Managed Care-Work in Progress or Stalled Experiment?

The symptomatic drugs currently on the market for Alzheimer's disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy: vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatment effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-amyloid-beta (anti-A beta) vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-up study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis that A beta immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclonal antibody targeting fibrillar A beta, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly and Company) was developed to target soluble, monomeric A beta. In two phase 3 studies, Solanezumab did not meet primary endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing of cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation of soluble A beta protofibrils, an A beta species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclonal antibody, mAb158, was developed to target A beta protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity for protofibrils as compared with monomers of A beta, thus targeting the toxic species of the peptide. A humanized version of mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisai without the safety concerns seen in previous phase 1 and 2a trials. Experiences from the field indicate the importance of initiating treatment early in the course of the disease and of enriching the trial population by improving the diagnostic accuracy. BAN2401 is a promising candidate for A beta immunotherapy in early AD. Other encouraging efforts in immunotherapy as well as in the small-molecule field offer hope for new innovative therapies for AD in the future

Effects of DHA- Rich n-3 Fatty Acid Supplementation on Gene Expression in Blood Mononuclear Leukocytes: The OmegAD Study

Background: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e. g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e. g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells. Methods and Findings: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up-and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e. g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e. g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels. Conclusions: We suggest that 6 months of dietary n-3 FA supplementatio

Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice

Performance on a pattern separation task by Alzheimer's patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E is an element of 4 status and cerebrospinal fluid amyloid-beta 42 levels

Introduction: Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) is an element of 4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-beta (A beta) plaques and an increase in the number of A beta-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) A beta 42 levels. Methods: The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF A beta 42 was measured. Results: ApoE is an element of 4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF A beta 42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF A beta 42, and thus the association was not due to increased impulsivity. Conclusions: These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to A beta 42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE is an element of 4 homocygotes

Performance on a pattern separation task by Alzheimer's patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E is an element of 4 status and cerebrospinal fluid amyloid-beta 42 levels

Introduction: Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) is an element of 4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-beta (A beta) plaques and an increase in the number of A beta-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) A beta 42 levels. Methods: The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF A beta 42 was measured. Results: ApoE is an element of 4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF A beta 42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF A beta 42, and thus the association was not due to increased impulsivity. Conclusions: These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to A beta 42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE is an element of 4 homocygotes

High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease

Background: Increased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-beta 42 peptide, are biomarkers of Alzheimer's disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome. Methods: Our sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2-11 years (median 4.9 years). Results: Individuals with CSF t-tau in the highest quartile (>= 900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95 % CI 1.24-3.80]; HR 2.37 [95 % CI 1.10-5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95 % CI 1.08-2.56), rapid decline in Mini Mental State Examination score (>= 4-point drop/12 months), and dying in severe dementia as outcomes. Conclusions: To our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo

Alzheimers sjukdom – diagnostik och behandling i dag och i framtiden

Alzheimer's disease is the most common cause of dementia. As many as 250,000 people in Sweden will have a dementia disease in 2050. The »amyloid cascade hypothesis« is a common model which explains how β-amyloid affects the function of the nerve cells. Alzheimer's disease has a long-lasting course and can present in typical and atypical forms. CSF analyses for »core AD CSF biomarkers« and synaptic proteins have been available for clinical diagnostics. PET scanning can detect either β-amyloid or tau aggregates in the brain of living humans. Current Alzheimer's disease therapy is based on two classes of cognition-enhancing drugs: acetylcholinesterase inhibitor and NMDA-receptor antagonist, which delays cognitive decline in most patients. The latest clinical development of potential therapy for Alzheimer's is active or passive immunotherapy against brain β-amyloid and tau, where several studies have shown varying but promising treatment effects. Non-pharmacological interventions in patients with AD aim to delay the loss of mental abilities, helping people to be independent in everyday life for as long as possible, and to increase their well-being and quality of life