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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: Yu, Jian | Tang, Wenyu | Sulaiman, Zubaidan | Ma, Xin | Wang, Jiayi | Shi, Zhongyong | Liu, Qidong | Xie, Zhongcong | Shen, Yuan
Article Type: Research Article
Abstract: Background: Surgery may be associated with postoperative cognitive impairment in elder participants, yet the extent of its association with mild cognitive impairment (MCI) remains undetermined. Objective: To determine the relationship between surgery and MCI. Methods: The data of participants from the Alzheimer’s Disease Neuroimaging Initiative were analyzed, including individuals with MCI or normal cognition. We focused on surgeries conducted after the age of 45, categorized by the number of surgeries, surgical risk, and the age at which surgeries occurred. Multivariable logistic regression was employed to determine the association between surgery and the development of MCI. …Results: The study is comprised of 387 individuals with MCI and 578 cognitively normal individuals. The overall surgery exposure (adjusted OR = 1.14, [95% CI 0.83, 1.56], p = 0.43) and the number of surgeries (adjusted OR = 0.92 [0.62, 1.36], p = 0.67 for single exposure, adjusted OR = 1.12 [0.71, 1.78], p = 0.63 for two exposures, adjusted OR = 1.38 [0.95, 2.01], p = 0.09 for three or more exposures compared to no exposure as the reference) were not associated with the development of MCI. However, high-risk surgeries (adjusted OR = 1.79 [1.00, 3.21], p = 0.049) or surgeries occurring after the age of 75 (adjusted OR = 2.01 [1.03, 3.90], p = 0.041) were associated with a greater risk of developing MCI. Conclusions: High risk surgeries occurring at an older age contribute to the development of MCI, indicating a complex of mechanistic insights for the development of postoperative cognitive impairment. Show more
Keywords: Aging, Alzheimer’s disease, elderly, geriatric, mild cognitive impairment, surgery
DOI: 10.3233/JAD-240467
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Alldred, Melissa J. | Pidikiti, Harshitha | Ibrahim, Kryillos W. | Lee, Sang Han | Heguy, Adriana | Hoffman, Gabriel E. | Mufson, Elliott J. | Stutzmann, Grace E. | Ginsberg, Stephen D.
Article Type: Research Article
Abstract: Background: Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer’s disease (AD) pathology during midlife, particularly in the hippocampal component of the medial temporal lobe memory circuit. However, molecular and cellular mechanisms underlying selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during DS/AD onset. This is compounded by evidence showing spatial (e.g., deep versus superficial) localization of pyramidal neurons (PNs) has profound effects on activity and innervation within the CA1 region. Objective: We investigated whether there is a spatial profiling difference in CA1 PNs in an aged female DS/AD mouse model. We posit …dysfunction may be dependent on spatial localization and innervation patterns within discrete CA1 subfields. Methods: Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region. Results: RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. The entire CA1 region displayed the most differentially expressed genes (DEGs) in trisomic mice reflecting innate DS vulnerability, while trisomic CA1a deep PNs exhibited fewer but more physiologically relevant DEGs, as evidenced by bioinformatic inquiry. Conclusions: CA1a deep neurons displayed numerous DEGs linked to cognitive functions whereas CA1a superficial neurons, with approximately equal numbers of DEGs, were not linked to pathways of dysregulation, suggesting the spatial location of vulnerable CA1 PNs plays an important role in circuit dissolution. Show more
Keywords: Alzheimer’s disease, bioinformatics, CA1, circuitry, Down syndrome, hippocampus, laser capture microdissection, RNA-seq, selective vulnerability, trisomy
DOI: 10.3233/JAD-240622
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2024
Authors: Halloway, Shannon | Volgman, Annabelle Santos | Barnes, Lisa L. | Schoeny, Michael E. | Wilbur, JoEllen | Pressler, Susan J. | Laddu, Deepika | Phillips, Shane A. | Vispute, Sachin | Hall, Gabriel | Shakya, Shamatree | Goodyke, Madison | Auger, Claire | Cagin, Kelly | Borgia, Jeffrey A. | Arvanitakis, Zoe A.
Article Type: Research Article
Abstract: Background: Vascular diseases, including atherosclerotic cardiovascular disease (ASCVD) and stroke, increase the risk of Alzheimer’s disease and cognitive impairment. Serum biomarkers, such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1), may be indicators of cognitive health. Objective: We examined whether vascular risk was associated with levels of cognition and serum biomarkers in older women with cardiovascular disease (CVD). Methods: Baseline data from a lifestyle trial in older women (n = 253) with CVD (NCT04556305) were analyzed. Vascular risk scores were calculated for ASCVD (ASCVD risk estimator) and stroke (CHA2 …DS2 -VASc) based on published criteria. Cognition-related serum biomarkers included BDNF, VEGF, and IGF-1. Cognition was based on a battery of neuropsychological tests that assessed episodic memory, semantic memory, working memory, and executive function. A series of separate linear regression models were used to evaluate associations of vascular risk scores with outcomes of cognition and serum biomarkers. All models were adjusted for age, education level, and racial and ethnic background. Results: In separate linear regression models, both ASCVD and CHA2 DS2 -VASc scores were inversely associated with semantic memory (β = –0.22, p = 0.007 and β = –0.15, p = 0.022, respectively), with no significant findings for the other cognitive domains. There were no significant associations between vascular risk scores and serum biomarkers. Conclusions: Future studies should prospectively examine associations between vascular risk and cognition in other populations and additionally consider other serum biomarkers that may be related to vascular risk and cognition. Show more
Keywords: Alzheimer’s disease, biomarkers, cardiovascular health, risk factors, stroke
DOI: 10.3233/JAD-240100
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Wang, Ruo-Tong | Sun, Zhen | Tan, Chen-Chen | Tan, Lan | Xu, Wei
Article Type: Research Article
Abstract: Background: The causal relationships of late-life body mass index (BMI) with Alzheimer’s disease (AD) remains debated. Objective: We aimed to assess the associations of dynamic BMI features (Δ BMIs) with cognitive trajectories, AD biomarkers, and incident AD risk. Methods: We analyzed an 8-year cohort of 542 non-demented individuals who were aged ≥65 years at baseline and had BMI measurements over the first 4 years. Δ BMIs were defined as changing extent (change ≤ or >5%), variability (standard deviation), and trajectories over the first 4 years measured using latent class trajectory modeling. Linear mixed-effect models were utilized …to examine the influence of Δ BMIs on changing rates of AD pathology biomarkers, hippocampus volume, and cognitive functions. Cox proportional hazards models were used to test the associations with AD risk. Stratified analyzes were conducted by the baseline BMI group and age. Results: Over the 4-year period, compared to those with stable BMI, individuals who experienced BMI decreases demonstrated accelerated declined memory function (p = 0.006) and amyloid-β deposition (p = 0.034) while BMI increases were associated with accelerated hippocampal atrophy (p = 0.036). Three BMI dynamic features, including stable BMI, low BMI variability, and persistently high BMI, were associated with lower risk of incident AD (p < 0.005). The associations were validated over the 8-year period after excluding incident AD over the first 4 years. No stratified effects were revealed by the BMI group and age. Conclusions: High and stable BMI in late life could predict better cognitive trajectory and lower risk of AD. Show more
Keywords: Alzheimer’s disease, amyloid-β, body mass index, cognitive, late life, trajectory
DOI: 10.3233/JAD-240292
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Wang, Wan | Gong, Zhenping | Wang, Yadan | Zhao, Ying | Lu, Yaru | Sun, Ruihua | Zhang, Haohan | Shang, Junkui | Zhang, Jiewen
Article Type: Research Article
Abstract: Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic …kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy. Show more
Keywords: Alzheimer’s disease, autophagy, CADASIL, mitochondrial dysfunction, NOTCH3ECD mutation, mitophagy
DOI: 10.3233/JAD-240273
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Rosen, Allyson C. | Lavacot, James A. | Klee, Victoria | Luria, Yuval | Rumbaugh, Malia
Article Type: Review Article
Abstract: Ethics Review began a decade ago with a mission to identify ethical concerns that hold back innovation and to promote solutions that would move the field forward. Over this time, blood biomarkers for brain pathology and medications that treat that pathology promise to transform research and care. A central problem is that the evidence needed to guide test interpretation and practice is accumulating and there are unanswered questions. At the same time, people living with and at risk for dementia want access to their test results and involvement in their care. We promote dialog among diverse people across many institutions …through collaboration with the Advisory Group on Risk Evidence Education for Dementia (AGREEDementia.org). Over the years Ethics Review continues to publish these dialogs and solutions to overcome the paralysis of indecision and ethical concerns. Show more
Keywords: Alzheimer’s disease, amyloid-beta, blood biomarker, diagnostics, ethics
DOI: 10.3233/JAD-240634
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2024
Authors: Pickert, Lena | Dias, Irundika H.K. | Thimm, Alexander | Weber, Johann | Abdullah, Sewa | Deelen, Joris | Polidori, M. Cristina
Article Type: Research Article
Abstract: Background: Among preventive strategies against dementia, nutrition is considered a powerful one and the recently established “nutritional cognitive neuroscience of aging” is a highly active research field. Objective: The present study was designed to deeply characterize older adults across the continuum from cognitive integrity to mild cognitive impairment (MCI) and better elucidate the prognostic role of lipophilic micronutrients within their lipidomic signature. Methods: 123 participants older than 65 years across the continuum from cognitive integrity to MCI were included [49 with subjective cognitive impairment, 29 women, 72.5±5.4 years, 26 MCI, 9 women, 74.5±5.8 years and 50 …without cognitive impairment, 21 women, 70.8±4.3 years]. All participants underwent neuropsychological and nutritional examination as well as comprehensive geriatric assessment with calculation of the Multidimensional Prognostic Index (MPI) as a proxy of frailty and biological age and blood withdrawal for the analyses of lipophilic micronutrients, metabolomics and oxylipidomics. One year after the evaluation, same tests are ongoing. Results: After adjustment for age, sex, daily fruit and vegetable intake and cholesterol, we found a significant positive correlation between lutein and the number of correct words in category fluency (p = 0.016). Conclusions: This result supports the importance of carotenoids as robust biomarkers of cognitive performance independent of the nutritional status and frailty of the participants, as the entire present study collective was robust (MPI 0–0.33). The complete analyses of the metabolome and the oxylipidome will hopefully shed light on the metabolic and prognostic signature of cognitive decline in the rapidly growing population at risk of frailty. Show more
Keywords: Alzheimer’s disease, frailty, micronutrients, mild cognitive impairment, subjective cognitive impairment
DOI: 10.3233/JAD-240654
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Leng, Fangda | Hinz, Rainer | Gentleman, Steve | Dani, Melanie | Brooks, David J. | Edison, Paul
Article Type: Research Article
Abstract: Background: Neuroinflammation in Alzheimer’s disease is known as an important process in the disease, yet how microglial activation affects disease progression remains unclear. Objective: The current study aims to interrogate the predictive value of neuroinflammation biomarker (11 C-PBR28 PET), together with A/T/N imaging markers on disease deterioration in a cognitively impaired patient cohort. Methods: The study included 6 AD and 27 MCI patients, who had MRI, 11 C-PBR28, 18 F-flutemetamol (amyloid marker), 18 F-AV1451 (tau marker) PET scans, and were followed up with multiple neuropsychological assessments for at least one year (1.6 and 2.8 years on …average for AD and MCI). The predictive values of imaging biomarkers on baseline and longitudinal cognition were interrogated using linear regression to identify the biomarkers that could explain disease progression. Results: Linear mixed models found the average intercepts (baseline) MMSE were 23.5 for AD and 28.2 for MCI patients, and the slope of MMSE (annual change) were –0.74 for AD and –0.52 for MCI patients. White matter microstructural integrity was predictive of baseline cognition, while PET markers of amyloid, tau and neuroinflammation were predictive of longitudinal cognitive decline. Both amyloid and neuroinflammation PET markers were predictors independent of each other. And a sub-group analysis showed the predictive effect of neuroinflammation on cognitive decline is independent of amyloid and tau. Conclusions: Our study highlights the prognostic value of disease specific markers (amyloid, tau and neuroinflammation) in clinically diagnosed AD and MCI patients and suggests that the effects of these molecular markers are mediated by structural damage to the brain. Show more
Keywords: Alzheimer’s disease, 11C-PBR28, mild cognitive impairment, neuroinflammation, positron emission tomography
DOI: 10.3233/JAD-230442
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Ferrer, Isidro
Article Type: Review Article
Abstract: Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity …progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging. Show more
Keywords: Alzheimer’s disease, amyloid-β , brain aging, primates, tau
DOI: 10.3233/JAD-240389
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Butterfield, D. Allan
Article Type: Review Article
Abstract: Activation of cell-cycle machinery in Alzheimer’s disease (AD) brain was reported by Mark Smith and colleagues and by other researchers. Among other biochemical processes underlying this activation, the notion that AD brain, under the onslaught of oxidative and nitrosative damage leading to neuronal loss, neurons would attempt to replenish their numbers by entering the cell cycle. However, being post-mitotic, neurons entering the cell cycle would become trapped therein, ultimately leading to death of these neurons. Yang and co-workers and the Butterfield laboratory first reported that similar activation of the cell cycle was present in the brains of individuals with amnestic …mild cognitive impairment (MCI), arguably the earliest clinical stage of AD, but who demonstrate normal activities of daily living and no dementia. Activation of the cell cycle in MCI brain is consonant with the concept that this process is an early aspect in the progression of AD. This brief review article discusses these findings and recognizes the contribution of Dr. Mark Smith to the investigation of cell-cycle activation in AD brain and other aspects of AD neuropathology. Show more
Keywords: Alzheimer’s disease, cell-cycle activation, mild cognitive impairment, oxidative damage, Pin1
DOI: 10.3233/JAD-240615
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2024
Authors: Mandal, Pravat K. | Maroon, Joseph C. | Samkaria, Avantika | Arora, Yashika | Sharma, Shallu | Pandey, Ashutosh
Article Type: Research Article
Abstract: Alzheimer’s disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-β (Aβ) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aβ plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate …of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research. Show more
Keywords: Alzheimer’s disease, clinical trials, iron-chelator, iron overload, oxidative stress, prooxidant
DOI: 10.3233/JAD-240605
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2024
Authors: Perry, George
Article Type: Introduction
DOI: 10.3233/JAD-249015
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2024
Authors: Rodini, Marta | Bonarota, Sabrina | Serra, Laura | Caltagirone, Carlo | Carlesimo, Giovanni Augusto
Article Type: Research Article
Abstract: Background: Recently, subjective cognitive decline (SCD) was proposed as an early risk factor for future Alzheimer’s disease (AD). Objective: In this study, we investigated whether accelerated long-term forgetting (ALF), assessed with extended testing intervals than those adopted in clinical practice, might be a cognitive feature of SCD. Using an explorative MRI analysis of the SCD sample, we attempted to investigate the areas most likely involved in the ALF pattern. Methods: We recruited 31 individuals with SCD from our memory clinic and subdivided them based on their rate of memory complaints into mild SCDs (n = 18) …and severe SCDs (n = 13). A long-term forgetting procedure, involving the recall of verbal and visuo-spatial material at four testing delays (i.e., immediate, 30 min, 24 h, and 7 days post-encoding) was used to compare the two sub-groups of SCDs with a healthy control group (HC; n = 16). Results: No significant between-group difference was found on the standard neuropsychological tests, nor in the immediate and 30 min recall of the experimental procedure. By contrast, on the verbal test severe SCDs forgot significantly more than HCs in the prolonged intervals (i.e., 24 h and 7 days), with the greatest decline between 30 min and 24 h. Finally, in the whole SCD sample, we found significant associations between functional connectivity values within some cortical networks involved in memory (default mode network, salience network, and fronto-parietal network) and verbal long-term measures. Conclusions: Our preliminary findings suggest that long-term forgetting procedures could be a sensitive neuropsychological tool for detecting memory concerns in SCDs, contributing to early AD detection. Show more
Keywords: Accelerated long-term forgetting, Alzheimer’s disease, functional connectivity, subjective cognitive decline
DOI: 10.3233/JAD-240218
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Avila, Jesús
Article Type: Short Communication
Abstract: Aging is the main risk for neurodegenerative disorders like Alzheimer’s disease. In this short review, I will comment on how delaying brain aging through the addition of Yamanaka Factors or small compounds that bind to the folate receptor alpha, which promote the expression of the Yamanaka Factors or by the decrease tau levels in brain cells from older subjects could serve as strategies to prevent Alzheimer’s disease.
Keywords: Aging, Alzheimer’s disease, tau protein, therapies
DOI: 10.3233/JAD-240500
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2024
Authors: Liu, Yan | Xu, Weiyue | Yang, Pan | Liu, Xingshun
Article Type: Research Article
Abstract: Background: Various virus infections are known to predispose to Alzheimer’s disease (AD), and a linkage between COVID-19 and AD has been established. COVID-19 infection modulates the gene expression of the genes implicated in progression of AD. Objective: Determination of molecular patterns and codon usage and context analysis for the genes that are modulated during COVID-19 infection and are implicated in AD was the target of the study. Methods: Our study employed a comprehensive array of research methods, including relative synonymous codon usage, Codon adaptation index analysis, Neutrality and parity analysis, Rare codon analyses, and codon context …analysis. This meticulous approach was crucial in determining the molecular patterns present in genes up or downregulated during COVID-19 infection. Results: G/C ending codons were preferred in upregulated genes while not in downregulated genes, and in both gene sets, longer genes have high expressivity. Similarly, T over A nucleotide was preferred, and selection was the major evolutionary force in shaping codon usage in both gene sets. Apart from stops codons, codons CGU – Arg, AUA – Ile, UUA – Leu, UCG – Ser, GUA – Val, and CGA – Arg in upregulated genes, while CUA – Leu, UCG – Ser, and UUA – Leu in downregulated genes were present below the 0.5%. Glutamine-initiated codon pairs have high residual values in upregulated genes. Identical codon pairs GAG-GAG and GUG-GUG were preferred in both gene sets. Conclusions: The shared and unique molecular features in the up- and downregulated gene sets provide insights into the complex interplay between COVID-19 infection and AD. Further studies are required to elucidate the relationship of these molecular patterns with AD pathology. Show more
Keywords: Alzheimer’s disease, codon context, codon usage, COVID-19, relative synonymous codon usage
DOI: 10.3233/JAD-240609
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Leinenga, Gerhard | Padmanabhan, Pranesh | Götz, Jürgen
Article Type: Review Article
Abstract: Alzheimer’s disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer’s disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. …They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions. Show more
Keywords: Alzheimer’s disease, amyloid-β, behavior, focused ultrasound, Fyn kinase, immunotherapy, neuromodulation, scanning ultrasound, tau
DOI: 10.3233/JAD-240616
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Liu, Yanchao | He, Benrong | Du, Kai | Zheng, Jie | Ke, Dan | Mo, Wen | Li, Yanni | Jiang, Tao | Xiong, Rui | Sun, Fei | Zhao, Shi | Wei, Wei | Xu, Zhipeng | Zhang, Shujuan | Li, Shihong | Wang, Xin | Zhou, Qiuzhi | Ye, Jinwang | Liang, Yi | Lin, Hao | Liu, Yong | Chen, Liangkai | Zhang, Huaqiu | Zhang, Yao | Gao, Yang | Wang, Jian-Zhi
Article Type: Research Article
Abstract: Background: The prevalence of Alzheimer’s disease (AD) is increasing, therefore, identifying biomarkers to predict those vulnerable to AD is imperative. Type 2 diabetes (T2D) serves as an independent risk factor for AD. Early prediction of T2D patients who may be more susceptible to AD, so as to achieve early intervention, is of great significance to reduce the prevalence of AD. Objective: To establish periphery biomarkers that could predict conversion of T2D into pre-AD-like cognitive decline. Methods: A follow-up study was carried out from 159 T2D patients at baseline. The correlations of cognitive states (by MMSE score) …with multi-periphery biomarkers, including APOE genotype, plasma amyloid-β level, platelet GSK-3β activity, and olfactory score were analyzed by logistic regression. ROC curve was used for establishing the prediction model. Additionally, MRI acquired from 38 T2D patients for analyzing the correlation among cognitive function, biomarkers and brain structure. Results: Compared with the patients who maintained normal cognitive functions during the follow-up period, the patients who developed MCI showed worse olfactory function, higher platelet GSK-3β activity, and higher plasma Aβ42 /Aβ40 ratio. We conducted a predictive model which T2D patients had more chance of suffering from pre-AD-like cognitive decline. The MRI data revealed MMSE scores were positively correlated with brain structures. However, platelet GSK-3β activity was negatively correlated with brain structures. Conclusions: Elevated platelet GSK-3β activity and plasma Aβ42 /Aβ40 ratio with reduced olfactory function are correlated with pre-AD-like cognitive decline in T2D patients, which used for predicting which T2D patients will convert into pre-AD-like cognitive decline in very early stage. Show more
Keywords: Alzheimer’s disease, biomarker, brain structure, mild cognitive impairment, prediction model, type 2 diabetes
DOI: 10.3233/JAD-240455
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Lee, Jae-Hong | Jia, Jianping | Ji, Yong | Kandiah, Nagaendran | Kim, SangYun | Mok, Vincent | Pai, Ming-Chyi | Senanarong, Vorapun | Suh, Chong Hyun | Chen, Christopher
Article Type: Review Article
Abstract: Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer’s disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek …diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients. Show more
Keywords: Alzheimer’s disease, amyloid-β, Asia, best practice, mild cognitive impairment
DOI: 10.3233/JAD-240684
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Boccardi, Virginia | Ruggiero, Carmelinda | Cecchetti, Roberta | Mecocci, Patrizia
Article Type: Editorial
Abstract: Aging is associated with a gradual decline in cellular stability, leading to a decrease in overall health. In the brain, this process is closely linked with an increased risk of neurodegenerative diseases, including Alzheimer’s disease. Understanding the mechanisms of brain aging is crucial for developing strategies aimed at enhancing both lifespan and health span. Recent advancements in geroscience, the study of the relationship between aging and age-related diseases, have begun to redefine our understanding of Alzheimer’s disease, guiding the development of preventive medical strategies that target the aging process itself rather than merely addressing the symptomatic manifestations of the disease.
Keywords: Aging, Alzheimer’s disease, geroscience, healthspan, longevity
DOI: 10.3233/JAD-240582
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2024
Authors: Wang, Wenzhang | Zhao, Fanpeng | Torres, Sandy | Harris, Peggy L.R. | Wang, Xinglong | Peng, Lihua | Siedlak, Sandra L. | Zhu, Xiongwei
Article Type: Research Article
Abstract: Background: Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer’s disease following space travel. Objective: In this study, we investigated the effects of irradiation by 56 Fe and 28 Si in CRND8 mice, an Alzheimer’s disease mouse model. Methods: Six-month-old CRND8 mice were exposed to whole body irradiation by 56 Fe and 28 Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiatio. …Results: The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56 Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28 Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction. Conclusions: Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models. Show more
Keywords: Alzheimer’s disease, microglia, PCNA, senescence, space radiation
DOI: 10.3233/JAD-240570
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
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