Journal of Alzheimer's Disease - Volume 29, issue 3

Authors: Morley, John E. | Farr, Susan A.

Article Type: Review Article

Abstract: Hormesis is the concept that low doses of a toxin can have beneficial effects while high doses are harmful. This is also known as the inverted-U shaped dose-response curve. Hormesis appears to be a universal law for the function of memory mimetics. Amyloid-β protein is widely recognized to be a toxic agent responsible for plaque formation in Alzheimer's disease. In high doses it also produces amnesia. In lower, physiological doses, it enhances long term potentiation and memory. Blocking amyloid-β protein in animals without overproduction of the protein results in amnesia. At low doses, amyloid-β also increases neurite outgrowth, produces presynaptic …enhancement, and may quench oxidative damage. It is postulated that both over- and underproduction of amyloid-β can lead to memory deficits. This is similar to a number of hormonal diseases, e.g., thyroid, where both low and high levels produce disease. Show more

Keywords: Alzheimer's disease, amyloid-β protein, dose response, memory, oxidative damage

DOI: 10.3233/JAD-2011-111928

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 487-492, 2012

Authors: Squitti, Rosanna | Polimanti, Renato

Article Type: Research Article

Abstract: Sporadic Alzheimer's disease (LOAD) is the most common form of dementia and has a high heritability. The genes associated with LOAD explain a small proportion of the genetic contribution to LOAD, leaving several genetic risk factors to be identified. Some authors have suggested a shift from the paradigm “common disease-common gene variants”, which is currently the basis for genome-wide association studies, to a “common disease-multiple rare gene variants” hypothesis aimed at identifying rarer allele variants with large effect size on LOAD onset, suggesting that they may account for the ‘missing’ heritability of LOAD. Recent studies have demonstrated the connection between …copper imbalance and LOAD. Some studies have pointed out the pivotal role of ‘free’ copper, the portion of serum copper non-bound to ceruloplasmin. Free copper has been already identified as a biological marker of Wilson's disease (WD), the paradigmatic disease of free copper toxicosis or accumulation. The ATP7B gene controls free copper levels, and its mutations cause WD. The paradigm shift to “common disease-multiple rare variants” may suitably fit the ATP7B gene; the high heterogeneity of the ATP7B gene may have hidden multiple rare variants with large effect sizes for LOAD. Demonstrating that the ATP7B gene harbors rare variants which may account for some of the missing hereditability of LOAD would support previous evidence of copper involvement in LOAD from a new and totally different perspective and would bring almost immediate benefits in the clinical community in terms of early diagnosis, treatment efficacy, LOAD prevention, and cost savings. Show more

Keywords: Alzheimer's disease, copper, genetic loci, genetic predisposition to disease

DOI: 10.3233/JAD-2011-111991

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 493-501, 2012

Authors: Petrofes Chapa, Rachel D. | Emery, Michael A. | Fawver, Janelle N. | Murray, Ian V.J.

Article Type: Research Article

Abstract: This paper propounds the Amyloids as Sensors and Protectors (ASAP) hypothesis. In this novel hypothesis, we provide evidence that amyloids are capable of sensing dysfunction, and after misfolding, initiate protective cellular responses. Amyloid proteins are initially protective, but chronic stress and overstimulation of the amyloid sensor leads to pathology. This proposed ASAP hypothesis has two sequential stages: (i) sensing, and then (ii) protection. Sensing involves a conformational change of amyloids in response to the cellular environment. The protection aspect translates conformational change into a cellular response via several mechanisms. The most obvious mechanism is that protein misfolding triggers the protective …unfolded protein response, and thus downregulates protein translation and increases chaperone proteins. Other documented responses include metabolic pathways and microRNAs. This ASAP hypothesis has precedence, as amyloid sensors exist (evidenced by CPEB and Sup35), and both prion and amyloid-β sensing redox stress and metals. Our hypothesis expands on previous observations to link sensing with inciting protective cellular response. Furthermore, we substantiate the ASAP hypothesis with previously published evidence from several amyloid diseases. This novel hypothesis links disparate findings in amyloid diseases: metabolic dysfunction, unfolding protein response/chaperones, modification of amyloids, and nutrient or caloric sensing. While this hypothesis can be applied to Alzheimer's disease, it goes beyond the Alzheimer's context. Thus all amyloid proteins can potentially act as sensors of misfolding-causing stress. Finally, this hypothesis will allow for the sensor mechanism and metabolic dysfunction to serve as biomarkers of the diseases as well as therapeutic targets early in disease pathology. Show more

Keywords: β-sheet, ER stress, prion, protein misfolding, uncoupling protein response

DOI: 10.3233/JAD-2012-112015

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 503-514, 2012

Authors: Xing, Yao-Yao | Yu, Jin-Tai | Cui, Wei-Zhen | Zhong, Xiao-Ling | Wu, Zhong-Chen | Zhang, Qun | Tan, Lan

Article Type: Short Communication

Abstract: Variants in the clusterin gene have been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels.

Keywords: Alzheimer's disease, concentration, clusterin, plasma, polymorphism

DOI: 10.3233/JAD-2011-111844

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 515-519, 2012

Authors: Ma, Xiao-Ying | Yu, Jin-Tai | Wu, Zhong-Chen | Zhang, Qun | Liu, Qiu-Yan | Wang, Hui-Fu | Wang, Wei | Tan, Lan

Article Type: Short Communication

Abstract: We conducted a replication study of the 2 genetic variants, rs11754661 and rs2073067, in MTHFD1L that have been recently reported to be associated with late-onset Alzheimer's disease (LOAD) in a genome-wide study in Caucasians. The associations were evaluated in a case-control sample comprising 1,189 Northern Han-Chinese individuals. The rs11754661 polymorphism is associated with LOAD (OR = 1.727; p = 0.016). For rs2073067, LOAD association was found only in APOEε4 carriers (OR = 0.400; p < 0.001). Haplotype analysis revealed the “AC” haplotype increased the risk of developing LOAD (OR = 1.730; p = 0.015). Our findings support a role of …MTHFD1L gene in LOAD. Show more

Keywords: Alzheimer's disease (AD), homocysteine, MTHFD1L, single nucleotide polymorphism

DOI: 10.3233/JAD-2011-111847

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 521-525, 2012

Authors: Dubois, Bruno | Zaim, Mohammed | Touchon, Jacques | Vellas, Bruno | Robert, Philippe | Murphy, Michael F. | Pujadas-Navinés, Francesc | Rainer, Michael | Soininen, Hilkka | Riordan, Henry J. | Kanony-Truc, Claire

Article Type: Research Article

Abstract: New criteria related to prodromal Alzheimer's disease (AD) have been proposed to overcome the issue of heterogeneity of patients with mild cognitive impairment (MCI) and to better define patients in early stage AD. Only few therapeutic trials, if any, have been reported using this newly defined population. The objective of this study was to assess the clinical efficacy and safety of a novel pro-cholinergic drug (V0191) in patients with prodromal AD. Two hundred forty two (242) patients with a diagnosis of prodromal AD were randomized in an approximately 1 : 1 ratio to receive either 1500 mg V0191 or matching …placebo once daily for 24 weeks. Changes in global cognitive functioning were assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog; responder rate as primary efficacy measure). Standardized measures of memory, executive function, attention, functional capacity, and apathy were also obtained. Despite some interesting trends at week 12 and conversion rates favoring V0191, no statistically significant differences in cognitive function between V0191 and placebo were noted. In addition to the absence of drug efficacy on this population, several design features may have hindered this study, including insufficient powering to assess changes in cognition over time, a relatively short duration of treatment, and the lack of validated clinical trial measures designed to assess the prodromal AD population. Lessons learned in AD study design optimization, including those presented in this paper, could be valuable for further investigation with pro-cholinergic drugs such as V0191. Show more

Keywords: Acetylcholine, Alzheimer's disease, cholinergic, drug, MCI, memory, prodromal Alzheimer's disease

DOI: 10.3233/JAD-2012-111370

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 527-535, 2012

Authors: Filippov, Valery | Song, Minwoo Andrew | Zhang, Kangling | Vinters, Harry V. | Tung, Spencer | Kirsch, Wolff M. | Yang, Jun | Duerksen-Hughes, Penelope J.

Article Type: Research Article

Abstract: Ceramide has been suggested to participate in the neuronal cell death that leads to Alzheimer's disease (AD), but its role is not yet well-understood. We compared the levels of six ceramide subspecies, which differ in the length of their fatty acid moieties, in brains from patients who suffered from AD, other neuropathological disorders, or both. We found elevated levels of Cer16, Cer18, Cer20, and Cer24 in brains from patients with any of the tested neural defects. Moreover, ceramide levels were highest in patients with more than one neuropathologic abnormality. Interestingly, the range of values was higher among brains with neural …defects than in controls, suggesting that the regulation of ceramide synthesis is normally under tight control, and that this tight control may be lost during neurodegeneration. These changes, however, did not alter the ratio between the tested ceramide species. To explore the mechanisms underlying this dysregulation, we evaluated the expression of four genes connected to ceramide metabolism: ASMase, NSMase 2, GALC, and UGCG. The patterns of gene expression were complex, but overall, ASMase, NSMase 2, and GALC were upregulated in specimens from patients with neuropathologic abnormalities in comparison with age-matched controls. Such findings suggest these genes as attractive candidates both for diagnostic purposes and for intervening in neurodegenerative processes. Show more

Keywords: Alzheimer's disease, ceramide, neurodegeneration, sphingolipid biosynthesis, sphingolipid regulation

DOI: 10.3233/JAD-2011-111202

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 537-547, 2012

Authors: Wang, Tao | Wang, Chun-Yan | Shan, Zhong-Yan | Teng, Wei-Ping | Wang, Zhan-You

Article Type: Research Article

Abstract: Metal dyshomeostasis in the brain helps promote amyloid-β (Aβ) deposition in Alzheimer's disease (AD). Therefore, targeting the interactions between metal and Aβ is a potential therapeutic approach for AD. The metal chelator, clioquinol (CQ), is thought to reduce Aβ deposits in the AD transgenic mouse brain, and attenuate the clinical symptoms of AD patients. However, whether oral administration of CQ reduces zinc accumulation in Aβ plaques and inhibits the amyloidogenic pathway have not been properly established in AD transgenic mice. By means of autometallographic analysis, we show for the first time that both the number and size of the zinc-containing …plaques were significantly reduced in the brain of amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double transgenic mice treated with CQ (30 mg/kg/day) orally for 2 months. This was accompanied by a reduction in Aβ burden in the CQ-treated mouse brain. Furthermore, CQ treatment markedly reduced the expression levels of AβPP protein, the β-site of AβPP cleaving enzyme 1 (BACE1), PS1, and the secreted β-secretase-derived fragments of AβPP (sAβPPβ). The present data indicate that CQ is able to reduce zinc accumulation in the neuritic plaques and inhibit amyloidogenic AβPP processing in the AβPP/PS1 mouse brain. Show more

Keywords: AβPP/PS1 transgenic mouse, Alzheimer's disease, amyloid-β, amyloidogenic pathway, clioquinol, zinc

DOI: 10.3233/JAD-2011-111874

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 549-559, 2012

Authors: Grima, Natalie A. | Pase, Matthew P. | Macpherson, Helen | Pipingas, Andrew

Article Type: Research Article

Abstract: Complementary medicine use is becoming increasingly popular with multivitamins being the most commonly used vitamin supplement. Although adequate vitamin and nutrient concentrations are necessary for optimal health and cognitive functioning, there is no scientific consensus as to whether multivitamin use prevents cognitive decline or improves mental functioning. The aim of the present study was to determine if multivitamins can be used efficaciously to improve cognitive abilities. A systematic review of randomized controlled trials was performed. Meta-analysis was performed on those cognitive tests used across the largest number of studies. Multiple electronic databases were searched until July 2011 by two authors. …Randomized, placebo-controlled trials were considered appropriate if they reported on the chronic effects (≥1 month) of oral multivitamin supplementation on any valid cognitive outcomes. Ten trials were included in review (n = 3,200). Meta-analysis indicated that multivitamins were effective in improving immediate free recall memory (SMD = 0.32; 95% CI: 0.09–0.56, p < 0.01) but not delayed free recall memory (SMD = −0.14; 95% CI: −0.43–0.14, p = 0.33) or verbal fluency (SMD = 0.06; 95% CI: −0.05–0.18, p = 0.26). There was no evidence of publication bias or heterogeneity. Other cognitive abilities sensitive to AD pathology, such as executive and visuospatial functions, were found to be under researched. In conclusion, multivitamins were found to enhance immediate free recall memory but no other cognitive domains. Show more

Keywords: Cognition, cognitive, dementia, memory, multivitamin, vitamin, nutrients, meta-analysis, review, pharmacology

DOI: 10.3233/JAD-2011-111751

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 561-569, 2012

Authors: Bakulski, Kelly M. | Dolinoy, Dana C. | Sartor, Maureen A. | Paulson, Henry L. | Konen, John R. | Lieberman, Andrew P. | Albin, Roger L. | Hu, Howard | Rozek, Laura S.

Article Type: Research Article

Abstract: Evidence supports a role for epigenetic mechanisms in the pathogenesis of late-onset Alzheimer's disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 …matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-β protein precursor post-translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets. Show more

Keywords: DNA methylation, epigenetics, late onset Alzheimer's disease, prefrontal cortex

DOI: 10.3233/JAD-2012-111223

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 571-588, 2012