Journal of Alzheimer's Disease - Volume 85, issue 2

Authors: Metsla, Kristel | Kirss, Sigrid | Laks, Katrina | Sildnik, Gertrud | Palgi, Mari | Palumaa, Teele | Tõugu, Vello | Palumaa, Peep

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper. Objective: In the current study, we follow the widely …accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands. Methods: We used cell culture, ICP MS, and Drosophila melanogaster models of AD. Results: We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells. Conclusion: Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD. Show more

Keywords: Alzheimer’s disease, copper metabolism, metalloneurochemistry, α-lipoic acid

DOI: 10.3233/JAD-215026

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 715-728, 2022

Authors: Wang, Fang | Xu, Jia | Xu, Shu-Jun | Guo, Jie-Jie | Wang, Feiming | Wang, Qin-Wen

Article Type: Research Article

Abstract: Background: COVID-19 pandemic is a global crisis which results in millions of deaths and causes long-term neurological sequelae, such as Alzheimer’s disease (AD). Objective: We aimed to explore the interaction between COVID-19 and AD by integrating bioinformatics to find the biomarkers which lead to AD occurrence and development with COVID-19 and provide early intervention. Methods: The differential expressed genes (DEGs) were found by GSE147507 and GSE132903, respectively. The common genes between COVID-19 and AD were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interactions (PPI) network analysis were carried out. Hub …genes were found by cytoscape. A multivariate logistic regression model was constructed. NetworkAnalyst was used for the analysis of TF-gene interactions, TF-miRNA coregulatory network, and Protein-chemical Interactions. Results: Forty common DEGs for AD and COVID-19 were found. GO and KEGG analysis indicated that the DEGs were enriched in the calcium signal pathway and other pathways. A PPI network was constructed, and 5 hub genes were identified (ITPR1, ITPR3, ITPKB, RAPGEF3, MFGE8 ). Four hub genes (ITPR1, ITPR3, ITPKB, RAPGEF3 ) which were considered as important factors in the development of AD that were affected by COVID-19 were shown by nomogram. Utilizing NetworkAnalyst, the interaction network of 4 hub genes and TF, miRNA, common AD risk genes, and known compounds is displayed, respectively. Conclusion: COVID-19 patients are at high risk of developing AD. Vaccination is required. Four hub genes can be considered as biomarkers for prediction and treatment of AD development caused by COVID-19. Compounds with neuroprotective effects can be used as adjuvant therapy for COVID-19 patients. Show more

Keywords: Alzheimer’s disease, bioinformatics, compound, COVID-19, differentially expressed genes, hub gene

DOI: 10.3233/JAD-215086

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 729-744, 2022

Authors: Chen, Ben | Espin, Melanie | Haussmann, Robert | Matthes, Claudia | Donix, Markus | Hummel, Thomas | Haehner, Antje

Article Type: Research Article

Abstract: Background: The olfactory system is affected very early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI), an early stage of AD. Objective: The aim of this randomized, prospective, controlled, blinded study was to evaluate whether olfactory training (OT) may have an effect on olfactory function, cognitive impairment, and brain activation in MCI patients after a 4-month period of frequent short-term exposure to various odors. Methods: A total of 38 MCI outpatients were randomly assigned to OT or a control training condition, which were performed …twice a day for 4 months. Olfactory testing, comprehensive neuropsychological assessment, and a passive odor perception task based on magnetic resonance imaging were performed before and after training. Results: The results suggested that OT exhibited no significant effect on olfaction and cognitive function. Additionally, OT exhibited a positive effect on frontal lobe activation (left middle frontal gyrus and orbital-frontal cortex) but exhibited no effect on grey matter volume. Moreover, the change of olfactory scores was positively associated with the change of frontal activation. Conclusion: OT was found to have a limited effect on olfaction and cognition in patients with MCI compared to a non-OT condition but increased their functional response to odors in frontal area. Show more

Keywords: Alzheimer’s disease, functional MRI, grey matter, mild cognitive impairment, olfactory training

DOI: 10.3233/JAD-215257

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 745-754, 2022

Authors: Sil, Annesha | Erfani, Arina | Lamb, Nicola | Copland, Rachel | Riedel, Gernot | Platt, Bettina

Article Type: Research Article

Abstract: Background: The prevalence of Alzheimer’s disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences. Methods: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration …(NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting. Results: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. Conclusion: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies. Show more

Keywords: Activity, amyloid-β, cognition, ER stress, female, inflammation, male, social, trophic factors

DOI: 10.3233/JAD-210523

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 755-778, 2022

Authors: Zhou, Haobin | Zhu, Zongyuan | Liu, Changsong | Bai, Yujia | Zhan, Qiong | Huang, Xingfu | Zeng, Qingchun | Ren, Hao | Xu, Dingli

Article Type: Research Article

Abstract: Background: Elevated blood pressure (BP) is a risk factor for cognitive impairment. Objective: We aim to explore the association between the duration of hypertension in early adulthood, with cognitive function in midlife. Furthermore, we investigate whether this asssociation is altered among participants with controlled BP. Methods: This prospective study included 2,718 adults aged 18–30 years without hypertension at baseline who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Duration of hypertension was calculated based on repeat measurements of BP performed at 2, 5, 7, 10, 15, 20, and 25 years after baseline. …Cognitive function was assessed at Year-25 using the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Stroop test. Results: After multivariable adjustment, a longer hypertension duration was associated with worse verbal memory (RAVLT, p trend = 0.002) but not with processing speed (DSST, p trend = 0.112) and executive function (Stroop test, p trend = 0.975). Among subgroups of participants with controlled (BP < 140/90 mmHg) and uncontrolled (SBP≥140 mmHg or DBP≥90 mmHg) BP at the time of cognitive assessment (i.e., Year-25 BP), longer duration of hypertension was associated with worse verbal memory. Similar results were observed in subgroups with controlled and uncontrolled average BP prior to cognitive assessment. Conclusion: Longer duration of hypertension during early adulthood is associated with worse verbal memory in midlife regardless of current or long-term BP control status. The potential risk of hypertension associated cognitive decline should not be overlooked in individuals with a long duration of hypertension, even if BP levels are controlled. Show more

Keywords: Cognitive function, DSST, duration, hypertension, RAVLT, stroop test

DOI: 10.3233/JAD-215070

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 779-789, 2022

Authors: Shang, Xianwen | Hill, Edward | Zhu, Zhuoting | Liu, Jiahao | Ge, Zongyuan | Wang, Wei | He, Mingguang

Article Type: Research Article

Abstract: Background: Little is known about the association between macronutrient intake and incident dementia. Objective: To identify an optimal range of macronutrient intake associated with reduced risk of dementia. Methods: Our analysis included 93,389 adults aged 60–75 years from the UK Biobank. Diet was assessed using a web-based 24-h recall questionnaire between 2009–2012. Dementia was ascertained using hospital inpatient, death records, and self-reported data up to January 2021. We calculated a macronutrient score based on associations between an individual’s macronutrient intake and incident dementia. Results: During a median follow-up of 8.7 …years, 1,171 incident dementia cases were documented. We found U-shape relationships for carbohydrate, fat, and protein intake with incident dementia. Compared to individuals with optimal carbohydrate intake, those with high intake (HR (95%CI): 1.48(1.15–1.91)) but not low intake (1.19(0.89–1.57)) had a higher risk of dementia. In the multivariable analysis, a low-fat intake (HR (95%CI): 1.42(1.11–1.82)) was associated with a higher risk of all-cause dementia. After adjustment for covariates, a high (HR (95%CI): 1.41(1.09–1.83)) but not low protein intake (1.22(0.94–1.57)) was associated with an increased risk of dementia. Individuals in quintiles 3–5 of optimal macronutrient score had a lower risk of dementia compared with those in quintile 1 (HR (95%CI): 0.76(0.64–0.91) for quintile 3, 0.71(0.60–0.85) for quintile 4, 0.74(0.61–0.91) for quintile 5). The association between macronutrient score and incident dementia was significant across subgroups of age, gender, education, and smoking. Conclusion: Moderate intakes of carbohydrate, fat, and protein were associated with the lowest risk of incident dementia. Show more

Keywords: Dementia, dietary carbohydrate, dietary fat, dietary protein, moderation analysis.

DOI: 10.3233/JAD-215042

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 791-804, 2022

Authors: Spartano, Nicole L. | Himali, Jayandra J. | Trinquart, Ludovic | Yang, Qiong | Weinstein, Galit | Satizabal, Claudia L. | Dukes, Kimberly A. | Beiser, Alexa S. | Murabito, Joanne M. | Vasan, Ramachandran S. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels. Objective: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort. Methods: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement or platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, …adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time. Results: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day in moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p  > 0.05). We observed a non-linear trend, where 15–50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β= –0.049±0.024, p  = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β= –0.216±0.079, p  = 0.01). Conclusion: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA. Show more

Keywords: Epidemiology, exercise, growth factor, sedentary time

DOI: 10.3233/JAD-215109

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 805-814, 2022

Authors: Gauci, Sarah | Young, Lauren M. | White, David J. | Reddan, Jeffery M. | Lassemillante, Annie-Claude | Meyer, Denny | Pipingas, Andrew | Scholey, Andrew

Article Type: Research Article

Abstract: Background: Cognitive decline is influenced by various factors including diet, cardiovascular disease, and glucose control. However, the combined effect of these risk factors on cognitive performance is yet to be fully understood. Objective: The current study aimed to explore the inter-relationship between these risk factors and cognitive performance in older adults at risk of future cognitive decline. Methods: The sample comprised 163 (Age: M  = 65.23 years, SD  = 6.50) participants. Food Frequency Questionnaire data was used to score diet quality and adherence to the Western Style Diet (WSD) and Prudent Style Diet (PSD). Glucose …control was gauged by serum levels of glycated hemoglobin (HbA1c) and arterial stiffness was measured using carotid to femoral pulse wave velocity. Cognitive performance was assessed using two subtests of the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) and Rey’s Verbal Learning Test (RVLT). Results: Diet quality, adherence to the WSD or PSD, and glucose control were not significantly related to cognitive outcomes. However, a significant negative association was found between arterial stiffness and the spatial working memory subtest of SUCCAB (β= –0.21, p  < 0.05). Arterial stiffness also significantly interacted with the PSD to impact total recall (F change (1,134) = 5.37, p  < 0.05) and the composite score of RVLT (F change (1,134) = 4.03, p  < 0.05). Conclusion: In this sample of older adults at risk of cognitive decline, diet alone was not found to predict cognitive performance; however, it was found to moderate the relationship between arterial stiffness and cognition. Show more

Keywords: Aging, arterial stiffness, cognition, diet, dietary patterns, glucose control, working memory

DOI: 10.3233/JAD-210567

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 815-828, 2022

Authors: Liu, Xi-Xi | Wu, Peng-Fei | Liu, Ying-Zi | Jiang, Ya-Ling | Wan, Mei-Dan | Xiao, Xue-Wen | Yang, Qi-Jie | Jiao, Bin | Liao, Xin-Xin | Wang, Jun-Ling | Liu, Shao-Hui | Zhang, Xuewei | Shen, Lu

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. Objective: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. Methods: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. Results: Compared with the …controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. Conclusion: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities. Show more

Keywords: Alzheimer’s disease, homocysteine, nutrient, vitamin

DOI: 10.3233/JAD-215104

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 829-836, 2022

Authors: Khajehpiri, Boshra | Moghaddam, Hamid Abrishami | Forouzanfar, Mohamad | Lashgari, Reza | Ramos-Cejudo, Jaime | Osorio, Ricardo S. | Ardekani, Babak A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Evaluating the risk of Alzheimer’s disease (AD) in cognitively normal (CN) and patients with mild cognitive impairment (MCI) is extremely important. While MCI-to-AD progression risk has been studied extensively, few studies estimate CN-to-MCI conversion risk. The Cox proportional hazards (PH), a widely used survival analysis model, assumes a linear predictor-risk relationship. Generalizing the PH model to more complex predictor-risk relationships may increase risk estimation accuracy. Objective: The aim of this study was to develop a PH model using an Xgboost regressor, based on demographic, genetic, neuropsychiatric, and neuroimaging predictors to estimate risk of AD in patients with …MCI, and the risk of MCI in CN subjects. Methods: We replaced the Cox PH linear model with an Xgboost regressor to capture complex interactions between predictors, and non-linear predictor-risk associations. We endeavored to limit model inputs to noninvasive and more widely available predictors in order to facilitate future applicability in a wider setting. Results: In MCI-to-AD (n  = 882), the Xgboost model achieved a concordance index (C-index) of 84.5%. When the model was used for MCI risk prediction in CN (n  = 100) individuals, the C-index was 73.3%. In both applications, the C-index was statistically significantly higher in the Xgboost in comparison to the Cox PH model. Conclusion: Using non-linear regressors such as Xgboost improves AD dementia risk assessment in CN and MCI. It is possible to achieve reasonable risk stratification using predictors that are relatively low-cost in terms of time, invasiveness, and availability. Future strategies for improving AD dementia risk estimation are discussed. Show more

Keywords: Alzheimer’s disease, brain, hippocampal atrophy, machine learning, magnetic resonance imaging, mild cognitive impairment, proportional hazards model, survival analysis, Xgboost

DOI: 10.3233/JAD-215266

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 837-850, 2022