Journal of Alzheimer's Disease - Volume 35, issue 1

Authors: Bondareff, William

Article Type: Review Article

Abstract: Alzheimer's disease is a neurodegenerative disease in which aging is not only a major risk factor but a major determinant of onset, course, and pathogenesis. The synthesis of amyloid-β (Aβ) peptides by neurons and their excretion into the extracellular space (ECS) is a core feature of AD that begins more than two decades before the onset of clinical symptoms. The ECS resembles a syncytium with the appearance in electron micrographs of continuous channels and lakes separating the outer membranes of the neurons, neuroglia, and vascular elements embedded in it. It consists primarily of a proteoglycan matrix through which circulates an …interstitial fluid, derived in part from cerebrospinal fluid (CSF). The process by which Aβ accumulates in the ECS includes decreased production of CSF, matrix proteoglycans, and ECS volume, all of which become more severe with advancing age and lead to an age-related increase in the Aβ pool. Although the relationship between Aβ and the appearance of cognitive symptoms is uncertain, available data support a strong relationship between the toxicity of Aβ for neurons and the total Aβ burden, including the soluble and fibrillar Aβ, the Aβ42 /Aβ40 ratio, and Aβ-proteoglycan reactivity. Proteoglycans have been shown to foster the formation of neurotoxic fibrillar Aβ42 and neuritic plaques that enhance neuronal and synaptic damage and eventual loss culminating in the onset and progression of dementia. As this process depends upon age-related events, it suggests that the successful control of AD lies in finding effective means of prevention. Show more

Keywords: Aging, Alzheimer's disease, brain, extracellular matrix, extracellular space

DOI: 10.3233/JAD-122305

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 1-6, 2013

Authors: Walton, J.R.

Article Type: Review Article

Abstract: The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed …to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD. Show more

Keywords: Aluminum compounds, Alzheimer's disease, amyloid-β protein precursor, animal, causality, disease models, intestinal absorption, neurofibrillary tangles, neurotoxicity syndromes, translational medical research

DOI: 10.3233/JAD-121909

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 7-43, 2013

Authors: Pottier, Cyril | Wallon, David | Rousseau, Stephane | Rovelet-Lecrux, Anne | Richard, Anne-Claire | Rollin-Sillaire, Adeline | Frebourg, Thierry | Campion, Dominique | Hannequin, Didier | GMAJ/COMAJ collaborators

Article Type: Short Communication

Abstract: The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD). In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls. Only the rs75932628-T variant (predicted to cause an R47H substitution) conferred a significant risk for early-onset AD (OR, 4.07; 95% CI, 1.3 to 16.9; p = 0.009). These results confirm the association between this …variant and AD and underline its involvement in early-onset cases. Show more

Keywords: Early onset Alzheimer's disease, rare variant, risk factor, TREM2

DOI: 10.3233/JAD-122311

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 45-49, 2013

Authors: Daborg, Jonny | Holmgren, Sandra | Abramsson, Alexandra | Andreasson, Ulf | Zetterberg, Madeleine | Nilsson, Staffan | Minthon, Lennart | Skoog, Ingmar | Blennow, Kaj | Pekna, Marcela | Hanse, Eric | Zetterberg, Henrik

Article Type: Research Article

Abstract: The complement system has been implicated in both physiological synapse elimination and Alzheimer's disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease …intensity/severity. Show more

Keywords: Alzheimer's disease, complement, microglia, single nucleotide polymorphisms

DOI: 10.3233/JAD-121930

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 51-57, 2013

Authors: Rhodehouse, Bryce C. | Erickson, Michelle A. | Banks, William A. | Bearden, Shawn E.

Article Type: Research Article

Abstract: Hyperhomocysteinemia (HHcy) is associated with cognitive impairment and Alzheimer's disease. Whether this association is mechanistic remains unclear. Here, we used a mouse model to test the hypothesis that HHcy increases levels of amyloid-β (Aβ) transporters in microvessels that form the blood-brain barrier, elevates Aβ content (Aβ40 and Aβ42 ) in the brain, and impairs cognitive performance. Mice with HHcy and age-matched, non-HHcy controls (Ctrl) were studied in two age groups: adult (6.2 ± 0.4 months of age) and old (19 ± 2.0 months of age). Levels of Aβ transporters, RAGE, LRP1, and Pgp, were not different between HHcy and …Ctrl mice. Though there was an increase in overall brain Aβ levels with age, there were no differences between HHcy and Ctrl groups in cortex, hippocampus, or midbrain/diencephalon. Despite the lack of difference in Aβ, old mice with HHcy showed significant cognitive impairment on Morris water maze tests compared with Ctrl mice. We conclude that HHcy leads to cognitive impairment without many of the changes currently thought to be relevant to promoting the AD phenotype. Show more

Keywords: Homocysteine, dementia, cognitive impairment, Alzheimer's disease, blood-brain barrier, microvessels, microvascular permeability

DOI: 10.3233/JAD-122347

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 59-66, 2013

Authors: Engelborghs, Sebastiaan | Sleegers, Kristel | Van der Mussele, Stefan | Le Bastard, Nathalie | Brouwers, Nathalie | Van Broeckhoven, Christine | De Deyn, Peter Paul

Article Type: Research Article

Abstract: A prospective, longitudinal study was set up to investigate possible genetic associations of behavioral and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) with two candidate genes in the serotonergic neurotransmitter pathway: serotonin transporter (SLC6A4) and brain-specific tryptophan hydroxylase (TPH2). Patients with probable AD (n = 249) were diagnosed according to NINCDS/ADRDA criteria. During follow-up, autopsy-confirmation of clinical diagnosis was obtained in 32 AD patients. Taking into account follow-up behavioral assessments by means of validated behavioral assessment scales (Middelheim Frontality Score and Behave-AD), behavioral ratings reflecting the highest scores on any behavioral item ever observed since dementia …onset were calculated and applied for statistical analyses. A functional insertion/deletion polymorphism in the promoter region of SLC6A4 (5-HTTLPR) and 10 selected SNPs within TPH2 were genotyped. Single-marker allelic association analyses (TPH2, 5-HTTLPR) were performed. TPH2 allelic analyses revealed significant associations with frontal lobe symptoms, as well as with diurnal rhythm disturbances. 5-HTTLPR S allele carriers had an increased risk to display loss of insight and judgment, another frontal lobe symptom. The present prospective, longitudinal study showed that mainly frontal lobe symptoms were significantly associated with TPH2 and 5-HTTLPR polymorphisms, pointing toward a role of the serotonergic neurotransmitter system in the pathophysiology of frontal lobe symptoms in AD. Show more

Keywords: Alzheimer's disease, behavior, behavioral and psychological signs and symptoms of dementia (BPSD), dementia, serotonin, TPH2

DOI: 10.3233/JAD-101305

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 67-73, 2013

Authors: Mitolo, Micaela | Gardini, Simona | Fasano, Fabrizio | Crisi, Girolamo | Pelosi, Annalisa | Pazzaglia, Francesca | Caffarra, Paolo

Article Type: Research Article

Abstract: Spatial abilities decline in normal aging and decrease faster and earlier in Alzheimer's disease (AD), but these deficits are under investigated. The main goals of this study were to assess visuospatial memory abilities in mild cognitive impairment (MCI), in order to verify whether these tasks might be valid as the standard cognitive test to differentiate MCI individuals from normal controls and to investigate the brain structural correlates of visuospatial deficits. Twenty MCI patients and fourteen healthy elderly controls underwent an experimental visuospatial battery, which also included self-rating spatial questionnaires, and structural MRI brain imaging. Compared to healthy elderly controls, MCI …patients scored significantly worse in almost all visuospatial tasks. ROC analysis showed that visuospatial tasks had an elevated discriminant power between groups (AUC >0.90). Voxel-based morphometry analysis, compared to controls, disclosed a higher level of atrophy in frontal and medio-temporal regions and a different pattern of correlation between grey matter values and visuospatial performance, with wider distributed areas of the occipital and middle temporal cortex in the map and route learning. This study indicates that visuospatial memory tests are valid tools in completing the diagnostic evaluation of MCI. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, mild cognitive impairment, spatial navigation, visuospatial memory

DOI: 10.3233/JAD-121288

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 75-90, 2013

Authors: Jiang, Xia | Jia, Lin-Wei | Li, Xiao-Hong | Cheng, Xiang-Shu | Xie, Jia-Zhao | Ma, Zhi-Wei | Xu, Wei-Jie | Liu, Yue | Yao, Yun | Du, Lai-Ling | Zhou, Xin-Wen

Article Type: Research Article

Abstract: Hyperphosphorylated tau aggregated into neurofibrillary tangles is a hallmark lesion of Alzheimer's disease (AD) and is linked to synaptic and cognitive impairments. In animal models, cold water stress (CWS) can cause cognitive disorder and tau hyperphosphorylation. Capsaicin (CAP), a specific TRPV1 agonist, is neuroprotective against stress-induced impairment, but the detailed mechanisms are still elusive. Here, we investigated whether CAP mitigates CWS-induced cognitive and AD-like pathological alterations in rats. The animals were administered CAP (10 mg/kg in 0.2 ml, 0.1% ethanol) or a control (0.2 ml normal saline, 0.1% ethanol) by intragastric infusion 1 h before CWS treatment. Our results showed …that CAP significantly attenuated CWS-induced spatial memory impairment and suppression of PP-DG long-term potentiation; CAP abolished CWS-induced dendritic regression and enhanced several memory-associated proteins decreased by CWS, such as synapsin I and PSD93; CAP also prevented CWS-induced tau hyperphosphorylation by abolishing inhibition of protein phosphatase 2A. Taken together, this study demonstrated that activation of TRPV1 can mitigate CWS-induced AD-like neuropathological alterations and cognitive impairment and may be a promising target for therapeutic intervention in AD. Show more

Keywords: Alzheimer's disease, capsaicin, dendritic arborization, spatial memory, tau hyperphosphorylation

DOI: 10.3233/JAD-121837

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 91-105, 2013

Authors: Hochard, Arnaud | Oumata, Nassima | Bettayeb, Karima | Gloulou, Olfa | Fant, Xavier | Durieu, Emilie | Buron, Nelly | Porceddu, Mathieu | Borgne-Sanchez, Annie | Galons, Hervé | Flajolet, Marc | Meijer, Laurent

Article Type: Research Article

Abstract: Increased production of amyloid-β (Aβ)42 peptide, derived from the amyloid-β protein precursor, and its subsequent aggregation into oligomers and plaques constitutes a hallmark of Alzheimer's disease (AD). We here report on a family of low molecular weight molecules, the Aftins (Amyloid-β Forty-Two Inducers), which, in cultured cells, dramatically affect the production of extracellular/secreted amyloid peptides. Aftins trigger β-secretase inhibitor and γ-secretase inhibitors (GSIs) sensitive, robust upregulation of Aβ42 , and parallel down-regulation of Aβ38 , while Aβ40 levels remain stable. In contrast, intracellular levels of these amyloids appear to remain stable. In terms of their effects on Aβ38 …/Aβ40 /Aβ42 relative abundance, Aftins act opposite to γ-secretase modulators (GSMs). Aβ42 upregulation induced by Aftin-5 is unlikely to originate from reduced proteolytic degradation or diminished autophagy. Aftin-5 has little effects on mitochondrial functional parameters (swelling, transmembrane potential loss, cytochrome c release, oxygen consumption) but reversibly alters the ultrastructure of mitochondria. Aftins thus alter the Aβ levels in a fashion similar to that described in the brain of AD patients. Aftins therefore constitute new pharmacological tools to investigate this essential aspect of AD, in cell cultures, allowing (1) the detection of inhibitors of Aftin induced action (potential ‘anti-AD compounds’, including GSIs and GSMs) but also (2) the identification, in the human chemical exposome, of compounds that, like Aftins, might trigger sustained Aβ42 production and Aβ38 down-regulation (potential ‘pro-AD compounds’). Show more

Keywords: Aftins, Alzheimer's disease, amyloid-β, Aβ38, Aβ40, Aβ42, γ-secretase, γ-secretase modulators, mitochondria

DOI: 10.3233/JAD-121777

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 107-120, 2013

Authors: Sjölander, Annica | Minthon, Lennart | Nuytinck, Lieve | Vanmechelen, Eugeen | Blennow, Kaj | Nilsson, Staffan

Article Type: Research Article

Abstract: Mannan-Binding lectin (MBL) is a serum lectin and an important constituent of the innate immune system. Processes linked to the innate immune response have previously been implicated in Alzheimer's disease (AD). MBL is associated with blood vessels in the brain and AD patients demonstrate lower MBL levels in the cerebrospinal fluid compared to controls. We investigated six single nucleotide polymorphisms, linked to MBL deficiency, in the corresponding MBL2 gene in AD patients and controls. Two MBL2 haplotypes, LXP and LYQ, were significantly associated with AD risk (OR = 1.6, p = 0.01 and OR = 1.5, p = 0.02, respectively). …The present study is the first investigating MBL2 genotypes and haplotypes in relation to AD. Our findings support that the MBL2 gene impact the disease risk. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, gene, immune response, Mannan-Binding lectin, single nucleotide polymorphism

DOI: 10.3233/JAD-122044

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 121-127, 2013