Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer's disease

Poirier, Judes; Miron, Justin; Picard, Cynthia; Gormley, Patrick; Théroux, Louise; Breitner, John; Dea, Doris

doi:10.1016/j.neurobiolaging.2014.03.037

Cited by 91 publications

(72 citation statements)

References 74 publications

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“…Identification of potentially modifiable risk factors for Alzheimer's disease can help us develop some effective interventions to reduce risk of Alzheimer's disease [43,44]. In addition, for individuals with high risk of Alzheimer's disease, early interventions may be necessary [45].…”

Section: Discussionmentioning

confidence: 99%

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

Hou

et al. 2015

Mol Neurobiol

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The association between Alzheimer's disease and uric acid levels had gained great interest in recent years, but there was still lack of definite evidence. A systematic review and meta-analysis of relevant studies was performed to comprehensively estimate the association. Relevant studies published before October 26, 2014, were searched in PubMed, Embase, and China Biology Medicine (CBM) databases. Study-specific data were combined using random-effects or fixed-effects models of meta-analysis according to between-study heterogeneity. Twenty-four studies (21 case-control and 3 cohort studies) were finally included into the meta-analysis. Those 21 case-control studies included a total of 1128 cases of Alzheimer's disease and 2498 controls without Alzheimer's disease. Those 3 cohort studies included a total of 7327 participants. Meta-analysis showed that patients with Alzheimer's disease had lower levels of uric acid than healthy controls (weighted mean difference (WMD) = -0.77 mg/dl, 95% CI -2.28 to -0.36, P = 0.0002). High serum uric acid levels were significantly associated with decreased risk of Alzheimer's disease (risk ratio (RR) = 0.66, 95% CI 0.52-0.85, P = 0.001). There was low risk of publication bias in the meta-analysis. There is an inverse association between serum uric acid levels and Alzheimer's disease. High serum uric acid level is a protective factor of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

Hou

et al. 2015

Mol Neurobiol

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“…It has been suggested that APOE4 can result in excessive amyloid build up, interference with Tau metabolism, and/or disrupt lipid homeostasis and reduced neuronal plasticity; upregulating APOE levels might thus be protective. There is thus a close relationship between cholesterol transport and amyloid deposition-although the precise interrelationship needs to be clarified [244,245]. Although an interesting effect, the possible influence of CBD on cholesterol efflux has not been further verified, and the precise molecular targets are not known; the concentrations required are also quite high.…”

Section: Cbd Transporter Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…Specifically, NMEs that target acetylcholinesterase (AChE) 18 or N-methyl-D-aspartate (NMDA) receptors 19 were discovered through research on these neurotransmitter pathways and were only later applied to AD therapy. Moreover, the most common genetic risk factor for both sporadic and familial forms of AD, the apolipoprotein E4 allele, 20 was first described as a risk factor for cardiovascular disease and is now considered an important biomarker in AD. In fact, 1 of the important strategies for current research is repurposing drugs from other indications.…”

Section: Introductionmentioning

confidence: 99%

Patterns of Innovation in Alzheimer’s Disease Drug Development: A Strategic Assessment Based on Technological Maturity

Beierlein

McNamee

Walsh

et al. 2015

Clinical Therapeutics

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This analysis suggests that AD drug discovery has followed a predictable pattern of innovation in which technological maturity is an important determinant of success in development. Quantitative analysis indicates that the lag in emergence of new products, and the much-heralded clinical failures of recent years, should be viewed in the context of the ongoing maturation of AD-related technologies. Although these technologies were not sufficiently mature to generate successful products a decade ago, they may be now. Analytical models of translational science can inform basic and clinical research results as well as strategic development of new therapeutic products.

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Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer's disease

Cited by 91 publications

References 74 publications

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

Molecular Targets of Cannabidiol in Neurological Disorders

Patterns of Innovation in Alzheimer’s Disease Drug Development: A Strategic Assessment Based on Technological Maturity

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