Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Purchase individual online access for 1 year to this journal.
Price: EUR 595.00Impact Factor 2023: 4
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: 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: 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: 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: Grant, William B. | Blake, Steven M.
Article Type: Review Article
Abstract: Diet is an important nonpharmacological risk-modifying factor for Alzheimer’s disease (AD). The approaches used here to assess diet’s role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15–20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors …including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N -oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries’ entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low–animal product diet with plenty of anti-inflammatory, low–glycemic load foods may be helpful. Show more
Keywords: Advanced glycation end products, Alzheimer’s disease, dementia, diet, meat, neuroinflammation, obesity, saturated fat, TMAO, ultraprocessed foods
DOI: 10.3233/JAD-230418
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-30, 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: 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: 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: Ly, Maria | Yu, Gary Z. | Chwa, Won Jong | Raji, Cyrus A.
Article Type: Systematic Review
Abstract: Background: Given the advent of large-scale neuroimaging data-driven endeavors for Alzheimer’s disease, there is a burgeoning need for well-characterized neuroimaging databases of healthy individuals. With the rise of initiatives around the globe for the rapid and unrestricted sharing of data resources, there is now an abundance of open-source neuroimaging datasets available to the research community. However, there is not yet a systematic review that fully details the demographic information and modalities actually available in all open access neuroimaging databases around the globe. Objective: This systematic review aims to provide compile a list of MR structural imaging databases encompassing …healthy individuals across the lifespan. Methods: In this systematic review, we searched EMBASE and PubMed until May 2022 for open-access neuroimaging databases containing healthy control participants of any age, race, with normal development and cognition having at least one structural T1-weighted neuroimaging scan. Results: A total of 403 databases were included, for up to total of 48,268 participants with all available demographic information and imaging modalities detailed in Supplementary Table 1 . There were significant trends noted when compiling normative databases for this systematic review, notably that 11.7% of databases included reported ethnicity in their participants, with underrepresentation of many socioeconomic groups globally. Conclusions: As efforts to improve primary prevention of AD may require a broader perspective including increased relevance of earlier stages in life, and strategies in addressing modifiable risk factors may be individualized to specific demographics, improving data characterization to be richer and more rigorous will greatly enhance these efforts. Show more
Keywords: Aging, Alzheimer’s disease, database, neuroimaging, normative, open-access, representation, social determinants of health
DOI: 10.3233/JAD-230738
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 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: Briceño, Emily M. | Dhakal, Usha | Sharma, Uttam | Adhikari, Nabin | Pradhan, Meeta S. | Shrestha, Lochana | Jalan, Pankaj | Rai, Janak | Langa, Kenneth M. | Lee, Jinkook | Ghimire, Dirgha | de Leon, Carlos F. Mendes
Article Type: Review Article
Abstract: The population of Nepal is rapidly aging, as in other low and middle-income countries, and the number of individuals living with Alzheimer’s Disease and related dementias (ADRD) is expected to increase. However, information about the neuropsychological assessment of ADRD in Nepal is lacking. We first aimed to examine the needs, challenges, and opportunities associated with the neuropsychological assessment of older adults in Nepal for population-based ADRD ascertainment. Second, we introduce the Chitwan Valley Family Study-Study of Cognition and Aging in Nepal (CVFS-SCAN), which is poised to address these needs, and its collaboration with the Harmonized Cognitive Assessment Protocol (HCAP) international …network. We reviewed the existing literature on the prevalence, risk factors, available neuropsychological assessment instruments, and sociocultural factors that may influence the neuropsychological assessment of older adults for ADRD ascertainment in Nepal. Our review revealed no existing population-based data on the prevalence of ADRD in Nepal. Very few studies have utilized formal cognitive assessment instruments for ADRD assessment, and there have been no comprehensive neuropsychological assessment instruments that have been validated for the assessment of ADRD in Nepal. We describe how the CVFS-SCAN study will address this need through careful adaptation of the HCAP instrument. We conclude that the development of culturally appropriate neuropsychological assessment instruments is urgently needed for the population-based assessment of ADRD in Nepal. The CVFS-SCAN is designed to address this need and will contribute to the growth of global and equitable neuropsychology and to the science of ADRD in low- and middle-income countries. Show more
Keywords: Alzheimer’s disease and related dementias, cognitive aging, cultural neuropsychology, global health, mild cognitive impairment
DOI: 10.3233/JAD-230906
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Axelsson Andrén, Elin | Kettunen, Petronella | Bjerke, Maria | Rolstad, Sindre | Zetterberg, Henrik | Blennow, Kaj | Wallin, Anders | Svensson, Johan
Article Type: Research Article
Abstract: Background: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. Objective: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer’s disease (AD), and mixed dementia (combined AD and SSVD). Methods: This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96). The CSF biomarkers were measured using immunoassays, and …their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated. Results: Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834–0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42 , total tau, and phosphorylated tau181 ) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830–0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838–0.968). Conclusions: The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, neurofilament light chain, soluble amyloid-β protein precursor β, subcortical small vessel type of dementia
DOI: 10.3233/JAD-230680
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Lopes Boschetti, Júlia Carolina | Soares, Karla Lírio | Carvalho, Glaucimeire Rocha | Filho, Abraão Carlos Verdin | Ton, Alyne Mendonça Marques | Pereira, Thiago de Melo Costa | Scherer, Rodrigo
Article Type: Research Article
Abstract: Background: The consumption of coffee has been associated with beneficial effects when it comes to Alzheimer’s disease (AD). However, to the best of our knowledge, there are no studies on Conilon coffee consumption in elderly people with AD. Objective: Evaluate the effects of Conilon coffee consumption in elderly with AD. Methods: The study was carried out with 9 participants who consumed a minimum of 2 cups (200 mL cup) of Conilon coffee per day for 90 days. Cognitive assessment was done before (T0) and after 90 days (T90). Blood analysis was conducted at T0 and T90, …as well as the assessment of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive species (TBARS). The levels of chlorogenic acids and caffeine in the coffee beverage were quantified by liquid chromatography. Results: During the treatment, the participants consumed at least 550 mg and 540 mg of CGAs and caffeine, respectively. A significant improvement in cognition between T0 and T90 was observed as per MMSE, CTP, and clock drawing tests. Furthermore, there was a significant reduction in AOPP (37%) and TBARS (60%), indicating a reduction in oxidative stress. The consumption of the coffee did not significantly alter any blood parameter, which confirms the safety of the coffee treatment during the 90 days. Conclusions: Our study demonstrated for the first time that regular consumption of coffee with high amounts of CGAs and caffeine improves cognitive functions and reduces oxidative stress, without altering blood parameters that indicate possible signs of toxicity in classical target organs. Show more
Keywords: Alzheimer’s disease, caffeine, chlorogenic acid, Coffea, coffee, Robusta
DOI: 10.3233/JAD-230843
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2023
Authors: Zeng, Xiao Xue | Zeng, Jie Bangzhe
Article Type: Review Article
Abstract: The traits of Alzheimer’s disease (AD) include amyloid plaques made of Aβ1-40 and Aβ1-42 , and neurofibrillary tangles by the hyperphosphorylation of tau protein. AD is a complex disorder that is heterogenous in genetical, neuropathological, and clinical contexts. Current available therapeutics are unable to cure AD. Systems medicine is a strategy by viewing the body as a whole system, taking into account each individual’s unique health profile, provide treatment and associated nursing care clinically for the patient, aiming for precision. Since the onset of AD can lead towards cognitive impairment, it is vital to intervene and diagnose early and …prevent further progressive loss of neurons. Moreover, as the individual’s brain functions are impaired due to neurodegeneration in AD, it is essential to reconstruct the neurons or brain cells to enable normal brain functions. Although there are different subtypes of AD due to varied pathological lesions, in the majority cases of AD, neurodegeneration and severe brain atrophy develop at the chronic stage. Novel approaches including RNA based gene therapy, stem cell based technology, bioprinting technology, synthetic biology for brain tissue reconstruction are researched in recent decades in the hope to decrease neuroinflammation and restore normal brain function in individuals of AD. Systems medicine include the prevention of disease, diagnosis and treatment by viewing the individual’s body as a whole system, along with systems medicine based nursing as a strategy against AD that should be researched further. Show more
Keywords: Alzheimer’s disease, gene therapy, synthetic biology, systems medicine
DOI: 10.3233/JAD-230739
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Tao, Shuqi | Fan, Wenyuan | Liu, Jinmeng | Wang, Tong | Zheng, Haoning | Qi, Gaoxiu | Chen, Yanchun | Zhang, Haoyun | Guo, Zhangyu | Zhou, Fenghua
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is currently the most prevalent neurological disease, and no effective and practical treatments and therapies exist. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (NLRP3) inflammasome is vital in the human innate immune response. However, when the NLRP3 inflammasome is overactivated by persistent stimulation, several immune-related diseases, including AD, atherosclerosis, and obesity, result. This review will focus on the composition and activation mechanism of the NLRP3 inflammasome, the relevant mechanisms of involvement in the inflammatory response to AD, and AD treatment targeting NLRP3 inflammasome. This review aims to reveal the pathophysiological mechanism of …AD from a new perspective and provide the possibility of more effective and novel strategies for preventing and treating AD. Show more
Keywords: Alzheimer’s disease, amyloid-β, inhibitors, NLRP3 inflammasome, tau, treatment
DOI: 10.3233/JAD-230567
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Grasso, Stephanie M. | Wagner Rodríguez, Camille A. | Montagut Colomer, Núria | Marqués Kiderle, Sonia-Karin | Sánchez-Valle, Raquel | Santos Santos, Miguel Ángel
Article Type: Research Article
Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by speech and/or language impairment with relatively spared cognition. Research investigating behavioral speech-language intervention and methods for cognitive-linguistic assessment in PPA has predominantly centered around monolingual speakers. This gap hinders the widespread adoption of evidence-based approaches and exacerbates the inequities faced by culturally and linguistically diverse populations living with PPA. Objective: This scoping review synthesizes the current evidence for assessment and treatment practices in bilingual PPA as well as the operationalization of bilingualism in PPA. Methods: Arksey & O’Malley’s scoping review methodology was utilized. Information was …extracted from each study and entered into a data-charting template designed to capture information regarding operationalization of bilingualism in PPA and assessment and treatment practices. Results: Of the 16 identified studies, 14 reported the results of assessments conducted in both languages. Three studies reported positive naming treatment outcomes. Thirteen studies included English-speaking participants, revealing linguistic bias. Most studies reported age of acquisition, proficiency, and patterns of language use rather than providing an operational definition for bilingualism. Conclusions: Neither formal assessment measures nor clear guidelines for assessment of bilingual PPA currently exist; however, language-specific measures are emerging. Speech-language intervention in bilingual PPA has been relatively unexplored, representing a significant gap in the literature. In order to improve diagnostic and treatment options for bilingual PPA, targeted efforts to increase representation of bilinguals from various sociocultural contexts, as well as those who speak a variety of language pairs, is necessary. Show more
Keywords: Alzheimer’s disease, aphasia, assessment, bilingualism, cultural and linguistic diversity, dementia, intervention, language, primary progressive aphasia, scoping review, speech-language pathology
DOI: 10.3233/JAD-230673
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2023
Article Type: Other
DOI: 10.3233/JAD-239012
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Li, Jie-Qiong | Zhong, Xiao-Ling | Song, Jing-Hui | Chi, Song | Xie, An-Mu | Tan, Lan | Yu, Jin-Tai
Article Type: Research Article
Abstract: Background: Recent genetic research identified a protective factor against late-onset Alzheimer’s disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. Objective: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer’s Disease Neuroimaging Initiative database (ADNI). Methods: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various …endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. Results: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Conclusion: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments. Show more
Keywords: Alzheimer’s disease, cognition, gene, single nucleotide polymorphisms, TREML2
DOI: 10.3233/JAD-230936
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023
Authors: Yang, Zhengshi | Banks, Sarah J. | Ritter, Aaron R. | Cummings, Jeffrey L. | Sreenivasan, Karthik | Kinney, Jefferson W. | Caldwell, Jessica K. | Wong, Christina G. | Miller, Justin B. | Cordes, Dietmar
Article Type: Research Article
Abstract: Background: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer’s disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18 F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18 F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. Objective: …The goal of this study was to study human GE180 from the perspective of the previous animal observations. Methods: With data from twenty-four participants having 18 F-GE180 and 18 F-AV45 PET scans, we evaluated the group differences of 18 F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18 F-GE180 and 18 F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. Results: Elevated 18 F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18 F-GE180 uptake. Consistent with mouse model, a two-stage association between 18 F-GE180 and 18 F-AV45 was observed. Conclusions: 18 F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18 F-GE180 and amyloid PET in human and mouse suggested that 18 F-GE180 uptake in human might be considerably influenced by microglial activation. Show more
Keywords: Alzheimer’s disease, amyloid, 18F-GE180, neuroinflammation, translocator protein
DOI: 10.3233/JAD-230631
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023
Authors: Bozkurt, Ahmet Sarper | Yílmaz, Şenay Görücü
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by two main pathological mechanisms, mostly hyperphosphorylated tau and amyloid-β toxicity. Although many studies focus on these basic mechanisms, ferroptosis draws attention as an important pathway responsible for neurodegeneration in AD. There is no definitive treatment for AD but alternative phytochemicals to drugs come into prominence. Betulin is usually obtained from the birch tree. It is an abundant triterpene and has a high antioxidant capacity. Isthmin-1 (ISM1) is a secreted adipokine. Objective: In this study, we investigated the potential treatment of AD in the ferroptosis-ISM1-betulin triangle. …Methods: For this, we created an AD model with okadaic acid (200 ng/kg)) in 36 Wistar albino male rats and treated with betulin (20 mg/kg/day, i.p). We evaluated ISM1 gene expression, iron accumulation, and total oxidative metabolism parameters (TAS, TOS, OSI) in hippocampal tissue. We analyzed cognitive recovery in AD with Morris Water Maze Test and general locomotor activity, explore, and anti-anxiolytic effect with Open Field Test. Results: We compared the obtained data with metabolic and genetic results. In conclusion, betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Conclusions: Betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Although this study suggests the corrective effect of betulin and ISM1 on cognitive gain and anxiety, it is the first study to show the total antioxidant capacity of betulin in AD. Show more
Keywords: Alzheimer’s disease, betulin, iron, ISM1, neurodegeneration, oxidative stress
DOI: 10.3233/JAD-230940
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Wang, Mu-Cyun | Chiou, Jeng-Min | Chen, Yen-Ching | Chen, Jen-Hau
Article Type: Research Article
Abstract: Background: Previous studies assessing olfactory function and cognition have mostly been cross-sectional, and few have investigated the Asian geriatric population. Objective: To examine the relationships of olfaction with global or domain-specific cognitive function in Taiwanese community-dwelling older adults. Methods: This cohort study (2015–2019) is part of the Taiwan Initiative for Geriatric Epidemiological Research. The Taiwanese version of the Montreal Cognitive Assessment (MoCA-T) and a battery of neuropsychological tests were assessed at baseline and at a two-year follow-up. The cross-culture modified Sniffin’ Sticks Identification Test (SSIT) was utilized to measure olfactory function. Generalized linear mixed models were …used to examine the association of olfaction with cognitive performance over two years. Results: Data were collected from 376 participants (55.1% women), with a mean age of 75.6 years. A one-point decrease in the SSIT score (worsening of olfaction) was associated with worse global cognition (MoCA-T: β ˆ = –0.13), memory ( β ˆ = –0.08 to –0.06), and verbal fluency ( β ˆ = –0.07). Compared with an SSIT score ≥ 11 (normosmia), an SSIT score < 8 (anosmia) was associated with worse global cognition (MoCA-T: β ˆ = –0.99), memory ( β ˆ = –0.48 to –0.42), executive function (Trail Making Test A: β ˆ = –0.36), attention (digit span backward: β ˆ = –0.34), and verbal fluency ( β ˆ = –0.45). After stratified analyses, the associations remained in older adults ≥ 75 years, males, and non-carriers of apolipoprotein E ɛ4 in terms of global cognition, memory, and verbal fluency. Conclusions: Odor identification deficits were associated with poor global or domain-specific cognitive function in a four-year cohort of community-dwelling older adults. Cognitive assessments should be conducted in dementia-free elderly individuals with impaired odor identification. Show more
Keywords: Cognition, Montreal Cognitive Assessment, odor identification, older adults, olfaction
DOI: 10.3233/JAD-230319
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023
Authors: Tian, Jing | Du, Eric | Jia, Kun | Wang, Tienju | Guo, Lan | Zigman, Jeffrey M. | Du, Heng
Article Type: Research Article
Abstract: Background: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer’s disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. Objective: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin …(hAβ KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. Methods: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAβ KI mice as well as primary neuron cultures. Results: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. Conclusions: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings. Show more
Keywords: Alzheimer’s disease, amyloid-β, ghrelin, growth hormone secretagogue receptor, hippocampal synaptic injury
DOI: 10.3233/JAD-231002
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | O’Bryant, Sid E.
Article Type: Research Article
Abstract: Background: Blood biomarkers have the potential to transform Alzheimer’s disease (AD) diagnosis and monitoring, yet their integration with common medical comorbidities remains insufficiently explored. Objective: This study aims to enhance blood biomarkers’ sensitivity, specificity, and predictive performance by incorporating comorbidities. We assess this integration’s efficacy in diagnostic classification using machine learning, hypothesizing that it can identify a confident set of predictive features. Methods: We analyzed data from 1,705 participants in the Health and Aging Brain Study-Health Disparities, including 116 AD patients, 261 with mild cognitive impairment, and 1,328 cognitively normal controls. Blood samples were assayed using …electrochemiluminescence and single molecule array technology, alongside comorbidity data gathered through clinical interviews and medical records. We visually explored blood biomarker and comorbidity characteristics, developed a Feature Importance and SVM-based Leave-One-Out Recursive Feature Elimination (FI-SVM-RFE-LOO) method to optimize feature selection, and compared four models: Biomarker Only, Comorbidity Only, Biomarker and Comorbidity, and Feature-Selected Biomarker and Comorbidity. Results: The combination model incorporating 17 blood biomarkers and 12 comorbidity variables outperformed single-modal models, with NPV12 at 92.78%, AUC at 67.59%, and Sensitivity at 65.70% . Feature selection led to 22 chosen features, resulting in the highest performance, with NPV12 at 93.76%, AUC at 69.22%, and Sensitivity at 70.69% . Additionally, interpretative machine learning highlighted factors contributing to improved prediction performance. Conclusions: In conclusion, combining feature-selected biomarkers and comorbidities enhances prediction performance, while feature selection optimizes their integration. These findings hold promise for understanding AD pathophysiology and advancing preventive treatments. Show more
Keywords: Alzheimer’s disease, blood biomarkers, comorbidities, machine learning, recursive feature elimination, support vector machine
DOI: 10.3233/JAD-230755
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023
Authors: Solis-Urra, Patricio | Rodriguez-Ayllon, María | Álvarez-Ortega, Miriam | Molina-Hidalgo, Cristina | Molina-Garcia, Pablo | Arroyo-Ávila, Cristina | García-Hermoso, Antonio | Collins, Audrey M. | Jain, Shivangi | Gispert, Juan Domingo | Liu-Ambrose, Teresa | Ortega, Francisco B. | Erickson, Kirk I. | Esteban-Cornejo, Irene
Article Type: Systematic Review
Abstract: Background: Accumulation of amyloid-β (Aβ) plaques is one of the main features of Alzheimer’s disease (AD). Physical performance has been related to dementia risk and Aβ, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aβ. Yet, no evidence synthesis has been performed in humans. Objective: To investigate the association of physical performance with Aβ in humans, including Aβ accumulation on brain, and Aβ abnormalities measured in cerebrospinal fluid (CSF) and blood. Methods: A systematic review with multilevel meta-analysis was performed from inception to June 16th , 2022. Studies were …eligible if they examined the association of physical performance with Aβ levels, including the measure of physical performance as a predictor and the measure of Aβ as an outcome in humans. Results: 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aβ in the brain (ES = 0.01; 95% CI –0.21 to 0.24; I2 = 69.9%), in the CSF (ES = –0.28; 95% CI –0.98 to 0.41; I2 = 91.0%) or in the blood (ES = –0.19; 95% CI –0.61 to 0.24; I2 = 99.75%). Significant heterogeneity was found across the results , which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. Conclusions: The association between physical performance and Aβ is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aβ levels in humans. Show more
Keywords: Alzheimer’s disease, amyloid, meta-analysis, physical performance
DOI: 10.3233/JAD-230586
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023
Authors: White, Joshua P. | Schembri, Adrian | Prenn-Gologranc, Carmen | Ondrus, Matej | Katina, Stanislav | Novak, Petr | Lim, Yen Ying | Edgar, Chris | Maruff, Paul
Article Type: Research Article
Abstract: Background: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer’s disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. Objective: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Methods: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for …MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Results: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79–0.88), and CDR > 0.5 (AUCs ∼ 0.89–0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. Conclusions: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity. Show more
Keywords: Alzheimer’s disease, cogstate brief battery, composites, dementia, discriminability, mild cognitive impairment
DOI: 10.3233/JAD-230352
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2023
Authors: Liu, Yan-Bing | Wang, Xue-Jie | Tan, Lan | Tan, Chen-Chen | Xu, Wei
Article Type: Research Article
Abstract: Background: APOE ɛ4 and PICALM are established genes associated with risk of late-onset Alzheimer’s disease (AD). Previous study indicated interaction of PICALM with APOE ɛ4 in AD patients. Objective: To explore whether PICALM variation could moderate the influences of APOE ɛ4 on AD pathology biomarkers and cognition in pre-dementia stage. Methods: A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ɛ4 carriers) were genotyped for PICALM rs3851179 and APOE ɛ4 at baseline and were followed for influences on changes …of cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis. Results: The interaction term of rs3851179×APOE ɛ 4 accounted for a significant amount of variance in baseline general cognition (p = 0.039) and memory function (p = 0.002). The relationships of APOE ɛ4 with trajectory of CSF Aβ 42 (p = 0.007), CSF P-tau181 (p = 0.003), CSF T-tau (p = 0.001), and memory function (p = 0.017) were also moderated by rs3851179 variation. Conclusions: APOE ɛ4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ɛ4 in pre-dementia stage. Show more
Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, cognition, interaction, memory, PICALM , tau protein
DOI: 10.3233/JAD-230516
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Lai, Dongbing | Zhang, Michael | Li, Rudong | Zhang, Chi | Zhang, Pengyue | Liu, Yunlong | Gao, Sujuan | Foroud, Tatiana
Article Type: Research Article
Abstract: Background: Except APOE , Alzheimer’s disease (AD) associated genes identified in recent large-scale genome-wide association studies (GWAS) had small effects and explained a small portion of heritability. Many AD-associated genes have even smaller effects thereby sub-threshold p -values in large-scale GWAS and remain to be identified. For some AD-associated genes, drug targeting them may have limited efficacies due to their small effect sizes. Objective: The purpose of this study is to identify AD-associated genes with sub-threshold p -values and prioritize drugs targeting AD-associated genes that have large efficacies. Methods: We developed a gene-based …polygenic risk score (PRS) to identify AD genes. It was calculated using SNPs located within genes and having the same directions of effects in different study cohorts to exclude cohort-specific findings and false positives. Gene co-expression modules and protein-protein interaction networks were used to identify AD-associated genes that interact with multiple other genes, as drugs targeting them have large efficacies via co-regulation or interactions. Results: Gene-based PRS identified 389 genes with 164 of them not previously reported as AD-associated. These 389 genes explained 56.12% –97.46% SNP heritability; and they were enriched in brain tissues and 164 biological processes, most of which are related to AD and other neurodegenerative diseases. We prioritized 688 drugs targeting 64 genes that were in the same co-expression modules and/or PPI networks. Conclusions: Gene-based PRS is a cost-effective way to identify AD-associated genes without substantially increasing the sample size. Co-expression modules and PPI networks can be used to identify drugs having large efficacies. Show more
Keywords: Alzheimer’s disease, gene-based polygenic risk score, gene-targeting drugs, gene co-expression module, protein-protein interaction network, SNP heritability
DOI: 10.3233/JAD-230510
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Gao, Yuan | Duan, Xiaocui | Li, Wanlin | Zhang, Xiaoyu | Xian, Xiaohui | Zhu, Yuan | Wang, Hualong
Article Type: Research Article
Abstract: Background: Recent studies have identified a relationship between elevated homocysteine levels and hypertension (HTN) with Alzheimer’s disease (AD), but its pathogenesis remains unclear. Objective: To evaluate elevated homocysteine levels and HTN as risk factors for cognitive impairment (CI) and determine their relationship with white matter hyperintensity (WMH) volume. Methods: A total of 521 subjects were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and divided into two groups according to the diagnostic criteria of the ADNI database. The CI group included 370 subjects, consisting of 122 with AD and 248 with mild CI, while the …cognitively normal (CN) group contained 151 subjects. The history of HTN, homocysteine levels, WMH volume and Mini-Mental State Examination (MMSE) scores were analyzed. Results: The study found that patients with CI had higher homocysteine levels than those with CN. Additionally, WMH volume was significantly correlated with homocysteine levels in CI patients, and MMSE scores decreased as WMH volume increased. Further analysis revealed that CI patients with HTN had significantly higher homocysteine levels than those without HTN. Furthermore, the correlation between WMH volume and homocysteine levels was significant only in CI patients with HTN and not in those without HTN. In CN patients, there was no correlation between WMH volume and homocysteine levels in either the HTN or non-HTN groups, and no difference was observed in homocysteine levels. Conclusions: It is indicated that elevated homocysteine levels in conjunction with HTN are associated with the increased volume of WMHs and CI. Show more
Keywords: Alzheimer’s disease, homocysteine, hypertension, white matter hyperintensities
DOI: 10.3233/JAD-230687
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2023
Authors: Lewis, John E. | McDaniel, H. Reginald | Woolger, Judi M. | Khan, Sher Ali
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a leading killer of Americans, imparting a tremendous societal toll. Relationships between immune function and inflammation with cognition are well-established in AD, but the Th1/Th2 ratio of immune function is unknown. Describing the Th1/Th2 ratio and its relationship with cognition may shed light on the disease’s clinical context. How the Th1/Th2 ratio responds to dietary supplementation is another unknown question in this population. Objective: The objectives of the study were to: 1) characterize the Th1/Th2 ratio according to IL-2/IL-10, IFN-γ/IL-10, IL-2/IL-4, IFN-γ/IL-4, IL-2/TNF-α, and IFN-γ/TNF-α in subjects with moderate-to-severe AD and in comparison …to healthy adults; 2) investigate the effect of an aloe polymannose multinutrient complex (APMC) dietary supplement on the Th1/Th2 ratios over 12 months; and 3) compare the changes in the Th1/Th2 ratios with the changes in cognition from baseline to 12 months. Methods: Subjects consumed 2.5 g of the APMC four times per day for 12 months, and they were assessed on cognition and cytokines at baseline and 12 months. Results: The Th1/Th2 ratios in AD patients were significantly higher than the healthy controls, and five of the six ratios decreased from baseline to 12 months follow-up (other than IL-2/TNF-α). Several significant relationships were noted between the changes in Th1/Th2 ratios with cognitive assessments. Conclusions: Our results showed an overall rebalancing of the Th1/Th2 ratio in response to APMC, these changes were related to improved cognition in subjects with moderate-to-severe AD, and the APMC supplement was safely tolerated. Show more
Keywords: Aloe, Alzheimer’s disease, cognition, cytokines, dietary supplements, immunology, polysaccharides
DOI: 10.3233/JAD-230659
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Giunti, Elisa | Collu, Roberto | Daley, Sarah | Querfurth, Henry | Morin, Peter | Killick, Richard | Melamed, Rachel D. | Xia, Weiming
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most predominant form of dementia. Rho-associated coiled coil kinase (ROCK) inhibitor, fasudil, is one of the candidate drugs against the AD progression. Objective: We aimed to investigate possible changes of AD associated markers in three-dimensional neuro-spheroids (3D neuro-spheroids) generated from induced pluripotent stem cells derived from AD patients or healthy control subjects (HC) and to determine the impact of pharmacological intervention with the ROCK inhibitor fasudil. Methods: We treated 3D neuro-spheroids with fasudil and tested the possible effect on AD markers by ELISA, transcriptomic and proteomic analyses. Results: …Transcriptomic analysis revealed a reduction in the expression of AKT serine/threonine-protein kinase 1 (AKT1) in AD neuro-spheroids, compared to HC. This decrease was reverted in the presence of fasudil. Proteomic analysis showed up- and down-regulation of proteins related to AKT pathway in fasudil-treated neuro-spheroids. We found an evident increase of phosphorylated tau at four different residues (pTau181, 202, 231, and 396) in AD compared to HC-derived neuro-spheroids. This was accompanied by a decrease of secreted clusterin (clu) and an increase of intracellular clu levels in AD patient-derived neuro-spheroids. Increases of phosphorylated tau in AD patient-derived neuro-spheroids were suppressed in the presence of fasudil. Conclusions: Fasudil modulates clu protein levels and enhances AKT1 that results in the suppression of AD associated tau phosphorylation. Show more
Keywords: Alzheimer’s disease, fasudil, induced pluripotent stem cells, ROCK
DOI: 10.3233/JAD-230551
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: El Kadiri, Wafa | Perrignon-Sommet, Manon | Delpont, Benoit | Graber, Mathilde | Mohr, Sophie | Mouillot, Thomas | Devilliers, Hervé | Grall, Sylvie | Lienard, Fabienne | Georges, Marjolaine | Brindisi, Marie-Claude | Brondel, Laurent | Bejot, Yannick | Leloup, Corinne | Jacquin-Piques, Agnès
Article Type: Research Article
Abstract: Background: The need for early diagnosis biomarkers in Alzheimer’s disease (AD) is growing. Only few studies have reported gustatory dysfunctions in AD using subjective taste tests. Objective: The main purpose of the study was to explore gustatory functions using subjective taste tests and recordings of gustatory evoked potentials (GEPs) for sucrose solution in patients with minor or major cognitive impairment (CI) linked to AD, and to compare them with healthy controls. The secondary objective was to evaluate the relationships between GEPs and the results of cognitive assessments and fasting blood samples. Methods: A total of 45 …subjects (15 healthy subjects, 15 minor CI patients, 15 major CI patients) were included to compare their gustatory functions and brain activity by recording GEPs in response to a sucrose stimulation. CI groups were combined in second analyses in order to keep a high power in the study. Correlations were made with cognitive scores and hormone levels (ghrelin, leptin, insulin, serotonin). Results: Increased P1 latencies and reduced N1 amplitudes were observed in minor or major patients compared to controls. GEPs were undetectable in 6 major and 4 minor CI patients. Thresholds for sucrose detection were significantly higher in the major CI group than in controls or the minor CI group. No correlation was found with hormone levels. Conclusions: The cortical processing of sensory taste information seems to be altered in patients with minor or major CI linked to AD. This disturbance was identifiable with subjective taste tests only later, at the major CI stage. Show more
Keywords: Alzheimer’s disease, diagnosis, ghrelin, gustatory evoked potential, taste
DOI: 10.3233/JAD-230270
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Tetzloff, Katerina A. | Duffy, Joseph R. | Clark, Heather M. | Pham, Nha Trang Thu | Machulda, Mary M. | Botha, Hugo | Jack Jr., Clifford R. | Dickson, Dennis W. | Lowe, Val J. | Josephs, Keith A. | Whitwell, Jennifer L. | Utianski, Rene L.
Article Type: Research Article
Abstract: Background: The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer’s disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. Objective: This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA …spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Methods: Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. Results: The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Conclusions: Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers. Show more
Keywords: Alzheimer’s disease, biomarkers, amyloid-β protein, tau protein
DOI: 10.3233/JAD-230912
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2023
Authors: Ding, Pingjian | Gurney, Mark | Perry, George | Xu, Rong
Article Type: Research Article
Abstract: Background: Epidemiological studies showed that COVID-19 increases risk of Alzheimer’s disease (AD). However, it remains unknown if there is a potential genetic predispositional effect. Objective: To examine potential effects of genetic susceptibility of COVID-19 on the risk and progression of AD, we performed a non-overlapping 2-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies (GWAS). Methods: Two-sample Mendelian randomization (MR) analysis of over 2.6 million subjects was used to examine whether genetic susceptibility of COVID-19 is not associated with the risk of AD, cortical amyloid burden, hippocampal volume, or AD progression score. Additionally, …a validation analysis was performed on a combined sample size of 536,190 participants. Results: We show that the AD risk was not associated with genetic susceptibility of COVID-19 risk (OR = 0.98, 95% CI 0.81–1.19) and COVID-19 severity (COVID-19 hospitalization: OR = 0.98, 95% CI 0.9–1.07, and critical COVID-19: OR = 0.98, 95% CI 0.92–1.03). Genetic predisposition to COVID-19 is not associated with AD progression as measured by hippocampal volume, cortical amyloid beta load, and AD progression score. These findings were replicated in a set of 536,190 participants. Consistent results were obtained across models based on different GWAS summary statistics, MR estimators and COVID-19 definitions. Conclusions: Our findings indicated that the genetic susceptibility of COVID-19 is not associated with the risk and progression of AD. Show more
Keywords: Alzheimer’s disease, Alzheimer’s disease progression score, cortical amyloid beta load, COVID-19, hippocampal volume, 2-sample Mendelian randomization analysis
DOI: 10.3233/JAD-230632
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023
Authors: García-Alberca, José María | de la Rosa, María Dolores | Solo de Zaldívar, Paloma | Ledesma, María | Oltra, Estela | Gris, Esther | Ocejo, Olga | Torrecilla, Javier | Zafra, Carmen | Sánchez-Fernández, Ana | Mancilla, Tomás | López-Romero, Mercedes | Jerez, Raquel | Santana, Nuria | Lara, José Pablo | Barbancho, Miguel Ángel | Blanco-Reina, Encarnación
Article Type: Research Article
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer’s disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD. Objective: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia. Methods: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n = 40) that received three times a …week one session per day of 20 minutes in the NSC and a control group (n = 37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis. Results: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score –18.87±5.56 versus –1.74±0.67, p = 0.004), agitation (mean change score –2.32±2.02 versus –0.78±1.44, p = 0.003) and irritability (mean change score –3.35±2.93 versus –1.42±1.31, p = 0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score –9.67±7.67 versus –7.66±6.08, p = 0.003). Conclusions: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia. Show more
Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, non-pharmacological intervention, nursing home
DOI: 10.3233/JAD-230391
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Monllor, Paloma | Kumar, Praktush | Lloret, Mari-Ángeles | Ftara, Artemis | Leon, Jose-Luis | Lopez, Begoña | Cervera-Ferri, Ana | Lloret, Ana
Article Type: Review Article
Abstract: There are several implications of the surge in the incidence of pandemics and epidemics in the last decades. COVID-19 being the most remarkable one, showed the vulnerability of patients with neurodegenerative diseases like Alzheimer’s disease (AD). This review studies the pathological interlinks and triggering factors between the two illnesses and proposes a multifactorial pathway of AD causation due to COVID-19. The article evaluates and describes all the postulated hypotheses which explain the etiology and possible pathogenesis of the disease in four domains: Inflammation & Neurobiochemical interactions, Oxidative Stress, Genetic Factors, and Social Isolation. We believe that a probable hypothesis of …an underlying cause of AD after COVID-19 infection could be the interplay of all these factors. Show more
Keywords: Alzheimer’s disease, inflammation, oxidative stress, SarsCoV-2 infection, social isolation
DOI: 10.3233/JAD-230396
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Chu, Chenyin | Low, Yi Ling Clare | Ma, Liwei | Wang, Yihan | Cox, Timothy | Doré, Vincent | Masters, Colin L. | Goudey, Benjamin | Jin, Liang | Pan, Yijun
Article Type: Review Article
Abstract: The accumulation of amyloid-β (Aβ) plaques in the brain is considered a hallmark of Alzheimer’s disease (AD). Mathematical modeling, capable of predicting the motion and accumulation of Aβ, has obtained increasing interest as a potential alternative to aid the diagnosis of AD and predict disease prognosis. These mathematical models have provided insights into the pathogenesis and progression of AD that are difficult to obtain through experimental studies alone. Mathematical modeling can also simulate the effects of therapeutics on brain Aβ levels, thereby holding potential for drug efficacy simulation and the optimization of personalized treatment approaches. In this review, we provide …an overview of the mathematical models that have been used to simulate brain levels of Aβ (oligomers, protofibrils, and/or plaques). We classify the models into five categories: the general ordinary differential equation models, the general partial differential equation models, the network models, the linear optimal ordinary differential equation models, and the modified partial differential equation models (i.e., Smoluchowski equation models). The assumptions, advantages and limitations of these models are discussed. Given the popularity of using the Smoluchowski equation models to simulate brain levels of Aβ, our review summarizes the history and major advancements in these models (e.g., their application to predict the onset of AD and their combined use with network models). This review is intended to bring mathematical modeling to the attention of more scientists and clinical researchers working on AD to promote cross-disciplinary research. Show more
Keywords: Alzheimer’s disease, amyloid-β, disease progression, mathematical modeling, Smoluchowski equation
DOI: 10.3233/JAD-230938
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023
Authors: Zhang, Xinghao | Wu, Pengfei | Zhao, Yue
Article Type: Article Commentary
Abstract: The potential link between COVID-19 and Alzheimer’s disease (AD) has been an intriguing topic in the global pandemic. Whether the susceptibility and severity of COVID-19 affects the onset and progression of AD is of great concern. Clinical studies suggested an increased risk of AD occurrence or cognitive deficit after COVID-19. Basic research found that severe COVID-19 induced changes resembling AD. Evidence synthesis should always take into account diverse study designs, both traditional and novel. The recent study by Ding et al. aimed to investigate the association of COVID-19 with AD using a non-overlapping two-sample Mendelian randomization analysis.
Keywords: Alzheimer’s disease, causal inference, COVID-19, genome-wide association study, Mendelian randomization
DOI: 10.3233/JAD-231151
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2023
Authors: Johnson, Carrie E. | Duncan, Marilyn J. | Murphy, M. Paul
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and …may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD. Show more
Keywords: Alzheimer’s disease, hormones, menopause, sex differences, sleep, women
DOI: 10.3233/JAD-230527
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-44, 2023
Authors: Wang, Xiaoping | Huang, Rui | Huang, Bin | Li, Xiaojia
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases. Objective: This study aimed to explore the role and possible mechanism of S1PR2 in AD. Methods: S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aβ25-35 to construct an AD cell model, …and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed. Results: The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aβ production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2. Conclusion: S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway. Show more
Keywords: AKT/mTOR pathway, Alzheimer’s disease, autophagy, S1PR2
DOI: 10.3233/JAD-230533
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Spampinato, Maria Vittoria | Ulber, Jenny L. | Fayyaz, Habiba | Sullivan, Allison | Collins, Heather R.
Article Type: Research Article
Abstract: Background: Neuropsychiatric symptoms (NPS) carry an increased risk of progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). There is a need to understand how to integrate NPS into the paradigm outlined in the 2018 NIA-AA Research Framework. Objective: To evaluate a prediction model of MCI-AD progression using a collection of variables, including NPS, cognitive testing, apolipoprotein E4 status (APOE4 ), imaging and laboratory AD biomarkers. Methods: Of 300 elderly subjects, 219 had stable MCI and 81 MCI-AD progression over a 5-year follow-up. NPS were measured using the Neuropsychiatric Inventory (NPI). A multivariate Cox Proportional …Hazards Regression Analysis assessed the effects of APOE4 , baseline NPI, baseline CSF amyloid-β, phosphorylated and total tau, baseline AD-signature MRI biomarker, baseline memory and executive function on MCI-AD progression. Results: 27% progressed to dementia (median follow-up = 43 months). NPS were found in stable MCI (62.6%) and MCI-AD converters (70.3%). The Cox model exhibited a good fit (p < 0.001), and NPS (HR = 1.033, p = 0.027), phosphorylated tau (HR = 1.011, p = 0.025), total tau (HR = 1.005, p = 0.024), AD-signature MRI biomarker (HR = 0.111, p = 0.002), executive function (HR = 0.727, p = 0.045), and memory performance (HR = 0.387, p < 0.001) were significantly associated with dementia. Conclusions: NPS may inform dementia risk assessment in conjunction with cognitive testing and imaging and laboratory AD biomarkers. NPS is independently associated with the risk of MCI-dementia progression, over and beyond the contributions of CSF biomarkers. Show more
Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, cognitive dysfunction, magnetic resonance imaging, neuropsychiatric symptoms
DOI: 10.3233/JAD-220835
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023
Authors: Meléndez, Juan C. | Satorres, Encarnación | Pitarque, Alfonso | Escudero, Joaquin | Delhom, Iraida | Navarro-Prados, Ana-Belén
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) stands as the prevailing type of dementia, marked by gradual memory loss and cognitive decline. Transcranial direct current stimulation (tDCS) is a non-invasive method used to regulate cortical brain function and has been explored as a potential treatment for cognitive impairment. Objective: This study aimed to compare the effects of daily home-based active or sham tDCS on cognitive function in patients with early-stage AD and its follow-up after one month. Methods: The study involved a randomized, blinded, and controlled-placebo design, with 18 participants enrolled. The primary outcome measures were general cognitive function, …immediate, and delayed recall, and executive function. Participants included in the study were randomly assigned to the anodal and sham tDCS groups. Participants were assessed before and after the intervention and one month after the end of treatment. The home-based intervention was applied for 5 consecutive days, daily. Results: The results showed a significant interaction between the active and sham groups; in particular, improvements in MMSE scores, immediate memory and delayed recall were observed at one-month follow-up in the active group. Conclusions: The positive effects of tDCS on cognitive function in AD patients observed suggest that tDCS may induce long-term neuroplastic changes, leading to sustained improvements in cognitive abilities. Show more
Keywords: Alzheimer’s disease, delayed memory, short-term memory, transcranial direct current stimulation, working memory
DOI: 10.3233/JAD-230826
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
sales@iospress.com
For editorial issues, like the status of your submitted paper or proposals, write to editorial@iospress.nl
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
info@iospress.nl
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office info@iospress.nl
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
china@iospress.cn
For editorial issues, like the status of your submitted paper or proposals, write to editorial@iospress.nl
如果您在出版方面需要帮助或有任何建, 件至: editorial@iospress.nl