Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Tian, Jing | Du, Eric | Jia, Kun | Wang, Tienju | Guo, Lan | Zigman, Jeffrey M. | Du, Heng

Article Type: Research Article

Abstract: Background: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer’s disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. Objective: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin …(hAβ KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. Methods: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAβ KI mice as well as primary neuron cultures. Results: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. Conclusions: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings. Show more

Keywords: Alzheimer’s disease, amyloid-β, ghrelin, growth hormone secretagogue receptor, hippocampal synaptic injury

DOI: 10.3233/JAD-231002

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Blood biomarkers have the potential to transform Alzheimer’s disease (AD) diagnosis and monitoring, yet their integration with common medical comorbidities remains insufficiently explored. Objective: This study aims to enhance blood biomarkers’ sensitivity, specificity, and predictive performance by incorporating comorbidities. We assess this integration’s efficacy in diagnostic classification using machine learning, hypothesizing that it can identify a confident set of predictive features. Methods: We analyzed data from 1,705 participants in the Health and Aging Brain Study-Health Disparities, including 116 AD patients, 261 with mild cognitive impairment, and 1,328 cognitively normal controls. Blood samples were assayed using …electrochemiluminescence and single molecule array technology, alongside comorbidity data gathered through clinical interviews and medical records. We visually explored blood biomarker and comorbidity characteristics, developed a Feature Importance and SVM-based Leave-One-Out Recursive Feature Elimination (FI-SVM-RFE-LOO) method to optimize feature selection, and compared four models: Biomarker Only, Comorbidity Only, Biomarker and Comorbidity, and Feature-Selected Biomarker and Comorbidity. Results: The combination model incorporating 17 blood biomarkers and 12 comorbidity variables outperformed single-modal models, with NPV12 at 92.78%, AUC at 67.59%, and Sensitivity at 65.70% . Feature selection led to 22 chosen features, resulting in the highest performance, with NPV12 at 93.76%, AUC at 69.22%, and Sensitivity at 70.69% . Additionally, interpretative machine learning highlighted factors contributing to improved prediction performance. Conclusions: In conclusion, combining feature-selected biomarkers and comorbidities enhances prediction performance, while feature selection optimizes their integration. These findings hold promise for understanding AD pathophysiology and advancing preventive treatments. Show more

Keywords: Alzheimer’s disease, blood biomarkers, comorbidities, machine learning, recursive feature elimination, support vector machine

DOI: 10.3233/JAD-230755

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023

Authors: Solis-Urra, Patricio | Rodriguez-Ayllon, María | Álvarez-Ortega, Miriam | Molina-Hidalgo, Cristina | Molina-Garcia, Pablo | Arroyo-Ávila, Cristina | García-Hermoso, Antonio | Collins, Audrey M. | Jain, Shivangi | Gispert, Juan Domingo | Liu-Ambrose, Teresa | Ortega, Francisco B. | Erickson, Kirk I. | Esteban-Cornejo, Irene

Article Type: Systematic Review

Abstract: Background: Accumulation of amyloid-β (Aβ) plaques is one of the main features of Alzheimer’s disease (AD). Physical performance has been related to dementia risk and Aβ, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aβ. Yet, no evidence synthesis has been performed in humans. Objective: To investigate the association of physical performance with Aβ in humans, including Aβ accumulation on brain, and Aβ abnormalities measured in cerebrospinal fluid (CSF) and blood. Methods: A systematic review with multilevel meta-analysis was performed from inception to June 16th , 2022. Studies were …eligible if they examined the association of physical performance with Aβ levels, including the measure of physical performance as a predictor and the measure of Aβ as an outcome in humans. Results: 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aβ in the brain (ES = 0.01; 95% CI –0.21 to 0.24; I2  = 69.9%), in the CSF (ES = –0.28; 95% CI –0.98 to 0.41; I2  = 91.0%) or in the blood (ES = –0.19; 95% CI –0.61 to 0.24; I2  = 99.75%). Significant heterogeneity was found across the results , which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. Conclusions: The association between physical performance and Aβ is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aβ levels in humans. Show more

Keywords: Alzheimer’s disease, amyloid, meta-analysis, physical performance

DOI: 10.3233/JAD-230586

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023

Authors: White, Joshua P. | Schembri, Adrian | Prenn-Gologranc, Carmen | Ondrus, Matej | Katina, Stanislav | Novak, Petr | Lim, Yen Ying | Edgar, Chris | Maruff, Paul

Article Type: Research Article

Abstract: Background: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer’s disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. Objective: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Methods: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for …MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Results: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79–0.88), and CDR > 0.5 (AUCs ∼ 0.89–0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. Conclusions: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity. Show more

Keywords: Alzheimer’s disease, cogstate brief battery, composites, dementia, discriminability, mild cognitive impairment

DOI: 10.3233/JAD-230352

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2023

Authors: Liu, Yan-Bing | Wang, Xue-Jie | Tan, Lan | Tan, Chen-Chen | Xu, Wei

Article Type: Research Article

Abstract: Background: APOE ɛ4 and PICALM are established genes associated with risk of late-onset Alzheimer’s disease (AD). Previous study indicated interaction of PICALM with APOE ɛ4 in AD patients. Objective: To explore whether PICALM variation could moderate the influences of APOE ɛ4 on AD pathology biomarkers and cognition in pre-dementia stage. Methods: A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ɛ4 carriers) were genotyped for PICALM rs3851179 and APOE ɛ4 at baseline and were followed for influences on changes …of cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis. Results: The interaction term of rs3851179×APOE ɛ 4 accounted for a significant amount of variance in baseline general cognition (p  = 0.039) and memory function (p  = 0.002). The relationships of APOE ɛ4 with trajectory of CSF Aβ 42 (p  = 0.007), CSF P-tau181 (p  = 0.003), CSF T-tau (p  = 0.001), and memory function (p  = 0.017) were also moderated by rs3851179 variation. Conclusions: APOE ɛ4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ɛ4 in pre-dementia stage. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, cognition, interaction, memory, PICALM , tau protein

DOI: 10.3233/JAD-230516

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Lai, Dongbing | Zhang, Michael | Li, Rudong | Zhang, Chi | Zhang, Pengyue | Liu, Yunlong | Gao, Sujuan | Foroud, Tatiana

Article Type: Research Article

Abstract: Background: Except APOE , Alzheimer’s disease (AD) associated genes identified in recent large-scale genome-wide association studies (GWAS) had small effects and explained a small portion of heritability. Many AD-associated genes have even smaller effects thereby sub-threshold p -values in large-scale GWAS and remain to be identified. For some AD-associated genes, drug targeting them may have limited efficacies due to their small effect sizes. Objective: The purpose of this study is to identify AD-associated genes with sub-threshold p -values and prioritize drugs targeting AD-associated genes that have large efficacies. Methods: We developed a gene-based …polygenic risk score (PRS) to identify AD genes. It was calculated using SNPs located within genes and having the same directions of effects in different study cohorts to exclude cohort-specific findings and false positives. Gene co-expression modules and protein-protein interaction networks were used to identify AD-associated genes that interact with multiple other genes, as drugs targeting them have large efficacies via co-regulation or interactions. Results: Gene-based PRS identified 389 genes with 164 of them not previously reported as AD-associated. These 389 genes explained 56.12% –97.46% SNP heritability; and they were enriched in brain tissues and 164 biological processes, most of which are related to AD and other neurodegenerative diseases. We prioritized 688 drugs targeting 64 genes that were in the same co-expression modules and/or PPI networks. Conclusions: Gene-based PRS is a cost-effective way to identify AD-associated genes without substantially increasing the sample size. Co-expression modules and PPI networks can be used to identify drugs having large efficacies. Show more

Keywords: Alzheimer’s disease, gene-based polygenic risk score, gene-targeting drugs, gene co-expression module, protein-protein interaction network, SNP heritability

DOI: 10.3233/JAD-230510

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Gao, Yuan | Duan, Xiaocui | Li, Wanlin | Zhang, Xiaoyu | Xian, Xiaohui | Zhu, Yuan | Wang, Hualong

Article Type: Research Article

Abstract: Background: Recent studies have identified a relationship between elevated homocysteine levels and hypertension (HTN) with Alzheimer’s disease (AD), but its pathogenesis remains unclear. Objective: To evaluate elevated homocysteine levels and HTN as risk factors for cognitive impairment (CI) and determine their relationship with white matter hyperintensity (WMH) volume. Methods: A total of 521 subjects were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and divided into two groups according to the diagnostic criteria of the ADNI database. The CI group included 370 subjects, consisting of 122 with AD and 248 with mild CI, while the …cognitively normal (CN) group contained 151 subjects. The history of HTN, homocysteine levels, WMH volume and Mini-Mental State Examination (MMSE) scores were analyzed. Results: The study found that patients with CI had higher homocysteine levels than those with CN. Additionally, WMH volume was significantly correlated with homocysteine levels in CI patients, and MMSE scores decreased as WMH volume increased. Further analysis revealed that CI patients with HTN had significantly higher homocysteine levels than those without HTN. Furthermore, the correlation between WMH volume and homocysteine levels was significant only in CI patients with HTN and not in those without HTN. In CN patients, there was no correlation between WMH volume and homocysteine levels in either the HTN or non-HTN groups, and no difference was observed in homocysteine levels. Conclusions: It is indicated that elevated homocysteine levels in conjunction with HTN are associated with the increased volume of WMHs and CI. Show more

Keywords: Alzheimer’s disease, homocysteine, hypertension, white matter hyperintensities

DOI: 10.3233/JAD-230687

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2023

Authors: Lewis, John E. | McDaniel, H. Reginald | Woolger, Judi M. | Khan, Sher Ali

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a leading killer of Americans, imparting a tremendous societal toll. Relationships between immune function and inflammation with cognition are well-established in AD, but the Th1/Th2 ratio of immune function is unknown. Describing the Th1/Th2 ratio and its relationship with cognition may shed light on the disease’s clinical context. How the Th1/Th2 ratio responds to dietary supplementation is another unknown question in this population. Objective: The objectives of the study were to: 1) characterize the Th1/Th2 ratio according to IL-2/IL-10, IFN-γ/IL-10, IL-2/IL-4, IFN-γ/IL-4, IL-2/TNF-α, and IFN-γ/TNF-α in subjects with moderate-to-severe AD and in comparison …to healthy adults; 2) investigate the effect of an aloe polymannose multinutrient complex (APMC) dietary supplement on the Th1/Th2 ratios over 12 months; and 3) compare the changes in the Th1/Th2 ratios with the changes in cognition from baseline to 12 months. Methods: Subjects consumed 2.5 g of the APMC four times per day for 12 months, and they were assessed on cognition and cytokines at baseline and 12 months. Results: The Th1/Th2 ratios in AD patients were significantly higher than the healthy controls, and five of the six ratios decreased from baseline to 12 months follow-up (other than IL-2/TNF-α). Several significant relationships were noted between the changes in Th1/Th2 ratios with cognitive assessments. Conclusions: Our results showed an overall rebalancing of the Th1/Th2 ratio in response to APMC, these changes were related to improved cognition in subjects with moderate-to-severe AD, and the APMC supplement was safely tolerated. Show more

Keywords: Aloe, Alzheimer’s disease, cognition, cytokines, dietary supplements, immunology, polysaccharides

DOI: 10.3233/JAD-230659

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Giunti, Elisa | Collu, Roberto | Daley, Sarah | Querfurth, Henry | Morin, Peter | Killick, Richard | Melamed, Rachel D. | Xia, Weiming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most predominant form of dementia. Rho-associated coiled coil kinase (ROCK) inhibitor, fasudil, is one of the candidate drugs against the AD progression. Objective: We aimed to investigate possible changes of AD associated markers in three-dimensional neuro-spheroids (3D neuro-spheroids) generated from induced pluripotent stem cells derived from AD patients or healthy control subjects (HC) and to determine the impact of pharmacological intervention with the ROCK inhibitor fasudil. Methods: We treated 3D neuro-spheroids with fasudil and tested the possible effect on AD markers by ELISA, transcriptomic and proteomic analyses. Results: …Transcriptomic analysis revealed a reduction in the expression of AKT serine/threonine-protein kinase 1 (AKT1) in AD neuro-spheroids, compared to HC. This decrease was reverted in the presence of fasudil. Proteomic analysis showed up- and down-regulation of proteins related to AKT pathway in fasudil-treated neuro-spheroids. We found an evident increase of phosphorylated tau at four different residues (pTau181, 202, 231, and 396) in AD compared to HC-derived neuro-spheroids. This was accompanied by a decrease of secreted clusterin (clu) and an increase of intracellular clu levels in AD patient-derived neuro-spheroids. Increases of phosphorylated tau in AD patient-derived neuro-spheroids were suppressed in the presence of fasudil. Conclusions: Fasudil modulates clu protein levels and enhances AKT1 that results in the suppression of AD associated tau phosphorylation. Show more

Keywords: Alzheimer’s disease, fasudil, induced pluripotent stem cells, ROCK

DOI: 10.3233/JAD-230551

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: El Kadiri, Wafa | Perrignon-Sommet, Manon | Delpont, Benoit | Graber, Mathilde | Mohr, Sophie | Mouillot, Thomas | Devilliers, Hervé | Grall, Sylvie | Lienard, Fabienne | Georges, Marjolaine | Brindisi, Marie-Claude | Brondel, Laurent | Bejot, Yannick | Leloup, Corinne | Jacquin-Piques, Agnès

Article Type: Research Article

Abstract: Background: The need for early diagnosis biomarkers in Alzheimer’s disease (AD) is growing. Only few studies have reported gustatory dysfunctions in AD using subjective taste tests. Objective: The main purpose of the study was to explore gustatory functions using subjective taste tests and recordings of gustatory evoked potentials (GEPs) for sucrose solution in patients with minor or major cognitive impairment (CI) linked to AD, and to compare them with healthy controls. The secondary objective was to evaluate the relationships between GEPs and the results of cognitive assessments and fasting blood samples. Methods: A total of 45 …subjects (15 healthy subjects, 15 minor CI patients, 15 major CI patients) were included to compare their gustatory functions and brain activity by recording GEPs in response to a sucrose stimulation. CI groups were combined in second analyses in order to keep a high power in the study. Correlations were made with cognitive scores and hormone levels (ghrelin, leptin, insulin, serotonin). Results: Increased P1 latencies and reduced N1 amplitudes were observed in minor or major patients compared to controls. GEPs were undetectable in 6 major and 4 minor CI patients. Thresholds for sucrose detection were significantly higher in the major CI group than in controls or the minor CI group. No correlation was found with hormone levels. Conclusions: The cortical processing of sensory taste information seems to be altered in patients with minor or major CI linked to AD. This disturbance was identifiable with subjective taste tests only later, at the major CI stage. Show more

Keywords: Alzheimer’s disease, diagnosis, ghrelin, gustatory evoked potential, taste

DOI: 10.3233/JAD-230270

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023