The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Cochrane review on 'Statins for the treatment of dementia'

OBJECTIVES: This review aimed to assess the clinical efficacy and tolerability of statins in the treatment of dementia. METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS, as well as many trials registries and grey literature sources (27 October 2008). Double-blind, randomized controlled trials of statins given for at least 6?months in people with a diagnosis of dementia were included. Two independent authors extracted and assessed data independently against the inclusion criteria. Data were pooled where appropriate and entered into a meta-analysis. RESULTS: Three studies were identified (748 participants, age range 50-90?years). All patients had a diagnosis of probable or possible Alzheimer's disease according to standard criteria, and most patients were established on a cholinesterase inhibitor. Change in Alzheimer's Disease Assessment Scale cognitive subscale from baseline was a primary outcome in three studies; when data were pooled, statins did not provide any beneficial effect in this cognitive measure (mean difference -1.12; 95% confidence interval -3.99, 1.75; p?=?0.44). All studies provided a change in Mini-Mental State Examination from baseline; there was no significant benefit from statins in this cognitive measure when the data were pooled (mean difference -1.53; 95% confidence interval -3.28; 0.21, p?=?0.08). There were no studies identified assessing the role of statins in treatment of vascular dementia. There was no evidence that statins were detrimental to cognition. CONCLUSIONS: There is insufficient evidence to recommend statins for the treatment of dementia. Copyright © 2012 John Wiley & Sons, Ltd.

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.

Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus

Nicastrin (NCSTN) is a component of the ?-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued ?-secretase activity and amyloid beta (Aß) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.

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.

Determining the minimum clinically important differences for outcomes in the DOMINO trial

Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these.

Risky decision making in younger and older adults:The role of learning.

Are older adults risk seeking or risk averse? Answering this question might depend on both the task used and the analysis performed. By modeling responses to the Balloon Analogue Risk Task (BART), our results illustrate the value of modeling as compared to relying on common analysis techniques. While analysis of overall measures suggested initially that older and younger adults do not differ in their risky decisions, our modeling results indicated that younger adults were at first more willing to take greater risks. Furthermore, older adults may be more cautious when their decision making is based on initial perceptions of risk, rather than learning following some experience with a task.

Risk of fatal injury in older adult drivers, passengers, and pedestrians

Objectives To compare risk of fatal injury in elderly road users (drivers, passengers, pedestrians) with that of younger age groups and to assess the contribution of elderly road users to the number of reported fatalities in the population. Design Fatality age was categorized as 21 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, or 70 and older, and road user was categorized as driver, passenger, or pedestrian. Estimated number of trips made by each age group was used to adjust for exposure and to measure individual risk. Setting Fatalities recorded in Britain between 1989 and 2009. Participants Population-wide fatal injury counts in Britain. Measurements Age of fatally injured drivers, passengers, and pedestrians. Estimated number of trips made per year by drivers, passengers, and pedestrians. Results Risk of fatal injury, but not fatality numbers in the population, were higher for older adult (=70) drivers than for younger age groups. Risk of fatal injury was also high for older adult passengers and pedestrians, who represented the majority of older adult fatalities. Conclusion Previous emphasis on driver impairment in older age has unduly focussed attention on elderly drivers, who represent a minority of all driver fatalities. Older adults represent a much larger proportion of passenger and pedestrian fatalities. Additional policy schemes and initiatives should be targeted at safeguarding older adult passengers and making the road environment safer for elderly pedestrians. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

Is the phenotypic combination A1B8Cw7DR3 a marker for male longevity?

To study whether individual Human Leucocyte Antigens (HLA) at the HLA 1 or 11 loci or the phenotypic combination A1B8Cw7DR3 were associated with longevity.

Studies to Reduce Unnecessary Medication Use in Frail Older Adults:A Systematic Review

BACKGROUND: Overuse of unnecessary medications in frail older adults with limited life expectancy remains an understudied challenge. OBJECTIVE: To identify intervention studies that reduced use of unnecessary medications in frail older adults. A secondary goal was to identify and review studies focusing on patients approaching end of life. We examined criteria for identifying unnecessary medications, intervention processes for medication reduction, and intervention effectiveness. METHODS: A systematic review of English articles using MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1966 to September 2012. Additional studies were identified by searching bibliographies. Search terms included prescription drugs, drug utilization, hospice or palliative care, and appropriate or inappropriate. A manual review of 971 identified abstracts for the inclusion criteria (study included an intervention to reduce chronic medication use; at least 5 participants; population included patients aged at least 65 years, hospice enrollment, or indication of frailty or risk of functional decline-including assisted living or nursing home residence, inpatient hospitalization) yielded 60 articles for full review by 3 investigators. After exclusion of review articles, interventions targeting acute medications, or studies exclusively in the intensive care unit, 36 articles were retained (including 13 identified by bibliography review). Articles were extracted for study design, study setting, intervention description, criteria for identifying unnecessary medication use, and intervention outcomes. RESULTS: The studies included 15 randomized controlled trials, 4 non-randomized trials, 6 pre-post studies, and 11 case series. Control groups were used in over half of the studies (n = 20). Study populations varied and included residents of nursing homes and assisted living facilities (n = 16), hospitalized patients (n = 14), hospice/palliative care patients (n = 3), home care patients (n = 2), and frail or disabled community-dwelling patients (n = 1). The majority of studies (n = 21) used implicit criteria to identify unnecessary medications (including drugs without indication, unnecessary duplication, and lack of effectiveness); only one study incorporated patient preference into prescribing criteria. Most (25) interventions were led by or involved pharmacists, 4 used academic detailing, 2 used audit and feedback reports targeting prescribers, and 5 involved physician-led medication reviews. Overall intervention effect sizes could not be determined due to heterogeneity of study designs, samples, and measures. CONCLUSIONS: Very little rigorous research has been conducted on reducing unnecessary medications in frail older adults or patients approaching end of life.

Pneumonia and lower respiratory infections in nursing home residents:Predictors of hospitalization and mortality

OBJECTIVES: To compare predictors of hospitalization and death in nursing home residents with pneumonia and other lower respiratory infections (LRIs). DESIGN: A nested cohort study. SETTING: Nine nursing homes in southern Ontario. PARTICIPANTS: Three hundred fifty-three nursing home residents with LRIs (enrolled in the control arm of a clinical trial). MEASUREMENTS: Comorbidities, vaccination status, age, health-related quality of life, functional status, and vital statistics were evaluated as potential predictors of hospitalization and mortality at 30 days. RESULTS: Moderate to high disease severity score on a practical severity scale was a strong independent predictor of hospitalization (odds ratio (OR)=7.12, P

Identifying research priorities on infections in older adults:Proceedings of an interdisciplinary workshop

Background: Infections pose a substantial burden to the health of older adults. In this report, we describe the proceedings of a workshop to formulate and prioritize research questions about infections in older adults using an interdisciplinary approach. Methods: Researchers from four sectors (basic science, clinical sciences, health services and epidemiology/determinants of health) and representatives from various Canadian local, provincial, and federal stakeholder groups were invited to a two-day workshop. Five multi-disciplinary groups and stakeholders from each of three healthcare settings (long term, acute care and community) discussed research priorities for each of the settings. Five to ten research questions were identified for each setting. Results: The research questions proposed ranged from risk factors and outcomes for different infections to the effect of nutrition on infection and the role of alternative and complementary medicine in treating infections. Health service issues included barriers to immunization, prolongation of hospital length of stay by infection, use of care paths for managing infections, and decision-making in determining the site of care for individuals with infections. Clinical questions included risk factor assessment for infection, the effectiveness of preventative strategies, and technology evaluation. Epidemiologic issues included the challenge of achieving a better understanding of respiratory infections in the community and determining the prevalence of colonization with multi-resistant bacteria. Conclusions: The questions are of direct relevance to researchers in a wide variety of fields. Bringing together a multi-disciplinary group of researchers to frame and prioritize research questions about aging is feasible, participants valued the opinions of people working in other areas.

Optimizing Research on End-of-Life Care for Seniors:The Collective New Emerging Team on End of Life Care for Seniors University of Ottawa, Institute of Palliative Care

Background: End-of-life care for seniors is an important and neglected area of research. The University of Ottawa Institute of Palliative Care has expanded its research capacity by developing a Canadian Institutes of Health Research (CIHR) funded new emerging team on end-of-life care for seniors. This initiative brings together an interdisciplinary team of researchers from palliative care and geriatrics to develop a comprehensive program of research. Methods: 1) A variety of investigators from the fields of palliative care and geriatrics and disciplines of epidemiology, medicine, nursing, psychology and social work will collaborate on the development of a research agenda focussed on end-of-life care for seniors. 2) The conceptual model for the research program consists of 4 broad interrelated domains that are congruent with the CIHR themes of health services, clinical issues, population health and psychosocial, cultural, spiritual and ethical issues; this framework will guide the research program and all studies emanating from the program. 3) Research studies will focus on 5 areas of inquiry that are central to end-of-life care for seniors: palliative end-of-life care for rural seniors, care settings, burden, role of volunteers, and delirium. Results: This new team has the potential to obtain peer-reviewed funding, recruit and train a new generation of researchers, and build a network of concerned researchers. Conclusions: The new team should ultimately contribute to an improved quality of care for seniors who are approaching death.

Encouraging lifestyle behaviour change in mild cognitive impairment patients:development of appropriate educational material

Objectives: A healthy lifestyle may help maintain cognitive function and reduce the risk of developing dementia. This study employed a focus group approach in order to gain insight into opinions of mild cognitive impairment (MCI) patients, caregivers (CG) and health professionals (HP) regarding lifestyle and its relationship with cognition. The qualitative data were used to design, develop and pilot test educational material (EM) to help encourage lifestyle behaviour change. Method: Data gathering phase: structured interviews were conducted with HP (n = 10), and focus groups with MCI patients (n = 24) and CG (n = 12). EM was developed and pilot tested with a new group of MCI patients (n = 21) and CG (n = 6). Results: HP alluded to the lack of clinical trial evidence for a lifestyle and MCI risk link. Although they felt that lifestyle modifications should be recommended to MCI patients, they appeared hesitant in communicating this information and discussions were often patient-driven. MCI patients lacked awareness of the lifestyle cognition link. Participants preferred EM to be concise, eye-catching and in written format, with personal delivery of information favoured. Most pilot testers approved of the EM but were heterogeneous in terms of lifestyle, willingness to change and support needed to change. Conclusion: MCI patients need to be made more aware of the importance of lifestyle for cognition. EM such as those developed here, which are specifically tailored for this population would be valuable for HP who, currently, appear reticent in initiating lifestyle-related discussions. Following further evaluation, the EM could be used in health promotion activities targeting MCI patients.

Depression associates with Mini Nutritional Assessment (MNA), Vitamin B12 and Folate status::Findings from Belfast Elderly Longitudinal Free-Living Ageing STudy (BELFAST)

Introduction: An association between depression and folate has been found in clinical studies. Depression and dementia can contribute to nutritional deficiency. This study clinical depression in in octo/nonagenarians from the BELFAST study.
Method: In the BELFAST study, 38 free-living octo/nonagenarians (mean age 82 years), who apparently well and cognitively intact were followed up at 5 years and assessed using the Geriatric Depression Scale (GDS), Folstein (30 point), Mini Nutritional Assessment Tool (MNA) together with serum folate and vitamin B12 levels.
Results: Mean GDS was 3.4 (SD 2.5), serum folate 7.1 umol/l (SD 5.3) and B12 553 umol/l (458). With mean MNA and Folstein -25.8 (SD 2.7) and 27.6 (SD 2.7) respectively with no sex difference (p = 0.78; p = 0.36). 25% of subjects showed a GDS >5 indicating risk of mild depression and 21% had compromised nutritional status. MNA associated with GDS in male (r2 = 0.56 p = 0.01), but not in female elderly subjects (r2 = 0.01; p = 0.44). GDS score and lower serum folate were associated (r2 = -0.23; p = 0.01).
Conclusion: Overall there was the suggestion that nutritional status and depression might be linked in male subjects at 5 year follow-up in octo/nonagenarians from the BEFLAST study. The lower folate in subjects categorised at risk of mild depression might suggest vitamin supplementation could be useful.