulties with memory and need for help from next of kin suggest that more effort is needed to help stroke survivors to start important preventive drug treatments after discharge from hospital

<it>BACE1 </it>gene variants do not influence BACE1 activity, levels of APP or Aβ isoforms in CSF in Alzheimer's disease

<p>Abstract</p> <p>The <it>BACE1 </it>gene encodes the beta-site APP-cleaving enzyme 1 and has been associated with Alzheimer's disease (AD). BACE1 is the most important β-secretase responsible for the generation of Alzheimer-associated amyloid β-proteins (Aβ) and may play a role in the amyloidogenic process in AD. We hypothesized that <it>BACE1 </it>gene variants might influence BACE1 activity or other markers for APP metabolism in the cerebrospinal fluid (CSF) and thereby contribute to the development of AD. We genotyped a Swedish sample of 269 AD patients for the rs638405 single nucleotide polymorphism (SNP) in the <it>BACE1 </it>gene and correlated genotype data to a broad range of amyloid-related biomarkers in CSF, including BACE1 activity, levels of Aβ₄₀, Aβ_42,α- and β-cleaved soluble APP (α-sAPP and β-sAPP), as well as markers for Alzheimer-type axonal degeneration, i.e., total-tau and phospho-tau₁₈₁. Gene variants of <it>BACE1 </it>were neither associated with amyloid-related biomarkers, nor with markers for axonal degeneration in AD.</p

Genetic Variants of GSK3B are Associated with Biomarkers for Alzheimer's Disease and Cognitive Function.

Background: Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood. Objective: To evaluate possible associations between gene variants of GSK3B and risk of AD. Methods: Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau181), and amyloid-β (Aβ42). Results: After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (pc = 0.04). Next, rs1154597 showed association with reduced Aβ42 levels (pc = 0.007). Lastly, rs3107669 was associated with lower MMSE scores (pc = 0.03). In addition, one more SNP was nominally significantly associated with reduced Aβ42 levels and another was associated with reduced MMSE. Conclusion: We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and Aβ42. To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (Aβ42). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis