Journal of Alzheimer's Disease - Volume 40, issue 1

Authors: Perez, Felipe P. | Bose, David | Maloney, Bryan | Nho, Kwangsik | Shah, Kavita | Lahiri, Debomoy K.

Article Type: Review Article

Abstract: Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder in older adults, affecting over 50% of those over age 85. Aging is the most important risk factor for the development of LOAD. Aging is associated with the decrease in the ability of cells to cope with cellular stress, especially protein aggregation. Here we describe how the process of aging affects pathways that control the processing and degradation of abnormal proteins including amyloid-β (Aβ). Genetic association studies in LOAD have successfully identified a large number of genetic variants involved in the development of the disease. However, there is a gap …in understanding the interconnections between these pathomolecular events that prevent us from discovering therapeutic targets. We propose novel, pertinent links to elucidate how the biology of aging affects the sequence of events in the development of LOAD. Furthermore we analyze and synthesize the molecular-pathologic-clinical correlations of the aging process, involving the HSF1 and FOXO family pathways, Aβ metabolic pathway, and the different clinical stages of LOAD. Our new model postulates that the aging process would precede Aβ accumulation, and attenuation of HSF1 is an “upstream” event in the cascade that results in excess Aβ and synaptic dysfunction, which may lead to cognitive impairment and/or trigger “downstream” neurodegeneration and synaptic loss. Specific host factors, such as the activity of FOXO family pathways, would mediate the response to Aβ toxicity and the pace of progression toward the clinical manifestations of AD. Show more

Keywords: Amyloid, autophagy, cognition, dementia, heat-shock, neurodegeneration, protein aggregation, protein degradation, stress, transcription factor

DOI: 10.3233/JAD-131544

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 1-17, 2014

Authors: Maltsev, Alexander V. | Santockyte, Rasa | Bystryak, Simon | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: We present a new model for etiology of Alzheimer's disease (AD) which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD. These neuroprotective mechanisms work in concert to regulate metabolic homeostasis in healthy neuronal cells, but contribute to the distinctive cytopathic phenotype of neuronal degeneration in AD. According to this model, two molecular/genetic hallmarks of AD, amyloid-β (Aβ) deposition and tau hyperphosphorylation, are associated with neuronal mechanisms for dissipating thermal energy associated with high levels of protein synthesis in highly temperature-sensitive neuronal cells. Development of effective methods of AD treatment will require a better understanding of how …this neuronal defense system is activated in response to cytopathological triggers in sporadic AD. The cause and effect link between synthesis and processing of amyloid-β protein precursor (AβPP) and the AD terminal phenotype of neurofibrillary tangles and neuron loss involve the formation of Aβ peptides that accumulate as oligomers, cannot be controlled by neurons, and are toxic to the surrounding neuronal membranes. We analyze experimental and clinical studies that have investigated the correlation between phosphorylation of some transport proteins and increased synthesis of proteins in neurons. We also review the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis, and that activation of defense systems, through which energy-rich molecules are eliminated from the site of protein synthesis and are sequestered to the peripheral neuronal areas, may bring about some of the distinctive morphological features of AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, amyloidosis, cellular defense factors, hyperphosphorylation, neuron loss, phosphorylation, tau protein

DOI: 10.3233/JAD-131562

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 19-32, 2014

Authors: Flanagan, Emma C. | Tu, Sicong | Ahmed, Samrah | Hodges, John R. | Hornberger, Michael

Article Type: Short Communication

Abstract: Memory and orientation were investigated as predictors of underlying Alzheimer's disease (AD) pathology in patients with logopenic (lv) and non-fluent (na) variants of primary progressive aphasia (PPA). Memory and orientation scores from Addenbrooke's Cognitive Examination were compared between 26 lv-PPA, 29 na-PPA, 59 AD, and 90 controls using analysis of variance. Forty-five patients underwent Pittsburgh compound B (PiB) positron emission tomography scans. Patients with lv-PPA performed poorer on memory and orientation than na-PPA and did not differ from the AD group. Post-hoc analysis on the PiB-scanned subgroup corroborated these results. Memory and orientation profiles may supplement language assessment in identifying …patients with AD pathology. Show more

Keywords: Memory, orientation, PiB, PPA, lv-PPA, na-PPA

DOI: 10.3233/JAD-131448

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 33-36, 2014

Authors: Khan, Wasim | Giampietro, Vincent | Ginestet, Cedric | Dell'Acqua, Flavio | Bouls, David | Newhouse, Steven | Dobson, Richard | Banaschewski, Tobias | Barker, Gareth J. | Bokde, Arun L.W. | Büchel, Christian | Conrod, Patricia | Flor, Herta | Frouin, Vincent | Garavan, Hugh | Gowland, Penny | Heinz, Anreas | Ittermann, Bernd | Lemaître, Hervé | Nees, Frauke | Paus, Tomas | Pausova, Zdenka | Rietschel, Marcella | Smolka, Michael N. | Ströhle, Andreas | Gallinat, Jean | Westman, Eric | Schumann, Gunther | Lovestone, Simon | Simmons, Andrew | the IMAGEN consortium ()

Article Type: Short Communication

Abstract: Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimer's disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE ε4 or ε2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these polymorphisms may only become apparent in later life.

Keywords: Apolipoprotein E, hippocampal volume, magnetic resonance imaging, young healthy adolescents

DOI: 10.3233/JAD-131841

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 37-43, 2014

Authors: Gussago, Cristina | Arosio, Beatrice | Casati, Martina | Ferri, Evelyn | Gualandris, Federica | Tedone, Enzo | Nicolini, Paola | Rossi, Paolo Dionigi | Abbate, Carlo | Mari, Daniela

Article Type: Short Communication

Abstract: The line between vascular dementia (VaD) and Alzheimer's disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2A R) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2A R mRNA in VaD compared to AD subjects. These data suggest that A2A R expression may help in the differential diagnosis between VaD and AD.

Keywords: Adenosine receptors, Alzheimer's disease, biomarker, vascular dementia

DOI: 10.3233/JAD-131652

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 45-49, 2014

Authors: Homma, Taku | Takubo, Hideki | Takahashi, Kazushi | Matsubara, Shiro | Takahashi, Manabu | Funata, Nobuaki | Mochizuki, Yoko | Mizutani, Toshio | Komori, Takashi | Uchihara, Toshiki

Article Type: Short Communication

Abstract: Corticobasal syndrome (CBS) is characterized by lateralized motor disturbance due to levodopa nonresponsive parkinsonism and progressive apraxia. Although CBS is neuropathologically heterogeneous, it remains unclear whether the clinical features of all CBS cases are the same. We report two autopsy cases diagnosed clinically as CBS and pathologically as Alzheimer's disease characterized by lateralized cerebral cortical degeneration and absence of significant nigrostriatial lesions. Cerebral cortical degeneration in both cases was contralateral to their motor disturbances. Thus, nigrostriatial lesions and contralateral cerebral cortical lesions can cause motor disturbances in CBS, necessitating the need for bedside examination in patients with CBS.

Keywords: Alzheimer's disease, cerebral cortex, corticobasal syndrome, parkinsonism, striatonigral system

DOI: 10.3233/JAD-131676

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 51-55, 2014

Authors: Delva, Fleur | Auriacombe, Sophie | Letenneur, Luc | Foubert-Samier, Alexandra | Bredin, Alain | Clementy, Anne | Latxague, Chrystelle | Puymirat, Emmanuel | Ballan, Guillaume | Delabrousse-Mayoux, Jean-Phillipe | Glénisson, Laurent | Mazat, Lise | Spampinato, Umberto | Rainfray, Muriel | Tison, François | Dartigues, Jean-François

Article Type: Research Article

Abstract: Background: Knowledge of functional evolution in dementia is crucial for the patients and their families as well as the clinician. Objective: This review identifies scales and outcomes used to describe the natural history of functional decline and describes the natural history of functional decline in a representative clinical population sample of published studies of patients with Alzheimer’s disease (AD). Methods: A search of three relevant databases was conducted and limited to articles published in English and French between 1998 to March 2012, using the keywords “Dementia”, “Activities of Daily Living”, “Instrumental Activities of Daily Living”, “Functional …Impairment”, “Prognosis”, and “Disease Progression”. Results: The search strategy displayed 683 articles, 20 of which were found to be related to the functional evolution of AD. In these studies, different scales were used to describe the evolution of the functional decline, except for the decline of instrumental activities, for which the Lawton scale was used in all studies. Thus, it is difficult to represent the evolution of the functional decline from a clinical point of view. Conclusion: Relatively little data are available to estimate the functional evolution of AD. A consensus with broadened thought is required to know if the progression of the incapacities in these scales is additive or hierarchical. Show more

Keywords: Activities of daily living, Alzheimer's disease, prognosis, review

DOI: 10.3233/JAD-131862

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 57-67, 2014

Authors: Feld, Mariana | Krawczyk, María C. | Sol Fustiñana, M. | Blake, Mariano G. | Baratti, Carlos M. | Romano, Arturo | Boccia, Mariano M.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) can be considered as a disease of memory in its initial clinical stages. Amyloid-β (Aβ) peptide accumulation is central to the disease initiation leading later to intracellular neurofibrillary tangles (NFTs) of cytoskeletal tau protein formation. It is under discussion whether different Aβ levels of aggregation, concentration, brain area, and/or time of exposure might be critical to the disease progression, as well as which intracellular pathways it activates. The aim of the present work was to study memory-related early molecular and behavioral alterations in a mouse model of AD, in which a subtle deregulation of the physiologic function …of Aβ can be inferred. For this purpose we used triple-transgenic (3xTg) mice, which develop Aβ and tau pathology resembling the disease progression in humans. Memory impairment in novel object recognition task was evident by 5 months of age in 3xTg mice. Hippocampus and prefrontal cortex extra-nuclear protein extracts developed differential patterns of Aβ aggregation. ERK1/MAPK showed higher levels of cytosolic activity at 3 months and higher levels of nuclear activity at 6 months in the prefrontal cortex. No significant differences were found in JNK and NF-κB activity and in calcineurin protein levels. Finally, intra-PFC administration of a MEK inhibitor in 6-month-old 3xTg mice was able to reverse memory impairment, suggesting that ERK pathway alterations might at least partially explain memory deficits observed in this model, likely as a consequence of memory trace disruption. Show more

Keywords: 3xTg mice, Alzheimer's disease, amyloid-β aggregation, calcineurin, ERK, JNK, NF-κB, object recognition memory

DOI: 10.3233/JAD-131076

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 69-82, 2014

Authors: Janicki, Sarah C. | Park, Naeun | Cheng, Rong | Lee, Joseph H. | Schupf, Nicole | Clark, Lorraine N.

Article Type: Research Article

Abstract: Background: Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer’s disease (AD) in women of different ethnicities. We investigated the influence of ESR2 polymorphisms on age at onset of AD in a multiethnic cohort of women. Objectives: To determine whether gene variants would affect risk for AD differently in women of different population ancestries. Methods: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), association with risk for AD was assessed for 20 ESR2 single-nucleotide polymorphisms (SNPs) using multivariate logistic regression, adjusting for …age at time of study enrollment, presence of an APOE 𝜀4 allele, years of education, and body mass index. Results: Increased risk for AD was associated with four ESR2 SNPs in women of predominantly Caucasian AIMS-defined ancestry: rs944045, rs1256062, rs10144225, and rs2274705 (OR range 1.6–1.9, empiric p-value range 0.002–0.004). A separate SNP (rs10137185) was associated with decreased risk for AD in women who identified themselves as Black (OR 0.6, 95% CI = 0.4–0.9). When vascular risk factors were included in the model, a separate SNP (rs1256059) was associated with increased risk for AD in women of admixed/Hispanic ancestry (OR 1.5, 95% CI = 1.1–2.4). Conclusions: ESR2 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry and self-identified ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid risk factors mediating SNP effect on risk for AD by group. Show more

Keywords: Alzheimer's disease, estrogen receptor 2, estrogen receptors beta, genetic association studies, Hispanic, women

DOI: 10.3233/JAD-130551

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 83-93, 2014

Authors: Rembach, Alan | Watt, Andrew D. | Wilson, William J. | Villemagne, Victor L. | Burnham, Samantha C. | Ellis, Kathryn A. | Maruff, Paul | Ames, David | Rowe, Christopher C. | Macaulay, S. Lance | Bush, Ashley I. | Martins, Ralph N. | Masters, Colin L. | Doecke, James D. | the AIBL Research Group

Article Type: Research Article

Abstract: Background: We evaluated the utility of longitudinal measures of plasma amyloid-β (Aβ) as a means to identify pre-symptomatic cognitive decline in Alzheimer’s disease (AD) when coupled to neuroimaging and neuropsychological parameters. Methods: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were grouped based upon cognitive change and changes in measurable levels of neocortical amyloid over 36 months. Participants were classified as those who transitioned for cognitive decline and change in neocortical amyloid, those healthy controls that did not transition, and stable AD participants over 36 months. Results: Comparisons of plasma Aβ levels between the …transition and non-transitional groups showed Aβ1-42 and the Aβ1-42 /Aβ1-40 ratio were significantly decreased at baseline (p = 0.008 and p = 0.002, respectively) and at 18 months (p = 0.003 and p = 0.004, respectively). Both measures of neocortical amyloid and two previously published composite scores validated the creation of the novel transitional grouping (p < 0.0001). In addition Aβn-42 performed well as a longitudinal prognostic indicator of transition toward cognitive decline, with a significant decrease in the transition group at the 18 month time point (p = 0.01). Conclusion: We demonstrated that baseline plasma Aβ1-42 and the Aβ1-42 /Aβ1-40 ratio were putative biomarkers indicative of cognitive decline and validated this result using 18 month data. We created a novel transitional grouping and validated this measure using published measures of neocortical amyloid and composite memory scores. These findings suggest that longitudinal plasma Aβ could contribute to a pre-symptomatic biomarker panel for AD. Show more

Keywords: Alzheimer's disease, biomarkers, diagnosis, neocortical amyloid burden, Pittsburgh compound B, plasma amyloid-β, positron emission topography

DOI: 10.3233/JAD-131802

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 95-104, 2014