Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6: 246-254

World Wide Development, Research and Development, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA.
The Pharmacogenomics Journal (Impact Factor: 4.23). 01/2006; 6(4):246-54. DOI: 10.1038/sj.tpj.6500369
Source: PubMed


Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

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Available from: Allen D Roses, May 10, 2014
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    • "Recent studies suggest an association between insulin resistance and AD (fat cell sensitivity to insulin can decline with aging): In clinical trials, a certain insulin sensitizer called "rosiglitazone" improved cognition in a subset of AD patients;[49] [50] in vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated.[51] These PPARγ agonists inhibit inflammatory gene expression, alter Amyloid homeostasis & exhibit neuroprotective effects. "
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    • "Through the advances in pharmacological therapy, many oral antidiabetic agents have become available. Interestingly, oral antidiabetic drugs such as thiazolidinedione and metformin have been shown to have beneficial effects to slow the progression of dementia in both clinical and animal studies [17] [18]. However, many of these pharmaceutical agents are associated with various undesirable side-effects, such as weight gain, fluid retention, and increased risk for heart failure, limiting their compliance and utility in clinical practice. "
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    ABSTRACT: Diabetes mellitus (DM) is a metabolic disorder affecting a large number of people worldwide. Numerous studies have demonstrated that DM can cause damage to multiple systems, leading to complications such as heart disease, cancer, and cerebrovascular disorders. Numerous epidemiological studies have shown that DM is closely associated with dementia and cognition dysfunction, with recent research focusing on the role of DM-mediated cerebrovascular damage in dementia. Despite the therapeutic benefits of antidiabetic agents for the treatment of DM-mediated cognitive dysfunction, most of these pharmaceutical agents are associated with various undesirable side-effects and their long-term benefits are therefore in doubt. Early evidence exists to support the use of traditional Chinese medicine (TCM) interventions, which tend to have minimal toxicity and side-effects. More importantly, these TCM interventions appear to offer significant effects in reducing DM-related complications beyond blood glucose control. However, more research is needed to further validate these claims and to explore their relevant mechanisms of action. The aims of this paper are (1) to provide an updated overview on the association between DM and cognitive dysfunction and (2) to review the scientific evidence underpinning the use of TCM interventions for the treatment and prevention of DM-induced cognitive dysfunction and dementia.
    International Journal of Endocrinology 06/2015; 2015. DOI:10.1155/2015/810439 · 1.95 Impact Factor
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    • "APOE4 is the greatest genetic risk factor for sporadic AD, increasing risk approximately 12-fold with two copies of the e4 allele compared to APOE3, whereas APOE2 reduces risk twofold (Verghese et al. 2011). Furthermore, APOE4 carriers respond differently in clinical trials, often negatively (Farlow et al. 1998; Risner et al. 2006; Sperling et al. 2012; Qiu et al. 2013). Although the impact of apolipoprotein E (apoE) on brain function is multifactorial, evidence indicates that the apoE isoforms differentially modulate neuroinflammation (Keene et al. 2011). "
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    ABSTRACT: Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory-receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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