Current Alzheimer Research - Volume 11, Issue 9, 2014

In view that several studies have shown a positive correlation between high cholesterol and an increase in the risk for developing Alzheimer’s disease (AD) statins have been proposed as alternative drugs for its treatment and/or prevention. However, the potential benefits of statins remain controversial. Although they have lipid-lowering properties, statins also have pleiotropic effects that are unrelated to cholesterol reduction and have a wide range of biological implications whose consequences in brain function have not been fully characterized. In this work we analyze different studies that have reported both, beneficial and toxic effects for statins in the central nervous system (CNS), and we revise the literature that claims their potential for treating AD. First, we present an overview of the cholesterol metabolism and its regulation in the brain in order to provide the framework for understanding the pathological association between altered cholesterol and AD. Then, we describe the cholesterol-lowering and pleiotropic properties of statins that have been reported in vivo and in in vitro models. We conclude that the effects of statins in the brain are broad and complex and that their use for treating several diseases including AD should be carefully analyzed given their multiple and broad effects.

Accumulating research supports the neuroprotective effects of pomegranate (Punica granatum) juice and extracts against Alzheimer’s disease (AD) but there is limited data available in animal models. Here we investigated the effects of a standardized pomegranate extract (PE) on AD pathology in an aged transgenic AD animal model (R1.40).The mice (age 24-30 months) received either PE (at 100 and 200 mg/kg) or a control solution daily for three weeks, and were evaluated in the Morris water maze and the Y-maze for improvements in spatial long-term and working memory functions. Cortical amyloid-β precursor protein (APP) and amyloid-β (Aβ) levels, along with other relevant biomarkers for AD, were measured in brain tissues. PE did not improve cognitive performance of the mice, but altered levels and ratio of the Aβ42 and Aβ40 peptides which would favor a diminution in AD pathogenesis. Further analysis revealed that this reversal could be the product of the modification of γ-secretase enzyme activity, the enzyme involved in the generation of these Aβ isoforms. Our findings support a specific anti-amyloidogenic mechanism of a pomegranate extract in this aged AD animal model.

Despite B vitamin supplementation playing an important role in cognitive function, the exact effect remains unknown. The aim of this study was to systematically review and quantitatively synthesize the efficacy of treatment with vitamins B supplementation in slowing the rate of cognitive, behavioral, functional and global decline in individuals with MCI or AD. A systematic literature search in PubMed, EMBASE, International Pharmaceutical Abstracts, clinicaltrials. gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry was conducted on April 2014, with no limit of date. Five trials met the eligibility criteria and were selected for this meta-analysis. Meta-analysis showed moderate beneficial effects of vitamins B supplementation on memory (SMD 0.60, 95% CI 0.20, 1.00), whereas no significant difference on general cognitive function (WMD -0.10, 95% CI -0.80, 0.59), executive function (SMD 0.05, 95% CI -0.11, 0.21) and attention (WMD -0.03, 95% CI -1.20, 1.14) were found in MCI patients. In addition, no significantly cognitive benefits on the Alzheimer’s Disease Assessment Scale (ADAS-cog) (WMD 1.01, 95% CI -0.68, 2.70) and Mini Mental State Examination (MMSE) (WMD -0.22, 95% CI -1.00, 0.57), functional (SMD 0.13, 95% CI -0.05, 0.31), behavioral (SMD 0.04, 95% CI -0.16, 0.25) or global (WMD 0.07, 95% CI -0.48, 0.62) change were observed in AD patients. Collectively, weak evidence of benefits was observed for the domains of memory in patients with MCI. Nevertheless, future standard RCTs are still needed to determine whether it was still significant in larger populations. However, the data does not yet provide adequate evidence of an effect of vitamins B on general cognitive function, executive function and attention in people with MCI. Similarly, folic acid alone or vitamins B in combination are unable to stabilize or slow decline in cognition, function, behavior, and global change of AD patients.

Background: Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer’s disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to determine which of the IADL-related Everyday Cognition (ECog) scale items are most sensitive for detection of early functional changes. Methods: We assessed 290 CN and 495 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative. We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using only the 17 participant-based and 17 informant-based ECog items related to IADL. We then performed Cox regression analyses to predict progression from CN to MCI. All analyses were adjusted for demographic characteristics. Results: We found that worse performance on “remembering a few shopping items” (participant and informant-based p<0.0001), “remembering appointments” (participant and informant-based p<0.0001), “developing a schedule in advance of anticipated events” (participant-based p=0.007), “balancing checkbook” (participant-based p=0.02), and “keeping mail and papers organized” (informant-based p=0.002) best discriminated MCI from CN. We found that worse performance on “keeping mail and papers organized” (participant-based Hazard Ratio (HR)=2.27, p=0.07) marginally predicted greater hazard of progressing from CN to MCI. Conclusions: Our results indicate that a few simple questions targeting early functional changes, addressed either to the individual or informant, can effectively distinguish between CN elderly and individuals with MCI. Additionally, one of the above questions related to organization suggested which CN individuals are likely to progress to MCI.

Diabetes is a well-known risk factor for Alzheimer`s disease (AD) development in the elderly. The molecular link between diabetes and AD is still not completely understood. Recent evidence suggests that platelet activation observed in diabetes may contribute to AD development. The present review summarizes the common molecular mechanisms involved in the pathophysiology of diabetes and AD and suggests novel therapeutic targets for prevention of the onset or slowing the progression of this disease.

Background: Alzheimer's disease (AD) is the most common type of age-related dementia. Effective anti-AD drugs against amyloid-β-protein-induced cognitive impairment are still lacking. Baicalein is the main component of Radix Scutellariae and has neuroprotective properties. In this study, we provide further insights into pharmacotherapy mechanisms and potential targets of baicalein in AD. Objective: To investigate the therapeutic effects and mechanism of action of baicalein in an AD rat model. Methods: Male rats were intracerebroventricularly injected with amyloid-β(Aβ) 1-40, and baicalein was orally administered. The therapeutic effect was evaluated with the Morris water maze test, and the mechanism of action was studied using a proteomics approach and western blotting. Results: Baicalein treatment significantly attenuated Aβ1-40-induced abnormalities in cognitive function. Additionally, the expression levels of 24 proteins in the cerebral cortex and hippocampus were significantly influenced by baicalein; approximately 50% of these proteins are related to energy metabolism and neurotransmission, whereas others are related to anti-apoptosis, anti-oxidation, the stress response, protein phosphorylation, the cytoskeleton, phospholipid metabolism and cell signaling. The expression of these proteins was increased, except for the proteins related to the cytoskeleton. The changes in the expression of 2 proteins were confirmed by western blotting. Conclusions: Baicalein ameliorates the Aβ1-40-induced dementia in rats and may be a novel and promising drug for the treatment of AD. The therapeutic mechanism may be related to modulation of a number of processes, mainly through the promotion of energy metabolism and neurotransmission, with the additional promotion of anti-apoptosis, anti-oxidation, protein phosphorylation, etc.

Alzheimer’s disease (AD) is the most common reason for dementia in elderly population. Its neuropathological features include senile plaques, neurofibril tangles and neuronal death. Scientists have established many AD animal models, including yeast, Caenorhabditis elegans, Drosophila melanogaster, mice, rats and non-human primates. Drosophila AD models are much more efficient for genetic manipulation and screening assay than mammals. microRNAs (miRNAs) are ~22nt small RNA molecules that fine-tune gene expression at posttranscriptional level. The dysregulation of miRNAs could participate in AD progression by influencing targets’ expression and functions. However, miRNA expression profile of AD flies has not yet been investigated. Using the latest µParaflo™ miRNA microarray assay, we found that 17 miRNAs that were consistently dysregulated in adult-onset AD Drosophila brains: eight of which were upregulated (miR- 8, miR-13b, miR-277, miR-279, miR-981, miR-995, miR-998, miR-1017) and nine were downregulated (let-7, miR-1, miR-9a, miR-184, miR-193, miR-263b, miR-276a, miR-285, miR-289). KEGG pathway annotations using DIANA miRPath or targets predicted by Targetscan identified 7 pathways (Valine, leucine and isoleucine degradation; MAPK signaling pathway; Dorso-ventral axis formation; Propanoate metabolism; Sphingolipid metabolism; Lysine degradation; Jak- STAT signaling pathway) which might be influenced by these miRNAs. Integrative miRNA/mRNA regulatory network analysis revealed functional cluster with transaminase activity to be potentially regulated by miRNAs in AD. Taken together, our profiling assay identified miRNAs as markers for adult onset AD Drosophila. Dysregulation of miRNA profile may participate in AD pathogenesis by interrupting the metabolism of amino acids in the brain.

We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer’s disease (AD) patients when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer’s disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to-moderate dementia (CDR 1- 2, n=13), and 15 healthy controls (HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and propidium iodide staining. The greatest susceptibility to H2O2-induced death was observed for lymphocytes from severe dementia patients, whereas those with mild-to-moderate dementia exhibited intermediate values, compared to healthy controls. A significant increase in the apoptosis/necrosis ratio was found in AD patients. Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibition significantly protected from H2O2-induced death of lymphocytes, whereby a lower degree of protection was observed in severe AD patients. Moreover, inhibition of PARP-1 abolished the differences in apoptosis/necrosis ratios observed between the three groups of patients. These results support the notion that AD is a systemic disorder, whereby enhanced susceptibility to H2O2-induced death in peripheral lymphocytes correlates with dementia severity and enhanced death in AD patients is attributable to a PARP-dependent increase in the apoptosis/necrosis ratio.

Background: Previous studies relating smoking and alcohol drinking with the incidence of dementia have been inconsistent. Objectives: We assessed whether smoking and alcohol drinking was associated with the risk of dementia, including Alzheimer disease (AD) and vascular dementia (VaD) after seven years of follow-up. Design: We prospectively analysed the incidence of dementia from 2004 to 2011 among 2959 elderly men, according to their smoking and alcohol drinking status. Setting: six neighbourhoods from three districts mentioned in Chongqing city. Participants: A total of 3170 men were followed up annually for 7 years. Measurements: Cox proportional hazards models were established to evaluate the association between smoking, alcohol drinking and the risk of dementia. Results: The incidences of AD and VaD were higher respectively in current smoking than never smoking, daily drinking than never drinking over 7 years of follow-up (p<0.01). After adjusting for age and other potential confounders, current smoking was associated with increased risk of AD (HR= 2.14, 95% CI 1.20-4.46) and VaD (HR= 3.28, 95% CI 1.14-4.52), meanwhile, daily drinking was related to increased risk of AD (HR= 2.25, 95% CI 1.43-3.97) and VaD (HR= 3.42, 95% CI 1.18-4.51). In addition, co-smoking and drinking were related to with a significantly higher risk of AD and VaD than non-smoking and drinking (HR= 3.03, 95% CI 1.65-4.19) and VaD (HR= 3.96, 95% CI 1.64-4.71). Moreover, co-smoking and drinking had higher risk of AD and VaD compared with current smoking and daily drinking. Conclusions: Current smoking and daily drinking were found to be significantly associated with dementia in elderly men.