Journal of Alzheimer's Disease - Volume 76, issue 4

Authors: Paul, Kimberly C. | Haan, Mary | Yu, Yu | Inoue, Kosuke | Mayeda, Elizabeth Rose | Dang, Kristina | Wu, Jun | Jerrett, Michael | Ritz, Beate

Article Type: Research Article

Abstract: Background: Ambient air pollution exposure has been associated with dementia. Additionally, epidemiologic evidence supports associations between air pollution and diabetes as well as diabetes and dementia. Thus, an indirect pathway between air pollution and dementia may exist through metabolic dysfunction. Objective: To investigate whether local traffic-related air pollution (TRAP) influences incident dementia and cognitive impairment, non-dementia (CIND) in a cohort of older Mexican Americans. We also assess how much of this estimated effect might be mediated through type 2 diabetes (T2DM). Methods: In a 10-year, prospective study of Latinos (n  = 1,564), we generated TRAP-NOx as …a surrogate for pollution from local traffic sources at participants’ residences during the year prior to enrollment. We used Cox proportional hazards modeling and mediation analysis to estimate the effects of TRAP-NOx on dementia and/or CIND and indirect pathways operating through T2DM. Results: Higher TRAP-NOx was associated with incident dementia (HR = 1.55 for the highest versus lower tertiles, 95% CI = 1.04, 2.55). Higher TRAP-NOx was also associated with T2DM (OR = 1.62, 95% CI = 1.27, 2.05); furthermore, T2DM was associated with dementia (HR = 1.94, 95% CI = 1.42, 2.66). Mediation analysis indicated that 20% of the estimated effect of TRAP-NOx on dementia/CIND was mediated through T2DM. Conclusion: Our results suggest that exposure to local traffic-related air pollution is associated with incident dementia. We also estimated that 20% of this effect is mediated through T2DM. Thus, ambient air pollution might affect brain health via direct damage as well as through indirect pathways related to diabetes and metabolic dysfunction. Show more

Keywords: Air pollution, CALINE4, cognitive decline, dementia, diabetes, Latino, mediation, nitrogen oxide, traffic-related air pollution

DOI: 10.3233/JAD-200320

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1477-1491, 2020

Authors: Garcia, Marc A. | Ortiz, Kasim | Arévalo, Sandra P. | Diminich, Erica D. | Briceño, Emily | Vega, Irving E. | Tarraf, Wassim

Article Type: Research Article

Abstract: Background: Age of migration has been shown to have a robust association with Latino immigrant health outcomes; however, the relationship between timing of migration and cognition is less understood. Objective: To examine associations between race/ethnicity, nativity, age of migration, and cognitive aging among US-born (USB) non-Latino Whites (NLW) and USB and foreign-born Latinos 50 years and older. Methods: We used longitudinal biennial data from the Health and Retirement Study (HRS; 2006-2014) to fit generalized linear and linear latent growth curve models for: 1) global cognition (Modified Telephone Interview for Cognitive Status; TICS-M); 2) memory and attention …subdomains of TICS-M; and 3) cognitive dysfunction. We also tested for sex modifications. Results: In age and sex adjusted models, all Latino subgroups, independent of nativity and age of migration, had lower global and domain-specific cognitive scores and higher propensity of cognitive impairment classification compared to USB-NLWs. Differences between USB Latinos, but not other Latino subgroups, and USB-NLWs remained after full covariate adjustment. Latinas, independent of nativity or age of migration, had poorer cognitive scores relative to NLW females. Differences between all Latinos and USB-NLWs were principally expressed at baseline. Racial/ethnic, nativity, and age of migration grouping was not associated with slope (nor explained variance) of cognitive decline. Conclusion: Older US-born Latinos, regardless of sex exhibit poorer cognitive function than older USB-NLWs and foreign-born Latinos. Social determinants that differentially affect cognitive function, particularly those that compensate for education and sex differences among US-born Latinos and foreign-born Latinos, require further exploration. Show more

Keywords: Alzheimer’s disease and related dementias, cognitive function, immigration, Latino, nativity, sex differences

DOI: 10.3233/JAD-191296

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1493-1511, 2020

Authors: Sun, Zhiqing | Sun, Lei | Tu, Lixiang

Article Type: Research Article

Abstract: Background: Oxidative stress has been implicated in Alzheimer’s disease (AD) as a common pathway underlying neuronal damage causing huge impacts on cognitive functions in the AD process. Objective: Reduction and remodeling of γ -aminobutyric acid (GABA) signaling in AD may promote neuronal survival by regulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABAB receptor as a novel therapeutic target for AD. Methods: To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABAB …receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABAB activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABAB and PI3K/Akt signaling pathway on apoptosis and oxidative stress injury were determined in vivo and in vitro using primary neuronal cultures. Results: We found that GABAB receptor activation restored spatial memory and learning ability of AD rats and suppressed the neuronal apoptosis and hippocampal atrophy by activating the PI3K/Akt signaling pathway. Additionally, GABAB receptor activation reduced the oxidative stress injury by lowering the MDA levels and increased the SOD, GSH-Px, and CAT levels via activation of the PI3K/Akt signaling pathway. Conclusion: Taken together, our results suggest that GABAB receptor activation repressed the oxidative stress injury implicated in neurons in AD rats via PI3K/Akt signaling pathway activation which may suggest a potential new therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, GABAB receptor, oxidative stress injury, PI3K/Akt signaling pathway

DOI: 10.3233/JAD-191032

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1513-1526, 2020

Authors: Gárate-Vélez, Lorena | Escudero-Lourdes, Claudia | Salado-Leza, Daniela | González-Sánchez, Armando | Alvarado-Morales, Ildemar | Bahena, Daniel | Labrada-Delgado, Gladis Judith | Rodríguez-López, José Luis

Article Type: Research Article

Abstract: Background: Iron nanoparticles, mainly in magnetite phase (Fe3 O4 NPs), are released to the environment in areas with high traffic density and braking frequency. Fe3 O4 NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration. Objective: To describe the interaction and toxicity of pollution-derived Fe3 O4 NPs on primary rat brain microvascular …endothelial cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3 O4 NPs that mimic the environmental ones (miFe3 O4 ) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays. Results: The miFe3 O4 NPs, with a mean diameter of 8.45±0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe3 O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3 O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3 O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage. Show more

Keywords: Blood-brain barrier, cytotoxicity, in vitro , magnetite nanoparticles

DOI: 10.3233/JAD-190929

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1527-1539, 2020

Authors: Ferguson, Amy C. | Tank, Rachana | Lyall, Laura M. | Ward, Joey | Celis-Morales, Carlos | Strawbridge, Rona | Ho, Frederick | Whelan, Christopher D. | Gill, Jason | Welsh, Paul | Anderson, Jana J. | Mark, Patrick B. | Mackay, Daniel F. | Smith, Daniel J. | Pell, Jill P. | Cavanagh, Jonathan | Sattar, Naveed | Lyall, Donald M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE ), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Objective: Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. Methods: After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential …associations between APOE genotypes and biomarkers. Results: Several biomarkers significantly associated with APOE ɛ 4 ‘risk’ and ɛ 2 ‘protective’ genotypes (versus neutral ɛ 3/ɛ 3). Most associations supported previous data: for example, ɛ 4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p  < 0.001) and ɛ 2 with lower LDL (b  = –0.456 SDs, p  < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ 4 and increased insulin-like growth factor (IGF-1) (b  = 0.017, p  < 0.001) where lower levels have been previously suggested as an AD risk factor. Conclusion: These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways. Show more

Keywords: Alzheimer’s disease, APOE, cholesterol, dementia, UK Biobank

DOI: 10.3233/JAD-200338

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1541-1551, 2020

Authors: Fan, Kang-Hsien | Feingold, Eleanor | Rosenthal, Samantha L. | Demirci, F. Yesim | Ganguli, Mary | Lopez, Oscar L. | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: The genetics of late-onset Alzheimer’s disease (AD) is complex due to the heterogeneous nature of the disorder. APOE*4 is the strongest genetic risk factor for AD. Genome-wide association studies have identified more than 30 additional loci, each having relatively small effect size. Known AD loci explain only about 30% of the genetic variance, and thus much of the genetic variance remains unexplained. To identify some of the missing heritability of AD, we analyzed whole-exome sequencing (WES) data focusing on non-APOE*4 carriers from two WES datasets: 720 cases and controls from the University of Pittsburgh and 7,252 cases and …controls from the Alzheimer’s Disease Sequencing Project. Following separate WES analyses in each dataset, we performed meta-analysis for overlapping markers present in both datasets. Among the four variants reaching the exome-wide significance threshold, three were from known AD loci: APOE /rs7412 (odds ratio (OR) = 0.40; p  = 5.46E–24), TOMM40 /rs157581 (OR = 1.49; p  = 4.04E–07), and TREM2 /rs75932628 (OR = 4.00; p  = 1.15E–07). The fourth significant variant, rs199533, was from a novel locus on chromosome 17 in the NSF gene (OR = 0.78; p  = 2.88E–07). NSF was also significant in the gene-based analysis (p  = 1.20E–05). In the GTEx data, NSF /rs199533 is a cis-eQTL for multiple genes in the brain and blood, including NSF that is highly expressed across all brain tissues, including regions that typically show amyloid-β accumulation. Further characterization of genes that are affected by NSF /rs199533 may help to shed light on the roles of these genes in AD etiology. Show more

Keywords: Alzheimer’s disease, genetics, NSF gene, whole-exome sequencing

DOI: 10.3233/JAD-200037

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1553-1565, 2020

Authors: Coppalle, Renaud | Mauger, Caroline | Quernet, Sophie | Dewald, Axel | Letortu, Odile | Desgranges, Béatrice | Groussard, Mathilde | Platel, Hervé

Article Type: Research Article

Abstract: Background: Encoding of new information is considered to be impossible in people with Alzheimer’s disease (PWAD) at a moderate to severe stage. However, a few case studies reported new learning under special circumstances, especially with music. Objective: This article aims at clarifying PWAD’s learning capacities toward unknown material under more ecological settings, which is repeated exposure without encoding instruction. Methods: Twenty-three PWAD (Age: m = 84.6(5.2), 5≤MMSE≤19) underwent presentations of unknown artistic pieces (targets) through 8 daily individual sessions. These sessions were followed by a test session, during which their knowledge of the targets was assessed through a …verbal and behavioral scale (the sense of familiarity scale) against a series of unknown items (distractors). Results: Through this design, we were able to objectify encoding of three types of targets (verses, paintings, and music) against distractors the day after exposure sessions, and 2 months after the last presentation (study 1). Music and paintings were eventually well-encoded by most participants, whereas poems encoding was poorer. When compared to distractors, target items were significantly better recognized. We then compared the recognition of target paintings against two types of painting distractors, either perceptually or semantically related (study 2). The targets were better recognized than all three painting distractors, even when they were very close to the targets. Conclusion: Despite massive anterograde amnesia, our results clearly showed that recognition-based learning without conscious memory of the encoding context is preserved in PWAD at a severe stage, revealed through an increasing sense of familiarity following repeated exposure. These findings could open new perspective both for researchers and clinicians and improve the way we understand and care for PWAD living in healthcare facilities. Show more

Keywords: Alzheimer’s disease, familiarity, learning, music, recognition-based memory

DOI: 10.3233/JAD-191318

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1567-1579, 2020

Authors: Secnik, Juraj | Xu, Hong | Schwertner, Emilia | Hammar, Niklas | Alvarsson, Michael | Winblad, Bengt | Eriksdotter, Maria | Garcia-Ptacek, Sara | Religa, Dorota

Article Type: Research Article

Abstract: Background: Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. Objective: Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. Methods: We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation …was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naïve subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Results: Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11–1.31] and lower probability of DPP-4i (0.72 [0.66–0.79]), GLP-1a (0.51 [0.41–0.63]), and SGLT-2i dispensation (0.44 [0.36–0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (–0.58%), GLP-1a (–0.13%), and SGLT-2i (–0.21%) dispensation in dementia patients compared to dementia-free controls. Conclusion: Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects. Show more

Keywords: Dementia, diabetes mellitus, hypoglycemic agents, pharmacoepidemiology

DOI: 10.3233/JAD-200618

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1581-1594, 2020

Authors: Luiu, Anna Laura | Favez, Nicolas | Betrancourt, Mireille | Szilas, Nicolas | Ehrler, Frederic

Article Type: Research Article

Abstract: Background: Family caregivers of people with Alzheimer’s disease are the most important support in concrete personal and economic terms. Family dynamics play a fundamental role in the provision of informal caregiving benefits. Objective: This review aims to identify factors related to the family caregiving of relatives with Alzheimer’s disease, taking specifically into account the construct of coping and expressed emotion. Methods: This is a systematic review including articles selected using search terms including “caregivers,” “Alzheimer’s,” “family,” and “relationship” in research databases. Findings were synthesized and categorized into themes. Results: A total of 454 abstracts …were identified. Following screening, lateral searches, and quality appraisal, 36 studies were included for synthesis. A total of 5 themes were identified: burden; demographics; coping strategies; caregiver mental health; and family dynamics and expressed emotions. Conclusion: The quality and level of evidence supporting each theme varied. We need further research into family dynamics ameliorating the caregiving and how to measure it. Show more

Keywords: Alzheimer’s disease, family caregivers, family relationship, systematic review

DOI: 10.3233/JAD-200125

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1595-1608, 2020

Authors: Muzambi, Rutendo | Bhaskaran, Krishnan | Brayne, Carol | Davidson, Jennifer A. | Smeeth, Liam | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: Bacterial infections may be associated with dementia, but the temporality of any relationship remains unclear. Objectives: To summarize existing literature on the association between common bacterial infections and the risk of dementia and cognitive decline in longitudinal studies. Methods: We performed a comprehensive search of 10 databases of published and grey literature from inception to 18 March 2019 using search terms for common bacterial infections, dementia, cognitive decline, and longitudinal study designs. Two reviewers independently performed the study selection, data extraction, risk of bias and overall quality assessment. Data were summarized through a narrative synthesis …as high heterogeneity precluded a meta-analysis. Results: We identified 3,488 studies. 9 met the eligibility criteria; 6 were conducted in the United States and 3 in Taiwan. 7 studies reported on dementia and 2 investigated cognitive decline. Multiple infections were assessed in two studies. All studies found sepsis (n  = 6), pneumonia (n  = 3), urinary tract infection (n  = 1), and cellulitis (n  = 1) increased dementia risk (HR 1.10; 95% CI 1.02–1.19) to (OR 2.60; 95% CI 1.84–3.66). The range of effect estimates was similar when limited to three studies with no domains at high risk of bias. However, the overall quality of evidence was rated very low. Studies on cognitive decline found no association with infection but had low power. Conclusion: Our review suggests common bacterial infections may be associated with an increased risk of subsequent dementia, after adjustment for multiple confounders, but further high-quality, large-scale longitudinal studies, across different healthcare settings, are recommended to further explore this association. Show more

Keywords: Cognition, dementia, infections, prevention, systematic review, Systematic review registration number: CRD42018119294, registered in December 2018

DOI: 10.3233/JAD-200303

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1609-1626, 2020

Authors: Mei, Xinchun | Zheng, Hai-Lin | Li, Cheng | Ma, Xin | Zheng, Hui | Marcantonio, Edward | Xie, Zhongcong | Shen, Yuan

Article Type: Research Article

Abstract: Background: Postoperative delirium is associated with adverse postoperative outcomes. However, whether intravenous and inhalation anesthetics are associated with different risks of postoperative delirium remains unknown. Objective: We set up to determine the incidence and duration of postoperative delirium in older patients who had surgery under the intravenous anesthetic propofol or the inhalational anesthetic sevoflurane. Methods: Participants were patients who had total hip/knee replacements and were randomized to propofol (N = 106) or sevoflurane (N = 103) anesthesia group. The Confusion Assessment Method was employed by investigators who were blinded to the anesthesia regimen to assess the incidence and duration (days …of postoperative delirium per person) of postoperative delirium on postoperative days 1, 2, and 3. Results: A total of 209 participants (71.2±6.7 years old, 29.2% male) were included in the final data analysis. The incidence of postoperative delirium was 33.0% with propofol anesthesia and 23.3% with sevoflurane anesthesia (p  = 0.119, Chi-square test ), and we estimated that we would need 316 participants in each arm to detect a potential statistically significant difference. Days of postoperative delirium per person were higher in the propofol (0.5±0.8) anesthesia group compared to the sevoflurane anesthesia group (0.3±0.5, p  = 0.049, Student ’s t-test ). Conclusion: This pilot study established a system to compare effects of different anesthetics and generated a hypothesis that propofol trended to have a higher incidence and had longer duration of postoperative delirium than sevoflurane. Additional studies with a larger sample size are needed to test this hypothesis. Show more

Keywords: Anesthesia, delirium, postoperative, propofol, sevoflurane

DOI: 10.3233/JAD-200322

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1627-1636, 2020

Authors: Guan, Qing | Hu, Xiaohui | Ma, Ning | He, Hao | Duan, Feiyan | Li, Xin | Luo, Yuejia | Zhang, Haobo

Article Type: Research Article

Abstract: Background: Both sleep quality and depression could affect cognitive performance in older adults. Previous studies have suggested that there are bi-directional relationships between sleep quality and depression. Possibly, the influence of sleep quality on cognition is partly mediated by depression, and vice versa. Objective: We aimed to assess the mediation effects of sleep quality and depression on each other’s relationship with various cognitive functions in non-demented older adults. Methods: Correlations were examined among sleep quality indices, depressive severity score, and five cognitive functions in 206 cognitively normal (CN) older adults and all participants that included these …CN and 40 mild cognitive impairment (MCI) individuals. We then analyzed the mediation effects for the significant cognitive correlations of sleep disturbance and depression using the bias-corrected Bootstrap method in the two populations. Results: Both sleep disturbance and depression were significantly correlated with memory recall and processing speed. In CN, depression could mediate the relationships of sleep disturbance with both cognitive functions, while sleep disturbance could only mediate the relationship of depression with processing speed, but not memory recall. However, in all participants, sleep disturbance could mediate the relationships of depression with both cognitive functions. Conclusion: Different mediation effects in the two models in CN older adults might suggest differential mechanisms underlying the pathways from sleep disturbance and depression to various cognitive functions. The mediation results in all participants might indicate that the mechanisms underlying the pathways from sleep disturbance and depression to memory recall were different between MCI and CN older adults. Show more

Keywords: Cognitive function, depression, mediation, mild cognitive impairment, older adults, sleep quality

DOI: 10.3233/JAD-190990

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1637-1650, 2020

Authors: Liu, Yanyong | Aisa, Haji Akber | Ji, Chao | Yang, Nan | Zhu, Haibo | Zuo, Pingping

Article Type: Correction

DOI: 10.3233/JAD-209006

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1651-1652, 2020