Probable Early-Onset Alzheimer's Disease in an Apolipoprotein E2 Homozygote

Objective: To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) epsilon 2/epsilon 2 homozygote. Background: Apo epsilon 2/epsilon 2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE epsilon 2 homozygotes has rarely been reported. Case Report/Methods: We report a 58-year-old Apo epsilon 2/epsilon 2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations. Results: The clinical course is typical of AD, with progressive cognitive and functional decline. Conclusion: Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur. Copyright (C) 2010 S. Karger AG, Base

Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease

Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD

Latrepirdine for Alzheimers disease: Trials and tribulations

Robust preclinical in vitro and in vivo data indicate that latrepirdine has a protective effect against neurotoxic changes, increasing the survival of neurons, inhibiting mitochondrial permeability and reducing mitochondrial instability. The drug has been shown to increase neurite outgrowth, cortical neuron process and branch length and mitochondrial concentration. Nevertheless, a clearly defined mechanism of action has yet to be defined. Speculation regarding its mechanism of action include a preservative effect on mitochondria resulting in neural preservation and it appears to be unrelated to inhibition of acetylcholinesterases and N-methyl-D-aspartic acid-receptor antagonism. Phase I-III studies show demonstrable safety and minimal toxicity in subjects treated with latrepirdine. A Phase II study demonstrated statistically significant cognitive and behavioral improvement in the treatment group and cognitive and behavioral decline from baseline in the placebo group in Russian Alzheimers disease subjects. However, the Phase III monotherapy multinational study failed to reproduce a robust clinical efficacy signal. The reasons for treatment failure are most likely due to the placebo group failing to decline as expected, the proposed mechanism of action maybe not having an effect on the Alzheimers disease process and the data in Phase II being incongruous owing to significant disparities in the populations recruited in the Phase II compared with the Phase III trial. © 2010 Future Medicine Ltd

Successes and failures for drugs in late-stage development for alzheimer\u27s disease

To date, symptomatic medications prevail as the mainstay of treatment options for Alzheimer\u27s disease (AD). There have been tremendous investments made to increase the numbers of drugs approved and the targets engaged, in an effort to alter the disease course or pathophysiology of AD. Unfortunately, almost all studies have not met expectations and no new drug (beyond medical foods) has been approved for the treatment of AD in the last decade. This review is a comparison of novel AD therapies in the late phases of clinical testing, including recent high-profile clinical failures, and agents in development with relatively unexplored mechanisms of action, with a focus on their potential as therapeutic agents and their proposed advantages over the treatments currently in use. © 2013 Springer International Publishing Switzerland

Investigational drugs in Alzheimer\u27s disease: Current progress

Introduction: Alzheimer\u27s disease is a progressive neurodegenerative disorder affecting millions of people worldwide. Yet, this disease is presently incurable and treatable only in terms of modest delay of symptomatic progression. The need for more effective pharmacological intervention is becoming more pronounced as the patient population increases. Areas covered: This paper outlines and evaluates the current landscape of interventions in early phases of clinical study. Data and analysis for this review were procured from PubMed, clinicaltrials.gov, review of posters, abstracts and presentations from American Neurological Association, American Academy of Neurology meetings, Alzheimer\u27s Association International Conference and Clinical Trials on Alzheimer\u27s disease. Keywords and criteria searched included: Phase 0, I, and II trials related to Alzheimer\u27s disease, amyloid-β, anti-tau, monoclonal antibodies and metabolism. Expert opinion: The development of novel pharmacological interventions would be more fruitful if multitarget therapies were introduced, and unexplored mechanisms of action were expanded upon. Additionally, there is a rationale for intervening earlier in the disease, perhaps preceding or at the advent of symptoms. © 2014 Informa UK, Ltd

Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with down syndrome and Alzheimer disease

Background: Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined. Objectives: To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death. Design/Methods: With the family\u27s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient\u27s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient\u27s diagnosis or PET measurements. Results: Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan. Conclusions: Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease. ©2011 American Medical Association. All rights reserved