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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Mamelak, Mortimer
Article Type: Review Article
Abstract: The deterioration of the brain’s microvasculature, particularly in the hippocampus, appears to be a very early event in the development of Alzheimer’s disease (AD), preceding even the deposition of amyloid-β. A damaged microvasculature reduces the supply of oxygen and glucose to this region and limits the production of energy, ATP. The damage may be a function of the rise with age in the expression and activity of NADPH oxidase (NOX) in these microvessels. This rise renders these vessels vulnerable to the effects of oxidative stress and inflammation. The rise in NOX activity with age is even more marked in the …AD brain where an inverse correlation has been demonstrated between NOX activity and cognitive ability. Apocynin, a putative NOX inhibitor, has been shown to block the damaging effects of NOX activation. Apocynin acts as a strong scavenger of H2 O2, and as a weak scavenger of superoxide. Like apocynin, sodium oxybate (SO) has also been shown to block the toxic effects of NOX activation. The application of SO generates NADPH and ATP. SO inhibits oxidative stress and maintains normal cerebral ATP levels under hypoxic conditions. Moreover, it acts epigenetically to attenuate the expression of NOX. SO may delay the onset and slow the progress of AD by suppling energy and maintaining an antioxidative environment in the brain throughout the night. The slow wave activity produced by SO may also activate the glymphatic system and promote the clearance of amyloid-β from the brain. Show more
Keywords: Alzheimer’s disease, amyloid-β , apocynin, cerebral microvasculature, NADPH, NADPH oxidase, oxidative stress, sodium oxybate
DOI: 10.3233/JAD-230415
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023
Authors: Zhao, Rangyin | Han, Xiaoyong | Jiang, Shangrong | Zhao, Weijing | Liu, Jia | Zhang, Hongxia | Mao, Xiaoliang | Zhang, Min | Lei, Lili | You, Hong
Article Type: Research Article
Abstract: Background: Dementia is a neuropsychiatric disorder with cognitive decline due to multiple factors. With the arrival of the aging population, the incidence of dementia has gradually increased. There is still no effective treatment for dementia, and therefore, the prevention of dementia has become crucial. Oxidative stress is considered to be one of the pathogenesis of dementia; therefore, antioxidant therapy and prevention of dementia have been gradually proposed. Objective: Our meta-analysis aimed to investigate the association of antioxidants with risk of dementia. Methods: We searched PubMed, Embase, and Web of Science databases for articles on antioxidants associated …with dementia risk, and those containing cohort studies with high-dose versus low-dose controls were included in our meta-analysis. The resulting risk ratios (RR) and hazard ratios (HR) and 95% confidence intervals were statistically analyzed using Stata12.0 free software. Results: A total of 17 articles were included in this meta-analysis. Of 98,264 participants, 7,425 had dementia after 3–23 years of follow-up. The results of the meta-analysis showed a trend towards a lower incidence of dementia with high intake of antioxidants (RR = 0.84, 95% CI 0.77–1.19 I 2 = 54.6%), but this was not statistically significant. High antioxidant intake significantly reduced the incidence of Alzheimer ‘s disease (RR = 0.85, 95% CI 0.79–0.92 I 2 = 45.5%), and we additionally carried out subgroup analyses by nutrient type, diet or supplement, region, and study quality score. Conclusion: Dietary intake of antioxidants or supplements reduces both the risk of dementia and the risk of Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, antioxidants, dementia, meta-analysis, risk
DOI: 10.3233/JAD-220909
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Soto-Mercado, Viviana | Mendivil-Perez, Miguel | Velez-Pardo, Carlos | Jimenez-Del-Rio, Marlene
Article Type: Research Article
Abstract: Background: Familial Alzheimer’s disease (FAD) is caused by mutations in one or more of 3 genes known as A β PP , PSEN1 , and PSEN2 . There are currently no effective therapies for FAD. Hence, novel therapeutics are needed. Objective: To analyze the effect of treatment with a combination of epigallocatechin-3-gallate (EGCG) and Melatonin (N-acetyl-5-methoxytryptamine, aMT) in a cerebral spheroid (CS) 3D in vitro model of PSEN 1 E280A FAD. Methods: We developed a CS in vitro model based on menstrual stromal cells derived from wild-type (WT) and mutant PSEN1 E280A …menstrual blood cultured in Fast-N-Spheres V2 medium. Results: Beta-tubulin III, choline acetyltransferase, and GFAP in both WT and mutant CSs spontaneously expressed neuronal and astroglia markers when grown in Fast-N-Spheres V2 medium for 4 or 11 days. Mutant PSEN1 CSs had significantly increased levels of intracellular AβPP fragment peptides and concomitant appearance of oxidized DJ-1 as early as 4 days, and phosphorylated tau, decreased ΔΨ m , and increased caspase-3 activity were observed on Day 11. Moreover, mutant CSs were unresponsive to acetylcholine. Treatment with a combination of EGCG and aMT decreased the levels of all typical pathological markers of FAD more efficiently than did EGCG or aMT alone, but aMT failed to restore Ca2 + influx in mutant CSs and decreased the beneficial effect of EGCG on Ca2 + influx in mutant CSs. Conclusion: Treatment with a combination of EGCG and aMT can be of high therapeutic value due to the high antioxidant capacity and anti-amyloidogenic effect of both compounds. Show more
Keywords: Alzheimer’s disease, cerebral spheroids, E280A, -(–) epigallocatechin 3-gallate, melatonin, menstrual mesenchymal stromal cell, mutation, presenilin
DOI: 10.3233/JAD-220903
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Zhou, Moran | Jiao, Qian | Wu, Zengrui | Li, Weihua | Liu, Guixia | Wang, Rui | Tang, Yun
Article Type: Research Article
Abstract: Background: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ ) in the field of understanding the mechanisms of Alzheimer’s disease (AD), a complicated and untreatable neurodegenerative disease. Objective: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms. Methods: In this study, a systematic workflow combining pharmacological experiments and computational prediction were proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data …on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation. Results: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan. Conclusion: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD. Show more
Keywords: Alzheimer’s disease, computational systems pharmacology, oxidative stress hypothesis, phenotypic screening, polypharmacology networks, therapeutic targets
DOI: 10.3233/JAD-220727
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023
Authors: Yang, Lei | Zhao, Fengxue | Sun, Yadi | Wang, Ziyi | Li, Qianwen | Wang, Hao | Lu, Ying
Article Type: Systematic Review
Abstract: Background: Mild cognitive impairment (MCI) is the prodromal stage of dementia. In this stage, reasonable intervention measures can help to delay the decline of cognitive function. Supplementation of n-3 polyunsaturated fatty acids (n-3PUFAs) may be beneficial to delay the decline of cognitive function in the elderly. Objective: To investigate the effectiveness of docosapentaenoic acid (DHA) or/and eicosapentaenoic acid (EPA) supplements in the elderly with MCI. Methods: Eight electronic databases, PubMed, Cochrane Library, Embase, VIP, SinoMed, Web of Science, CNKI, and WANFANG DATA, were searched for related articles from inception until January 2022. Subgroup analyses and sensitivity …analyses were performed to detect confounding variables. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots. Stata12.0 was used for Begg’s and Egger’s test to quantify whether publication bias. Linear relationship between global cognition and covariates was examined in meta-regression analysis. Results: Twelve studies (n = 1,124) were included. The methodological quality of research is mostly medium. Compared with placebo, n-3PUFAs supplements have benefits on global cognition [SMD = 0.51, 95% CI(0.12, 0.91), p = 0.01]. No significant differences were observed between intervention group and placebo on language fluency, executive functions, and depression. Conclusion: Our findings indicated DHA and/or EPA supplements have benefits on global cognition, and it may also reduce the level of blood amyloid-β (Aβ)-related biomarkers (e.g., Aβ 40 , Aβ 42 ) and inflammatory factors (e.g., 1L-6, 1L-10). Since there are only two relative articles, more research is needed in the future to clarify the relationship. Show more
Keywords: Elderly, meta-analysis, mild cognitive impairment, n-3 polyunsaturated fatty acids
DOI: 10.3233/JAD-220863
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Bian, Zhihong | Yu, Haibo | Hu, Xinran | Bian, Yuting | Sun, Hongming | Tadokoro, Koh | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Fukui, Yusuke | Morihara, Ryuta | Abe, Koji | Yamashita, Toru
Article Type: Research Article
Abstract: Background: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer’s disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. Objective: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. Methods: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aβ-overexpressed transgenic AD mice model (APP23, …n = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n = 9) was assessed. Results: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aβ deposition after 16 months. Conclusion: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment. Show more
Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, NOX2, oxidative stress, Tocovid
DOI: 10.3233/JAD-220761
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022
Authors: Nelson, Doug | Thompson, Kevin J. | Wang, Lushan | Wang, Zengtao | Eberts, Paulina | Azarin, Samira M. | Kalari, Krishna R. | Kandimalla, Karunya K.
Article Type: Research Article
Abstract: Background: A strong body of evidence suggests that cerebrovascular pathologies augment the onset and progression of Alzheimer’s disease (AD). One distinctive aspect of this cerebrovascular dysfunction is the degeneration of brain pericytes—often overlooked supporting cells of blood-brain barrier endothelium. Objective: The current study investigates the influence of pericytes on gene and protein expressions in the blood-brain barrier endothelium, which is expected to facilitate the identification of pathophysiological pathways that are triggered by pericyte loss and lead to blood-brain barrier dysfunction in AD. Methods: Bioinformatics analysis was conducted on the RNA-Seq expression counts matrix (GSE144474), which compared …solo-cultured human blood-brain barrier endothelial cells against endothelial cells co-cultured with human brain pericytes in a non-contact model. We constructed a similar cell culture model to verify protein expression using western blots. Results: The insulin resistance and ferroptosis pathways were found to be enriched. Western blots of the insulin receptor and heme oxygenase expressions were consistent with those observed in RNA-Seq data. Additionally, we observed more than 5-fold upregulation of several genes associated with neuroprotection, including insulin-like growth factor 2 and brain-derived neurotrophic factor. Conclusions: Results suggest that pericyte influence on blood-brain barrier endothelial gene expression confers protection from insulin resistance, iron accumulation, oxidative stress, and amyloid deposition. Since these are conditions associated with AD pathophysiology, they imply mechanisms by which pericyte degeneration could contribute to disease progression. Show more
Keywords: Alzheimer’s disease, blood-brain barrier, cerebrovascular dysfunction, computational biology, endothelial cells, pericytes
DOI: 10.3233/JAD-230907
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Mandal, Pravat K.
Article Type: Editorial
DOI: 10.3233/JAD-240217
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Sigurdsson, Einar M.
Article Type: Review Article
Abstract: The tau protein undergoes pathological changes in Alzheimer’s disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of …some antibodies targeting amyloid-β in Alzheimer’s disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer’s disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell. Show more
Keywords: Alzheimer’s disease, antibody, clinical trials, immunotherapy, tau protein, tauopathies, vaccine
DOI: 10.3233/JAD-231238
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Weinberg, Marc S. | He, Yingnan | Kivisäkk, Pia | Arnold, Steven E. | Das, Sudeshna
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Objective: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. Methods: We analyzed plasma and CSF proteomics data collected previously …(ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. Results: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Conclusions: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, clinical trial, metformin, plasma
DOI: 10.3233/JAD-230899
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Hambali, Aqilah | Jusril, Nor Atiqah | Md Hashim, Nur Fariesha | Abd Manan, Nizar | Adam, Siti Khadijah | Mehat, Muhammad Zulfadli | Adenan, Mohd Ilham | Stanslas, Johnson | Abdul Hamid, Hafizah
Article Type: Research Article
Abstract: Background: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer’s disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown. Objective: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells. Methods: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested …for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α , IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting. Results: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α , IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p < 0.001) by SECA and its fractions. SECA and some of its fractions can activate the Nrf2/HO-1 signaling pathway by significantly enhancing (p < 0.05) the Nrf2 and HO-1 protein expressions. Conclusions: This study suggests that the inhibitory activity of SECA and its fractions on pro-inflammatory and oxidative stress events may be the result of the activation of antioxidant defense systems. The potential of SECA and its fractions in reducing neuroinflammation and oxidative stress can be further studied as a potential therapeutic strategy for AD. Show more
Keywords: Alzheimer’s disease, Centella asiatica , HO-1, neuroinflammation, Nrf2, oxidative stress
DOI: 10.3233/JAD-230875
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Noori, Ayush | Jayakumar, Rojashree | Moturi, Vaishnavi | Li, Zhaozhi | Liu, Rongxin | Serrano-Pozo, Alberto | Hyman, Bradley T. | Das, Sudeshna
Article Type: Research Article
Abstract: Background: Recent Alzheimer’s disease (AD) discoveries are increasingly based on studies from a variety of omics technologies on large cohorts. Currently, there is no easily accessible resource for neuroscientists to browse, query, and visualize these complex datasets in a harmonized manner. Objective: Create an online portal of public omics datasets for AD research. Methods: We developed Alzheimer DataLENS, a web-based portal, using the R Shiny platform to query and visualize publicly available transcriptomics and genetics studies of AD on human cohorts. To ensure consistent representation of AD findings, all datasets were processed through a uniform bioinformatics …pipeline. Results: Alzheimer DataLENS currently houses 2 single-nucleus RNA sequencing datasets, over 30 bulk RNA sequencing datasets from 19 brain regions and 3 cohorts, and 2 genome-wide association studies (GWAS). Available visualizations for single-nucleus data include bubble plots, heatmaps, and UMAP plots; for bulk expression data include box plots and heatmaps; for pathways include protein-protein interaction network plots; and for GWAS results include Manhattan plots. Alzheimer DataLENS also links to two other knowledge resources: the AD Progression Atlas and the Astrocyte Atlas. Conclusions: Alzheimer DataLENS is a valuable resource for investigators to quickly and systematically explore omics datasets and is freely accessible at https://alzdatalens.partners.org . Show more
Keywords: Alzheimer’s disease, database, genetics, multiomics, single-cell RNA-seq, transcriptomics
DOI: 10.3233/JAD-230884
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Wang, Yongchun | Jiang, Richeng | Li, Mingxi | Wang, Zicheng | Yang, Yu | Sun, Li
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia, causing a huge socioeconomic burden. In parallel with the widespread uptake of single-cell RNA sequencing (scRNA-seq) technology, there has been a rapid accumulation of data produced by researching AD at single-cell resolution, which is more conductive to explore the neuroimmune-related mechanism of AD. Objective: To explore the potential features of T cells in the peripheral blood and cerebrospinal fluid of AD patients. Methods: Two datasets, GSE181279 and GSE134578, were integrated from GEO database. Seurat, Monocle, CellChat, scRepertoire, and singleR packages were mainly …employed for data analysis. Results: Our analysis demonstrated that in peripheral blood, T cells were significantly expanded, and these expanded T cells were possessed effector function, such as CD8+ TEMRA , CD4+ TEMRA , and CD8+ TEM . Interestingly, CD8+ TEMRA and CD4+ TEMRA cells positioned adjacently after dimensions reduction and clustering. Notably, we identified that the expanded T cells were developed from Naïve T cells and TCM cells, and TEM cells was in the intermediate state of this developing process. Additionally, in cerebrospinal fluid of AD patients, the amplified T cells were mainly CD8+ TEMRA cells, and the number and strength of communication between CD4+ TEM , CD8+ TEM , and CD8+ TEMRA were decreased in AD patients. Conclusions: Our comprehensive analyses identified the cells in cerebrospinal fluid from AD patients are expanded TEMRA or TEM cells and the TEMRA cells communicating with other immune cells is weakened, which may be an important immune feature that leads to AD. Show more
Keywords: Alzheimer’s disease, analysis of immune characteristics, immune cell subpopulation, single-cell RNA sequencing, TCR repertoire
DOI: 10.3233/JAD-230784
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Snytnikova, Olga | Telegina, Darya | Savina, Ekaterina | Tsentalovich, Yuri | Kolosova, Nataliya
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease. Objective: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs. Methods: High resolution 1 H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model …of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the “preclinical” period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control. Results: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups. Conclusions: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans. Show more
Keywords: Aging, Alzheimer’s disease, hippocampal metabolome, hypotaurine, nuclear magnetic resonance spectroscopy, OXYS rats, scyllo-inositol
DOI: 10.3233/JAD-230706
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023
Authors: Syed, Rafay Ali | Hayat, Mahnoor | Qaiser, Hammad | Uzair, Mohammad | Al-Regaiey, Khalid | Khallaf, Roaa | Kaleem, Imdad | Bashir, Shahid
Article Type: Review Article
Abstract: Aging is an intrinsic aspect of an organism’s life cycle and is characterized by progressive physiological decline and increased susceptibility to mortality. Many age-associated disorders, including neurological disorders, are most commonly linked with the aging process, such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the effects of aging and AD on the molecular pathways and levels of different proteins in the brain, including metalloproteins, neurotrophic factors, amyloid proteins, and tau proteins. AD is caused by the aggregation of amyloid proteins in the brain. Factors such as metal ions, protein ligands, and the oligomerization state …of amyloid precursor protein significantly influence the proteolytic processing of amyloid-β protein precursor (AβPP). Tau, a disordered cytosolic protein, serves as the principal microtubule-associated protein in mature neurons. AD patients exhibit decreased levels of nerve growth factor within their nervous systems and cerebrospinal fluid. Furthermore, a significant increase in brain-derived neurotrophic factor resulting from the neuroprotective effect of glial cell line-derived neurotrophic factor suggests that the synergistic action of these proteins plays a role in inhibiting neuronal degeneration and atrophy. The mechanism through which Aβ and AβPP govern Cu2+ transport and their influence on Cu2+ and other metal ion pools requires elucidation in future studies. A comprehensive understanding of the influence of aging and AD on molecular pathways and varying protein levels may hold the potential for the development of novel diagnostic and therapeutic methods for the treatment of AD. Show more
Keywords: Alzheimer’s disease, apoptosis, brain-derived neurotrophic factor, neurotrophic factors, oxidative stress
DOI: 10.3233/JAD-230801
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Jehu, Deborah A. | Pottayil, Faheem | Dong, Yanbin | Zhu, Haidong | Sams, Richard | Young, Lufei
Article Type: Research Article
Abstract: Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition : Montreal Cognitive Assessment; executive function : Trail-Making Test, Digit Span Forward Test; perception and orientation : Benton Judgement of Line Orientation Test; …language : Boston Naming Test; learning and memory : Rey Auditory Verbal Learning Test; complex attention : Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer’s disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (p s < 0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes. Show more
Keywords: Accelerometry, actigraphy, Alzheimer’s disease, cognition, cognitive domains, dementia, physical activity
DOI: 10.3233/JAD-230594
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Lazarova, Maria I. | Tsvetanova, Elina R. | Georgieva, Almira P. | Stefanova, Miroslava O. | Uzunova, Diamara N. | Denev, Petko N. | Tasheva, Krasimira N.
Article Type: Research Article
Abstract: Background: The cholinergic neuronal loss in the basal forebrain and increasing brain oxidative stress are one of the main features of the brain suffering from Alzheimer’s disease. Marrubium vulgare (M. vulgare ), commonly known as ‘white horehound,’ possesses a variety of valuable properties, such as antioxidative, anti-inflammatory, and antidiabetic activities. Moreover, it possesses neuromodulatory properties that could potentially impact short-term memory functions. Objective: The present study was undertaken to investigate the preventive effects of water M. vulgare extract on working memory, cholinergic neurotransmission, and oxidative stress in rats with scopolamine (Sco)-induced dementia. Methods: Male …Wistar rats (200–250 g) were divided into four experimental groups. The plant extract was administered orally for 21 days, and Sco (2 mg/kg) was administered intraperitoneally for 11 consecutive days. The behavioral performance of the animals was evaluated by the T-maze test. The effect of the extract on acetylcholinesterase (AChE) activity and antioxidant status in cortex and hippocampus were also monitored. Results: Our experimental data revealed that treatment with M. vulgare significantly increased the percentage of correct choices of rats with Sco-induced dementia in the T maze test (by 38%, p < 0.05). Additionally, it reduced AChE activity in the hippocampus (by 20%, p < 0.05) and alleviated oxidative stress induced by Sco, particularly in the cortex. Conclusions: M. vulgare water extract demonstrated working memory preserving effect in rats with Sco-induced dementia, AChE inhibitory activity and in vivo antioxidant potential, and deserve further attention. Show more
Keywords: Acetylcholinesterase, Alzheimer’s disease, Marrubium vulgare, oxidative stress, scopolamine-induced dementia, T-maze test
DOI: 10.3233/JAD-231011
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Gordon, Scott | Lee, Jong Soo | Scott, Tammy M. | Bhupathiraju, Shilpa | Ordovas, Jose | Kelly, Rachel S. | Tucker, Katherine L. | Palacios, Natalia
Article Type: Research Article
Abstract: Background: Recent studies have identified plasma metabolites associated with cognitive decline and Alzheimer’s disease; however, little research on this topic has been conducted in Latinos, especially Puerto Ricans. Objective: This study aims to add to the growing body of metabolomics research in Latinos to better understand and improve the health of this population. Methods: We assessed the association between plasma metabolites and global cognition over 12 years of follow-up in 736 participants of the Boston Puerto Rican Health Study (BPRHS). Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. We used covariable adjusted linear …mixed models (LMM) with a metabolite * time interaction term to identify metabolites (of 621 measured) associated with ∼12 years cognitive trajectory. Results: We observed strong inverse associations between medium-chain fatty acids, caproic acid, and the dicarboxylic acids, azelaic and sebacic acid, and global cognition. N-formylphenylalanine, a tyrosine pathway metabolite, was associated with improvement in cognitive trajectory. Conclusions: The metabolites identified in this study are generally consistent with prior literature and highlight a role medium chain fatty acid and tyrosine metabolism in cognitive decline. Show more
Keywords: Alzheimer’s disease, cognitive decline, Latinos, metabolomics, Puerto rican
DOI: 10.3233/JAD-230053
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Beckers, Elise | Riphagen, Joost M. | Van Egroo, Maxime | Bennett, David A. | Jacobs, Heidi I.L.
Article Type: Short Communication
Abstract: Tau accumulation in and neurodegeneration of locus coeruleus (LC) neurons is observed in Alzheimer’s disease (AD). We investigated whether tangle and neuronal density in the rostral and caudal LC is characterized by an asymmetric pattern in 77 autopsy cases of the Rush Memory and Aging Project. We found left-right equivalence for tangle density across individuals with and without AD pathology. However, neuronal density, particularly in the caudal-rostral axis of the LC, is asymmetric among individuals with AD pathology. Asymmetry in LC neuronal density may signal advanced disease progression and should be considered in AD neuroimaging studies of LC neurodegeneration.
Keywords: Alzheimer’s disease, asymmetry, autopsy, brainstem, locus coeruleus, neurons, tangles
DOI: 10.3233/JAD-231328
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2024
Authors: Bini, Jason
Article Type: Article Commentary
Abstract: Excess cortisol is associated with more severe cognitive decline, Alzheimer’s disease, and related dementia phenotypes. The intracellular enzyme 11β-HSD1 regenerates active cortisol from inactive cortisone. In this current issue, high regional brain occupancy of Xanamemtrademark, determined by [11 C]TARACT PET imaging of 11β-HSD1, in cognitively normal individuals and mild cognitive impartment/Alzheimer’s disease (AD) patients is presented. In the future, comprehensive kinetic modeling using arterial sampling for occupancy studies, and whole-body PET imaging of 11β-HSD1 enzyme levels, in combination with stable isotope studies of cortisol metabolism, can provide broad insight into enzyme levels and activity in AD and other relevant diseases.
Keywords: Alzheimer’s disease, cortisol, positron emission tomography, 11β-hydroxysteroid dehydrogenase type 1
DOI: 10.3233/JAD-231463
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: Dorado-Martínez, Claudia | Montiel-Flores, Enrique | Ordoñez-Librado, Jose Luis | Gutierrez-Valdez, Ana Luisa | Garcia-Caballero, Cesar Alfonso | Sanchez-Betancourt, Javier | Reynoso-Erazo, Leonardo | Tron-Alvarez, Rocio | Rodríguez-Lara, Vianey | Avila-Costa, Maria Rosa
Article Type: Research Article
Abstract: Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2 O5 ) causes cytoskeletal alterations suggesting that V2 O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer’s disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2 O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-β (Aβ) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control …(deionized water) and experimental (0.02 M V2 O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2 O5 inhalation. We also noted NFTs, Aβ plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage. Show more
Keywords: Alzheimer’s disease experimental model, Aβ plaques, cell death, dendritic spine loss, inhaled exposure, neurofibrillary tangles, Vanadium pentoxide
DOI: 10.3233/JAD-230818
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2024
Authors: Das, Sudeshna
Article Type: Introduction
DOI: 10.3233/JAD-240272
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: Zhang, Zheting | Lim, Mervyn Jun Rui
Article Type: Review Article
Abstract: Post-stroke cognitive impairment and dementia (PSCID) is a complication that affects long-term functional outcomes after stroke. Studies on dementia after long-term follow-up in stroke have focused predominantly on ischemic stroke, which may be different from the development of dementia after spontaneous intracerebral hemorrhage (ICH). In this review, we summarize the existing data and hypotheses on the development of dementia after spontaneous ICH, review the management of post-ICH dementia, and suggest areas for future research. Dementia after spontaneous ICH has a cumulative incidence of up to 32.0–37.4% at 5 years post-ICH. Although the pathophysiology of post-ICH dementia has not been fully …understood, two main theoretical frameworks can be considered: 1) the triggering role of ICH (both primary and secondary brain injury) in precipitating cognitive decline and dementia; and 2) the contributory role of pre-existing brain pathology (including small vessel disease and neurodegenerative pathology), reduced cognitive reserve, and genetic factors predisposing to cognitive dysfunction. These pathophysiological pathways may have synergistic effects that converge on dysfunction of the neurovascular unit and disruptions in functional connectivity leading to dementia post-ICH. Management of post-ICH dementia may include screening and monitoring, cognitive therapy, and pharmacotherapy. Non-invasive brain stimulation is an emerging therapeutic modality under investigation for safety and efficacy. Our review highlights that there remains a paucity of data and standardized reporting on incident dementia after spontaneous ICH. Further research is imperative for determining the incidence, risk factors, and pathophysiology of post-ICH dementia, in order to identify new therapies for the treatment of this debilitating condition. Show more
Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, hemorrhagic stroke, intracerebral hemorrhage, stroke
DOI: 10.3233/JAD-240111
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Tahami Monfared, Amir Abbas | Khachatryan, Artak | Hummel, Noemi | Kopiec, Agnieszka | Martinez, Marta | Zhang, Raymond | Zhang, Quanwu
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) and mild cognitive impairment (MCI) have negative quality of life (QoL) and economic impacts on patients and their caregivers and may increase along the disease continuum from MCI to mild, moderate, and severe AD. Objective: To assess how patient and caregiver QoL, indirect and intangible costs are associated with MCI and AD severity. Methods: An on-line survey of physician-identified patient-caregiver dyads living in the United States was conducted from June–October 2022 and included questions to both patients and their caregivers. Dementia Quality of Life Proxy, the Care-related Quality of Life, Work Productivity …and Activity Impairment, and Dependence scale were incorporated into the survey. Regression analyses investigated the association between disease severity and QoL and cost outcomes with adjustment for baseline characteristics. Results: One-hundred patient-caregiver dyads were assessed with the survey (MCI, n = 27; mild AD, n = 27; moderate AD, n = 25; severe AD, n = 21). Decreased QoL was found with worsening severity in patients (p < 0.01) and in unpaid (informal) caregivers (n = 79; p = 0.02). Dependence increased with disease severity (p < 0.01). Advanced disease severity was associated with higher costs to employers (p = 0.04), but not with indirect costs to caregivers. Patient and unpaid caregiver intangible costs increased with disease severity (p < 0.01). A significant trend of higher summed costs (indirect costs to caregivers, costs to employers, intangible costs to patients and caregivers) in more severe AD was observed (p < 0.01). Conclusions: Patient QoL and functional independence and unpaid caregiver QoL decrease as AD severity increases. Intangible costs to patients and summed costs increase with disease severity and are highest in severe AD. Show more
Keywords: Alzheimer’s disease, cost of illness, employer health costs, global burden of disease, health expenditure, indirect expenditure, intangible cost, mild cognitive impairment, quality of life
DOI: 10.3233/JAD-231259
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Chong, Terence W.H. | Macpherson, Helen
Article Type: Article Commentary
Abstract: Dementia is a global public health priority. Physical activity has myriad health benefits, including for reducing dementia risk. To increase physical activity, detailed understanding of influencing factors is needed. Socioeconomic deprivation affects many aspects of health and wellbeing. Qualitative research with older people experiencing socioeconomic deprivation is needed to explore barriers and enablers to engaging in physical activity, with the view to co-designing interventions for implementation trials. A whole of society approach is pivotal to improving effectiveness of physical activity interventions for older adults with cognitive impairment, and target support for people experiencing socioeconomic deprivation, to improve their health outcomes.
Keywords: Alzheimer’s disease, cognitive health, cognitive impairment, dementia, physical activity, socioeconomic disadvantage
DOI: 10.3233/JAD-240095
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Khaled, Mohamad | Al-Jamal, Hadi | Tajer, Layla | El-Mir, Reem
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is a neurodegenerative condition that displays a high prevalence in Lebanon causing a local burden in healthcare and socio-economic sectors. Unfortunately, the lack of prevalence studies and clinical trials in Lebanon minimizes the improvement of AD patient health status. In this review, we include over 155 articles to cover the different aspects of AD ranging from mechanisms to possible treatment and management tools. We highlight some important modifiable and non-modifiable risk factors of the disease including genetics, age, cardiovascular diseases, smoking, etc. Finally, we propose a hypothetical genetic synergy model between APOE4 and TREM2 genes …which constitutes a potential early diagnostic tool that helps in reducing the risk of AD based on preventative measures decades before cognitive decline. The studies on AD in Lebanon and the Middle East are scarce. This review points out the importance of genetic mapping in the understanding of disease pathology which is crucial for the emergence of novel diagnostic tools. Hence, we establish a rigid basis for further research to identify the most influential genetic and environmental risk factors for the purpose of using more specific diagnostic tools and possibly adopting a local management protocol. Show more
Keywords: Alzheimer’s disease, APOE, genetic factors, Lebanon, TREM2
DOI: 10.3233/JAD-231432
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Choi, Yu Yong | Lee, Jang Jae | te Nijenhuis, Jan | Choi, Kyu Yeong | Park, Jongseong | Ok, Jongmyoung | Choo, IL Han | Kim, Hoowon | Song, Min-Kyung | Choi, Seong-Min | Cho, Soo Hyun | Chae, Youngshik | Kim, Byeong C. | Lee, Kun Ho
Article Type: Research Article
Abstract: Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59–89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, …magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, Δ AUC = + 0.04, D = 4.10, p < 0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases. Show more
Keywords: Alzheimer’s disease, brain aging, ethnic difference, magnetic resonance imaging, norm
DOI: 10.3233/JAD-231182
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Boujelbane, Mohamed Ali | Trabelsi, Khaled | Salem, Atef | Ammar, Achraf | Glenn, Jordan M. | Boukhris, Omar | AlRashid, Maha M. | Jahrami, Haitham | Chtourou, Hamdi
Article Type: Research Article
Abstract: Background: Alzheimer’s disease and mild cognitive impairment (MCI) progress silently, making early diagnosis challenging, especially in less educated populations. The visual paired comparison (VPC) task, utilizing eye-tracking movement (ETM) technology, offers a promising alternative for early detection of memory decline. Objective: This systematic review and meta-analysis evaluated the efficacy of the VPC task, utilizing ETM as a tool for assessing age-related cognitive changes. Methods: A comprehensive search across five databases and grey literature focused on healthy and impaired memory participants assessed through the ETM-based VPC task. The primary outcomes were novelty preference scores and eye movement …metrics. The risk of bias of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Random-effects meta-analyses calculated Hedges’ g effect size. Sensitivity and specificity of the VPC were meta-analytically pooled. Results: The systematic review included 12 articles, involving 1,022 participants (aged 18 to 90 years, with education ranging from 6.5 to 20.0 years), with a low risk of bias and minimal applicability concerns across all items. Five studies contributed to the meta-analysis, revealing a significant effect favoring the VPC task for recognition memory detection (k = 9, g = –1.03). Pooled sensitivity and specificity analyses demonstrated VPC effectiveness as a recognition memory assessment tool (0.84 and 0.75, respectively). Conclusions: The VPC task, utilizing ETM, may serve as a biomarker for early memory decline detection. Its use as a digital eye-tracking tool presents a possible alternative to traditional tests, warranting further research for application in neurodegenerative disease diagnosis. Show more
Keywords: Alzheimer’s disease, cognition, dementia, eye movements, novelty preference score, sensitivity, specificity
DOI: 10.3233/JAD-240028
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Yoo, Han Soo | Kim, Han-Kyeol | Lee, Jae-Hoon | Chun, Joong-Hyun | Lee, Hye Sun | Grothe, Michel J. | Teipel, Stefan | Cavedo, Enrica | Vergallo, Andrea | Hampel, Harald | Ryu, Young Hoon | Cho, Hanna | Lyoo, Chul Hyoung
Article Type: Research Article
Abstract: Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer’s disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aβ]-negative cognitively unimpaired, 6 Aβ-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18 F-florbetaben PET for Aβ, 18 F-flortaucipir PET for tau, and detailed cognitive …testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aβ and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aβ, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aβ accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aβ and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function. Show more
Keywords: Alzheimer’s disease, amyloid-beta, basal forebrain, cognition, tau
DOI: 10.3233/JAD-230975
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Etekochay, Maudlyn O. | Amaravadhi, Amoolya Rao | González, Gabriel Villarrubia | Atanasov, Atanas G. | Matin, Maima | Mofatteh, Mohammad | Steinbusch, Harry Wilhelm | Tesfaye, Tadele | Praticò, Domenico
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with a global impact. The past few decades have witnessed significant strides in comprehending the underlying pathophysiological mechanisms and developing diagnostic methodologies for AD, such as neuroimaging approaches. Neuroimaging techniques, including positron emission tomography and magnetic resonance imaging, have revolutionized the field by providing valuable insights into the structural and functional alterations in the brains of individuals with AD. These imaging modalities enable the detection of early biomarkers such as amyloid-β plaques and tau protein tangles, facilitating early and precise diagnosis. Furthermore, the emerging technologies encompassing blood-based biomarkers and neurochemical profiling exhibit …promising results in the identification of specific molecular signatures for AD. The integration of machine learning algorithms and artificial intelligence has enhanced the predictive capacity of these diagnostic tools when analyzing complex datasets. In this review article, we will highlight not only some of the most used diagnostic imaging approaches in neurodegeneration research but focus much more on new tools like artificial intelligence, emphasizing their application in the realm of AD. These advancements hold immense potential for early detection and intervention, thereby paving the way for personalized therapeutic strategies and ultimately augmenting the quality of life for individuals affected by AD. Show more
Keywords: Alzheimer’s disease, artificial intelligence, biomarker, machine learning, neuroimaging
DOI: 10.3233/JAD-231135
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Nakanishi, Miharu | Yamasaki, Syudo | Nakashima, Taeko | Miyamoto, Yuki | Cooper, Claudia | Richards, Marcus | Stanyon, Daniel | Sakai, Mai | Yoshii, Hatsumi | Nishida, Atsushi
Article Type: Research Article
Abstract: Background: The emotional impact of the coronavirus disease 2019 (COVID-19) pandemic on people with dementia has been quantified. However, little is known about the impact of change in home-care use owing to the pandemic. Objective: To determine the longitudinal association between dementia, change in home-care use, and depressive symptoms during the pandemic. Methods: We included data of 43,782 home-dwelling older adults from the English Longitudinal Study of Ageing (ELSA), Study of health, Ageing and Retirement in Europe (SHARE), and National Health and Aging Trends Study (NHATS). This study considered the latest main wave …survey prior to the pandemic as the baseline, and the COVID-19 survey as follow-up. In a series of coordinated analyses, multilevel binomial logistic regression model was used to examine the association between baseline dementia, change in home-care use at follow-up, and presence of depressive symptoms. Results: Dementia, using the ELSA, SHARE, and NHATS datasets, was identified in 2.9%, 2.3%, and 6.5% of older adults, and home-care use reduced in 1.7%, 2.8%, and 1.1% of individuals with dementia, respectively. Dementia was significantly associated with the increased risk of depressive symptoms in all three cohorts. However, the interaction between dementia and period (follow-up) was non-significant in SHARE and NHATS. Across all three cohorts, home-care use during the pandemic, regardless of change in amount, was significantly associated with increased depressive symptoms, compared to the non-use of home care. Conclusions: These results highlight the need for tailoring dementia care at home to promote independence and provide sustainable emotional support. Show more
Keywords: Alzheimer’s disease, cohort studies, dementia, depression, home care services, SARS-CoV 2, social interaction
DOI: 10.3233/JAD-240097
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Cai, Jie | Xie, Danni | Kong, Fanjing | Zhai, Zhenwei | Zhu, Zhishan | Zhao, Yanru | Xu, Ying | Sun, Tao
Article Type: Systematic Review
Abstract: Background: Alzheimer’s disease (AD), the most common form of dementia, remains long-term and challenging to diagnose. Furthermore, there is currently no medication to completely cure AD patients. Rapamycin has been clinically demonstrated to postpone the aging process in mice and improve learning and memory abilities in animal models of AD. Therefore, rapamycin has the potential to be significant in the discovery and development of drugs for AD patients. Objective: The main objective of this systematic review and meta-analysis was to investigate the effects and mechanisms of rapamycin on animal models of AD by examining behavioral indicators …and pathological features. Methods: Six databases were searched and 4,277 articles were retrieved. In conclusion, 13 studies were included according to predefined criteria. Three authors independently judged the selected literature and methodological quality. Use of subgroup analyses to explore potential mechanistic effects of rapamycin interventions: animal models of AD, specific types of transgenic animal models, dosage, and periodicity of administration. Results: The results of Morris Water Maze (MWM) behavioral test showed that escape latency was shortened by 15.60 seconds with rapamycin therapy, indicating that learning ability was enhanced in AD mice; and the number of traversed platforms was increased by 1.53 times, indicating that the improved memory ability significantly corrected the memory deficits. CONCLUSIONS: Rapamycin therapy reduced age-related plaque deposition by decreasing AβPP production and down-regulating β-secretase and γ-secretase activities, furthermore increased amyloid-β clearance by promoting autophagy, as well as reduced tau hyperphosphorylation by up-regulating insulin-degrading enzyme levels. Show more
Keywords: KeywordsAlzheimer’s disease, animal models, cholesterol metabolism, meta-analysis, oxidative stress, rapamycin, systematic review
DOI: 10.3233/JAD-231249
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-32, 2024
Authors: Sighinolfi, Giovanni | Mitolo, Micaela | Pizzagalli, Fabrizio | Stanzani-Maserati, Michelangelo | Remondini, Daniel | Rochat, Magali Jane | Cantoni, Elena | Venturi, Greta | Vornetti, Gianfranco | Bartiromo, Fiorina | Capellari, Sabina | Liguori, Rocco | Tonon, Caterina | Testa, Claudia | Lodi, Raffaele
Article Type: Research Article
Abstract: Background: Being able to differentiate mild cognitive impairment (MCI) patients who would eventually convert (MCIc) to Alzheimer’s disease (AD) from those who would not (MCInc) is a key challenge for prognosis. Objective: This study aimed to investigate the ability of sulcal morphometry to predict MCI progression to AD, dedicating special attention to an accurate identification of sulci. Methods: Twenty-five AD patients, thirty-seven MCI and twenty-five healthy controls (HC) underwent a brain-MR protocol (1.5T scanner) including a high-resolution T1-weighted sequence. MCI patients underwent a neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 2.3 …years. At follow-up, 12 MCI were classified as MCInc and 25 as MCIc. Sulcal morphometry was investigated using the BrainVISA framework. Consistency of sulci across subjects was ensured by visual inspection and manual correction of the automatic labelling in each subject. Sulcal surface, depth, length, and width were retrieved from 106 sulci. Features were compared across groups and their classification accuracy in predicting MCI conversion was tested. Potential relationships between sulcal features and cognitive scores were explored using Spearman’s correlation. Results: The width of sulci in the temporo-occipital region strongly differentiated between each pair of groups. Comparing MCIc and MCInc, the width of several sulci in the bilateral temporo-occipital and left frontal areas was significantly altered. Higher width of frontal sulci was associated with worse performances in short-term verbal memory and phonemic fluency. Conclusions: Sulcal morphometry emerged as a strong tool for differentiating HC, MCI, and AD, demonstrating its potential prognostic value for the MCI population. Show more
Keywords: Alzheimer’s disease, brain sulci, cortical thickness, MCI conversion, mild cognitive impairment, sulcalmorphometry
DOI: 10.3233/JAD-231192
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Chandrasekaran, Ganesh | Xie, Sharon X.
Article Type: Research Article
Abstract: Background: Missing data is prevalent in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). It is common to deal with missingness by removing subjects with missing entries prior to statistical analysis; however, this can lead to significant efficiency loss and sometimes bias. It has yet to be demonstrated that the imputation approach to handling this issue can be valuable in some longitudinal regression settings. Objective: The purpose of this study is to demonstrate the importance of imputation and how imputation is correctly done in ADNI by analyzing longitudinal Alzheimer’s Disease Assessment Scale –Cognitive Subscale 13 (ADAS-Cog 13) scores and their …association with baseline patient characteristics. Methods: We studied 1,063 subjects in ADNI with mild cognitive impairment. Longitudinal ADAS-Cog 13 scores were modeled with a linear mixed-effects model with baseline clinical and demographic characteristics as predictors. The model estimates obtained without imputation were compared with those obtained after imputation with Multiple Imputation by Chained Equations (MICE). We justify application of MICE by investigating the missing data mechanism and model assumptions. We also assess robustness of the results to the choice of imputation method. Results: The fixed-effects estimates of the linear mixed-effects model after imputation with MICE yield valid, tighter confidence intervals, thus improving the efficiency of the analysis when compared to the analysis done without imputation. Conclusions: Our study demonstrates the importance of accounting for missing data in ADNI. When deciding to perform imputation, care should be taken in choosing the approach, as an invalid one can compromise the statistical analyses. Show more
Keywords: Alzheimer’s disease, biomarkers, imputation, longitudinal study, missing data
DOI: 10.3233/JAD-231047
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
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