Journal of Alzheimer's Disease - Volume 42, issue 1

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.

Keywords: Alzheimer's disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine

DOI: 10.3233/JAD-140402

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 1-68, 2014

Authors: ManafiRad, Arash | Farzadfar, Farshad | Habibi, Laleh | Azhdarzadeh, Morteza | Aghaverdi, Haniyeh | Tehrani, Khadijeh H. | Lotfi, Mina | Kehoe, Patrick G. | Sheidaei, Ali | Ghasemian, Anoosheh | Darzi, Ehsan Rezaei | Mahmoodi, Ramin | Mahmoudi, Morteza

Article Type: Research Article

Abstract: Two decades of the amyloid-β (Aβ) hypothesis in Alzheimer's disease (AD) and the prominence of Aβ-targeting strategies have yet to meet the levels of original expectation. Disappointing results in numerous Phase II/III studies have called for a re-examination of the validity of the Aβ-targeting approaches as an intervention strategy in AD. The mid-life onset of chronic conditions (e.g., hypertension, diabetes, insulin intolerance, and depression nominated as risk factors for the later development of AD) points to the possibility that each condition could involve mechanisms, which while relatively modest over a short-term, could have significant accumulative effects. What may also not …be fully appreciated is that a number of these conditions involve potential disturbances to multivalent cations (MC) levels through various mechanisms such as autophagy, oxidative stress, and apoptosis. Furthermore, some MCs have intimate associations with the mechanisms by which Aβ pathology manifests. Considering various lines of evidence and incorporating statistical analysis on Disability–Adjusted Life Years (DALYs) data of both causes of and prevalence of multifactorial risk factors in different world regions, we propose an MC hypothesis for AD. More specifically, we suggest that MC imbalance marks many chronic conditions and because of their involvement with Aβ pathology, could reflect that Aβ may be a vital manifestation and marker of underlying MC imbalance. Thus, careful targeting of MC imbalance may provide an alternative or complementary interventional approach to current Aβ treatment strategies. Show more

Keywords: Alzheimer's disease, amyloid-β pathology, cellular integrity, chronic conditions, lifestyle, multivalent cations homeostasis, risk factors

DOI: 10.3233/JAD-140321

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 69-85, 2014

Authors: Pesini, Alba | Iglesias, Eldris | Garrido, Nuria | Bayona-Bafaluy, M. Pilar | Montoya, Julio | Ruiz-Pesini, Eduardo

Article Type: Research Article

Abstract: We present a new hypothesis on the contribution of a dysfunction of the oxidative phosphorylation system, through a decrease in the de novo synthesis of pyrimidine nucleotides, to the pathogenesis of late onset Alzheimer's disease (AD). In the light of this proposition, different treatments for AD patients, such as enhancing the electron flow downstream the coenzyme Q10 of the mitochondrial respiratory chain or increasing mitochondrial biogenesis or directly providing pyrimidines, would be possible. AD is a multifactorial disorder and not all patients would benefit from these treatments. Those healthy individuals harboring mtDNA haplotypes related to a coupled OXPHOS function …would probably be the better candidates for these preventive therapies. Show more

Keywords: Alzheimer's disease, coenzyme Q10, de novo pyrimidine biosynthesis, dihydroorotate dehydrogenase, mitochondrial DNA, oxidative phosphorylation

DOI: 10.3233/JAD-140384

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 87-96, 2014

Authors: Pujol-Gimenez, Jonai | Martisova, Eva | Perez-Mediavilla, Alberto | Lostao, María Pilar | Ramirez, Maria J.

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) might be conceptualized as a metabolic disease with progressive impairment of the brain's capacity to utilize glucose. One of the last glucose transporters discovered is GLUT12. The aim of the present work was to investigate the expression of GLUT12 in frontal cortex from AD patients. Human samples from young control donors barely expressed GLUT12. The level of expression of GLUT12 was significantly higher in AD compare to aged controls. Expression of GLUT12 and Ox-42, a microglia marker, correlate in controls but not in AD. The implications of these findings in AD are discussed further.

Keywords: Frontal cortex, glucose transport, microglia, western blot

DOI: 10.3233/JAD-132498

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 97-101, 2014

Authors: Maya-Vetencourt, José Fernando | Carucci, Nicola Maria | Capsoni, Simona | Cattaneo, Antonino

Article Type: Short Communication

Abstract: Autosomal dominant forms of familial Alzheimer's disease are linked to an aberrant processing of the amyloid-β protein precursor, which results in an increased production of amyloid-β (Aβ) peptides that first form oligomers and eventually aggregate in the form of extracellular amyloid plaques in the brain. The accumulation of Aβ peptides oligomers seems to correlate with alterations of synaptic transmission in experimental models of Alzheimer's disease. Whether Aβ aggregation disrupts synaptic function independently of amyloid plaques deposition still needs further research. Here we report an amyloid plaque-independent deficit of neuronal plasticity after short-term sensory deprivation in the visual system of 5XFAD …mice. Show more

Keywords: 5XFAD, amyloid-β peptides, plasticity impairment, sensory deprivation, visual system

DOI: 10.3233/JAD-140453

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 103-107, 2014

Authors: Müller, Ulrich | Winter, Pia | Bolender, Claus | Nolte, Dagmar

Article Type: Short Communication

Abstract: Mutations in the gene PSEN2 are a rare cause of early onset Alzheimer's disease (EOAD). PSEN2 sequence variants are often only found in one patient and pathogenicity cannot be formally documented. Here we describe a previously unrecognized sequence change (c.376G>A) in PSEN2 in an EOAD patient and her likewise affected mother. This change results in the exchange of amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). Pathogenicity of the mutation is shown by segregation with disease, evolutionary conservation of E126, and in silico analysis of the mutation.

Keywords: Alzheimer's disease, early onset Alzheimer disease, E126K PSEN2 mutation, familial segregation, PSEN2

DOI: 10.3233/JAD-140399

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 109-113, 2014

Authors: O'Day, Danton H. | Catalano, Andrew

Article Type: Short Communication

Abstract: Reports that Lyme disease (LD) causes Alzheimer's disease (AD) have appeared in academic journals and online. If the biological agent Borrelia burgdorferi that causes LD also causes AD, then areas with the highest levels of LD should have significantly higher numbers of deaths due to AD compared to low LD areas. Here we show there is no statistically significant correlation between the incidence of LD and deaths due to AD in the US. Furthermore, the 13 states with the highest deaths due to AD were statistically different (p < 0.0001) from those with high LD incidence.

Keywords: Alzheimer's disease, Borrelia burgdorferi, disease incidence, lyme disease

DOI: 10.3233/JAD-140552

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 115-118, 2014

Authors: Di Marco, Luigi Yuri | Marzo, Alberto | Muñoz-Ruiz, Miguel | Ikram, M. Arfan | Kivipelto, Miia | Ruefenacht, Daniel | Venneri, Annalena | Soininen, Hilkka | Wanke, Isabel | Ventikos, Yiannis A. | Frangi, Alejandro F.

Article Type: Research Article

Abstract: Background: Numerous population-based longitudinal studies suggest an association between modifiable lifestyle factors and late-life dementia. A comprehensive description of these factors and their quantification criteria is an important preliminary step toward the elucidation of causes and mechanisms underlying the onset and progression of dementia. Objective: To present a systematic review of modifiable lifestyle factors associated with dementia risk in longitudinal observational cohort-studies. Methods: A systematic review of original articles, published in English until December 2013, listed in four electronic databases (including PubMed, MEDLINE, PsycINFO) was conducted. Results: 75 papers from 33 epidemiologic studies met …the inclusion criteria. Included papers focused on dietary habits (n = 26), leisure activities (social, physical, mental) (n = 23), beverages (juice, tea, coffee, alcohol) (n = 15), smoking (n = 13), social network (n = 6), and combined lifestyle factors (n = 2). Conclusions: Broad consensus emerged on the protective role against dementia of leisure activities. Conflicting results were found for the association between dementia and putative risk factors (smoking) and protective factors (mild-to-moderate alcohol consumption, dietary antioxidants, Mediterranean diet, and living with others). However, studies varied largely in the quantification of lifestyle factors in terms of intensity, frequency and duration of exposure, and in the choice of confounders in statistical analyses. The need for standardized quantification criteria emerges, together with the current limitation in reliably tracking the past history of each patient, from childhood and young adulthood to midlife. Show more

Keywords: Alzheimer's disease, dementia, longitudinal observational cohort studies, modifiable lifestyle factors

DOI: 10.3233/JAD-132225

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 119-135, 2014

Authors: de Bruijn, Renée F.A.G. | Janssen, Joseph A.M.J.L. | Brugts, Michael P. | van Duijn, Cornelia M. | Hofman, Albert | Koudstaal, Peter J. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Insulin-like growth factor-I (IGF-I) is a pleiotropic hormone. Several studies have related IGF-I levels to dementia, but evidence remains inconclusive. IGF-I receptor stimulating activity is a more direct measure of biologically available IGF-I than total IGF-I levels. Objective: To investigate whether IGF-I receptor stimulating activity is associated with prevalent and incident dementia. Methods: IGF-I receptor stimulating activity was measured using an IGF-I kinase receptor activation assay in 1,014 persons from the Rotterdam Study. Dementia was assessed at baseline (1997–1999) and continuously during follow-up until September 2011. Associations of IGF-I receptor stimulating activity with prevalent dementia …were investigated using logistic regression and with incident dementia using Cox proportional hazards models. All models were adjusted for age and gender, and additionally for hypertension, glucose, waist circumference, APOE-ε4 carrier status, total cholesterol, and HDL-cholesterol. Results: Thirty participants had prevalent dementia and during 8,589 person-years of follow-up, 135 persons developed incident dementia. A higher level of IGF-I receptor stimulating activity was associated with a higher prevalence of dementia (fully adjusted odds ratio 1.47; 95% CI 1.10–1.97) and with a higher risk of incident dementia (fully adjusted hazard ratio 1.15; 95% CI 1.00–1.33). Similar associations were found for Alzheimer’s disease and in persons without diabetes mellitus. Conclusions: Higher levels of IGF-I receptor stimulating activity are associated with a higher prevalence and with a higher incidence of dementia. These results suggest that IGF-I increases in response to neuropathological changes in dementia and could reflect a state of IGF-I resistance in dementia. Show more

Keywords: Alzheimer's disease, dementia, epidemiology, insulin-like growth factor-I

DOI: 10.3233/JAD-140186

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 137-142, 2014

Authors: Araya, Juan A. | Ramírez, Alejandra E. | Figueroa-Aroca, Daniela | Sotes, Gastón J. | Pérez, Claudia | Becerra, Jose | Saez-Orellana, Francisco | Guzmán, Leonardo | Aguayo, Luis G. | Fuentealba, Jorge

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive and neurodegenerative disorder and one of the current therapies involves strengthening the cholinergic tone in central synapses. Neuroprotective properties for nicotine have been described in AD, through its actions on nicotinic receptors and the further activation of the PI3K/Akt/Bcl-2 survival pathway. We have tested a quinolizidine alkaloid extract (TM0112) obtained from Teline monspessulanna (L.) K. Koch seeds to evaluate its action on nicotinic acetylcholine receptor (nAChR) in a neuronal AD model. Our data show that PC-12 cells pretreated with amyloid-β (Aβ) peptide for 24 h in presence of TM0112 modified Aβ-reduction on cellular viability …(Aβ = 80 ± 3%; +TM0112 = 113 ± 4%, n = 15). In addition, this effect was blocked with atropine, MLA, and α-BTX (+TM0112+atropine = 87 ± 4%; +TM0112+MLA = 86 ± 4%; +TM0112+α-BTX = 92 ± 3%). Furthermore, similar protective effects were observed in rat cortical neurons (Aβ = 63 ± 6%; +TM0112 = 114 ± 8%), but not in HEK293T cells (Aβ = 61.4 ± 6.1%; +TM0112 = 62.8 ± 5.2) that do not express α7 nAChR. Moreover, the frequency of synaptic activity in the neuronal network (Aβ = 51.6 ± 16.9%; +TM0112 = 210.8 ± 47.9%, n > 10), as well as the intracellular Ca2+ transients were recovered by TM0112 (Aβ = 61.4 ± 6.9%; +TM0112 = 112.0 ± 5.7%; n = 3) in rat hippocampal neurons. TM0112 increased P-Akt, up to 250% with respect to control, and elevated Bcl-2/Bax percentage (Aβ = 61.0 ± 8.2%; +TM0112 = 105.4 ± 19.5%, n = 4), suggesting a coupling between nAChR activation and an intracellular neuroprotective pathway. Our results suggest that TM0112 could be a new potential source for anti-AD drugs. Show more

Keywords: Alkaloids, Alzheimer's disease, neuroprotection, nicotinic receptor, Teline monspessulana

DOI: 10.3233/JAD-132045

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 143-155, 2014