JAD - Volume 35, Number 2

Volume 35, Number 2, April 2013

Pages 217-225
Review
Afsaneh Porzoor, Ian G. Macreadie
Application of Yeast to Study the Tau and Amyloid-β Abnormalities of Alzheimer’s Disease
Abstract: The major molecules associated with Alzheimer’s disease, the phosphorylated protein tau and the 42 amino acid peptide, amyloid-β (Aβ), have recently been analyzed in yeast. These yeast studies have provided major new insights into the effects of tau and Aβ and, at the same time, offered new approaches to rapidly search for chemicals that may be involved in prevention of Alzheimer’s disease. The following review summarizes the role of yeast and its contribution in Alzheimer’s disease research, and highlights important studies that have been conducted in this model organism.

Pages 227-240
Hypothesis
Emiliano Bruner*, Heidi I.L. Jacobs* *These authors contributed equally to this work.
Alzheimer’s Disease: The Downside of a Highly Evolved Parietal Lobe?
Abstract: Clinical grade Alzheimer’s disease (AD) is only described in humans. Recent imaging studies in early AD patients showed that the parietal areas display the most prominent metabolic impairments. So far, neuroimaging studies have not been able to explain why the medial parietal regions possess this hub characteristic in AD. Paleoneurological and neuroanatomical studies suggest that our species, Homo sapiens, has a unique and derived organization of the parietal areas, which are involved in higher cognitive functions. Combining evidence from neuroimaging, paleontology, and comparative anatomy, we suggest that the vulnerability of the parietal lobe to neurodegenerative processes may be associated with the origin of our species. The species-specific parietal morphology in modern humans largely influenced the brain spatial organization, and it involved changes in vascularization and energy management, which may underlie the sensitivity of these areas to metabolic impairment. Metabolic constraints and anatomical evolutionary changes in the medial parietal regions of modern humans may be important in early AD onset. Taking into account the species-specific adaptations of the modern human parietal areas and their association with AD, we hypothesize that AD can be the evolutionary drawback of the specialized structure of our parietal lobes. The cognitive advantage is associated with increased sensitivity to neurodegenerative processes which, being limited to the post-reproductive period, have a minor effect on the overall genetic fitness. The changes of energy requirements associated with form and size variations at the parietal areas may support the hypothesis of AD as a metabolic syndrome.

Pages 241-246
Short Communication
Angelique P.A Vermeiren, Hans Bosma, Pieter-Jelle Visser, Maurice P. Zeegers, Caroline Graff, Michael Ewers, Giovanni B. Frisoni, Lutz Frölich, Harald Hampel, Roy W. Jones, Patrick G. Kehoe, Hermine Lenoir, Lennart Minthon, Flavio M. Nobili, Marcel Olde Rikkert, Anne-Sophie Rigaud, Philip Scheltens, Hilkka Soininen, Luiza Spiru, Magda Tsolaki, Lars-Olof Wahlund, Bruno Vellas, Gordon Wilcock, Lyzel S. Elias-Sonnenschein, Frans R.J. Verhey
The Association between APOE ε4 and Alzheimer-type Dementia among Memory Clinic Patients is Confined to those with a Higher Education. The DESCRIPA Study
Abstract:We assessed the interaction between the APOE ε4 allele and education level in the etiology of Alzheimer’s disease (AD) among memory clinic patients from the multicenter DESCRIPA study. Subjects (n=544) were followed for 1 to 5 years. We used Cox’s stratified survival modeling, adjusted for age, gender, and center. APOE ε4 predicted the onset of AD-type dementia in middle (HR 3.45 95% CI 1.79-6.65, n=222) and high (HR 3.67 95%CI 1.36-9.89, n=139) but not in low educated subjects (HR 0.81, 95% CI 0.38-1.72, n=183). This suggests that mechanisms in developing Alzheimer-type dementia may differ between educational groups that raises questions related to Alzheimer-type dementia prevention.

Supplementary Data for Vermeiren et al. article (PDF)

Pages 247-252
Thomas Benke, Margarete Delazer, Günter Sanin, Helena Schmidt, Stephan Seiler, Gerhard Ransmayr, Peter Dal-Bianco, Margarete Uranüs, Josef Marksteiner, Friedrich Leblhuber, Peter Kapeller, Christian Bancher, Reinhold Schmidt on behalf of the PRODEM Study Group
Cognition, Gender, and Functional Abilities in Alzheimer’s Disease: How are They Related?
Abstract: Background: Few studies have investigated in detail which factors influence activities of daily (ADL) in Alzheimer’s disease (AD). Objective: To assess the influence of cognitive, gender, and other factors on ADL in patients with mild to moderate AD. Methods: This study is part of the Prospective Registry on Dementia in Austria (PRODEM) project, a multicenter dementia research project. A cohort of 221 AD patients (130 females; means: age 76 years, disease duration 34.4 months, MMSE 22.3) was included in a cross-sectional analysis. Everyday abilities were assessed with the Disability Assessment for Dementia scale, and cognitive functions with the CERAD plus neuropsychological test battery. Two models of multiple linear regressions were performed to find factors predicting functional decline, one entering demographical and disease related factors, and a joint model combining demographical and disease variables with neuropsychological scores. Results: Non-cognitive factors explained 18%, whereas the adding of neuropsychological variables explained 39% of variance. Poor figural and verbal memory, constructional abilities, old age, longer disease duration, depression, and male gender were independent risk factors for reduced ADL. Instrumental and basic ADL were predicted by similar factors, except gender (predicting only instrumental ADL) and phonological fluency (predictor of basic ADL). Conclusion: In addition to demographical factors, disease duration, and depression, neuropsychological variables are valuable predictors of the functional status in AD in an early disease stage.

Pages 253-265
Amber S. Watts, Natalia Loskutova, Jeffrey M. Burns, David K. Johnson (Handling Associate Editor: Rex Cannon)
Metabolic Syndrome and Cognitive Decline in Early Alzheimer’s Disease and Healthy Older Adults
Abstract: Metabolic syndrome (MetS) is a cluster of risk factors (i.e., abdominal obesity, hypertension, dyslipidemia, glucose and insulin dysregulation) that is associated with cardiovascular disease, diabetes, and dementia. Recent studies addressing the association of MetS with cognitive performance and risk for dementia report mixed results. An important step in clarifying these conflicting results is determining whether cognition is influenced by the effects of individual MetS components versus the additive effects of multiple components. We assessed the effect of MetS on cognitive performance and decline over two years in 75 cases of early Alzheimer’s disease (AD) and 73 healthy older adult controls in the Brain Aging Project. Using factor analytic techniques, we compared the effect of a combined MetS factor to the effect of individual MetS components on change in attention, verbal memory, and mental status. In healthy controls, a combined MetS factor did not significantly predict cognitive performance, though higher insulin predicted poorer cognitive performance outcomes. In the AD group, higher scores on a combined MetS factor predicted better cognitive outcomes. Our findings suggest that MetS does not have the same association with cognitive decline in healthy older adults and those with early AD. We suggest that individual MetS components should not be evaluated in isolation and that careful methodological approaches are needed to understand the timing and non-linear relationships among these components over time.

Pages 267-283
Emilie Faivre, Christian Hölscher
D-Ala2GIP Facilitated Synaptic Plasticity and Reduces Plaque Load in Aged Wild Type Mice and in an Alzheimer’s Disease Mouse Model
Abstract: Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer’s disease (AD). We have previously shown that glucose-dependent insulinotropic polypeptide (GIP) analogues that originally have been developed to treat diabetes have neuroprotective effects in the brains of the APPswe/PS1ΔE9 mouse model of AD. In a previous study, the analogue D-Ala2GIP intraperitoneally (i.p.) in 12 months old animals, an age that represents early phase AD, D-Ala2GIP improved memory in wild type (WT) mice and rescued the cognitive decline of 12 months old AβPP/PS1 mice. Synapse numbers and synaptic plasticity was also protected. Importantly, the amyloid plaque load in the cortex was reduced. In the present study, we tested D-Ala2GIP in 19 months old AβPP/PS1 mice or littermate controls to find out if the drug may have protective effects even at an advanced stage of AD. Mice were injected for 21 days at 25 nmol/kg i.p. once daily. Interestingly, the age-related reduction of synaptic numbers in the DG and cortex was prevented in WT control mice. D-Ala2GIP facilitated synaptic plasticity in AβPP/PS1 and WT mice and reduced the number of amyloid plaques and activated microglia in the cortex of AβPP/PS1 mice. The results show that D-Ala2GIP not only has protective but also regenerative properties in the brain of aged WT mice, and on key biomarkers found in AD in AβPP/PS1 mice. This suggests that novel GIP analogues may have beneficial effects in non-demented aged people and perhaps even in AD patients even when the disease is further progressed.

Pages 285-295
Vesna Jelic, Göran Hagman, Natsuko Goto Yamamoto, Yasuhiro Teranishi, Takeshi Nishimura, Bengt Winblad, Pavel F. Pavlov
Abnormal Platelet Amyloid-β Protein Precursor (AβPP) Metabolism in Alzheimer’s Disease: Identification and Characterization of a New AβPP Isoform as Potential Biomarker
Abstract: Previous findings demonstrated an altered pattern of amyloid-β protein precursor (AβPP) expression in platelets of Alzheimer’s disease (AD) patients compared with either healthy control subjects or patients with non-Alzheimer-type dementia. In an attempt to explore the diagnostic potential of platelet AβPP metabolism, we have generated monoclonal antibodies directed to the N-terminal part of AβPP. We have observed two different antibody recognition patterns of AβPP: one resembling previously described 130 kDa and 105 kDa species and a novel AβPP 115 kDa form. This form was significantly increased in platelets of the mild cognitive impairment and AD group as compared to control subjects. The abundance of AβPP 115 kDa species correlated with the previously described AβPP 130/105 kDa ratio as well as with Mini-Mental State Examination score. Despite the inability of these particular monoclonal antibodies to recognize native forms of AβPP, identification of a new AβPP isoform in platelets as a potential AD biomarker can provide an additional tool for the development of a reliable diagnostic test to detect preclinical stages of AD.

Supplementary Data for Jelic et al. article (PDF)

Pages 297-306
Andrea Slachevsky, Marilu Budinich, Claudia Miranda-Castillo, Javier Núñez-Huasaf, Jaime R. Silva, Carlos Muñoz-Neira, Sergio Gloger, Oscar Jimenez, Bernardo Martorell, Carolina Delgado
The CUIDEME Study: Determinants of Burden in Chilean Primary Caregivers of Patients with Dementia
Abstract: Background: Caring for a person with dementia is associated with well-documented increases in burden and distress and decreases in mental health and wellbeing. Studies assessing burden in caregivers of patients with dementia and its determinants are scarce in Latin America. Objective: The main objective of this study was to assess the extent and the determinants of burden in informal primary caregivers of patients with dementia in Chile. Methods: A descriptive study was conducted using clinically validated scales to assess dementia characteristics and to measure caregiver variables. Family socio-demographic characteristics and functional status, patient functional dependency and behavioral disturbances, and caregiver psychiatric morbidity were analyzed as independent variables to determine caregiver burden. Results: Two hundred and ninety-two informal caregivers were included. There were more female (80%) than male caregivers, consisting mainly of daughters and spouses of the patients. Severe burden was reported in 63% of the caregivers, and 47% exhibited psychiatric morbidity. Burden was associated with caregiver psychiatric distress, family dysfunction, severity of neuropsychiatric symptoms and functional disability, but neither patient age, gender, nor socioeconomic status impacted burden. Conclusion: Our results underscore the importance of assessing the consequences of dementia in both caregivers and patients in order to evaluate the real biopsychosocial impact of dementia, as well as the importance of planning appropriate and effective public health interventions in Latin American countries. In addition, interventions targeting caregiver psychological distress, caregiver familial dysfunction, patient neuropsychiatric disorders, and patient functional disability could potentially diminish caregiver burden.

Pages 307-312
Pashtun Shahim*, Andrea E. Bochem*, Niklas Mattsson, Ronald Lautner, Kaj Blennow, G. Kees Hovingh, M. Mahdi Motazacker, Henrik Zetterberg (Handling Associate Editor: Sanna-Kaisa Herukka) *These authors contributed equally to this study.
Plasma Amyloid-β in Patients with Tangier Disease
Abstract: Tangier disease (TD) is a rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, which results in impaired cellular cholesterol efflux and high-density lipoprotein cholesterol deficiency. Animal and in vitro studies indicate that ABCA1 is involved in the production of amyloid-β (Aβ), a pivotal protein in Alzheimer’s disease. We here examined whether plasma Aβ levels are altered in TD patients. Plasma from 5 TD patients and 5 controls were analyzed for Aβ1-40, Aβ1-42, AβX-40, and AβX-42 but no differences were found. In conclusion, loss of ABCA1 function may not have any profound effect on Aβ metabolism in humans, at least not in the periphery, as reflected by plasma Aβ levels.

Pages 313-318
Paola Piscopo, Roberto Rivabene, Daniela Galimberti, Alessio Crestini, Giuseppina Talarico, Nicola Vanacore, Elio Scarpini, Giuseppe Bruno, Annamaria Confaloni (Handling Associate Editor: Diego Albani)
Gender Effects on Plasma PGRN Levels in Patients with Alzheimer’s Disease: A Preliminary Study
Abstract: Plasma progranulin (PGRN) levels constitute a potentially invaluable biomarker for neurodegenerative diseases including frontotemporal lobar dementia (FTLD) and, perhaps, Alzheimer’s disease (AD). We assessed plasma PGRN levels in 107 AD patients, 36 FTLD patients, and 107 controls. We found that, in female AD patients, there is a positive correlation between PGRN levels and age. Although no significant differences were found between patients and controls, we observed higher levels in females compared to males; in AD patients, a positive correlation between PGRN levels and age was observed in females. In conclusion, our data suggest that PGRN may not be a good biomarker for AD; moreover, gender may influence the plasma PGRN levels of AD patients.

Pages 319-334
Karla I. Lira-De León, Ponciano García-Gutiérrez, Iris N. Serratos, Marianela Palomera-Cárdenas, María del P. Figueroa-Corona, Victoria Campos-Peña, Marco A. Meraz-Ríos (Handling Associate Editor: Emilio Di Maria)
Molecular Mechanism of Tau Aggregation Induced by Anionic and Cationic Dyes
Abstract: Abnormal tau filaments are a hallmark of Alzheimer’s disease. Anionic dyes such as Congo Red, Thiazine Red, and Thioflavin S are able to induce tau fibrillization in vitro. SH-SY5Y cells were incubated with each dye for seven days leading to intracellular aggregates of tau protein, with different morphological characteristics. Interestingly, these tau aggregates were not observed when the Methylene Blue dye was added to the cell culture. In order to investigate the molecular mechanisms underlying this phenomenon, we developed a computational model for the interaction of the tau paired helical filament (PHF) core with every dye by docking analysis. The polar/electrostatic and nonpolar contribution to the free binding energy in the tau PHF core-anionic dye interaction was determined. We found that the tau PHF core can generate a positive net charge within the binding site localized at residuesLys311 and Lys340 (numbering according to the longest isoform hTau40). These residues are important for the binding affinity of the negative charges present in the anionic dyes causing an electrostatic environment that stabilizes the complex. Tau PHF core protofibril-Congo Red interaction has a stronger binding affinity compared to Thiazine Red or Thioflavin S. By contrast, the cationic dye Methylene Blue does not bind to nor stabilize the tau PHF core protofibrils. These results characterize the driving forces responsible for the binding of tau to anionic dyes leading to their self-aggregation and suggest that Methylene Blue may act as a destabilizing agent of tau aggregates.

Pages 335-348
Sébastien S. Hébert, Wang-Xia Wang, Qi Zhu, Peter T. Nelson
A Study of Small RNAs from Cerebral Neocortex of Pathology-Verified Alzheimer’s Disease, Dementia with Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, and Non-Demented Human Controls
Abstract: MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual diseases such as Alzheimer’s disease (AD), making disease-to-disease comparisons impossible. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n=2), AD (n=5), dementia with Lewy bodies (n=4), hippocampal sclerosis of aging (n=4), and frontotemporal lobar dementia (FTLD) (n=5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at a nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n=8) and FTLD (n=14) cases when compared to controls (n=8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies.

Supplementary Data for Hébert et al. article (PDF)
Supplementary Figure 1 for Hébert et al. article (PDF)
Supplementary Figure 2 for Hébert et al. article (PDF)
Supplementary Table 1 for Hébert et al. article (xls)
Supplementary Table 2 for Hébert et al. article (xls)
Supplementary Table 3 for Hébert et al. article (xls)

Pages 349-361
Simona Gabriella Di Santo, Federica Prinelli, Fulvio Adorni, Carlo Caltagirone, Massimo Musicco
A Meta-Analysis of the Efficacy of Donepezil, Rivastigmine, Galantamine, and Memantine in Relation to Severity of Alzheimer’s Disease
Abstract: Background: Randomized clinical trials have evaluated the efficacy of acetylcholinesterase inhibitors (AChE-Is) and memantine across a wide range of Alzheimer’s disease (AD) severity. However, these drugs are prescribed and reimbursed according to precise upper and lower cut off scores of cognitive tests. Objectives: To verify whether the efficacy of pharmacological treatment had any dependence on the severity of dementia in AD patients. Methods: Published English-language randomized, placebo-controlled trials evaluating the efficacy of AChE-Is or memantine at any dose, over any length of time, in patients with any severity of dementia due to AD were included. Cognitive, behavioral, and functional outcomes were extracted from each study and multiple outcomes from the same trial were pooled to obtain a unique indicator of efficacy for cognition, functional impairment, and behavioral and psychological disturbances. The existence of a relationship between size of the treatment effect and severity of dementia, measured with the Mini-Mental State Examination, was determined using parametric and non-parametric correlation analyses. Results: Both AChE-Is and memantine had significant effects on cognition. Functional and psycho-behavioral outcomes were reported less frequently but also showed significant efficacy of treatment. High heterogeneity among studies was found within and between the different drugs. The efficacy of all drugs except memantine was independent from dementia severity in all domains. Memantine effect on functional impairment was better in more severe patients. Conclusions: The modest beneficial effects of anti-dementia drugs on cognition are independent from dementia severity. Memantine is more effective on functional incompetence only in severe patients.

Pages 363-371
James R. Hall, April R. Wiechmann, Leigh A. Johnson, Melissa Edwards, Robert C. Barber, A. Scott Winter, Meharvan Singh, Sid E. O’Bryant, for the Texas Alzheimer’s Research and Care Consortium (Handling Associate Editor: Andrew Ford)
Biomarkers of Vascular Risk, Systemic Inflammation, and Microvascular Pathology and Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract: Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer’s disease (AD). The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides, and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild AD. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable AD. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview with caretakers/family members using the Neuropsychiatric Inventory. For the total sample, IL15, VCAM (vascular adhesion molecule), and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms, and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender, different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology, and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in AD supporting a vascular and inflammatory component of psychiatric disorders found in AD. Gender differences suggest distinct impact of specific risks with total cholesterol, a measure of cardiovascular risk, being the strongest marker for males and IL-15, a marker of inflammation, being the strongest for females.

Pages 373-386
Guangchun Han*, Jiajia Wang*, Fan Zeng*, Xuemei Feng, Jun Yu, Hong-Yuan Cao, Xu Yi, Huadong Zhou, Lee-Way Jin, Yong Duan, Yan-Jiang Wang, Hongxing Lei (Handling Associate Editor: Zhi-Ying Wu) *These authors contributed equally to this manuscript.
Characteristic Transformation of Blood Transcriptome in Alzheimer’s Disease
Abstract: Blood transcriptome has emerged as a potential resource for the discovery of biomarkers for Alzheimer’s disease (AD). However, the validity of blood transcriptome in the early diagnosis of AD has yet to be extensively tested. In this work, we analyzed published data on AD blood transcriptome and revealed the characteristic perturbation of cellular functional units, including upregulation of environmental responses (immune response, survival/death signaling, and cellular recycling) and down-regulation of core metabolism (energy metabolism and translation/splicing). This characteristic perturbation was unique to AD based on the comparison with blood transcriptome from other neurological disorders and complex diseases. More importantly, similar perturbation was observed in both AD and mild cognitive impairment (MCI) groups. This perturbation pattern was further validated in our independent microarray experiment in a small Chinese cohort. In addition, the potential effect of aging and lifestyle on blood transcriptome was discussed. Based on the analyses, we propose that the transformation of the blood transcriptome in AD is an integrated part of the disease mechanism and has potential to serve as a reliable biomarker for assisting the early diagnosis as well as monitoring purpose. Therefore, more independent studies on blood transcriptome of AD and MCI with larger sample size are warranted.

Supplementary Data for Han et al. article (PDF)

Pages 387-394
Yanan Wen, Akinori Miyashita, Nobutaka Kitamura, Tamao Tsukie, Yuko Saito, Hiroyuki Hatsuta, Shigeo Murayama, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyasu Akatsu, Takayuki Yamamoto, Kenji Kosaka, Haruyasu Yamaguchi, Kohei Akazawa, Yasuo Ihara, Ryozo Kuwano; and Japanese Alzheimer’s Disease Neuroimaging Initiative
SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer’s Disease
Abstract: SORL1 was shown to be genetically associated with late-onset Alzheimer’s disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [=0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva’s SNP 7], and rs4598682) were encompassed by a 5’ linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3’ LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.

Supplementary Data for Wen et al. article (PDF)

Pages 395-402
Sangmook Lee*, Jill Zemianek*, Thomas B. Shea *These authors contributed equally to this research.
Rapid, Reversible Impairment of Synaptic Signaling in Cultured Cortical Neurons by Exogenously-Applied Amyloid-β
Abstract: Alzheimer’s disease is accompanied by the accumulation of amyloid-β (Aβ) and the microtubule-associated protein tau. Aβ toxicity is dependent upon its form as well as concentration. Soluble Aβ oligomers, rather than the fibrillar forms that comprise senile plaques, represent the toxic form and are correlated with the extent of dementia. Since soluble Aβ perturbs synaptic function, we examined the impact of exogenously applied Aβ on signaling in neurons cultured on multi-electrode arrays. We observed that subcytotoxic levels (10 nm–5 µM) of human Aβ1-42 perturbed synaptic transmission within hours. This perturbation suggests that mild cognitive problems, perhaps undetected by traditional clinical approaches, can accompany critical accumulation of Aβ. This effect was prevented by the calcium chelator BAPTA, indicating a requirement for calcium for inhibition of signaling by Aβ. Aβ-induced inhibition of signaling was not prevented by application of MK-801 or nimodipine (antagonists of the NMDA receptor and L-type voltage-sensitive calcium channel, respectively) suggesting that Aβ may induce influx by either channel, or additional channels, or that neurons contained sufficient calcium to mediate the impact of Aβ. Signaling returned to original levels within 120 h after administration of a single dosage of Aβ, or within 24 h after replacement of medium with fresh medium lacking Aβ, suggesting that intervention to reduce Aβ levels at their first appearance may prevent permanent neurotoxicity.

Pages 403-412
Amalia Martinez-Mir, Antonio González-Pérez, Javier Gayán, Carmen Antúnez, Juan Marín, Mercé Boada, Jesús María Lopez-Arrieta, Alzheimer’s Disease Neuroimaging Initiative, Evaristo Fernández, Reposo Ramírez-Lorca, María Eugenia Sáez, Agustín Ruiz, Francisco G. Scholl, Luis Miguel Real
Genetic Study of Neurexin and Neuroligin Genes in Alzheimer’s Disease
Abstract: The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer’s disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1,256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR=0.851, p=0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR=0.742, 95% CI=0.632-0.872, p=0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males.

Supplementary Data for Martinez-Mir et al. article (PDF)

Pages 413-421
Marie-Noël Vercambre, Claudine Berr, Karen Ritchie, Jae H. Kang
Caffeine and Cognitive Decline in Elderly Women at High Vascular Risk
Abstract: Background: Persons with vascular disorders are at higher risk of cognitive decline. Objective: To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk. Methods: We included 2,475 women aged 65+ years in the Women’s Antioxidant Cardiovascular Study, a randomized trial of antioxidants and B vitamins for cardiovascular disease secondary prevention. We ascertained regular caffeine intake at baseline (1995-1996) using a validated 116 item-food frequency questionnaire. From 1998-2000 to 2005-2006, we administered four telephone cognitive assessments at two-year intervals evaluating global cognition, verbal memory, and category fluency. The primary outcome was the change in global cognitive score, which was the average of the z-scores of all tests. We used generalized linear models for repeated measures that were adjusted for various sociodemographic, health, and lifestyle factors to evaluate the difference in cognitive decline rates across quintiles of caffeine intake. Results: We observed significantly slower rates of cognitive decline with increasing caffeine intake (p-trend=0.02). The rate difference between the highest and lowest quintiles of usual caffeine intake (> 371 versus < 30 mg/day) was equivalent to that observed between those who were 7 years apart in age (p=0.006). Consumption of caffeinated coffee was significantly related to slower cognitive decline (p-trend=0.05), but not other caffeinated products (e.g., decaf, tea, cola, chocolate). We conducted interaction analyses and observed stronger associations in women assigned to vitamin B supplementation (p-interaction = 0.02). Conclusions: Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.

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