Anthony Peter Passmore

Drug repositioning for Alzheimer's disease

Existing drugs for Alzheimers disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimers-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimers disease.

Inflammation and anti-inflammatory strategies for Alzheimer's disease--a mini-review.

Until recently, the central nervous system (CNS) has been thought to be an immune privileged organ. However, it is now understood that neuroinflammation is linked with the development of several CNS diseases including late-onset Alzheimer’s disease (LOAD). The development of inflammation is a complex process involving a wide array of molecular interactions which in the CNS remains to be further characterized. The development of neuroinflammation may represent an important link between the early stages of LOAD and its pathological outcome. It is proposed that risks for LOAD, which include genetic, biological and environmental factors can each contribute to impairment of normal CNS regulation and function. The links between risk factors and the development of neuroinflammation are numerous and involve many complex interactions which contribute to vascular compromise, oxidative stress and ultimately neuroinflammation. Once this cascade of events is initiated, the process of neuroinflammation can become overactivated resulting in further cellular damage and loss of neuronal function. Additionally, neuroinflammation has been associated with the formation of amyloid plaques and neurofibrillary tangles, the pathological hallmarks of LOAD. Increased levels of inflammatory markers have been correlated with an advanced cognitive impairment. Based on this knowledge, new therapies aimed at limiting onset of neuroinflammation could arrest or even reverse the development of the disease.

Expression and activity of β-site amyloid precursor protein cleaving enzyme in Alzheimer's disease

Several lines of evidence indicate that the Aβ peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer9s disease). The N-terminus of Aβ is generated by cleavage of the Met-Asp bond at position 671–672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called β-secretase. Two ‘β-secretase’ proteases have been identified: BACE (β-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/β-secretase activity in brain regions affected by the disease. We have demonstrated that robust β-secretase activity is also detectable in platelets that contain APP and release Aβ. This review considers the current evidence for alterations in β-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

Butyrylcholinesterase K variant is genetically associated with late onset Alzheimer's disease in Northern Ireland

Alzheimers disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E ε4 (APOE ε4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (χ2=23.68, df=2, p<<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (χ2=16.39, df=1, p<<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2.20-6.07). This risk increased in subjects 75 years and older (OR=5.50, 95% CI 2.56-11.87). At the same time the APOE ε4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE ε4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.

Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer’s disease

The rising number of people with cognitive impairment is placing health care budgets under significant strain. Dementia related behavioural change is a major independent risk factor for admission to expensive institutional care, and aggressive symptoms in particular are poorly tolerated by carers and frequently precipitate the collapse of home coping strategies. Aggressive change may result from known genetic risk factors for Alzheimer’s disease (AD) and therefore accompany conventional markers such as apolipoprotein E (ApoE). We tested this hypothesis in 400 moderately to severely affected AD patients who were phenotyped for the presence of aggressive or agitated behaviour during the month prior to interview using the Neuropsychiatric Inventory with Caregiver Distress. The proportion of subjects with aggression/agitation in the month prior to interview was 51.8%. A significantly higher frequency of the e4 allele was found in individuals recording aggression/agitation in the month prior to interview (χ2 = 6.69, df = 2, p = 0.03). The additional risk for aggression/agitation conferred by e4 was also noted when e4 genotypes were compared against non-e4 genotypes (χ2 = 5.45, df = 1, p = 0.02, OR = 1.60, confidence interval (CI) 1.06 to 2.43). These results indicate that advanced Alzheimer’s disease patients are at greater risk of aggressive symptoms because of a genetic weakness in apolipoprotein E.

Systematic review: blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia

Hypertension and cognitive impairment are prevalent in older people. Hypertension is a direct risk factor for vascular dementia, and recent studies suggest hypertension also impacts on the prevalence of Alzheimer’s disease. The question is therefore whether treatment of hypertension lowers the rate of cognitive decline. To assess the effects of blood pressure (BP) lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease. Trials were identified through a search of the Cochrane Dementia and Cognitive Impairment Group’s Specialised Register which contains records from CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL. Relevant journals were searched, drug companies, colleagues and researchers were contacted, and reference lists of all trials identified were screened. Randomised, double blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower BP were given for at least 6 months. Two independent reviewers assessed trial …

Cathepsin D gene exon 2 polymorphism and sporadic Alzheimer's disease

It has recently been reported that a genetic polymorphism in exon 2 of the cathepsin D gene conferred increased risk for development of Alzheimers disease (AD). Because of the potential importance of this report we tested this association in a clinically well-defined group of AD patients and age and sex matched control subjects from the relatively genetically homogeneous Northern Ireland population. This study failed to confirm the reported association between the cathepsin D exon 2 polymorphism and AD. We conclude that if an association exists between this polymorphism and AD it is likely to be small.

Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and L-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer's disease.

This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer’s disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7μm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L-Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients ‘at risk’ from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification.

Executive functioning in Alzheimer's disease and vascular dementia†

To compare performance of patients with mild‐moderate Alzheimers disease (AD) and vascular dementia (VaD) on tests of executive functioning and working memory.

The development of effective biomarkers for Alzheimer's disease: a review

There is a widely recognised need to develop effective Alzheimers disease (AD) biomarkers to aid the development of disease‐modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers.