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Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Background People with dementia (PwD) face unique challenges with medicines management, yet little is known about these challenges from the perspectives of primary healthcare professionals, particularly general practitioners (GPs) and community pharmacists. Few medicines management interventions have been developed which are aimed at community-dwelling PwD. This study sought to develop an intervention to improve medicines management for PwD in primary care using a theory-informed approach. Methods Semi-structured interviews were conducted with GPs ( n  = 15) and community pharmacists ( n  = 15) to explore participants’ views and experiences of medicines management for PwD, and their perceptions of barriers and facilitators to successful medicines management for PwD. The 14-domain Theoretical Domains Framework was the underpinning theoretical guide, allowing key theoretical domains to be identified and mapped to behaviour change techniques (BCTs) which are considered the ‘active ingredients’ of an intervention. Draft interventions were developed to operationalise selected BCTs and were presented to GPs and community pharmacists during task groups. Final selection of an intervention for feasibility testing was guided by feedback provided during these task groups and through application of the APEASE (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety, Equity) criteria. Results Participants expressed a number of concerns about medicines management for PwD, particularly monitoring adherence to medication regimens and conducting medication review. Two draft interventions comprising selected BCTs (‘Modelling or demonstration of behaviour’; ‘Salience of consequences’; ‘Health consequences’; ‘Social and environmental consequences’; ‘Action planning’; Social support or encouragement’, ‘Self-monitoring of behaviour’) were developed, each targeting GPs and community pharmacists. Following the task groups and discussions within the research team, the community pharmacy-based intervention was selected for future feasibility testing. The intervention will target community pharmacists to conduct a medication review (incorporating an adherence check) with a PwD, delivered as an online video demonstrating key behaviours. The video will include feedback emphasising positive outcomes of performing the behaviours. Action planning and a quick reference guide will be used as complementary intervention components. Conclusions A community pharmacist-based intervention has been developed targeting medicines management for PwD in primary care using a systematic, theory-informed approach. Future work will determine the usability and acceptability of implementing this intervention in clinical practice.

Introduction The increasing number of people with dementia (PwD) is a significant health and financial challenge for countries. PwD often transition to a care home. This study explored factors predicting transition to care homes for PwD and the place and causes of death. Methods Data about dementia medication, care home transitions, demographic characteristics, deaths, and hospital admissions were extracted from national databases from 2010 to 2016. Results PwD (n = 25,418) were identified through prescriptions of dementia medication, from which 11,930 transitioned to care homes. A logistic regression showed that increased age, female sex, living in less deprived and urban areas, and hospital admissions predicted this transition. PwD who transition to care homes are more likely to die there. The most common cause of death was dementia. Discussion Certain demographic characteristics are significant predictors for care home transitions and they should be considered in the development of early community‐based care services to delay transitions. In the last decades, dementia has been reported more frequently in death certificates.

Julie Williams, Michael Owen and colleagues report staged follow-up and meta-analyses of genome-wide association studies for Alzheimer's disease from the GERAD+ consortium. They identify common variants at ABCA7 and MS4A6A/MS4A4E associated with Alzheimer's disease and support for several additional susceptibility loci. We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10 −5 . We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 −17 ; including ADGC data, meta P = 5.0 × 10 −21 ) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 −14 ; including ADGC data, meta P = 1.2 × 10 −16 ) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 −4 ; including ADGC data, meta P = 8.6 × 10 −9 ), CD33 (GERAD+, P = 2.2 × 10 −4 ; including ADGC data, meta P = 1.6 × 10 −9 ) and EPHA1 (GERAD+, P = 3.4 × 10 −4 ; including ADGC data, meta P = 6.0 × 10 −10 ).

Julie Williams and colleagues report a genome-wide association study for Alzheimer's disease. They identify variants at the CLU and PICALM loci associated with susceptibility to late-onset Alzheimer's disease. We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E ( APOE ) locus (most significant SNP, rs2075650, P = 1.8 × 10 −157 ) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ ) gene (rs11136000, P = 1.4 × 10 −9 ) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10 −8 ). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10 −10 , odds ratio = 0.86; rs3851179, P = 1.3 × 10 −9 , odds ratio = 0.86).

Deposition of β-amyloid in the brains of patients with Alzheimer's disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor α (TNF-α) leads to increased risk of Alzheimer's disease and vascular dementia. A polymorphism in the regulatory region of the TNF- α gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimer's disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLADR locus. The distribution of TNF-α genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2·51 (95% CI 1·49–4·21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimer's disease associated with carriage of the apolipoprotein ɛ4 allele (odds ratio 2·73 [1·68–4·44] for those with apolipoprotein E ɛ4 but no TNF-α T, vs 4·62 [2·38–8·96] for those with apolipoprotein E ɛin;4 and TNF-α T; p=0·03). Possession of the TNF-α T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimer's disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimer's disease, and perhaps especially in patients who have had a stroke.

ObjectiveTo compare the performance of patients with mild–moderate Alzheimer's disease (AD) and vascular dementia (VaD) on tests of information processing and attention.MethodPatients with AD (n=75) and VaD (n=46) were recruited from a memory clinic along with dementia-free participants (n=28). They underwent specific tests of attention from the Cognitive Drug Research battery, and pen and paper tests including Colour Trails A and B and Stroop. All patients had a CT brain scan that was independently scored for white-matter change/ischaemia.ResultsAttention was impaired in both AD and VaD patients. VaD patients had more impaired choice reaction times and were less accurate on a vigilance test measuring sustained attention. Deficits in selective and divided attention occurred in both patient groups and showed the strongest correlations with Mini Mental State Examination scores.ConclusionThis study demonstrates problems with the attentional network in mild–moderate AD and VaD. The authors propose that attention should be tested routinely in a memory clinic setting.

Recent years have seen a growing recognition that dementia is a terminal illness and that patients with advanced dementia nearing the end of life do not currently receive adequate palliative care. However, research into palliative care for these patients has thus far been limited. Furthermore, there has been little discussion in the literature regarding medication use in patients with advanced dementia who are nearing the end of life, and discontinuation of medication has not been well studied despite its potential to reduce the burden on the patient and to improve quality of life. There is limited, and sometimes contradictory, evidence available in the literature to guide evidence-based discontinuation of drugs such as acetylcholinesterase inhibitors, antipsychotic agents, HMG-CoA reductase inhibitors (statins), antibacterials, antihypertensives, antihyperglycaemic drugs and anticoagulants. Furthermore, end-of-life care of patients with advanced dementia may be complicated by difficulties in accurately estimating life expectancy, ethical considerations regarding withholding or withdrawing treatment, and the wishes of the patient and/or their family. Significant research must be undertaken in the area of medication discontinuation in patients with advanced dementia nearing the end of life to determine how physicians currently decide whether medications should be discontinued, and also to develop the evidence base and provide guidance on systematic medication discontinuation.

The behavioral and psychological symptoms of Alzheimer's disease (AD) are associated with significant patient and caregiver distress and increased likelihood of institutionalization. We attempted to characterize in detail these symptoms and the distress they cause to caregivers. Patients with probable AD were assessed with the Mini-Mental State Exam (MMSE), Functional Assessment Staging (FAST), and the Neuropsychiatric Inventory With Caregiver Distress (NPI–D). Four hundred and thirty-five patients were recruited. Neuropsychiatric symptoms of all types were highly prevalent. The most common and most persistent symptom was apathy (75%). Delusional symptoms were the least persistent. Depressive and apathetic symptoms were the earliest to appear, and hallucinations, elation/euphoria, and aberrant motor behavior were the latest symptoms to emerge. Hallucinations were significantly more common in severe dementia. Symptoms of irritability were most prevalent in early disease. Total Neuropsychiatric Symptom score was significantly correlated with MMSE and FAST score. Caregivers rated their own emotional distress levels as moderate or severe for 10 out of 12 symptom domains. The sum total of caregiver distress was strongly correlated with total NPI–D but not cognition or functional state. Distress levels did not vary when analyzed according to the patients' place of residence. Potentially treatable neuropsychiatric symptoms are common in AD and represent a major source of distress among caregivers. The extent of neuropsychiatric symptomatology is seen to correlate with the level of functional and cognitive disability although some symptoms are variably persistent and related to disease stage.

Healthcare systems worldwide are facing an unprecedented demographic change as globally, the number of older people will triple to 2 billion by the year 2050. The resulting pressures on acute services have been instrumental in the development of intermediate care (IC) as a new healthcare model, which has its origins in the National Health Service in the UK. IC is an umbrella term for patient services that do not require the resources of a general hospital but are beyond the scope of a traditional primary care team. IC aims to promote timely discharge from hospital, prevent unnecessary hospital admissions and reduce the need for long-term residential care by optimizing functional independence. Various healthcare providers around the world have adopted similar models of care to manage changing healthcare needs. Polypharmacy, along with age-related changes, places older people at an increased risk of adverse drug events, including inappropriate prescribing, which has been shown to be prevalent in this population in other healthcare settings. Medicines management (the practice of maximizing health through optimal use of medicines) of older people has been discussed in the literature in a variety of settings; however, its place within IC is largely unknown. Despite IC being a multidisciplinary healthcare model, there is a lack of evidence to suggest that enhanced pharmaceutical involvement is core to the service provided within IC. This review article highlights the gap in the literature surrounding medicines management within IC and identifies potential solutions aimed at improving patient outcomes in this setting.