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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Qaiser, Hammad | Uzair, Mohammad | Al-Regaiey, Khalid | Rafiq, Shafia | Arshad, Muhammad | Yoo, Woo-Kyoung | Arain, Osama Zahid | Kaleem, Imdad | Abualait, Turki | Wang, Lan | Wang, Ran | Bashir, Shahid
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is the most common form of dementia and a public health problem. It exhibits significant oxidative stress and redox alterations. The antioxidant enzyme systems defend the cellular environment from oxidative stress. One of the redox systems is the thioredoxin system (TS), which exerts decisive control over the cellular redox environment. We aimed to review the protective effects of TS, which include thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH. In the following, we discussed the physiological functioning and the role of the TS in maintaining the cellular redox-homeostasis in the AD-damaged brain. Trx protects the cellular environment from …oxidative stress, while TrxR is crucial for the cellular detoxification of reactive oxygen species in the brain. However, TS dysregulation increases the susceptibility to cellular death. The changes in Trx and TrxR levels are significantly associated with AD progression. Though the data from human, animal, and cellular models support the neuroprotective role of TS in the brain of AD patients, the translational potential of these findings to clinical settings is not yet applied. This review summarizes the current knowledge on the emerging role of the TrxR-Trx system in AD. Show more
Keywords: Alzheimer’s disease, antioxidant enzymes, oxidative stress, reactive oxygen species, redox enzymes, thioredoxin, thioredoxin reductase
DOI: 10.3233/JAD-230394
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023
Authors: Puentes-Díaz, Nicolás | Chaparro, Diego | Reyes-Marquez, Viviana | Morales-Morales, David | Flores-Gaspar, Areli | Alí-Torres, Jorge
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-β peptide (Aβ) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within …the search protocols of multifunctional agents for AD’s treatment. Objective: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. Methods: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. Results: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. Conclusion: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms. Show more
Keywords: Alzheimer’s disease, copper binding affinities, density functional theory calculations, salen-type ligands, standard reduction potentials
DOI: 10.3233/JAD-230542
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Chum, Phoebe P. | Bishara, Mary A. | Solis, Summer R. | Behringer, Erik J.
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is associated with impaired cerebral circulation which underscores diminished delivery of blood oxygen and nutrients to and throughout the brain. In the 3xTg-AD mouse model, we have recently found that > 10 cerebrovascular miRNAs pertaining to vascular permeability, angiogenesis, and inflammation (e.g., let-7d, miR-99a, miR-132, miR-133a, miR-151-5p, and miR-181a) track early development of AD. Further, endothelial-specific miRNAs (miR-126-3p, miR-23a/b, miR-27a) alter with onset of overall AD pathology relative to stability of smooth muscle/pericyte-specific miRNAs (miR-143, miR-145). Objective: We tested the hypothesis that cerebrovascular miRNAs indicating AD pathology share mRNA targets that regulate key endothelial cell functions …such as angiogenesis, vascular permeability, and blood flow regulation. Methods: As detected by NanoString nCounter miRNA Expression panel for 3xTg-AD mice, 61 cerebrovascular miRNAs and respective mRNA targets were examined using Ingenuity Pathway Analysis for canonical Cardiovascular (Cardio) and Nervous System (Neuro) Signaling. Results: The number of targets regulated per miRNA were 21±2 and 33±3 for the Cardio and Neuro pathways respectively, whereby 14±2 targets overlap among pathways. Endothelial miRNAs primarily target members of the PDE, PDGF, SMAD, and VEGF families. Individual candidates regulated by≥4 miRNAs that best mark AD pathology presence in 3xTg-AD mice include CFL2, GRIN2B, PDGFB, SLC6A1, SMAD3, SYT3, and TNFRSF11B. Conclusion: miRNAs selective for regulation of endothelial function and respective downstream mRNA targets support a molecular basis for dysregulated cerebral blood flow regulation coupled with enhanced cell growth, proliferation, and inflammation. Show more
Keywords: Alzheimer’s disease, brain endothelium, mRNA targets, vascular dysfunction
DOI: 10.3233/JAD-230300
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-48, 2023
Authors: Liang, Jingjing | LaFleur, Bonnie | Hussainy, Sadiya | Perry, George
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly marked by central nervous system (CNS) neuronal loss and amyloid plaques. FAM222A , encoding an amyloid plaque core protein, is an AD brain atrophy susceptibility gene that mediates amyloid-β aggregation. However, the expression interplay between FAM222A and other AD-related pathway genes is unclear. Objective: Our goal was to study FAM222A ’s whole-genome co-expression profile in multiple tissues and investigate its interplay with other AD-related genes. Methods: We analyzed gene expression correlations in Genotype-Tissue Expression (GTEx) tissues to identify FAM222A co-expressed …genes and performed functional enrichment analysis on identified genes in CNS system. Results: Genome-wide gene expression profiling identified 673 genes significantly correlated with FAM222A (p < 2.5×10–6 ) in 48 human tissues, including 298 from 13 CNS tissues. Functional enrichment analysis revealed that FAM222A co-expressed CNS genes were enriched in multiple AD-related pathways. Gene co-expression network analysis for identified genes in each brain region predicted other disease associated genes with similar biological function. Furthermore, co-expression of 25 out of 31 AD-related pathways genes with FAM222A was replicated in brain samples from 107 aged subjects from the Aging, Dementia and TBI Study. Conclusion: This gene co-expression study identified multiple AD-related genes that are associated with FAM222A , indicating that FAM222A and AD-associated genes can be active simultaneously in similar biological processes, providing evidence that supports the association of FAM222A with AD. Show more
Keywords: Alzheimer’s disease, FAM222A, gene co-expression network analysis, neurodegeneration, transcriptomics
DOI: 10.3233/JAD-221241
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Lardelli, Michael | Baer, Lachlan | Hin, Nhi | Allen, Angel | Pederson, Stephen Martin | Barthelson, Karissa
Article Type: Research Article
Abstract: The degree to which non-human animals can be used to model Alzheimer’s disease is a contentious issue, particularly as there is still widespread disagreement regarding the pathogenesis of this neurodegenerative dementia. The currently popular transgenic models are based on artificial expression of genes mutated in early onset forms of familial Alzheimer’s disease (EOfAD). Uncertainty regarding the veracity of these models led us to focus on heterozygous, single mutations of endogenous genes (knock-in models) as these most closely resemble the genetic state of humans with EOfAD, and so incorporate the fewest assumptions regarding pathological mechanism. We have generated a number of …lines of zebrafish bearing EOfAD-like and non-EOfAD-like mutations in genes equivalent to human PSEN1 , PSEN2 , and SORL1 . To analyze the young adult brain transcriptomes of these mutants, we exploited the ability of zebrafish to produce very large families of simultaneous siblings composed of a variety of genotypes and raised in a uniform environment. This “intra-family” analysis strategy greatly reduced genetic and environmental “noise” thereby allowing detection of subtle changes in gene sets after bulk RNA sequencing of entire brains. Changes to oxidative phosphorylation were predicted for all EOfAD-like mutations in the three genes studied. Here we describe some of the analytical lessons learned in our program combining zebrafish genome editing with transcriptomics to understand the molecular pathologies of neurodegenerative disease. Show more
Keywords: Alzheimer’s disease, early onset Alzheimer’s disease, gene expression profiling, genetic, models, transcriptome, zebrafish
DOI: 10.3233/JAD-230522
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Puoyan-Majd, Samira | Parnow, Abdolhossein | Rashno, Masome | Heidarimoghadam, Rashid | Komaki, Alireza
Article Type: Research Article
Abstract: Background: Oxidative stress plays a major role in the progression of Alzheimer’s disease (AD)-related cognitive deficits. Objective: This study was done to determine the protective effects of coenzyme Q10 (CoQ10) and high-intensity interval training (HIIT) alone and in combination for eight continuous weeks, on oxidative status, cognitive functions, and histological changes in the hippocampus in amyloid-β (Aβ)-induced AD rats. Methods: Ninety male Wistar rats were randomly assigned to the sham, control, Q10 (50 mg/kg of CoQ10; P.O.), HIIT (high intensity: 4 min running at 85–90% VO2max, low intensity: 3 min running at 50–60% VO2max), Q10 + HIIT, AD, AD+Q10, AD+HIIT, and …AD+Q10 + HIIT groups. Results: The results showed that Aβ injection reduced cognitive functions in the Morris water maze (MWM) test and recognition memory in the novel object recognition test (NORT), which was accompanied by a decrease in total thiol groups, catalase, and glutathione peroxidase activities, an increase in malondialdehyde levels, and neuronal loss in the hippocampus. Interestingly, pretreatment with CoQ10, HIIT, or both, could markedly improve the oxidative status and cognitive decline in the MWM and NOR tests, and hinder neuronal loss in the hippocampus of Aβ-induced AD rats. Conclusion: Therefore, a combination of CoQ10 and HIIT can improve Aβ-related cognitive deficits, probably through an amelioration in hippocampal oxidative status and prevention of neuronal loss. Show more
Keywords: Alzheimer’s disease, coenzyme Q10, high-intensity interval training, Morris water maze, novel object recognition test, oxidative status, rat
DOI: 10.3233/JAD-230096
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Yan, Ran | Wang, Wenjing | Yang, Wen | Huang, Masha | Xu, Wei
Article Type: Research Article
Abstract: Background: Late-onset Alzheimer’s disease (LOAD) is the most common type of dementia, but its pathogenesis remains unclear, and there is a lack of simple and convenient early diagnostic markers to predict the occurrence. Objective: Our study aimed to identify diagnostic candidate genes to predict LOAD by machine learning methods. Methods: Three publicly available datasets from the Gene Expression Omnibus (GEO) database containing peripheral blood gene expression data for LOAD, mild cognitive impairment (MCI), and controls (CN) were downloaded. Differential expression analysis, the least absolute shrinkage and selection operator (LASSO), and support vector machine recursive feature elimination …(SVM-RFE) were used to identify LOAD diagnostic candidate genes. These candidate genes were then validated in the dataset validation group and clinical samples, and a LOAD prediction model was established. Results: LASSO and SVM-RFE analyses identified 3 mitochondria-related genes (MRGs) as candidate genes, including NDUFA1, NDUFS5, and NDUFB3. In the verification of 3 MRGs, the AUC values showed that NDUFA1 , NDUFS5 had better predictability. We also verified the candidate MRGs in MCI groups, the AUC values showed a good performance. We then used NDUFA1, NDUFS5 and age to build a LOAD diagnostic model and AUC was 0.723. Results of qRT-PCR experiments showed that the three candidate genes were expressed significantly lower in the LOAD and MCI groups when compared to CN. Conclusion: Two mitochondrial-related candidate genes, NDUFA1 and NDUFS5, were identified as diagnostic markers for LOAD and MCI. Combining these two candidate genes with age, a LOAD diagnostic prediction model was successfully constructed. Show more
Keywords: Alzheimer’s disease, biomarker, late-onset Alzheimer’s disease, immune cells, machine learning, mild cognitive impairment, mitochondria related genes
DOI: 10.3233/JAD-230314
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2023
Authors: Daly, Timothy
Article Type: Review Article
Abstract: Maintaining diversity in drug development in research into Alzheimer’s disease (AD) is necessary to avoid over-reliance on targeting AD neuropathology. Treatments that reduce or prevent the generation of oxidative stress, frequently cited for its causal role in the aging process and AD, could be useful in at-risk populations or diagnosed AD patients. However, in this review, it is argued that clinical research into antioxidants in AD could provide more useful feedback as to the therapeutic value of the oxidative stress theory of AD. Improving comparability between randomized controlled trials (RCTs) is vital from a waste-reduction and priority-setting point of view …for AD clinical research. For as well as attempting to improve meaningful outcomes for patients, RCTs of antioxidants in AD should strive to maximize the extraction of clinically useful information and actionable feedback from trial outcomes. Solutions to maximize information flow from RCTs of antioxidants in AD are offered here in the form of checklist questions to improve ongoing and future trials centered around the following dimensions: adhesion to reporting guidelines like CONSORT, biomarker enrichment, simple tests of treatment, and innovative trial design. Show more
Keywords: Alzheimer’s disease, antioxidants, biomarkers, clinical trials, drug pipeline, information flow, oxidative stress, standardization, trial innovation
DOI: 10.3233/JAD-230308
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Huang, Yiyao | Driedonks, Tom A.P. | Cheng, Lesley | Turchinovich, Andrey | Pletniková, Olga | Redding-Ochoa, Javier | Troncoso, Juan C. | Hill, Andrew F. | Mahairaki, Vasiliki | Zheng, Lei | Witwer, Kenneth W.
Article Type: Research Article
Abstract: Background: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer’s disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. Objective: This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. Methods: bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) …that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. Results: Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. Conclusions: Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis. Show more
Keywords: Alzheimer’s disease, brain, ectosomes, exosomes, extracellular vesicles, microvesicles, miRNAs, non-coding RNAs, RNA sequencing, tRNAs
DOI: 10.3233/JAD-230872
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Sultana, Munira | Camicioli, Richard | Dixon, Roger A. | Whitehead, Shawn | Pieruccini-Faria, Frederico | Petrotchenko, Evgeniy | Speechley, Mark | Borchers, Christoph H. | Montero-Odasso, Manuel
Article Type: Research Article
Abstract: Background: Older adults presenting with dual-decline in cognition and walking speed face a 6-fold higher risk for dementia compared with those showing no decline. We hypothesized that the metabolomics profile of dual-decliners would be unique even before they show signs of decline in cognition and gait speed. Objective: The objective of this study was to determine if plasma metabolomics signatures can discriminate dual-decliners from no decliners, purely cognitive decliners, and purely motor decliners prior to decline. Methods: A retrospective cross-sectional study using baseline plasma for untargeted metabolomics analyses to investigate early signals of later dual-decline status …in study participants (n = 76) with convenient sampling. Dual-decline was operationalized as decline in gait speed (>10 cm/s) and cognition (>2 points decline in Montreal Cognitive Assessment score) on at least two consecutive 6-monthly assessments. The participants’ decliner status was evaluated 3 years after the blood sample was collected. Pair-wise comparison of detected compounds was completed using principal components and hierarchical clustering analyses. Results: Analyses did not detect any cluster separation in untargeted metabolomes across baseline groups. However, follow-up analyses of specific molecules detected 4 compounds (17-Hydroxy-12-(hydroxymethyl)-10-oxo-8 oxapentacyclomethyl hexopyranoside, Fleroxacin, Oleic acid, and 5xi-11,12-Dihydroxyabieta-8(14),9(11),12-trien-20-oic acid) were at significantly higher concentration among the dual-decliners compared to non-decliners. The pure cognitive decliner group had significantly lower concentration of six compounds (1,3-nonanediol acetate, 4-(2-carboxyethyl)-2-methoxyphenyl beta-D-glucopyranosiduronic acid, oleic acid, 2E-3-[4-(sulfo-oxy)phenyl] acrylic acid, palmitelaidic acid, and myristoleic acid) compared to the non-decliner group. Conclusions: The unique metabolomics profile of dual-decliners warrants follow-up metabolomics analysis. Results may point to modifiable pathways. Show more
Keywords: Aging, Alzheimer’s disease, cognition, diagnosis, gait, metabolomics
DOI: 10.3233/JAD-230683
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023
Authors: Mamelak, Mortimer
Article Type: Review Article
Abstract: The deterioration of the brain’s microvasculature, particularly in the hippocampus, appears to be a very early event in the development of Alzheimer’s disease (AD), preceding even the deposition of amyloid-β. A damaged microvasculature reduces the supply of oxygen and glucose to this region and limits the production of energy, ATP. The damage may be a function of the rise with age in the expression and activity of NADPH oxidase (NOX) in these microvessels. This rise renders these vessels vulnerable to the effects of oxidative stress and inflammation. The rise in NOX activity with age is even more marked in the …AD brain where an inverse correlation has been demonstrated between NOX activity and cognitive ability. Apocynin, a putative NOX inhibitor, has been shown to block the damaging effects of NOX activation. Apocynin acts as a strong scavenger of H2 O2, and as a weak scavenger of superoxide. Like apocynin, sodium oxybate (SO) has also been shown to block the toxic effects of NOX activation. The application of SO generates NADPH and ATP. SO inhibits oxidative stress and maintains normal cerebral ATP levels under hypoxic conditions. Moreover, it acts epigenetically to attenuate the expression of NOX. SO may delay the onset and slow the progress of AD by suppling energy and maintaining an antioxidative environment in the brain throughout the night. The slow wave activity produced by SO may also activate the glymphatic system and promote the clearance of amyloid-β from the brain. Show more
Keywords: Alzheimer’s disease, amyloid-β , apocynin, cerebral microvasculature, NADPH, NADPH oxidase, oxidative stress, sodium oxybate
DOI: 10.3233/JAD-230415
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023
Authors: Zhao, Rangyin | Han, Xiaoyong | Jiang, Shangrong | Zhao, Weijing | Liu, Jia | Zhang, Hongxia | Mao, Xiaoliang | Zhang, Min | Lei, Lili | You, Hong
Article Type: Research Article
Abstract: Background: Dementia is a neuropsychiatric disorder with cognitive decline due to multiple factors. With the arrival of the aging population, the incidence of dementia has gradually increased. There is still no effective treatment for dementia, and therefore, the prevention of dementia has become crucial. Oxidative stress is considered to be one of the pathogenesis of dementia; therefore, antioxidant therapy and prevention of dementia have been gradually proposed. Objective: Our meta-analysis aimed to investigate the association of antioxidants with risk of dementia. Methods: We searched PubMed, Embase, and Web of Science databases for articles on antioxidants associated …with dementia risk, and those containing cohort studies with high-dose versus low-dose controls were included in our meta-analysis. The resulting risk ratios (RR) and hazard ratios (HR) and 95% confidence intervals were statistically analyzed using Stata12.0 free software. Results: A total of 17 articles were included in this meta-analysis. Of 98,264 participants, 7,425 had dementia after 3–23 years of follow-up. The results of the meta-analysis showed a trend towards a lower incidence of dementia with high intake of antioxidants (RR = 0.84, 95% CI 0.77–1.19 I 2 = 54.6%), but this was not statistically significant. High antioxidant intake significantly reduced the incidence of Alzheimer ‘s disease (RR = 0.85, 95% CI 0.79–0.92 I 2 = 45.5%), and we additionally carried out subgroup analyses by nutrient type, diet or supplement, region, and study quality score. Conclusion: Dietary intake of antioxidants or supplements reduces both the risk of dementia and the risk of Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, antioxidants, dementia, meta-analysis, risk
DOI: 10.3233/JAD-220909
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Soto-Mercado, Viviana | Mendivil-Perez, Miguel | Velez-Pardo, Carlos | Jimenez-Del-Rio, Marlene
Article Type: Research Article
Abstract: Background: Familial Alzheimer’s disease (FAD) is caused by mutations in one or more of 3 genes known as A β PP , PSEN1 , and PSEN2 . There are currently no effective therapies for FAD. Hence, novel therapeutics are needed. Objective: To analyze the effect of treatment with a combination of epigallocatechin-3-gallate (EGCG) and Melatonin (N-acetyl-5-methoxytryptamine, aMT) in a cerebral spheroid (CS) 3D in vitro model of PSEN 1 E280A FAD. Methods: We developed a CS in vitro model based on menstrual stromal cells derived from wild-type (WT) and mutant PSEN1 E280A …menstrual blood cultured in Fast-N-Spheres V2 medium. Results: Beta-tubulin III, choline acetyltransferase, and GFAP in both WT and mutant CSs spontaneously expressed neuronal and astroglia markers when grown in Fast-N-Spheres V2 medium for 4 or 11 days. Mutant PSEN1 CSs had significantly increased levels of intracellular AβPP fragment peptides and concomitant appearance of oxidized DJ-1 as early as 4 days, and phosphorylated tau, decreased ΔΨ m , and increased caspase-3 activity were observed on Day 11. Moreover, mutant CSs were unresponsive to acetylcholine. Treatment with a combination of EGCG and aMT decreased the levels of all typical pathological markers of FAD more efficiently than did EGCG or aMT alone, but aMT failed to restore Ca2 + influx in mutant CSs and decreased the beneficial effect of EGCG on Ca2 + influx in mutant CSs. Conclusion: Treatment with a combination of EGCG and aMT can be of high therapeutic value due to the high antioxidant capacity and anti-amyloidogenic effect of both compounds. Show more
Keywords: Alzheimer’s disease, cerebral spheroids, E280A, -(–) epigallocatechin 3-gallate, melatonin, menstrual mesenchymal stromal cell, mutation, presenilin
DOI: 10.3233/JAD-220903
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Zhou, Moran | Jiao, Qian | Wu, Zengrui | Li, Weihua | Liu, Guixia | Wang, Rui | Tang, Yun
Article Type: Research Article
Abstract: Background: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ ) in the field of understanding the mechanisms of Alzheimer’s disease (AD), a complicated and untreatable neurodegenerative disease. Objective: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms. Methods: In this study, a systematic workflow combining pharmacological experiments and computational prediction were proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data …on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation. Results: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan. Conclusion: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD. Show more
Keywords: Alzheimer’s disease, computational systems pharmacology, oxidative stress hypothesis, phenotypic screening, polypharmacology networks, therapeutic targets
DOI: 10.3233/JAD-220727
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023
Authors: Yang, Lei | Zhao, Fengxue | Sun, Yadi | Wang, Ziyi | Li, Qianwen | Wang, Hao | Lu, Ying
Article Type: Systematic Review
Abstract: Background: Mild cognitive impairment (MCI) is the prodromal stage of dementia. In this stage, reasonable intervention measures can help to delay the decline of cognitive function. Supplementation of n-3 polyunsaturated fatty acids (n-3PUFAs) may be beneficial to delay the decline of cognitive function in the elderly. Objective: To investigate the effectiveness of docosapentaenoic acid (DHA) or/and eicosapentaenoic acid (EPA) supplements in the elderly with MCI. Methods: Eight electronic databases, PubMed, Cochrane Library, Embase, VIP, SinoMed, Web of Science, CNKI, and WANFANG DATA, were searched for related articles from inception until January 2022. Subgroup analyses and sensitivity …analyses were performed to detect confounding variables. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots. Stata12.0 was used for Begg’s and Egger’s test to quantify whether publication bias. Linear relationship between global cognition and covariates was examined in meta-regression analysis. Results: Twelve studies (n = 1,124) were included. The methodological quality of research is mostly medium. Compared with placebo, n-3PUFAs supplements have benefits on global cognition [SMD = 0.51, 95% CI(0.12, 0.91), p = 0.01]. No significant differences were observed between intervention group and placebo on language fluency, executive functions, and depression. Conclusion: Our findings indicated DHA and/or EPA supplements have benefits on global cognition, and it may also reduce the level of blood amyloid-β (Aβ)-related biomarkers (e.g., Aβ 40 , Aβ 42 ) and inflammatory factors (e.g., 1L-6, 1L-10). Since there are only two relative articles, more research is needed in the future to clarify the relationship. Show more
Keywords: Elderly, meta-analysis, mild cognitive impairment, n-3 polyunsaturated fatty acids
DOI: 10.3233/JAD-220863
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Bian, Zhihong | Yu, Haibo | Hu, Xinran | Bian, Yuting | Sun, Hongming | Tadokoro, Koh | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Fukui, Yusuke | Morihara, Ryuta | Abe, Koji | Yamashita, Toru
Article Type: Research Article
Abstract: Background: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer’s disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. Objective: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. Methods: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aβ-overexpressed transgenic AD mice model (APP23, …n = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n = 9) was assessed. Results: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aβ deposition after 16 months. Conclusion: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment. Show more
Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, NOX2, oxidative stress, Tocovid
DOI: 10.3233/JAD-220761
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022
Authors: Nelson, Doug | Thompson, Kevin J. | Wang, Lushan | Wang, Zengtao | Eberts, Paulina | Azarin, Samira M. | Kalari, Krishna R. | Kandimalla, Karunya K.
Article Type: Research Article
Abstract: Background: A strong body of evidence suggests that cerebrovascular pathologies augment the onset and progression of Alzheimer’s disease (AD). One distinctive aspect of this cerebrovascular dysfunction is the degeneration of brain pericytes—often overlooked supporting cells of blood-brain barrier endothelium. Objective: The current study investigates the influence of pericytes on gene and protein expressions in the blood-brain barrier endothelium, which is expected to facilitate the identification of pathophysiological pathways that are triggered by pericyte loss and lead to blood-brain barrier dysfunction in AD. Methods: Bioinformatics analysis was conducted on the RNA-Seq expression counts matrix (GSE144474), which compared …solo-cultured human blood-brain barrier endothelial cells against endothelial cells co-cultured with human brain pericytes in a non-contact model. We constructed a similar cell culture model to verify protein expression using western blots. Results: The insulin resistance and ferroptosis pathways were found to be enriched. Western blots of the insulin receptor and heme oxygenase expressions were consistent with those observed in RNA-Seq data. Additionally, we observed more than 5-fold upregulation of several genes associated with neuroprotection, including insulin-like growth factor 2 and brain-derived neurotrophic factor. Conclusions: Results suggest that pericyte influence on blood-brain barrier endothelial gene expression confers protection from insulin resistance, iron accumulation, oxidative stress, and amyloid deposition. Since these are conditions associated with AD pathophysiology, they imply mechanisms by which pericyte degeneration could contribute to disease progression. Show more
Keywords: Alzheimer’s disease, blood-brain barrier, cerebrovascular dysfunction, computational biology, endothelial cells, pericytes
DOI: 10.3233/JAD-230907
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Bergamino, Maurizio | Keeling, Elizabeth | McElvogue, Molly | Schaefer, Sydney Y. | Burke, Anna | Prigatano, George | Stokes, Ashley M.
Article Type: Research Article
Abstract: Background: Dementia is characterized by a cognitive decline in memory and other domains that lead to functional impairments. As people age, subjective memory complaints (SMC) become common, where individuals perceive cognitive decline without objective deficits on assessments. SMC can be an early sign and may precede amnestic mild cognitive impairment (MCI), which frequently advances to Alzheimer’s disease (AD). Objective: This study aims to investigate white matter microstructure in individuals with SMC, in cognitively impaired (CI) cohorts, and in cognitively normal individuals using diffusion kurtosis imaging (DKI) and free water imaging (FWI). The study also explores voxel-based …correlations between DKI/FWI metrics and cognitive scores to understand the relationship between brain microstructure and cognitive function. Methods: Twelve healthy controls (HCs), ten individuals with SMC, and eleven CI individuals (MCI or AD) were enrolled in this study. All participants underwent MRI 3T scan and the BNI Screen (BNIS) for Higher Cerebral Functions. Results: The mean kurtosis tensor and anisotropy of the kurtosis tensor showed significant differences across the three groups, indicating altered white matter microstructure in CI and SMC individuals. The free water volume fraction (f ) also revealed group differences, suggesting changes in extracellular water content. Notably, these metrics effectively discriminated between the CI and HC/SMC groups. Additionally, correlations between imaging metrics and BNIS scores were found for CI and SMC groups. Conclusions: These imaging metrics hold promise in discriminating between individuals with CI and SMC. The observed differences indicate their potential as sensitive and specific biomarkers for early detection and differentiation of cognitive decline. Show more
Keywords: Alzheimer’s disease, BNI Screen for Higher Cerebral Functions, dementia, diffusion kurtosis imaging, free-water imaging, subjective memory complaints
DOI: 10.3233/JAD-230952
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2024
Authors: Terao, Itsuki | Kodama, Wakako
Article Type: Systematic Review
Abstract: Background: The Food and Drug Administration (FDA) has approved lecanemab and aducanumab and is reviewing donanemab, but they have questionable efficacy, serious side effects and are costly, whereas melatonin administration and aerobic exercise for a short time may overcome these problems. Objective: We aim to compare the efficacy on cognitive function, tolerability and acceptability of melatonin administration and aerobic exercise for a short time with donanemab, lecanemab, and aducanumab in people with mild AD and MCI. Methods: We systematically reviewed relevant randomized placebo-controlled trials (RCTs) in PubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov …and performed network meta-analyses. Results: The analysis included 10 randomized placebo-controlled trials with 4,599 patients. Although melatonin and aerobic exercise for a short time were significantly more effective than donanemab, lecanemab, aducanumab and placebo in the primary analysis, there was significant heterogeneity. In the sensitivity analysis excluding exercise, melatonin was significantly more effective than donanemab, lecanemab, aducanumab and placebo, with no significant heterogeneity. Aerobic exercise for a short time was significantly less acceptable than donanemab, aducanumab and placebo. Donanemab, lecanemab, and aducanumab were significantly less tolerable than placebo and donanemab and lecanemab were significantly less acceptable than placebo. CONCLUSIONS: Melatonin may be a better potential disease-modifying treatment for cognitive decline in mild AD and MCI. Aerobic exercise for a short time might also be better than donanemab, lecanemab and aducanumab if continued, as it is well tolerated and more effective, although less valid due to heterogeneity. Another limitation is the small number of participants. Show more
Keywords: Aducanumab, Alzheimer’s disease, donanemab, exercise, melatonin, meta-analysis
DOI: 10.3233/JAD-230911
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Luo, Xiao | Hong, Hui | Li, Kaicheng | Zeng, Qingze | Liu, Xiaocao | Hong, Luwei | Li, Jixuan | Zhang, Xinyi | Zhong, Siyan | Xu, Xiaopei | Chen, Yanxing | Zhang, Minming | Huang, Peiyu
Article Type: Research Article
Abstract: Background: Financial capacity is vital for the elderly, who possess a substantial share of global wealth but are vulnerable to financial fraud. Objective: We explored the link between small vessel disease (SVD) and financial capacity in cognitively unimpaired (CU) older adults via both cross-sectional and longitudinal analyses. Methods: 414 CU participants underwent MRI and completed the Financial Capacity Instrument-Short Form (FCI-SF). Subsequent longitudinal FCI-SF data were obtained from 104, 240, and 141 participants at one, two, and four years, respectively. SVD imaging markers, encompassing white matter hyperintensities (WMH), cerebral microbleeds (CMB), and lacune …were evaluated. We used linear regression analyses to cross-sectionally explore the association between FCI-SF and SVD severity, and linear mixed models to assess how baseline SVD severity impacted longitudinal FCI-SF change. The false discovery rate method was used to adjust multiple comparisons. Results: Cross-sectional analysis revealed a significant association between baseline WMH and Bank Statement (BANK, β=-0.194), as well as between lacune number and Financial Conceptual Knowledge (FC, β= –0.171). These associations were stronger in APOE ɛ4 carriers, with β= –0.282 for WMH and BANK, and β= –0.366 for lacune number and FC. Longitudinally, higher baseline SVD total score was associated with severe FCI-SF total score decrease (β= –0.335). Additionally, baseline WMH burden predicted future decreases in Single Checkbook/Register Task (SNG, β= –0.137) and FC (β= –0.052). Notably, the association between baseline WMH and SNG changes was amplified in APOE ɛ4 carriers (β= –0.187). Conclusions: Severe SVD was associated with worse FCI-SF and could predict the decline of financial capacity in CU older adults. Show more
Keywords: Alzheimer’s disease, cerebral microbleed, cognitive decline, financial capacity, longitudinal study, positron emission tomography, small vessel disease, white matter hyperintensities
DOI: 10.3233/JAD-231089
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Seltmann, Henriette | Teichmann, Birgit
Article Type: Research Article
Abstract: Background: The number of people with dementia (PwD) in acute care hospitals is steadily increasing, posing a challenge for those who work closely with patients. To date, no German study has addressed the extent to which prospective nurses benefit from dementia training in terms of their knowledge, attitudes, and confidence in caring for PwD. Objective: The aim of this study is to investigate whether a validated dementia training for registered nurses can positively change nursing students’ knowledge about dementia, their attitude toward PwD, and their confidence in caring for them, as well as the stability over …time. Methods: In the one-group pre-test, post-test design, a sample of 81 nursing students was recruited from two nursing schools in Germany between May and June 2023. They completed a questionnaire consisting of the Dementia Knowledge Assessment Scale, the Dementia Attitude Scale, and the Confidence in Dementia Scale, as well as sociodemographic questions and experiences with PwD at three measurement points. The data were analyzed using the Wilcoxon test and repeated measures ANOVA. Results: The training has a significant effect on knowledge in dementia (z = –5.07, p < 0.001), attitude toward PwD (z = –4.42, p < 0.001), and confidence in caring for them at the post-test (z = –3. 21, p < 0.001, r = 0.36). The repeated measures ANOVA shows stability over time only for dementia knowledge. Conclusions: The results indicate the need for further research in this field as well as the validation of the dementia training specifically addressing nursing students. Show more
Keywords: Alzheimer’s disease, attitude, communication, confidence, dementia, intervention, knowledge, nursing students
DOI: 10.3233/JAD-231338
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Mandal, Pravat K.
Article Type: Editorial
DOI: 10.3233/JAD-240217
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Zhong, Ping | Cao, Qing | Yan, Zhen
Article Type: Research Article
Abstract: Background: The impairment of neural circuits controlling cognitive processes has been implicated in the pathophysiology of Alzheimer’s disease and related disorders (ADRD). However, it is largely unclear what circuits are specifically changed in ADRD, particularly at the early stage. Objective: Our goal of this study is to reveal the functional changes in the circuit of entorhinal cortex (EC), an interface between neocortex and hippocampus, in AD. Methods: Electrophysiological, optogenetic and chemogenetic approaches were used to examine and manipulate entorhinal cortical circuits in amyloid-β familial AD model (5×FAD) and tauopathy model (P301S Tau). Results: We …found that, compared to wild-type mice, electrical stimulation of EC induced markedly smaller responses in subiculum (hippocampal output) of 5×FAD mice (6-month-old), suggesting that synaptic communication in the EC to subiculum circuit is specifically blocked in this AD model. In addition, optogenetic stimulation of glutamatergic terminals from prefrontal cortex (PFC) induced smaller responses in EC of 5×FAD and P301S Tau mice (6-month-old), suggesting that synaptic communication in the PFC to EC pathway is compromised in both ADRD models. Chemogenetic activation of PFC to EC pathway did not affect the bursting activity of EC neurons in 5×FAD mice, but partially restored the diminished EC neuronal activity in P301S Tau mice. Conclusions: These data suggest that 5×FAD mice has a specific impairment of short-range hippocampal gateway (EC to subiculum), which may be caused by amyloid-β deposits; while two ADRD models have a common impairment of long-range cortical to hippocampal circuit (PFC to EC), which may be caused by microtubule/tau-based transport deficits. These circuit deficits provide a pathophysiological basis for unique and common impairments of various cognitive processes in ADRD conditions. Show more
Keywords: Alzheimer’s disease, electrophysiology, entorhinal cortex, 5×FAD, neural circuits, optogenetics, P301S Tau, prefrontal cortex, subiculum
DOI: 10.3233/JAD-231413
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Zhang, Xueyi | Gomez, Lissette | Below, Jennifer E. | Naj, Adam C. | Martin, Eden R. | Kunkle, Brian W. | Bush, William S.
Article Type: Research Article
Abstract: Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer’s disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis -regulatory window were used to train tissue-specific models of each gene. …We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer’s Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6 . Show more
Keywords: Alzheimer’s disease, bioinformatics, elastic net regression, gene expression, gene prediction, sex differences, transcriptome, X chromosome
DOI: 10.3233/JAD-231075
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Papadimitriou, Amelia | Dawson, Aprill Z. | Thorgerson, Abigail | Bhandari, Sanjay | Martinez, Martin | Egede, Leonard E.
Article Type: Research Article
Abstract: Background: The prevalence of type 2 diabetes is increasing with the burden disproportionately falling on older adults and racial/ethnic minorities. Older adults with diabetes show greater cognitive decline and there are disparities in cognitive function by race/ethnicity that can be explained by social determinants such as wealth. Objective: To understand whether there is a differential relationship between wealth and cognitive function by race/ethnicity among older U.S. adults with diabetes. Methods: Data on 9,006 adults aged 50+ with diabetes from the Health and Retirement Study (2006–2016) were analyzed. The primary outcome, cognitive function, was a score ranging …from range 0–27 categorized as: normal [12–27], mild cognitive impairment (MCI) [7–11], and dementia including Alzheimer’s disease [0–6]. Three modeled outcomes were: 1) normal versus MCI, 2) normal versus dementia, 3) MCI versus dementia. Wealth was log transformed and used as continuous and binary (≥median, <median). Logistic generalized estimating equation models were used to examine the relationship between wealth and cognitive function and models were stratified by race/ethnicity. Models were adjusted for demographics, lifestyle, functional limitations, and comorbidities. Results: In adjusted models, greater wealth was significantly associated with lower odds of MCI and dementia for all groups. Similarly, having wealth less than the sample median was associated with higher odds of MCI and dementia compared to wealth≥sample median. Conclusions: Increased wealth was significantly protective against MCI and dementia for all ethnic groups. Wealth less than the sample median was associated with greater odds of dementia for NHB and NHW. Show more
Keywords: Alzheimer’s disease, cognitive function, dementia, diabetes, mild cognitive impairment, older adults, racial/ethnic disparities, wealth
DOI: 10.3233/JAD-231107
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Cabrera-León, Ylermi | Báez, Patricio García | Fernández-López, Pablo | Suárez-Araujo, Carmen Paz
Article Type: Systematic Review
Abstract: Background: The growing number of older adults in recent decades has led to more prevalent geriatric diseases, such as strokes and dementia. Therefore, Alzheimer’s disease (AD), as the most common type of dementia, has become more frequent too. Background: Objective: The goals of this work are to present state-of-the-art studies focused on the automatic diagnosis and prognosis of AD and its early stages, mainly mild cognitive impairment, and predicting how the research on this topic may change in the future. Methods: Articles found in the existing literature needed to fulfill …several selection criteria. Among others, their classification methods were based on artificial neural networks (ANNs), including deep learning, and data not from brain signals or neuroimaging techniques were used. Considering our selection criteria, 42 articles published in the last decade were finally selected. Results: The most medically significant results are shown. Similar quantities of articles based on shallow and deep ANNs were found. Recurrent neural networks and transformers were common with speech or in longitudinal studies. Convolutional neural networks (CNNs) were popular with gait or combined with others in modular approaches. Above one third of the cross-sectional studies utilized multimodal data. Non-public datasets were frequently used in cross-sectional studies, whereas the opposite in longitudinal ones. The most popular databases were indicated, which will be helpful for future researchers in this field. Conclusions: The introduction of CNNs in the last decade and their superb results with neuroimaging data did not negatively affect the usage of other modalities. In fact, new ones emerged. Show more
Keywords: Alzheimer’s disease, blood, computer-assisted diagnosis, deep learning, gait, genes, mild cognitive impairment, neural networks (computer), neuropsychological tests, speech
DOI: 10.3233/JAD-231271
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-31, 2024
Authors: Aljassabi, Ali | Zieneldien, Tarek | Kim, Janice | Regmi, Deepika | Cao, Chuanhai
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is an extremely complex and heterogeneous pathology influenced by many factors contributing to its onset and progression, including aging, amyloid-beta (Aβ) plaques, tau fibril accumulation, inflammation, etc. Despite promising advances in drug development, there is no cure for AD. Although there have been substantial advancements in understanding the pathogenesis of AD, there have been over 200 unsuccessful clinical trials in the past decade. In recent years, immunotherapies have been at the forefront of these efforts. Immunotherapy alludes to the immunological field that strives to identify disease treatments via the enhancement, suppression, or induction of immune responses. Interestingly, …immunotherapy in AD is a relatively new approach for non-infectious disease. At present, antibody therapy (passive immunotherapy) that targets anti-Aβ aimed to prevent the fibrillization of Aβ peptides and disrupt pre-existing fibrils is a predominant AD immunotherapy due to the continuous failure of active immunotherapy for AD. The most rational and safe strategies will be those targeting the toxic molecule without triggering an abnormal immune response, offering therapeutic advantages, thus making clinical trial design more efficient. This review offers a concise overview of immunotherapeutic strategies, including active and passive immunotherapy for AD. Our review encompasses approved methods and those presently under investigation in clinical trials, while elucidating the recent challenges, complications, successes, and potential treatments. Thus, immunotherapies targeting Aβ throughout the disease progression using a mutant oligomer-Aβ stimulated dendritic cell vaccine may offer a promising therapy in AD. Show more
Keywords: Alzheimer’s disease, amyloid-β , dendritic cell, immunotherapies, vaccine
DOI: 10.3233/JAD-231163
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Martínez-Dubarbie, Francisco | López-García, Sara | Lage, Carmen | Di Molfetta, Guglielmo | Fernández-Matarrubia, Marta | Pozueta-Cantudo, Ana | García-Martínez, María | Corrales-Pardo, Andrea | Bravo, María | Jiménez-Bonilla, Julio | Quirce, Remedios | Marco de Lucas, Enrique | Drake-Pérez, Marta | Tordesillas, Diana | López-Hoyos, Marcos | Irure-Ventura, Juan | Valeriano-Lorenzo, Elizabeth | Blennow, Kaj | Ashton, Nicholas J. | Zetterberg, Henrik | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual
Article Type: Research Article
Abstract: Background: Plasma biomarkers of Alzheimer’s disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We …also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid. Show more
Keywords: Alzheimer’s disease, longitudinal study, p-tau231, plasma biomarkers, presymptomatic stages
DOI: 10.3233/JAD-231479
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Podger, Lauren | Stewart, Walter F. | Serrano, Daniel | Lipton, Richard B. | Gomez-Ulloa, David | Ayasse, Nicolai D. | Barnes, Frederick B. | Davis, E. Anne | Runken, M. Chris
Article Type: Research Article
Abstract: Background: A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer’s disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). Objective: To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized ‘target’ stages …of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Methods: Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. Results: For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (–4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS. Conclusions: Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework. Show more
Keywords: Alzheimer’s disease, AMBAR, cognition, endpoint staging framework, function, outcome measures, quality of life, trial endpoints
DOI: 10.3233/JAD-231197
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: O’Shea, Deirdre M. | Camacho, Simone | Ezzeddine, Reem | Besser, Lilah | Tolea, Magdalena I. | Wang, Lily | Galvin, Conor | Gibbs, Gregory | Galvin, James E.
Article Type: Research Article
Abstract: Background: Lifestyle factors are linked to differences in brain aging and risk for Alzheimer’s disease, underscored by concepts like ‘cognitive reserve’ and ‘brain maintenance’. The Resilience Index (RI), a composite of 6 factors (cognitive reserve, physical and cognitive activities, social engagement, diet, and mindfulness) provides such a holistic measure. Objective: This study aims to examine the association of RI scores with cognitive function and assess the mediating role of cortical atrophy. Methods: Baseline data from 113 participants (aged 45+, 68% female) from the Healthy Brain Initiative were included. Life course resilience was estimated with the RI, …cognitive performance with Cognivue® , and brain health using a machine learning derived Cortical Atrophy Score (CAS). Mediation analysis probed the relationship between RI, cognitive outcomes, and cortical atrophy. Results: In age and sex adjusted models, the RI was significantly associated with CAS (β= –0.25, p = 0.006) and Cognivue® scores (β= 0.32, p < 0.001). The RI-Cognivue® association was partially mediated by CAS (β= 0.07; 95% CI [0.02, 0.14]). Conclusions: Findings revealed that the collective effect of early and late-life lifestyle resilience factors on cognition are partially explained by their association with less brain atrophy. These findings underscore the value of comprehensive lifestyle assessments in understanding the risk and progression of cognitive decline and Alzheimer’s disease in an aging population. Show more
Keywords: Alzheimer’s disease, cognitive reserve, cognitive resilience, cortical atrophy, mild cognitive impairment
DOI: 10.3233/JAD-231346
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Soares Martins, Tânia | Ferreira, Maria | Magalhães, Sandra | Leandro, Kevin | Almeida, Luís P. de | Vogelgsang, Jonathan | Breitling, Benedict | Hansen, Niels | Esselmann, Hermann | Wiltfang, Jens | da Cruz e Silva, Odete A.B. | Nunes, Alexandra | Henriques, Ana Gabriela
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) diagnosis is difficult, and new accurate tools based on peripheral biofluids are urgently needed. Extracellular vesicles (EVs) emerged as a valuable source of biomarker profiles for AD, since their cargo is disease-specific and these can be easily isolated from easily accessible biofluids, as blood. Fourier Transform Infrared (FTIR) spectroscopy can be employed to analyze EVs and obtain the spectroscopic profiles from different regions of the spectra, simultaneously characterizing carbohydrates, nucleic acids, proteins, and lipids. Objective: The aim of this study was to identify blood-derived EVs (bdEVs) spectroscopic signatures with AD discriminatory potential. …Methods: Herein, FTIR spectra of bdEVs from two biofluids (serum and plasma) and distinct sets of Controls and AD cases were acquired, and EVs’ spectra analyzed. Results: Analysis of bdEVs second derivative peaks area revealed differences between Controls and AD cases in distinct spectra regions, assigned to carbohydrates and nucleic acids, amides, and lipids. Conclusions: EVs’ spectroscopic profiles presented AD discriminatory value, supporting the use of bdEVs combined with FTIR as a screening or complementary tool for AD diagnosis. Show more
Keywords: Alzheimer’s disease, biomarker, diagnosis, extracellular vesicles, lipids, nucleic acids, proteins
DOI: 10.3233/JAD-231239
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Ramadan, Ferris A. | Arani, Gayatri | Jafri, Ayan | Thompson, Tingting | Bland, Victoria L. | Renquist, Benjamin | Raichlen, David A. | Alexander, Gene E. | Klimentidis, Yann C.
Article Type: Research Article
Abstract: Background: Late-onset Alzheimer’s disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted …glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD. Show more
Keywords: Alzheimer’s disease, glutamine, Mendelian randomization, metabolites
DOI: 10.3233/JAD-231063
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Shen, Zhiwei | Yang, Xinyi | Lan, Yulong | Chen, Gao
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no “curative” drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory …can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα , CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ , CSF1 R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD. Show more
Keywords: Alzheimer’s disease, microenvironment, microglia, neuro-inflammation, stem cell
DOI: 10.3233/JAD-231159
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Sigurdsson, Einar M.
Article Type: Review Article
Abstract: The tau protein undergoes pathological changes in Alzheimer’s disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of …some antibodies targeting amyloid-β in Alzheimer’s disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer’s disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell. Show more
Keywords: Alzheimer’s disease, antibody, clinical trials, immunotherapy, tau protein, tauopathies, vaccine
DOI: 10.3233/JAD-231238
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Weinberg, Marc S. | He, Yingnan | Kivisäkk, Pia | Arnold, Steven E. | Das, Sudeshna
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Objective: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. Methods: We analyzed plasma and CSF proteomics data collected previously …(ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. Results: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Conclusions: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, clinical trial, metformin, plasma
DOI: 10.3233/JAD-230899
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Hambali, Aqilah | Jusril, Nor Atiqah | Md Hashim, Nur Fariesha | Abd Manan, Nizar | Adam, Siti Khadijah | Mehat, Muhammad Zulfadli | Adenan, Mohd Ilham | Stanslas, Johnson | Abdul Hamid, Hafizah
Article Type: Research Article
Abstract: Background: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer’s disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown. Objective: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells. Methods: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested …for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α , IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting. Results: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α , IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p < 0.001) by SECA and its fractions. SECA and some of its fractions can activate the Nrf2/HO-1 signaling pathway by significantly enhancing (p < 0.05) the Nrf2 and HO-1 protein expressions. Conclusions: This study suggests that the inhibitory activity of SECA and its fractions on pro-inflammatory and oxidative stress events may be the result of the activation of antioxidant defense systems. The potential of SECA and its fractions in reducing neuroinflammation and oxidative stress can be further studied as a potential therapeutic strategy for AD. Show more
Keywords: Alzheimer’s disease, Centella asiatica , HO-1, neuroinflammation, Nrf2, oxidative stress
DOI: 10.3233/JAD-230875
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Noori, Ayush | Jayakumar, Rojashree | Moturi, Vaishnavi | Li, Zhaozhi | Liu, Rongxin | Serrano-Pozo, Alberto | Hyman, Bradley T. | Das, Sudeshna
Article Type: Research Article
Abstract: Background: Recent Alzheimer’s disease (AD) discoveries are increasingly based on studies from a variety of omics technologies on large cohorts. Currently, there is no easily accessible resource for neuroscientists to browse, query, and visualize these complex datasets in a harmonized manner. Objective: Create an online portal of public omics datasets for AD research. Methods: We developed Alzheimer DataLENS, a web-based portal, using the R Shiny platform to query and visualize publicly available transcriptomics and genetics studies of AD on human cohorts. To ensure consistent representation of AD findings, all datasets were processed through a uniform bioinformatics …pipeline. Results: Alzheimer DataLENS currently houses 2 single-nucleus RNA sequencing datasets, over 30 bulk RNA sequencing datasets from 19 brain regions and 3 cohorts, and 2 genome-wide association studies (GWAS). Available visualizations for single-nucleus data include bubble plots, heatmaps, and UMAP plots; for bulk expression data include box plots and heatmaps; for pathways include protein-protein interaction network plots; and for GWAS results include Manhattan plots. Alzheimer DataLENS also links to two other knowledge resources: the AD Progression Atlas and the Astrocyte Atlas. Conclusions: Alzheimer DataLENS is a valuable resource for investigators to quickly and systematically explore omics datasets and is freely accessible at https://alzdatalens.partners.org . Show more
Keywords: Alzheimer’s disease, database, genetics, multiomics, single-cell RNA-seq, transcriptomics
DOI: 10.3233/JAD-230884
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Wang, Yongchun | Jiang, Richeng | Li, Mingxi | Wang, Zicheng | Yang, Yu | Sun, Li
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia, causing a huge socioeconomic burden. In parallel with the widespread uptake of single-cell RNA sequencing (scRNA-seq) technology, there has been a rapid accumulation of data produced by researching AD at single-cell resolution, which is more conductive to explore the neuroimmune-related mechanism of AD. Objective: To explore the potential features of T cells in the peripheral blood and cerebrospinal fluid of AD patients. Methods: Two datasets, GSE181279 and GSE134578, were integrated from GEO database. Seurat, Monocle, CellChat, scRepertoire, and singleR packages were mainly …employed for data analysis. Results: Our analysis demonstrated that in peripheral blood, T cells were significantly expanded, and these expanded T cells were possessed effector function, such as CD8+ TEMRA , CD4+ TEMRA , and CD8+ TEM . Interestingly, CD8+ TEMRA and CD4+ TEMRA cells positioned adjacently after dimensions reduction and clustering. Notably, we identified that the expanded T cells were developed from Naïve T cells and TCM cells, and TEM cells was in the intermediate state of this developing process. Additionally, in cerebrospinal fluid of AD patients, the amplified T cells were mainly CD8+ TEMRA cells, and the number and strength of communication between CD4+ TEM , CD8+ TEM , and CD8+ TEMRA were decreased in AD patients. Conclusions: Our comprehensive analyses identified the cells in cerebrospinal fluid from AD patients are expanded TEMRA or TEM cells and the TEMRA cells communicating with other immune cells is weakened, which may be an important immune feature that leads to AD. Show more
Keywords: Alzheimer’s disease, analysis of immune characteristics, immune cell subpopulation, single-cell RNA sequencing, TCR repertoire
DOI: 10.3233/JAD-230784
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Snytnikova, Olga | Telegina, Darya | Savina, Ekaterina | Tsentalovich, Yuri | Kolosova, Nataliya
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease. Objective: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs. Methods: High resolution 1 H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model …of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the “preclinical” period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control. Results: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups. Conclusions: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans. Show more
Keywords: Aging, Alzheimer’s disease, hippocampal metabolome, hypotaurine, nuclear magnetic resonance spectroscopy, OXYS rats, scyllo-inositol
DOI: 10.3233/JAD-230706
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023
Authors: Syed, Rafay Ali | Hayat, Mahnoor | Qaiser, Hammad | Uzair, Mohammad | Al-Regaiey, Khalid | Khallaf, Roaa | Kaleem, Imdad | Bashir, Shahid
Article Type: Review Article
Abstract: Aging is an intrinsic aspect of an organism’s life cycle and is characterized by progressive physiological decline and increased susceptibility to mortality. Many age-associated disorders, including neurological disorders, are most commonly linked with the aging process, such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the effects of aging and AD on the molecular pathways and levels of different proteins in the brain, including metalloproteins, neurotrophic factors, amyloid proteins, and tau proteins. AD is caused by the aggregation of amyloid proteins in the brain. Factors such as metal ions, protein ligands, and the oligomerization state …of amyloid precursor protein significantly influence the proteolytic processing of amyloid-β protein precursor (AβPP). Tau, a disordered cytosolic protein, serves as the principal microtubule-associated protein in mature neurons. AD patients exhibit decreased levels of nerve growth factor within their nervous systems and cerebrospinal fluid. Furthermore, a significant increase in brain-derived neurotrophic factor resulting from the neuroprotective effect of glial cell line-derived neurotrophic factor suggests that the synergistic action of these proteins plays a role in inhibiting neuronal degeneration and atrophy. The mechanism through which Aβ and AβPP govern Cu2+ transport and their influence on Cu2+ and other metal ion pools requires elucidation in future studies. A comprehensive understanding of the influence of aging and AD on molecular pathways and varying protein levels may hold the potential for the development of novel diagnostic and therapeutic methods for the treatment of AD. Show more
Keywords: Alzheimer’s disease, apoptosis, brain-derived neurotrophic factor, neurotrophic factors, oxidative stress
DOI: 10.3233/JAD-230801
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Jehu, Deborah A. | Pottayil, Faheem | Dong, Yanbin | Zhu, Haidong | Sams, Richard | Young, Lufei
Article Type: Research Article
Abstract: Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition : Montreal Cognitive Assessment; executive function : Trail-Making Test, Digit Span Forward Test; perception and orientation : Benton Judgement of Line Orientation Test; …language : Boston Naming Test; learning and memory : Rey Auditory Verbal Learning Test; complex attention : Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer’s disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (p s < 0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes. Show more
Keywords: Accelerometry, actigraphy, Alzheimer’s disease, cognition, cognitive domains, dementia, physical activity
DOI: 10.3233/JAD-230594
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Carr, Rachel H. | Eom, Gina D. | Brown, Eric E.
Article Type: Systematic Review
Abstract: Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition now recognized to persist into older adulthood, has been postulated to be a risk factor for neurocognitive disorders given the overlap in clinical features and neurobiology, as well as the complex interplay between ADHD and known risk factors for dementia. Studies have emerged assessing this relationship, but there has not yet been a comprehensive systematic review addressing this topic. Objective: To assess whether ADHD is a risk factor for neurocognitive disorders and to explore possible mechanisms for such an association. Methods: A systematic review of …the literature was conducted using Medline, Embase, and PsycINFO from inception until June 4, 2023. Studies were included if they assessed whether or how ADHD may be a risk factor for neurocognitive disorders. Studies were excluded if they were not primary literature, not published in a peer-reviewed journal, not in English, and/or used non-human subjects. Study quality was assessed using the QualSyst tool. Results: Sixteen studies met inclusion criteria. Seven studies found a positive association between ADHD and neurocognitive disorders (all-cause dementia in four studies, Alzheimer’s disease in three studies, Lewy body dementia in two studies, and mild cognitive impairment in one study). Four studies did not find an association. Five studies pertained to possible mechanisms for an association, including genetics, with minimal significant findings. Conclusions: ADHD may be a risk factor for certain neurocognitive disorders, although the evidence base is limited, and the absolute risk is small. Possible explanations include genetic and lifestyle factors. Show more
Keywords: Aged, Alzheimer’s disease, attention deficit disorder with hyperactivity, cognitive dysfunction, dementia, Lewy body disease, systematic review
DOI: 10.3233/JAD-230904
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Cao, Jing | Tang, Yating | Chen, Shujian | Yu, Siqi | Wan, Ke | Yin, Wenwen | Zhen, Wenhui | Zhao, Wenming | Zhou, Xia | Zhu, Xiaoqun | Sun, Zhongwu
Article Type: Research Article
Abstract: Background: The hippocampus consists of histologically and functionally distinct subfields, which shows differential vulnerabilities to Alzheimer’s disease (AD)-associated pathological changes. Objective: To investigate the atrophy patterns of the main hippocampal subfields in patients with mild cognitive impairment (MCI) and AD and the relationships among the hippocampal subfield volumes, plasma biomarkers and cognitive performance. Methods: This cross-sectional study included 119 patients stratified into three categories: normal cognition (CN; N = 40), MCI (N = 39), and AD (N = 40). AD-related plasma biomarkers were measured, including amyloid-β (Aβ)42 , Aβ 40 , Aβ 42 /Aβ 40 …ratio, p-tau181, and p-tau217, and the hippocampal subfield volumes were calculated using automated segmentation and volumetric procedures implemented in FreeSurfer. Results: The subiculum body, cornu ammonis (CA) 1-head, CA1-body, CA4-body, molecular_layer_HP-head, molecular_layer_HP-body, and GC-ML-DG-body volumes were smaller in the MCI group than in the CN group. The subiculum body and CA1-body volumes accurately distinguished MCI from CN (area under the curve [AUC] = 0.647–0.657). The subiculum-body, GC-ML-DG-body, CA4-body, and molecular_layer_HP-body volumes accurately distinguished AD from MCI (AUC = 0.822–0.833) and AD from CN (AUC = 0.903–0.905). The p-tau 217 level served as the best plasma indicator of AD and correlated with broader hippocampal subfield volumes. Moreover, mediation analysis demonstrated that the subiculum-body volume mediated the associations between the p-tau217 and p-tau181 levels, and the Montreal Cognitive Assessment and Auditory Verbal Learning Test recognition scores. Conclusions: Hippocampal subfields with distinctive atrophy patterns may mediate the effects of tau pathology on cognitive function. The subiculum-body may be the most clinically meaningful hippocampal subfield, which could be an effective target region for assessing disease progression. Show more
Keywords: Alzheimer’s disease, cognitive performance, hippocampal subfield volumes, mild cognitive impairment, plasma biomarkers
DOI: 10.3233/JAD-231114
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Zhai, Modi | Zhang, Yu | Yan, Dongxue | Wang, Yuzhen | Li, Wenzhong | Sun, Jie
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is an increasing public health concern with the aging of the global population. Understanding the genetic correlation and potential causal relationships between blood metabolites and AD may provide important insights into the metabolic dysregulation underlying this neurodegenerative disorder. Objective: The aim of this study was to investigate the causal relationship between blood metabolites and AD using Mendelian randomization (MR) analysis. Methods: Association data were obtained from three large-scale genome-wide association studies of 486 blood metabolites (N = 7,824), AD (71,880 cases and 383,378 controls), early-onset AD (N = 303,760), and late-onset …AD (N = 307,112). Causal associations between blood metabolites and AD were assessed using inverse variance weighting (IVW), MR-Egger, and weighted median methods. Bidirectional two-sample MR analysis was used to identify causal blood metabolites. MR-PRESSO, MR-Egger, and Cochran-Q were used to quantify instrumental variable heterogeneity and horizontal pleiotropy. Results: Using MR and sensitivity analysis, we identified 40 blood metabolites with potential causal associations with AD. After applying false discovery rate (FDR) correction, two metabolites, gamma-glutamylphenylalanine (OR = 1.15, 95% CI: 1.06–1.24, p = 3.88×10–4 , q = 0.09) and X-11317 (OR = 1.16, 95% CI: 1.08–1.26, p = 1.14×10–4 , q = 0.05), retained significant associations with AD. Reverse MR analysis indicated no significant causal effect of AD on blood metabolites. No significant instrumental variable heterogeneity or horizontal pleiotropy was found. Conclusions: This two-sample MR study provides compelling evidence for a potential causal relationship between blood metabolic dysregulation and susceptibility to AD. Further investigation of the biological relevance of the identified metabolites to AD and additional supporting evidence is warranted. Show more
Keywords: Alzheimer’s disease, blood metabolites, causal inference, Mendelian randomization
DOI: 10.3233/JAD-230985
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Lazarova, Maria I. | Tsvetanova, Elina R. | Georgieva, Almira P. | Stefanova, Miroslava O. | Uzunova, Diamara N. | Denev, Petko N. | Tasheva, Krasimira N.
Article Type: Research Article
Abstract: Background: The cholinergic neuronal loss in the basal forebrain and increasing brain oxidative stress are one of the main features of the brain suffering from Alzheimer’s disease. Marrubium vulgare (M. vulgare ), commonly known as ‘white horehound,’ possesses a variety of valuable properties, such as antioxidative, anti-inflammatory, and antidiabetic activities. Moreover, it possesses neuromodulatory properties that could potentially impact short-term memory functions. Objective: The present study was undertaken to investigate the preventive effects of water M. vulgare extract on working memory, cholinergic neurotransmission, and oxidative stress in rats with scopolamine (Sco)-induced dementia. Methods: Male …Wistar rats (200–250 g) were divided into four experimental groups. The plant extract was administered orally for 21 days, and Sco (2 mg/kg) was administered intraperitoneally for 11 consecutive days. The behavioral performance of the animals was evaluated by the T-maze test. The effect of the extract on acetylcholinesterase (AChE) activity and antioxidant status in cortex and hippocampus were also monitored. Results: Our experimental data revealed that treatment with M. vulgare significantly increased the percentage of correct choices of rats with Sco-induced dementia in the T maze test (by 38%, p < 0.05). Additionally, it reduced AChE activity in the hippocampus (by 20%, p < 0.05) and alleviated oxidative stress induced by Sco, particularly in the cortex. Conclusions: M. vulgare water extract demonstrated working memory preserving effect in rats with Sco-induced dementia, AChE inhibitory activity and in vivo antioxidant potential, and deserve further attention. Show more
Keywords: Acetylcholinesterase, Alzheimer’s disease, Marrubium vulgare, oxidative stress, scopolamine-induced dementia, T-maze test
DOI: 10.3233/JAD-231011
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Cesana, Bruno Mario | Bergh, Sverre | Ciccone, Alfonso | Cognat, Emmanuel | Fabbo, Andrea | Fascendini, Sara | Frisoni, Giovanni B. | Froelich, Lutz | Handels, Ron | Jori, Maria Cristina | Mecocci, Patrizia | Merlo, Paola | Peters, Oliver | Tsolaki, Magda | Defanti, Carlo Alberto
Article Type: Research Article
Abstract: Background: Nursing home placement (NHP) can be the final step of patients with Alzheimer’s disease. Objective: We aimed to identify NHP predictors among 508 people with dementia with a 3-year follow-up. Methods: We analyzed data from the international observational RECage study, involving 508 people with especially Alzheimer’s disease and comparing a cohort enrolled by five centers with a Special Care Unit for BPSD (behavioral and psychological symptoms of dementia) and another one enrolled by six centers lacking this facility. The tertiary objective of the study was to assess the possible role of the SCU-B in delaying …NHP. We assessed the relationship of the baseline characteristics with NHP by means of univariate analysis followed by Cox’s multivariate model. Results: Patients’ mean age was 78.1 years, 54.9% were women. Diagnosis mean age was 75.4 (±8.32) years; the main diagnosis was Alzheimer’s disease (296; 58.4%). During follow-up, 96 (18.9%) patients died and 153 (30.1%) were institutionalized without a statistically significant difference between the two cohorts (p = 0.9626). The mean NHP time was 902 (95% CI: 870–934). The multivariable analysis without death as a competing risk retained four independent predictors of NHP: age increase (hazard ratio (HR) = 1.023, 95% CI: 1.000–1.046), patient education level increase (HR = 1.062, 95% CI: 1.024–1.101), Neuropsychiatric Inventory total increase (HR = 1.018; 95% CI: 1.011–1.026), and total Mini-Mental State Examination as a favorable factor (HR = 0.948, 95% CI: 0.925–0.971). Gender (females versus males: HR = 1.265, 95% CI: 0.899–1.781) was included in the final Cox’s model for adjusting the estimates for. Conclusions: Our data partially agree with the predictors of NHP in literature including the effect of high education level. No caregivers’ factors were statistically significant. Clinical trial registration: NCT03507504. Show more
Keywords: Alzheimer’s disease, dementia, nursing home placement, predictive factors
DOI: 10.3233/JAD-230878
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Sánchez-Soblechero, Antonio | López-García, Sara | Lage, Carmen | Fernández-Matarrubia, Marta | Irure, Juan | López-Hoyos, Marcos | Jiménez-Bonilla, Julio | Quirce, Remedios | de Arcocha-Torres, María | Cuenca-Vera, Oriana | Martín-Arroyo, Juan | Martínez-Dubarbie, Francisco | Pozueta, Ana | García-Martínez, María | Infante, Jon | Sánchez-Juan, Pascual | Rodríguez-Rodríguez, Eloy
Article Type: Research Article
Abstract: Background: The optimal cut-off for Alzheimer’s disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11 C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aβ1–42 , pTau, tTau, and Aβ1–42 /Aβ1–40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) …were performed in all the patients. We established a cut-off for each single biomarker and Aβ1–42 /Aβ1–40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aβ1–42 /Aβ1–40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample’s best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer’s. Show more
Keywords: Alzheimer’s disease, amyloid positron emission tomography (a-PET), ATN classification, cerebrospinal fluid biomarkers (tTau, pTau, Aβ1–42 and Aβ1–42/Aβ1–40), 11C-Pittsburgh compound B, cut-off, data-driven cut-off, PET-driven cut-off
DOI: 10.3233/JAD-230678
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Ceyzériat, Kelly | Jaques, Emma | Gloria, Yesica | Badina, Aurélien | Millet, Philippe | Koutsouvelis, Nikolaos | Dipasquale, Giovanna | Frisoni, Giovanni B. | Zilli, Thomas | Garibotto, Valentina | Tournier, Benjamin B.
Article Type: Research Article
Abstract: Background: Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer’s disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. Objective: As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Methods: Females …were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. Results: A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. Conclusions: A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD. Show more
Keywords: Alzheimer’s disease, amyloid, low-dose radiation therapy, microglial response
DOI: 10.3233/JAD-231153
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Xie, Xin-Yan | Huang, Lin-Ya | Cheng, Gui-Rong | Liu, Dan | Hu, Fei-Fei | Zhang, Jing-Jing | Han, Gang-Bin | Liu, Xiao-Chang | Wang, Jun-Yi | Zhou, Juan | Zeng, De-Yang | Liu, Jing | Nie, Qian-Qian | Song, Dan | Yu, Ya-Fu | Hu, Chen-Lu | Fu, Yi-Di | Li, Shi-Yue | Cai, Cheng | Cui, Yu-Yang | Cai, Wan-Ying | Li, Yi-Qing | Fan, Ren-Jia | Wan, Hong | Xu, Lang | Ou, Yang-Ming | Chen, Xing-Xing | Zhou, Yan-Ling | Chen, Yu-Shan | Li, Jin-Quan | Wei, Zhen | Wu, Qiong | Mei, Yu-Fei | Tan, Wei | Song, Shao-Jun | Zeng, Yan
Article Type: Research Article
Abstract: Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were …employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5 , PM10 , O3 , and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings. Show more
Keywords: Air pollution, Hubei Memory and Aging Cohort Study, mild cognitive impairment, older Chinese population
DOI: 10.3233/JAD-231186
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Trieu, Calvin | van Harten, Argonde C. | Leeuwis, Anna E. | Exalto, Lieza G. | Hooghiemstra, Astrid M. | Verberk, Inge M.W. | Allaart, Cor P. | Brunner-La Rocca, Hans-Peter | Kappelle, L. Jaap | van Oostenbrugge, Robert J. | Biessels, Geert-Jan | Teunissen, Charlotte E. | van der Flier, Wiesje M.
Article Type: Research Article
Abstract: Background: We hypothesize that Alzheimer’s disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40 ), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models …with terms for biomarker, time and biomarker* time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (–0.14±0.04) and memory (–0.31±0.09) and with steeper decline in global cognition (–0.07±0.02), memory (–0.09±0.04), attention (–0.05±0.02), and language (–0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (–0.22±0.05), memory (–0.43±0.10), attention (–0.14±0.06), language (–0.15±0.05), and executive functioning (–0.15±0.05) and steeper decline in global cognition (–0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (–0.16±0.04), memory (–0.28±0.09), attention (–0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases. Show more
Keywords: Alzheimer’s disease, carotid stenosis, cognitive dysfunction, heart failure, vascular dementia
DOI: 10.3233/JAD-231096
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
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Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
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For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]