Journal of Alzheimer's Disease - Volume 76, issue 3

Authors: Haghani, Amin | Morgan, Todd E. | Forman, Henry Jay | Finch, Caleb E.

Article Type: Review Article

Abstract: Epidemiological studies are associating elevated exposure to air pollution with increased risk of Alzheimer’s disease and other neurodegenerative disorders. In effect, air pollution accelerates many aging conditions that promote cognitive declines of aging. The underlying mechanisms and scale of effects remain largely unknown due to its chemical and physical complexity. Moreover, individual responses to air pollution are shaped by an intricate interface of pollutant mixture with the biological features of the exposed individual such as age, sex, genetic background, underlying diseases, and nutrition, but also other environmental factors including exposure to cigarette smoke. Resolving this complex manifold requires more detailed …environmental and lifestyle data on diverse populations, and a systematic experimental approach. Our review aims to summarize the modest existing literature on experimental studies on air pollution neurotoxicity for adult rodents and identify key gaps and emerging challenges as we go forward. It is timely for experimental biologists to critically understand prior findings and develop innovative approaches to this urgent global problem. We hope to increase recognition of the importance of air pollution on brain aging by our colleagues in the neurosciences and in biomedical gerontology, and to support the immediate translation of the findings into public health guidelines for the regulation of remedial environmental factors that accelerate aging processes. Show more

Keywords: Air pollution, Alzheimer’s disease, rodent models, O3 , particulate matter

DOI: 10.3233/JAD-200377

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 773-797, 2020

Authors: Wang, Si-Yu | Gong, Peng-Yu | E, Yan | Zhang, Ying-Dong | Jiang, Teng

Article Type: Review Article

Abstract: Late-onset Alzheimer’s disease (AD) accounts for most of all AD casesand is currently considered a complex disorder caused by a combination of environmental and genetic factors. As an important family member of triggering receptor expressed on myeloid cells (TREM ), TREM-like transcript 2 gene (TREML2 ) locates on human chromosome 6p21.1, a newly-identified hot zone for AD susceptibility, and encodes atransmembrane immune receptor. Emerging evidence implied a potential role of TREML2 in the susceptibility and pathogenesis of AD. Here, we review the recent literature about the association of TREML2 variants with AD risk and disease endophenotypes. Moreover, we …summarize the latest findings regarding cellular localization and biological functions of TREML2 and speculate its possible role in AD pathogenesis. In addition, we discuss future research directions of TREML2 and AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , genetics, microglia, TREML2

DOI: 10.3233/JAD-200406

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 799-806, 2020

Authors: Liu, Rui-Ming | Chong, Zechen | Chen, Jiu-Chiuan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is a major cause of dementia in the elderly. Although the early-onset (familial) AD is attributed to mutations in the genes coding for amyloid-β protein precursor (AβPP) and presenilin1/presenilin 2 (PS1/PS2), the cause for the late-onset AD (LOAD), which accounts for more than 95% of AD cases, remains unclear. Aging is the greatest risk factor for LOAD, whereas the apolipo protein E4 allele (APOE ɛ 4) is believed to be a major genetic risk factor in acquiring LOAD, with female APOE ɛ 4 carriers at highest risk. Nonetheless, not all the elderly, …even older female APOE ɛ 4 carriers, develop LOAD, suggesting that other factors, including environmental exposure, must play a role. This review summarizes recent studies that show a potential role of environmental exposure, especially ozone and particulate matter exposure, in the development of AD. Interactions between environmental exposure, genetic risk factor (APOE ɛ 4), and sex in AD pathophysiology are also discussed briefly. Identification of environmental risk factor(s) and elucidation of the complex interactions between genetic and environmental risk factors plus aging and female sex in the onset of AD will be a key to our understanding of the etiology and pathogenesis of AD and the development of the strategies for its prevention and treatment. Show more

Keywords: Alzheimer’s disease, animal models, epidemiology, ozone, particulate matters

DOI: 10.3233/JAD-200435

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 807-824, 2020

Authors: Attademo, Luigi | Bernardini, Francesco

Article Type: Research Article

Abstract: As a global problem that has increasingly been causing worldwide concern, air pollution poses a significant and serious environmental risk to health. Risks of cardiovascular and respiratory diseases, as well as various types of cancer, have been consistently associated with the exposure to air pollutants. More recently, various studies have also shown that the central nervous system is also attacked by air pollution. Air pollution appears to be strongly associated with a higher risk of cognitive defects, neurodevelopmental (e.g., schizophrenia) and neurodegenerative (e.g., Alzheimer’s disease) disorders. Subjects with schizophrenia, as well as subjects with Alzheimer’s disease, experience a variety of …neuropsychological deficits and cognitive impairments. This determines an adverse effect on social and professional functioning, and it contributes to the long-term disease burden. However, no final conclusions have been drawn on the matter of the direct relationship between schizophrenia and Alzheimer’s disease. In recent years, the topic of urbanicity and mental health has become increasingly important. Urban exposure to environmental toxins and pollution is currently described as a reliable risk factor for schizophrenia and other psychoses, and it has been demonstrated more and more how exposure to air pollutants is associated with increased risk of dementia. Pathways by which air pollution can target and damage the brain, leading to an increased risk for developing schizophrenia and Alzheimer’s disease, are multiple and complex. Results from epidemiological studies suggest potential associations, but are still insufficient to confirm causality. Further studies are needed in order to verify this hypothesis. And if confirmed, the clinical implications could be of substantial relevance for both public and mental health. Show more

Keywords: Air pollution, Alzheimer’s disease, public health, schizophrenia

DOI: 10.3233/JAD-200289

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 825-830, 2020

Authors: Mantovani, Elisa | Zucchella, Chiara | Schena, Federico | Romanelli, Maria Grazia | Venturelli, Massimo | Tamburin, Stefano

Article Type: Research Article

Abstract: Background: The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer’s disease (AD) and other neurodegenerative disorders in the future. Because of the absence of drugs that can modify the neuropathological substrate of AD, research is focusing on the application of preemptive and disease-modifying strategies in the pre-symptomatic period of the disease. In this perspective, the identification of people with cognitive frailty (CF), i.e., those individuals with higher risk of developing dementia, on solid pathophysiological bases and with clear operational clinical criteria is of paramount importance. Objective/Methods: This hypothesis paper reviews the …current definitions of CF, presents and discusses some of their limitations, and proposes a framework for updating and improving the conceptual and operational definition of the CF construct. Results: The potential for reversibility of CF should be supported by the assessment of amyloid, tau, and neuronal damage biomarkers, especially in younger patients. Physical and cognitive components of frailty should be considered as separate entities, instead of part of a single macro-phenotype. CF should not be limited to the geriatric population, because trajectories of amyloid accumulation are supposed to start earlier than 65 years in AD. Operational criteria are needed to standardize assessment of CF. Conclusion: Based on the limitations of current CF definitions, we propose a revised one according to a multidimensional subtyping. This new definition might help stratifying CF patients for future trials to explore new lifestyle interventions or disease-modifying pharmacological strategies for AD and dementia. Show more

Keywords: Biomarkers, cognitive frailty, dementia, frailty, mild cognitive impairment, neuropathology, subjective cognitive impairment

DOI: 10.3233/JAD-200137

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 831-843, 2020

Authors: van der Willik, Kimberly D. | Schagen, Sanne B. | Ikram, M. Arfan

Article Type: Short Communication

Abstract: There is an ongoing debate about how cancer and dementia relate to each other, and whether their relation is biologically determined or caused by surveillance and survival bias. We aimed to circumvent these biases by determining the relation between the tumor marker carcinoembryonic antigen (CEA) and the risk of dementia in 6,692 participants from the population-based Rotterdam Study. We found that higher levels of CEA were associated with a higher risk of dementia (HR per standard deviation increase in CEA = 1.11, 95% CI 1.04; 1.18). This finding may indicate that cancer and dementia are positively associated, but the mechanisms underlying the …relation between CEA and dementia warrant further investigation. Show more

Keywords: Carcinoembryonic antigen, cohort studies, dementia, epidemiology

DOI: 10.3233/JAD-200440

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 845-851, 2020

Authors: Reyes-Pablo, Aldelmo Emmanuel | Campa-Córdoba, B. Berenice | Luna-Viramontes, Nabil Itzi | Ontiveros-Torres, Miguel Ángel | Villanueva-Fierro, Ignacio | Bravo-Muñoz, Marely | Sáenz-Ibarra, Bárbara | Barbosa, Oralia | Guadarrama-Ortíz, Parménides | Garcés-Ramírez, Linda | de la Cruz, Fidel | Harrington, Charles R. | Martínez-Robles, Sandra | González-Ballesteros, Erik | Perry, George | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: We recently developed the National Dementia Biobank in México (BioBanco Nacional de Demencias, BND) as a unit for diagnosis, research, and tissue transfer for research purposes. BND is associated with the Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de Mexico (UNAM), Mexico. The donation of fluids, brain, and other organs of deceased donors is crucial for understanding the underlying mechanisms of neurodegenerative diseases and for the development of successful treatment. Our laboratory research focuses on 1) analysis of the molecular processing of the proteins involved in those neurodegenerative diseases termed tauopathies and 2) the search for biomarkers for the …non-invasive and early diagnosis of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β , BioBank, brain tissue, neurodegenerative disease, tau protein, tauopathies

DOI: 10.3233/JAD-191015

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 853-862, 2020

Authors: Roy, Maggie | Rheault, François | Croteau, Etienne | Castellano, Christian-Alexandre | Fortier, Mélanie | St-Pierre, Valérie | Houde, Jean-Christophe | Turcotte, Éric E. | Bocti, Christian | Fulop, Tamas | Cunnane, Stephen C. | Descoteaux, Maxime

Article Type: Research Article

Abstract: Background: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer’s disease (AD), glucose and ketones, the brain’s two main fuels, are rarely quantified in white matter in AD. Objective: Using a dual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with mild cognitive impairment (MCI; n  = 51) and AD (n  = 13) compared to cognitively healthy age-matched …controls (Controls; n  = 14). Methods: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18 F-fluorodeoxyglucose) and ketone (11 C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle. Results: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (–22%; p  = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD. Conclusion: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum. Show more

Keywords: Alzheimer’s disease, diffusion MRI, FDG, ketones, PET, white matter

DOI: 10.3233/JAD-200213

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 863-881, 2020

Authors: Hu, Yueming | Meuret, Cristiana | Go, Scholastica | Yassine, Hussein N. | Nedelkov, Dobrin

Article Type: Research Article

Abstract: Background: The mechanisms of how APOE ɛ 4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated. Objective: To determine the impact of APOE genotype on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma via a newly developed mass spectrometric immunoassay (MSIA) assay. Methods: Total glycosylation and isoform-specific glycosylation were analyzed in plasma and CSF from a group of non-demented older individuals (n  = 22), consisting of homozygous ɛ 3 and ɛ …4 or heterozygous ɛ 3/ɛ 4, ɛ 2/ɛ 3, or ɛ 2/ɛ 4 carriers. The glycan structures were further confirmed after treatment with sialidase. Results: In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O -linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In plasma and CSF, a trend of decreasing glycosylation was observed from apoE2 > apoE3 > apoE4. The difference in the percentage of secondary glycosylation in CSF was significantly greater in apoE4 compared to the other isoforms. Conclusion: The new MSIA apoE assay robustly distinguishes among apoE isoforms and glycoforms in plasma and CSF. ApoE4 is the predominant isoform and least glycosylated in CSF. Assessing apoE isoform-specific glycosylation by MSIA may help clarify brain apoE metabolism and AD risk. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, glycan, isoform, mass spectrometry

DOI: 10.3233/JAD-200203

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 883-893, 2020

Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Sakai, Toshihiro | Rakugi, Hiromi | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Very few studies have investigated the impact of cognitive frailty in clinical settings, especially in memory clinic populations. Objective: To examine the impact of cognitive frailty on activities of daily living (ADL), cognitive function, and conversion to dementia among memory clinic patients with mild cognitive impairment (MCI). Methods: The subjects of this retrospective study were 248 MCI patients (mean age, 76.3±5.4 years; females, 60.9%). All subjects completed a comprehensive geriatric assessment at baseline and at least one assessment during 3-year follow-up. Frailty was defined by generating a frailty index (FI), and MCI patients with frailty …(FI≥0.25) were considered to represent cognitive frailty. As primary outcomes, the Barthel Index, Mini-Mental State Examination, and incident dementia were evaluated during follow-up. At baseline, patients were assessed for apolipoprotein E (APOE ) phenotype. A linear mixed model, as well as a Cox proportional hazards regression model with adjustment for confounding variables, was performed. Results: Of these patients, 75 (30.2%) were classified as cognitive frail. APOE ɛ 4 carriers accounted for 26.7% of those with cognitive frailty and 44.5% of those without (p  = 0.008). Cognitive frail patients showed a faster ADL decline (estimate, –1.04; standard error, 0.38; p  = 0.007) than patients without cognitive frailty. Cognitive frailty was not associated with cognitive decline and incident dementia. Conclusion: Our findings demonstrated cognitive frailty increases the risk of dependence but not cognitive outcomes. Cognitive frailty may have heterogeneous conditions, including APOE ɛ 4-related pathologies, which may affect the cognitive trajectories of patients with MCI. Show more

Keywords: Cognitive frailty, disability, frailty, memory clinic, mild cognitive impairment, older persons

DOI: 10.3233/JAD-191135

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 895-903, 2020