Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial

OBJECTIVE: To assess the efficacy and safety of galantamine in Alzheimer's disease at 3 months using flexible dose escalation. METHODS: A randomised, double blind, placebo controlled trial in 43 centres in the United States, Canada, Great Britain, South Africa, Australia, and New Zealand. Patients with probable Alzheimer's disease (n=386; 171 women) with a score of 11-24 on the mini mental state examination, and a score> or =12 on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog) were randomised to placebo, or galantamine escalated over 4 weeks to a maintenance dose of 24 or 32 mg/day. The primary outcome measures were the change in ADAS-cog score and the clinician's interview based impression of change plus caregiver input (CIBIC-plus) score. Activities of daily living (ADL) and behavioural symptoms were secondary outcomes. To compare the effects of highest levels of dosing, an observed cases (OC) analysis was undertaken, with classic intention to treat (ITT) and ITT with last observation carried forward (LOCF) as confirmatory analyses. RESULTS: At 3 months, galantamine (24-32 mg/day) produced a significantly better outcome on cognitive function than placebo (treatment difference=1.9 points on ADAS-cog, p=0.002) and a significantly better global response than placebo, as measured by CIBIC-plus (deterioration in 21% of patients on galantamine v 37% on placebo; p<0.001). Galantamine produced significant benefits on basic and instrumental ADL. Behavioural symptoms did not change significantly from baseline levels in either group. Adverse events (primarily gastrointestinal) were of mild to moderate intensity. There were no important differences between the OC, ITT, and ITT/LOCF analyses. Most patients (82%) who were maintained on the higher dose of galantamine completed the study. CONCLUSIONS: Patients on galantamine, compared with those on placebo, experienced benefits in cognitive function and instrumental and basic activities of daily living. Flexible dose escalation of galantamine was well tolerated.     

Natural progression of Alzheimer's disease (AD): a perspective on possible therapies for advanced AD]

Patients with Alzheimer's disease (AD) show progressive deterioration in cognitive function without a spontaneous improvement in their course. Currently, acetylcholine esterase inhibitors (AchEIs) are generally used for treating AD and their beneficial effects have been confirmed for mild to moderate AD. Treatment options for patients with severe or advanced AD are limited; however, previous studies suggested that AchEIs, such as donepezil and galantamine, can provide some benefits for improving cognitive deficits even in patients with advanced AD. Furthermore, evidence of long-term benefits of donepezil treatment was reported by a recent study. Thus, AchEIs may have a wide spectrum of beneficial effects than we previously considered. Antiamyloid therapeutic strategies, including inhibition of the generation of amyloid beta-protein (A beta) and acceleration of A beta clearance, are likely to be highly effective for AD. A recent study of conditional transgenic mouse models of other neurodegenerative diseases suggested that a continuous influx of toxic aggregates of a mutant protein is required to maintain the pathological progression of the disease. Thus, although A beta generation and deposition are upstream of the amyloid cascade, it is likely that antiamyloid therapies can slow the natural progression of AD even in an advanced stage of the disease.     

Missense substitutions associated with behavioural disturbances in Alzheimer's disease (AD)

Behavioural and psychological symptoms in dementia, or BPSD, occur in the majority of Alzheimer's disease (AD) patients. They are associated with considerable patient morbidity and greater care-giver stress. There is some evidence suggesting that BPSD have a genetic component and a large number of studies have examined the association of candidate genes with these symptoms. This review provides a comprehensive summary of all the published studies investigating the association of candidate gene missense substitutions with BPSD. Missense substitutions could potentially alter protein function or render the protein non-functional, resulting in phenotypic consequences. More than 80 studies investigating the association of 8 missense substitutions in 7 genes with BPSD were identified. However, results of these studies are contradictory and do not provide firm support for these associations. Larger studies and more systematic approaches will delineate the association of missense substitutions with behavioural symptoms in AD.     

Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial

BACKGROUND: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD. METHODS: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). FINDINGS: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05). INTERPRETATION: 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD. FUNDING: Myriad Pharmaceuticals.     

The therapeutic potential of thyrotropin releasing hormone (TRH) in Alzheimer's disease (AD)

In recent years it has been established that patients with AD have a relatively specific loss of cerebral cortical and hippocampal cholinergic nerve terminals. This may be a reflection of degeneration of cholinergic neurons originating in the nucleus basalis of Meynert and septum which project to the cortex and hippocampus, respectively. In view of the long-standing association of cholinergic mechanisms with cognitive processes and the recognition of selective cholinergic deficits in AD, therapeutic attempts to enhance CNS cholinergic function have been undertaken in patients with AD. While only limited success with this strategy has been achieved to date, the use of TRH may offer a novel, yet rational, approach to treating AD. This assumption is predicated on the extensive literature documenting unique, facilitatory interactions of this peptide with cholinergic neurons throughout the neuraxis. Furthermore, the same rationale may account for the recently reported therapeutic benefit of TRH in patients with amyotrophic lateral sclerosis, which like AD, is a disease whose symptoms are manifested through a progressive degeneration of a subpopulation of CNS cholinergic neurons.     

Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles

K. E. Funk, R. E. Mrak and J. Kuret (2011) Neuropathology and Applied Neurobiology 37, 295–306
Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late‐stage autophagic organelles Aims: Granulovacuolar degeneration involves the accumulation of large, double membrane‐bound bodies within certain neurones during the course of Alzheimer's disease (AD) and other adult‐onset dementias. Because of the two‐layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalls in AD. Methods: Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for granulovacuolar degeneration (GVD) bodies, was evaluated in hippocampal sections prepared from post mortem Braak stage IV and V AD cases using double‐label confocal fluorescence microscopy. Results: GVD bodies colocalized weakly with early‐stage autophagy markers LC3 and p62, but strongly with late‐stage marker lysosome‐associated membrane protein 1 (LAMP1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with charged multivesicular body protein 2B (CHMP2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D. Conclusions: The resultant immunohistochemical signature suggests that granulovacuolar degeneration bodies (GVBs) do contain late‐stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. The data further suggest that failure to complete autolysosome formation may be an important correlate of GVB accumulation.     

A large,community-based,open-label trial of donepezil in the treatment of Alzheimer's disease

This phase III trial was conducted to evaluate the safety and efficacy of donepezil in Alzheimer's disease (AD) patients with a greater range of comorbid conditions and concomitant medication use than those previously evaluated in placebo-controlled studies. Patients (n = 1,035) with mild to moderate probable or possible AD were enrolled from 255 sites in the USA; 894 (86%) completed the trial. Mean age was 74.9 years (+/- 7.8); baseline standardized Mini-Mental State Examination (sMMSE) score was 19.77 (+/- 5.4). Nearly all patients had at least 1 prior or comorbid medical condition (97%) or were taking at least 1 concomitant medication (93%). Safety assessments included recording treatment-emergent adverse events (AEs). To confirm comparability with past studies, efficacy was measured using the sMMSE. Over the 12-week study period, the mean sMMSE score increased by 1.54 points over baseline (p < 0.0001) in donepezil-treated patients. Most AEs (64%) were mild, and the occurrence of cholinergic-induced AEs was significantly lower after a dose increase at 4 weeks than that seen with a dose increase after 1 week in previous trials. Risk ratios for gastrointestinal side effects were not significantly increased by the use of aspirin or nonsteroidal anti-inflammatory drugs. Risk ratios for bradycardia were not significantly increased by the use of beta-blockers, nondihydropyridine calcium channel blockers or digoxin. Therefore, donepezil improved cognition, as measured by the sMMSE, and was well tolerated despite high concomitant medication use and extensive comorbidity. These results highlight donepezil as a safe and effective treatment for AD patients typically seen by community-based physicians.     

Cost‐effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO‐AD trial)

Objective

Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild‐to‐moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost‐effective for community‐dwelling, moderate‐to‐severe Alzheimer's disease patients.

Methods

Cost‐effectiveness analysis was based on a 52‐week, multicentre, double‐blind, placebo‐controlled, factorial clinical trial. A total of 295 community‐dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine.

Results

Continuing donepezil for 52 weeks was more cost‐effective than discontinuation, considering cognition, activities of daily living and health‐related quality of life. Starting memantine was more cost‐effective than donepezil discontinuation. Donepezil–memantine combined is not more cost‐effective than donepezil alone.

Conclusions

Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.