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Valentin Blanchard, Stephane Ramin-Mangata, Stephanie Billon-Crossouard, Audrey Aguesse, Manon Durand, Kevin Chemello, Brice Nativel, Laurent Flet, Maud Chetiveaux, David Jacobi, Jean-Marie Bard, Khadija Ouguerram, Gilles Lambert, Michel Krempf, Mikael Croyal
Human apolipoprotein E (apoE) exhibits three major isoforms (apoE2, apoE3, and apoE4) corresponding to polymorphism in the APOE gene. Total plasma apoE concentrations are closely related to these isoforms but the underlying mechanisms are unknown. We aimed to describe the kinetics of apoE individual isoforms to explore the mechanisms for variable total apoE plasma concentrations. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to discriminate between isoforms by identifying specific peptide sequences in subjects (3 E2/E3, 3 E3/E3 and 3 E3/E4 phenotypes) who received a primed constant infusion of2 H3 -leucine for 14 hours...
March 14, 2018: Journal of Lipid Research
J W Gause, R J Day, C A Caraway, W W Poon, T T Rohn
Recent studies have supported a role for the proteolytic cleavage of apolipoprotein E4 (APOE4) as a potential mechanism for the enhanced dementia risk associated with Alzheimer's disease. To determine whether APOE4 fragmentation is correlated with AD, ELISA assays were performed with cerebral spinal fluid (CSF) and plasma samples utilizing an antibody that specifically detects a 17 kDa amino-terminal fragment (p17) of APOE (nApoECF antibody). In CSF samples, levels of APOE fragmentation were minimal in both neuropathological normals (NPNs) and AD cases and there were no significant differences between the two cohorts across APOE genotypes...
September 2017: Journal of Neurology and Neurological Disorders
Veronica Tisato, Giovanni Zuliani, Marco Vigliano, Giovanna Longo, Eugenia Franchini, Paola Secchiero, Giorgio Zauli, Elvezia Maria Paraboschi, Ajay Vikram Singh, Maria Luisa Serino, Beatrice Ortolani, Amedeo Zurlo, Cristina Bosi, Antonio Greco, Davide Seripa, Rosanna Asselta, Donato Gemmati
Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086)...
2018: PloS One
Gaël Chételat
Over the last ten years, we have conducted research in Alzheimer's disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques...
February 28, 2018: Journal of Alzheimer's Disease: JAD
Ivayla Apostolova, Catharina Lange, Per Suppa, Lothar Spies, Susanne Klutmann, Gerhard Adam, Michel J Grothe, Ralph Buchert
PURPOSE: Increased blood glucose level (BGL) has been reported to cause alterations of FDG uptake in the brain that mimic Alzheimer's disease (AD), even within the "acceptable" range ≤ 160 mg/dl. The aim of this study was (i) to confirm this in a large sample of well-characterized normal control (NC) subjects, and (ii) to analyze its impact on the prediction of AD dementia (ADD) in mild cognitive impairment (MCI). METHODS: The study included NCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) that were cognitively stable for ≥36 months after PET (n = 87, 74...
March 3, 2018: European Journal of Nuclear Medicine and Molecular Imaging
Qiu-Lan Ma, Edmond Teng, Xiaohong Zuo, Mychica Jones, Bruce Teter, Evan Y Zhao, Cansheng Zhu, Tina Bilousova, Karen H Gylys, Liana G Apostolova, Mary Jo LaDu, Mir Ahamed Hossain, Sally A Frautschy, Gregory M Cole
Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking...
February 28, 2018: Neurobiology of Disease
Sylvia Villeneuve, Jacob W Vogel, Julie Gonneaud, Alexa Pichet Binette, Pedro Rosa-Neto, Serge Gauthier, Randall J Bateman, Anne M Fagan, John C Morris, Tammie L S Benzinger, Sterling C Johnson, John C S Breitner, Judes Poirier
Importance: Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. Objective: To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia. Design, Setting, and Participants: This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period)...
February 26, 2018: JAMA Neurology
Laura Prieto Del Val, Jose L Cantero, Daniel Baena, Mercedes Atienza
In mild cognitive impairment (MCI), the APOE4 genotype is associated with accelerated memory decline, likely due to the impact of neuropathology on main cerebral networks required for successful memory retrieval and/or to decreased capacity for recruiting secondary networks that might compensate for that brain damage. Here, we tested this hypothesis in twenty-six healthy older adults and thirty-four MCI patients, of which sixteen were APOE4 carriers. Compared to controls, MCI showed hippocampal volume reduction, cortical thinning in frontal, temporal and parietal regions, and dysfunctional EEG oscillations across fronto-temporal networks...
February 2, 2018: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
Qing Ye, Haifeng Chen, Fan Su, Hao Shu, Liang Gong, Chunming Xie, Hong Zhou, Feng Bai
OBJECTIVE: Higher functional connectivity (FC) in resting-state networks has been shown in individuals at risk of Alzheimer's disease (AD) by many studies. However, the longitudinal trajectories of the FC remain unknown. The present 35-month follow-up study aimed to explore longitudinal changes in higher FC in multiple resting-state networks in subjects with the apolipoprotein E ε4 allele (ApoE4) and/or amnestic mild cognitive impairment (aMCI). METHODS: Fifty-one subjects with aMCI and 64 cognitively normal (CN) subjects underwent neuropsychological tests and resting-state functional magnetic resonance imaging (fMRI) scans twice from April 2011 to June 2015...
February 20, 2018: Journal of Clinical Psychiatry
Elizabeth S Chan, Christopher Chen, Tuck Wah Soong, Boon-Seng Wong
Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), where inheritance of this isoform predisposes development of AD in a gene dose-dependent manner. Although the mode of action of ApoE4 on AD onset and progression remains unknown, we have previously shown that ApoE4, and not ApoE3 expression, resulted in insulin signaling deficits in the presence of amyloid beta (Aβ). However, these reports were not conducted with clinical samples that more accurately reflect human disease...
February 15, 2018: Neuromolecular Medicine
Frank Jessen, Annika Spottke, Henning Boecker, Frederic Brosseron, Katharina Buerger, Cihan Catak, Klaus Fliessbach, Christiana Franke, Manuel Fuentes, Michael T Heneka, Daniel Janowitz, Ingo Kilimann, Christoph Laske, Felix Menne, Peter Nestor, Oliver Peters, Josef Priller, Verena Pross, Alfredo Ramirez, Anja Schneider, Oliver Speck, Eike Jakob Spruth, Stefan Teipel, Ruth Vukovich, Christine Westerteicher, Jens Wiltfang, Steffen Wolfsgruber, Michael Wagner, Emrah Düzel
BACKGROUND: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. METHODS: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics...
February 7, 2018: Alzheimer's Research & Therapy
María Eugenia López, Agustín Turrero, María Luisa Delgado, Inmaculada Concepción Rodríguez-Rojo, Juan Arrazola, Ana Barabash, Fernando Maestú, Alberto Fernández
AIM: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. METHODS: Firstly, we explored the isolated role of the APOE ɛ4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i...
February 7, 2018: Dementia and Geriatric Cognitive Disorders
Jonathan B Rosenberg, Michael Kaplitt, Bishnu P De, Alvin Chen, Thomas Flagiello, Christiana O Salami, Eduard Pey, Lingzhi Zhao, Rodolfo Ricart Arbona, Sebastien Monette, Jonathan Dyke, Douglas Ballon, Stephen M Kaminsky, Dolan Sondhi, Gregory Petsko, Steven Paul, Ronald G Crystal
Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly 1 in 9 elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas, APOE2 homozygotes are protected from late onset AD. We hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage...
February 6, 2018: Human Gene Therapy. Clinical Development
J K Chhetri, P de Souto Barreto, C Cantet, M Cesari, N Coley, S Andrieu, B Vellas
Defining the primary cognitive endpoint is a major decision for Alzheimer's disease preventive trials. As an example for further trials we present in detail the three-year cognitive decline in the placebo group of MAPT trial, a randomized controlled trial (RCT) using a cognitive composite score (MAPT-PACC). Participants were dementia-free adults 70 years or older, with subjective memory complaints. Our findings as expected showed subjects with older age (>75), higher beta amyloid brain deposition, APOE-ε4 allele carriers, with low RBC DHA+EPA levels and higher CDR level are at higher risk of cognitive decline...
2018: Journal of Prevention of Alzheimer's Disease
Konstantinos Ioannis Avgerinos, Grigorios Kalaitzidis, Antonia Malli, Dimitrios Kalaitzoglou, Pavlos Gr Myserlis, Vasileios-Arsenios Lioutas
BACKGROUND AND AIMS: Due to common pathophysiological findings of Alzheimer's disease (AD) with diabetes mellitus (DM), insulin has been suggested as a possible treatment of AD or mild cognitive impairment (MCI). A safe alternative of IV insulin is intranasal (IN) insulin. The aim of this systematic review is to investigate the effects of IN insulin on cognitive function of patients with either AD or MCI. METHODS: A literature search of the electronic databases Medline, Scopus and CENTRAL was performed to identify RCTs investigating the effect of IN insulin administration on cognitive tasks, in patients with AD or MCI...
February 1, 2018: Journal of Neurology
Jaeho Kim, Seongbeom Park, Heejin Yoo, Hyemin Jang, Yeshin Kim, Ko Woon Kim, Young Kyoung Jang, Jin San Lee, Sung Tae Kim, Seonwoo Kim, Jong Min Lee, Chang-Seok Ki, Duk L Na, Sang Won Seo, Hee Jin Kim
We evaluated how the impact of apolipoprotein E4 (APOE4) differs according to age in Alzheimer's disease (AD) patients. We recruited 846 AD patients and 815 cognitively normal controls and categorized into three groups with respect to their age (<65, 65-74, and ≥75 years). We evaluated the risk of AD in APOE4 carriers and compared cortical thickness and cognitive function according to APOE4 status in each age group. At the point of this study, in young (<65 years) AD, APOE4 noncarriers had the most severe frontal and perisylvian atrophy, while in old (≥75 years) AD, APOE4 carriers had the most severe medial temporal atrophy...
2018: Journal of Alzheimer's Disease: JAD
Fabian Corlier, George Hafzalla, Joshua Faskowitz, Lewis H Kuller, James T Becker, Oscar L Lopez, Paul M Thompson, Meredith N Braskie
Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77...
January 18, 2018: NeuroImage
E Schmukler, D M Michaelson, R Pinkas-Kramarski
Since its discovery as a genetic risk factor for Alzheimer's disease, the APOE4 allele has been linked to the majority of the pathological findings associated with the disease progression. These include abnormalities of the endocytic, autophagic, and lysosomal machineries, which begin at the most early stages of Alzheimer's disease development. Considering that these three vesicular systems share common features and, in fact, comprise an interconnected cargo-trafficking and degradation network, some of the effects of APOE4 are interrelated, while others are system-specific...
January 20, 2018: Molecular Neurobiology
Hugo Girard, Olivier Potvin, Scott Nugent, Caroline Dallaire-Théroux, Stephen Cunnane, Simon Duchesne
Sporadic Alzheimer's disease (AD), as opposed to its autosomal dominant form, is likely caused by a complex interaction of genetic, environmental, and health lifestyle factors. Twin studies indicate that sporadic AD heritability could be between 58% and 79%, around half of which is explained by the ε4 allele of the apolipoprotein E (APOE4). We hypothesized that genes associated with known risk factors for AD, namely hypertension, hypercholesterolemia, obesity, diabetes, and cardiovascular disease, would contribute significantly to the remaining heritability...
December 7, 2017: Neurobiology of Aging
David Bergeron, Rik Ossenkoppele, Robert Jr Laforce
BACKGROUND: Amyloid-β positron emission tomography (PET) allows for in vivo detection of fibrillar amyloid plaques, a pathologic hallmark of Alzheimer's disease (AD). However, amyloid-β PET interpretation is limited by the imperfect correlation between PET and autopsy, and the fact that it is positive in about 20% to 30% of cognitively normal individuals and non-AD dementias, especially when older or carrying the ε4 allele of apolipoprotein E (ApoE4). When facing a positive amyloid PET, clinicians have to evaluate the probability of a pathologic false positive as well as the probability of amyloid positivity being age-related, comorbid to a primary non-AD dementia (clinicopathologic false positive)...
January 12, 2018: Alzheimer Disease and Associated Disorders
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