Allelic variation at the A218C tryptophan hydroxylase polymorphism influences agitation and aggression in Alzheimer's disease

The behavioural and psychological symptoms of dementia are common, distressing to carers, and directly linked to the requirement for institutional care. Symptoms of aggression and agitation are particularly difficult for carers to tolerate. The origin of these features is unclear although genetic and environmental modification of pre-frontal serotonergic circuitry which regulates the control of negative emotions is proposed. Following the suggestion that the A218C intronic polymorphism of the tryptophan hydroxylase gene influences aggression and anger in non-demented individuals, we tested the influence of A218C on symptoms of agitation/aggression in 396 Alzheimer's disease patients using the Neuropsychiatric Inventory. Overall, 50% of participants experienced agitation/aggression in the month prior to interview. It was observed that male patients with a history of agitation/aggression were more likely to possess C-containing genotypes (P = 0.044, OR = 1.65, CI = 0.98-2.76). We conclude that aggression in male subjects with Alzheimer's disease may be genetically linked to polymorphic variation at the tryptophan hydroxylase gene.

A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease

This 12-week, multinational study compared the tolerability and cognitive effects of donepezil (up to 10 mg once daily) and rivastigmine (up to 6 mg twice daily) in 111 patients with mild to moderate Alzheimer's disease. Both medications were administered open label according to recommended dosing regimens from the respective product labelling available during the conduct of the study. More patients in the donepezil group (89.3%) completed the study compared with the rivastigmine group (69.1%; p=0.009), and 10.7% of the donepezil group and 21.8% of the rivastigmine group discontinued due to adverse events (AEs); 87.5% of donepezil-treated patients and 47.3% of rivastigmine-treated patients remained on the maximum approved dose of each drug at the last study visit. Both groups showed comparable improvements on the ADAS-cog administered by raters blind to study medication at weeks 4 and 12. Thus, using the recommended dosing schedules, donepezil was better tolerated with fewer discontinuations due to AEs, and both agents improved cognition to a similar extent.

Apolipoprotein E polymorphism and serum concentration in Alzheimer's disease in nine European centres:the ApoEurope study. ApoEurope group

As part of the ApoEurope Project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the epsilon4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p

Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS)

Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

No consistent evidence for association between mtDNA variants and Alzheimer disease

Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.

Donepezil and memantine for moderate-to-severe Alzheimer's disease

Background: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.
Results: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
Conclusions: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035).

A multi-center study of ACE and the risk of late-onset Alzheimer's disease

A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-ß (Aß) peptide. Thus, altered Aß degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aß-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.

Sleep disturbances in spousal caregivers of individuals with Alzheimer's disease

Background: Although sleep problems are commonly reported among dementia caregivers, the nature and frequency of caregiver sleep disruptions, and their relationship to health status, has received little empirical attention to date. Methods: The current study investigated the sleep situations of a sample of 60 spousal caregivers currently residing with a Alzheimer disease care recipient, including the frequency of nocturnal disruptions by the care recipient, and the reasons for these disruptions. In addition, exploratory correlations were computed between caregiver sleep variables and health outcomes. Results: Some 63% of spousal caregivers reported sleep disruptions due to the nocturnal behavior of the recipients of their care. Poorer caregiver sleep quality was associated with higher frequency of nocturnal disruptions by the care recipient, the care recipient needing to use the bathroom, and wandering, higher caregiver depressive symptoms, and higher levels of caregiver role burden. The frequency of nocturnal disruptions was associated with poorer mental health status and a greater number of depressive symptoms. Conclusions: Results suggest that nocturnal disruptions by the care recipient may have adverse health consequences for spousal caregivers, and that further study of the determinants of caregiver sleep quality and health outcomes are warranted. © 2007 International Psychogeriatric Association.

Age-Related Macular Degeneration-Associated Genes in Alzheimer Disease

Objectives: Given the clinical and pathological similarities between age-relatedmacular degeneration (AMD) and Alzheimer disease (AD), to assess whether AMDassociatedsingle nucleotide polymorphisms (SNPs), including those from complementrelatedgenes, are associated with AD. 
Design: A case-control association study-typedesign. 
Setting: A UK tertiary care dementia clinic. 
Participants: 322 cognitivelynormal participants and 258 cases with a clinical diagnosis of AD.
Measurements:Polymorphisms in the following genes were studied: CFH, ARMS2, C2/CFB, C3, CFI/PLA2G12a, SERPING1, TLR3, TLR4, CRP, APOE, and TOMM40. Haplotypes were analysedfor CFH, TOMM40, and APOE. Univariate analysis was performed for each geneticchange and case-comparator status, and then correction for multiple testing performed. 
Results: The presence of an ε4 APOE allele was significantly associated with AD. Noassociation was evident between CFH SNPs or haplotypes, or other AMD-associated SNPstested, and AD. The exceptions were TOMM40 SNPs, which were associated with AD evenafter correction for multiple comparisons. The associations disappeared, however, whenentered into a regression model including APOE genotypes. 
Conclusions: The resultsfor most SNPs tested, as well as CFH haplotypes, are novel. The functional effects ofabnormal complement activity in AD’s pathogenesis may be contradictory, butmethodological reasons may underlie the lack of association—for example, geneticchanges other than SNPs being involved.