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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: 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: Wu, Yaxuan | Tan, Ming | Gao, Yanling | Geng, Na | Zhong, Weibin | Sun, Hairong | Li, Zhenguang | Wu, Chenxi | Li, Xuemei | Zhang, Jinbiao
Article Type: Research Article
Abstract: Background: The complement system plays crucial roles in cognitive impairment and acute ischemic stroke (AIS). High levels of complement proteins in plasma astrocyte-derived exosomes (ADEs) were proven to be associated with Alzheimer’s disease. We aimed to investigate the relationship of complement proteins in serum ADEs with poststroke cognitive impairment in type 2 diabetes mellitus (T2DM) patients. Methods: This study analyzed 197 T2DM patients who suffered AIS. The Beijing version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. Complement proteins in serum ADEs were quantified using ELISA kits. Results: Mediation analyses showed that …C5b-9 and C3b in serum ADEs partially mediate the impact of obstructive sleep apnea (OSA), depression, small vessel disease (SVD), and infarct volume on cognitive function at the acute phase of AIS in T2DM patients. After adjusting for age, sex, time, and interaction between time and complement proteins in serum ADEs, the mixed linear regression showed that C3b and complement protein Factor B in serum ADEs were associated with MoCA scores at three-, six-, and twelve-months after AIS in T2DM patients. Conclusions: Our study suggested that the impact of OSA, depression, SVD, and infarct volume on cognitive impairment in the acute stage of AIS may partially mediate through the complement proteins in serum ADEs. Additionally, the complement proteins in serum ADEs at the acute phase of AIS associated with MoCA scores at three-, six-, twelve months after AIS in T2DM patients. REGISTRATION: URL: http://www.chictr.org.cn/,ChiCTR1900021544 Show more
Keywords: Keywords: Alzheimer’s disease, astrocyte-derived exosomes, complement proteins, post stroke cognitive impairment, type 2 diabetes mellitus
DOI: 10.3233/JAD-231235
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Huang, Zhen
Article Type: Review Article
Abstract: Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aβ and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aβ-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer’s disease (AD). Specifically, I discuss evidence that Aβ and ApoE, two crucial players …in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aβ and inhibiting its assembly into toxic oligomers. Conversely, Aβ oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of “eat-me” signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aβ-orchestrated plasticity, in which sleep is not only induced by Aβ but is also required for Aβ-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research. Show more
Keywords: Alzheimer’s disease, amyloid-β, ApoE, dendritic spine, DNA damage repair, homeostatic plasticity, mGluR5, phosphatidylserine, sleep, synaptic competition
DOI: 10.3233/JAD-240042
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2024
Authors: Cetinsoy, Ozde | Anyanwu, Ijeoma | Krishnanand, Harikrishnan | Natarajan, Gokulakrishnan | Ramachandran, Naveen | Thomas, Alan | Brookes, Keeley J.
Article Type: Research Article
Abstract: Background: The role of the innate immune system has long been associated with Alzheimer’s disease (AD). There is now accumulating evidence that the soluble Urokinase Plasminogen Activator Receptor pathway, and its genes, PLAU and PLAUR may be important in AD, and yet there have been few genetic association studies to explore this. Objective: This study utilizes the DNA bank of the Brains for Dementia Research cohort to investigate the genetic association of common polymorphisms across the PLAU and PLAUR genes with AD. Methods: TaqMan genotyping assays were used with standard procedures followed …by association analysis in PLINK. Results: No association was observed between the PLAU gene and AD; however, two SNPs located in the PLAUR gene were indicative of a trend towards association but did not surpass multiple testing significance thresholds. Conclusions: Further genotyping studies and exploration of the consequences of these SNPs on gene expression and alternative splicing are warranted to fully uncover the role this system may have in AD. Show more
Keywords: Alzheimer’s disease, association, BDR, innate immune system, PLAUR , PLAU , suPAR
DOI: 10.3233/JAD-231383
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Kim, Minjae | Song, Yoo Sung | Han, Kyunghwa | Bae, Yun Jung | Han, Ji Won | Kim, Ki Woong
Article Type: Research Article
Abstract: Background: Impaired glymphatic flow on the Alzheimer’s disease (AD) spectrum may be evaluated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Objective: We aimed to validate impaired glymphatic flow and explore its association with gray matter volume, cognitive status, and cerebral amyloid deposition on the AD spectrum. Methods: 80 participants (mean age, 76.9±8.5 years; 57 women) with AD (n = 65) and cognitively normal (CN) (n = 15) who underwent 3T brain MRI including DTI and/or amyloid PET were included. After adjusting for age, sex, apolipoprotein E status, and burden of white matter hyperintensities, the ALPS-index …was compared according to the AD spectrum. The association between the ALPS-index and gray matter volume, cognitive status, and quantitative amyloid from PET was assessed. Results: The ALPS-index in the AD was significantly lower (mean, 1.476; 95% CI, 1.395–1.556) than in the CN (1.784;1.615–1.952; p = 0.026). Volumes of the entorhinal cortex, hippocampus, temporal pole, and primary motor cortex showed significant associations with the ALPS-index (all, p < 0.05). There was a positive correlation between the ALPS-index and MMSE score (partial r = 0.435; p < 0.001), but there was no significant correlation between the ALPS-index and amyloid SUVRs (all, p > 0.05). Conclusions: Decreased glymphatic flow measured by DTI-ALPS in AD may serve as a marker of neurodegeneration correlating with structural atrophy and cognitive decline. Show more
Keywords: Alzheimer’s disease, amyloid PET, diffusion tensor, g;ymphatic function, volumetry
DOI: 10.3233/JAD-231131
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Duff, Kevin | Hammers, Dustin B. | Koppelmans, Vincent | King, Jace B. | Hoffman, John M.
Article Type: Research Article
Abstract: Background: Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) remain understudied, especially with how they compare to biomarkers of AD. Objective: The current study sought to add to this growing literature. Methods: Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 …status. Results: The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons. Conclusion: Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted. Show more
Keywords: Alzheimer’s disease, amyloid, biomarkers, brain imaging, effect sizes, mild cognitive impairment, neuropsychological testing, practice effects
DOI: 10.3233/JAD-231392
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Peng, Lang | Xiang, Qingwei | Zhou, Yong | Yin, Renyi
Article Type: Research Article
Abstract: Background: The joint associations of handgrip strength (HGS) weakness and asymmetry with cognitive decline remain understudied in older adults. Objective: To investigate the associations between HGS weakness, asymmetry, and lower cognitive function in a nationally representative sample of older Americans. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey 2011–2014. Weakness was defined as HGS <26 kg for men and <16 kg for women. Asymmetry was determined by calculating the ratio of dominant to non-dominant HGS. Participants with an HGS ratio <0.90 or >1.10 were classified as having any HGS …asymmetry. Those with an HGS ratio >1.10 exhibited dominant HGS asymmetry, while those with an HGS ratio <0.90 displayed nondominant HGS asymmetry, respectively. Lower cognitive functioning was defined as global cognitive composite scores more than 1 standard deviation below the mean. Covariate-adjusted logistic regression models were used to analyze the associations between HGS asymmetry/weakness and lower cognitive functioning. Results: Compared to individuals with non-weak and symmetric HGS, those with any HGS asymmetry alone and weakness alone had 1.017 (95% confidence interval [CI]: 0.707–1.463) and 1.391 (95% CI: 0.542–3.571) greater odds for cognitive decline, while co-occurrence of both HGS asymmetry and weakness was associated with 3.724 (95% CI: 1.711–8.107) greater odds for lower cognitive function after controlling for confounders. Cnclusions: Individuals exhibiting both diminished and asymmetrical HGS demonstrated an elevated susceptibility to cognitive impairment, thereby implying that the inclusion of HGS asymmetry assessment in conjunction with weakness evaluation may enhance the accuracy of prognosticating cognitive decline. Show more
Keywords: Alzheimer’s disease, cognitive dysfunction, cross-sectional study, geriatrics, handgrip strength
DOI: 10.3233/JAD-231375
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Butler, Tracy | Wang, Xiuyuan | Chiang, Gloria | Xi, Ke | Niogi, Sumit | Glodzik, Lidia | Li, Yi | Razlighi, Qolamreza Ray | Zhou, Liangdong | Hojjati, Seyed Hani | Ozsahin, Ilker | Mao, Xiangling | Maloney, Thomas | Tanzi, Emily | Rahmouni, Nesrine | Tissot, Cécile | Lussier, Firoza | Shah, Sudhin | Shungu, Dikoma | Gupta, Ajay | De Leon, Mony | Mozley, P. David | Pascoal, Tharick | Rosa-Neto, Pedro
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem …in 71 subjects (43 controls scanned using 11 C-PK11195; 20 controls and 8 AD subjects scanned using 11 C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004) In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD—an opposite pattern than in cortex—highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed. Show more
Keywords: Alzheimer’s disease, inferior colliculus, inflammation, neuroinflammation, reticular formation, TSPO PET
DOI: 10.3233/JAD-231312
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Kim, Donghyun | Jamrasi, Parivash | Li, Xinxing | Ahn, Soyoung | Sung, Yunho | Ahn, Seohyun | Kang, Yuseon | Song, Wook
Article Type: Research Article
Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been demonstrated to have high diagnostic accuracy in differentiating Alzheimer’s disease (AD) patients from healthy individuals. However, it is yet unclear whether exercise can lower the level of AD7c-NTP in urine among active Korean elderly. Objective: To assess the effect of exercise on AD7c-ntp levels in urine and cognitive function among active Korean elderly. Methods: In total, 40 Korean elderly (≥65 years) were divided into Active Control group (CG, n = 10), Aerobic exercise group (AG, n = 18), and combined Resistance/Aerobic exercise group (RAG, n = 12). A total of 12 …weeks of exercise intervention was implemented. At week 0 and 12, cognitive performance (Korean Mini-Mental State Examination, Korean-Color Word Stroop test), grip strength, and body composition (muscle mass and body fat percentage) were measured. Also, a morning urine sample was obtained from each subject. The level of AD7c-NTP was measured using competitive enzyme-linked immunosorbent assay (ELISA). Results: After 12 weeks of exercise intervention, there was a significant difference of AD7c-NTP levels between RAG and CG (p = 0.026), AG and CG (p = 0.032), respectively. Furthermore, the AD7c-NTP levels in urine showed negative correlation with K-MMSE scores (r = –0.390, p = 0.013) and grip strength (r = –0.376, p = 0.017), among all participants after exercise intervention. Conclusions: This is the first study to investigate urine biomarker through exercise intervention. In future stuides, participants who have low cognitive function and low activity levels need to be recruited to observe more significant ‘Exercise’ effect. Show more
Keywords: AD7C-NTP, Alzheimer’s disease, cognitive function, exercise, urine biomarker
DOI: 10.3233/JAD-230946
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Thomas, Kelsey R. | Clark, Alexandra L. | Weigand, Alexandra J. | Edwards, Lauren | Durazo, Alin Alshaheri | Membreno, Rachel | Luu, Britney | Rantins, Peter | Ly, Monica T. | Rotblatt, Lindsay J. | Bangen, Katherine J. | Jak, Amy J.
Article Type: Research Article
Abstract: Background: Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer’s disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. Objective: This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. Methods: Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline …characteristics as well as 1-year changes in everyday functioning and global cognition. Results: The cluster analysis identified 3 groups. Group 1 (n = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. CONCLUSIONS: Psychiatric and health factors likely contributed to Group 2’s low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans’ co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans. Show more
Keywords: Alzheimer’s disease, amyloid, cognition, phenotypes, PTSD, Veterans
DOI: 10.3233/JAD-240077
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Marr, Calum | McDowell, Bethany | Holmes, Clive | Edwards, Christopher J. | Cardwell, Christopher | McHenry, Michelle | Meenagh, Gary | Teeling, Jessica L. | McGuinness, Bernadette
Article Type: Research Article
Abstract: Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer’s disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the …primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = –1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = –0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention. Show more
Keywords: Alzheimer’s disease, inflammation, mild cognitive impairment, rheumatoid arthritis, tumor necrosis factor-alpha
DOI: 10.3233/JAD-231329
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Morrow, Christopher B. | Pontone, Gregory M.
Article Type: Article Commentary
Abstract: The following commentary discusses a review by Cressot et al. entitled: ‘Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review’. The authors describe the epidemiology and phenomenology of psychosis across neurodegenerative dementias. Dementia with Lewy bodies had the highest reported prevalence of psychosis at 74% followed by Alzheimer’s disease, 54% and frontotemporal degeneration, 42% . Detailed characterization of psychosis shows differences in the types of hallucinations and delusions by dementia type. These findings suggest that different types of dementia related pathology are associated with high rates of psychosis with more specific symptom profiles than previously appreciated. Understanding the differences and variety …of psychotic experiences across dementia types may have diagnostic and therapeutic implications for treating hallucinations and delusions in populations suffering from neurodegenerative diseases. Show more
Keywords: Alzheimer’s disease, delusions, dementia, dementia with Lewy bodies, frontotemporal dementia, hallucinations, neurodegeneration, psychosis
DOI: 10.3233/JAD-240328
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: Um, Yoo Hyun | Wang, Sheng-Min | Kang, Dong Woo | Kim, Sunghwan | Lee, Chang Uk | Kim, Donghyeon | Choe, Yeong Sim | Kim, Regina E.Y. | Lee, Soyoung | Lee, Min-Kyung | Lim, Hyun Kook
Article Type: Research Article
Abstract: Background: Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer’s disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4 ). Objective: This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition. Methods: A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC …discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values. Results: The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. Conclusions: These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies. Show more
Keywords: Alzheimer’s disease, apolipoprotein E4, functional connectivity, locus coeruleus, preclinical
DOI: 10.3233/JAD-240065
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: García-Carlos, Carlos Antonio | Basurto-Islas, Gustavo | Perry, George | Mondragón-Rodríguez, Siddhartha
Article Type: Research Article
Abstract: Background: Cognitive deficits observed in Alzheimer’s disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive study, neurofibrillary tangles and amyloid plaques have been proposed as responsible for brain activity alterations. Aiming to unveil the mechanism, researchers have developed several transgenic models of AD. Nevertheless, the variability in hippocampal oscillatory alterations found in different genetic backgrounds and ages remains unclear. Objective: To assess the oscillatory alterations in relation to animal developmental age and protein inclusion, amyloid-β (Aβ) load, and abnormally phosphorylated tau (pTau), we reviewed and analyzed the published data on peak …power, frequency, and quantification of theta-gamma cross-frequency coupling (modulation index values). Methods: To ensure that the search was as current as possible, a systematic review was conducted to locate and abstract all studies published from January 2000 to February 2023 that involved in vivo hippocampal local field potential recording in transgenic mouse models of AD. Results: The presence of Aβ was associated with electrophysiological alterations that are mainly reflected in power increases, frequency decreases, and lower modulation index values. Concomitantly, pTau accumulation was associated with electrophysiological alterations that are mainly reflected in power decreases, frequency decreases, and no significant alterations in modulation index values. Conclusions: In this study, we showed that electrophysiological parameters are altered from prodromal stages to the late stages of pathology. Thus, we found that Aβ deposition is associated with brain network hyperexcitability, whereas pTau deposition mainly leads to brain network hypoexcitability in transgenic models Show more
Keywords: Alzheimer’s disease, amyloid-β, cross-frequency coupling, hippocampus, network hyperexcitability, network hypoexcitability, oscillatory activity, phospho-tau
DOI: 10.3233/JAD-231365
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Ngo, Sang | Jackson, Ashley J. | Manivannan, Madhumitha | Young, J. Clayton | Leggins, Brandon | Cryns, Noah G. | Tran, Sheila T. | Grant, Harli E. | Knudtson, Marguerite V. | Chiong, Winston
Article Type: Research Article
Abstract: Background: Whereas clinical experience in dementia indicates high risk for financial mismanagement, there has been little formal study of real world financial errors in dementia. Objective: We aimed to compare caregiver-reported financial mistakes among people with Alzheimer’s disease, behavioral variant frontotemporal dementia (bvFTD), and primary progressive aphasia (PPA). Methods: Caregivers reported whether participants with dementia had made financial mistakes within the last year; and if so, categorized these as resulting from: (a) being too trusting or gullible, (b) being wasteful or careless with money, or (c) trouble with memory. In a pre-registered analysis https://archive.org/details/osf-registrations-vupj7-v1 ), we …examined the hypotheses that (1) financial mistakes due to impaired socioemotional function and diminished sensitivity to negative outcomes are more prevalent in bvFTD than in Alzheimer’s disease, and (2) financial mistakes due to memory are more prevalent in Alzheimer’s disease than in bvFTD. Exploratory analyses addressed vulnerability in PPA and brain-behavior relationships using voxel-based morphometry. Results: Concordant with our first hypothesis, bvFTD was more strongly associated than Alzheimer’s disease with mistakes due to being too trusting/gullible or wasteful/careless; contrary to our second hypothesis, both groups were similarly likely to make mistakes due to memory. No differences were found between Alzheimer’s disease and PPA. Exploratory analyses indicated associations between financial errors and atrophy in right prefrontal and insular cortex. Conclusions: Our findings cohere with documented socioemotional and valuation impairments in bvFTD, and with research indicating comparable memory impairment between bvFTD and Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, decision making, financial activities, financial management, frontotemporal dementia, primary progressive aphasia
DOI: 10.3233/JAD-231021
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Scharf, Annelie | Kleinke, Fabian | Michalowsky, Bernhard | Rädke, Anika | Pfitzner, Stefanie | Mühlichen, Franka | Buchholz, Maresa | van den Berg, Neeltje | Hoffmann, Wolfgang
Article Type: Research Article
Abstract: Background: The healthcare needs of People living with Dementia (PlwD) (such as Alzheimer’s disease) are often unmet. Information about the needs of community-dwelling PlwD and their association with sociodemographic and clinical characteristics is needed to fill the knowledge gap regarding factors influencing unmet needs among PlwD and to conduct a comprehensive needs assessment to develop tailored interventions. Objective: To describe sociodemographic and clinical characteristics of the InDePendent study population with particular reference to determinants of unmet needs. Methods: We analyzed baseline data of the multi-centre cluster-randomized controlled trial (InDePendent) using descriptive statistics to describe patients’ sociodemographic …and clinical characteristics and Poisson regression models to predict unmet needs, separated by sex. Data were collected personally via face-to-face interviews. Results: Most of the n = 417 participating PlwD were mild to moderately cognitively impaired, were not depressed, had an average of 10.8 diagnoses, took 6.7 medications, and had, on average, 2.4 unmet needs (62% of PlwD had at least one unmet need) measured by the Camberwell Assessment of Need for the Elderly (CANE). Low social support, a high body-mass-index, a lower education, functional impairment, and worse health status were associated with more unmet needs, regardless of sex. In women, higher unmet needs were associated with more depressive symptoms, a poor financial situation, living alone and not being recently treated by a general practitioner. In males, unmet needs increased with the number of medications taken. Conclusions: PlwD had a broad array of unmet healthcare needs, indicating primary healthcare provision improvement potentials. The results underscore the significance of early assessment of patient’s clinical characteristics and unmet needs as a basis for individualized gender-sensible intervention strategies.∥ClinicalTrials.gov Identifier: NCT04741932, Registered on February 5, 2021 Show more
Keywords: KeywordsAlzheimer’s disease, Camberwell Assessment of Need for the Elderly (CANE), dementia, elderly population, health services research, needs assessment, people with dementia, primary care, randomized controlled trial
DOI: 10.3233/JAD-231173
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Miller, Morgan R. | Lariviere, Lavender | Pagnier, Guillaume J. | Aygar, Sema | Wieckiewic, Natalia | Maesako, Masato | Bacskai, Brian J. | Kastanenka, Ksenia V.
Article Type: Short Communication
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease with limited therapeutic strategies. NB-02 is a novel botanical drug that has shown promise as a protective and therapeutic treatment for AD in an APP/PS1 preclinical mouse model. In this paper, we investigate the underlying mechanisms by which NB-02 provides these therapeutic advantages using in vitro neuron-astrocyte co-cultures. Pretreatment with NB-02 prevented pathological calcium elevations in neurons and astrocytes after application of toxic soluble amyloid-β (Aβ) oligomers. NB-02 also prevented cell death associated with the addition of soluble Aβ oligomers suggesting NB-02 is effective at protecting both neurons and astrocytes from …Aβ-mediated damage. Show more
Keywords: Alzheimer’s disease, amyloid, astrocyte, calcium, DA-9803, NB-02, neuron, oligomer, therapy
DOI: 10.3233/JAD-231387
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2024
Authors: Liu, Mengqing | Ma, Nenghong | Yang, Xiao | Sun, Miao | Li, Xiaowen | Liu, Yuhui | Chang, Qing | Hei, Changchun
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. Objective: This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-β (Aβ) metabolism in vitro . …Methods: In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aβ. Results: Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro . Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aβ. Conclusions: GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD. Show more
Keywords: Aging, Alzheimer’s disease, amyloid-β, glucagon-like peptide-1 (GLP-1), tau protein phosphorylation
DOI: 10.3233/JAD-240001
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-09, 2024
Authors: Libard, Sylwia | Hodik, Monika | Cesarini, Kristina Giuliana | Dragomir, Anca | Alafuzoff, Irina
Article Type: Research Article
Abstract: Background: Amyloid-β (Aβ) is one of the hallmark lesions of Alzheimer’s disease (AD). During the disease process, Aβ undergoes biochemical changes, producing toxic Aβ variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aβ variants in their brain biopsies, obtained during shunting. Objective: To study the cellular compartmentalization of different Aβ variants in brain biopsies from iNPH subjects. Methods: We studied the cellular localization of different …proteoforms of Aβ using antibodies towards different amino acid sequences or post-translational modifications of Aβ, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aβ and Aβ protein precursor (AβPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). Results: In LM all Aβ variants were detected. In LMst and EM, the Aβ 4G8, 6F/3D, and the pyroglutamylated Aβ were detected. The AβPP was visualized by all methods. The Aβ labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AβPP was seen both intra- and extracellularly. Conclusions: The Aβ markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aβ in the human brain. No intracellular Aβ pathology was seen. AβPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles. Show more
Keywords: Alzheimer’s disease, Alzheimer’s disease neuropathological change, amyloid-β, idiopathic normal pressure hydrocephalus
DOI: 10.3233/JAD-240167
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Duran, Tugce | Gaussoin, Sarah A. | Latham, Lauren A. | Rundle, Melissa M. | Espeland, Mark A. | Williams, Benjamin J. | Hughes, Timothy M. | Craft, Suzanne | Sachs, Bonnie C. | Bateman, James R. | Lockhart, Samuel N.
Article Type: Research Article
Abstract: Background: The preclinical Alzheimer’s cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-β. Methods: We …examined 648 participants’ neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-β deposition. Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, amyloid-beta, cognitive composite, cognitive decline, MRI, PET, reliability, telehealth testing
DOI: 10.3233/JAD-231435
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Bulycheva, Irina | Watanabe, Yumi | Kitamura, Kaori | Kabasawa, Keiko | Saito, Toshiko | Takahashi, Akemi | Kobayashi, Ryosaku | Oshiki, Rieko | Takachi, Ribeka | Tsugane, Shoichiro | Yamazaki, Osamu | Watanabe, Kei | Nakamura, Kazutoshi
Article Type: Research Article
Abstract: Background: Sleep is a potentially modifiable factor associated with dementia, including Alzheimer’s disease, but current evidence supporting this is insufficient. Objective: This study aimed to determine whether sleep duration and bedtime patterns are associated with the risk of dementia among middle-aged and older people. Methods: This cohort study had an eight-year follow-up period. Participants were 13,601 community-dwelling people aged 40–74 years living in Murakami (Niigata, Japan). Data were collected using a self-administered questionnaire. Predictors were self-reported sleep duration and bedtime, and the outcome was newly-diagnosed dementia determined using the long-term care insurance database. Covariates were demographic …characteristics, body mass index, smoking, alcohol consumption, total physical activity, insomnia symptoms, disease history, and either bedtime or sleep duration. Cox proportional hazard models were used to calculate hazard ratios (HRs). Results: The mean age of participants at baseline was 59.2 years. Over a mean follow-up period of 8.0 years, 319 cases of dementia were observed. A long self-reported sleep duration relative to the reference sleep duration (7 hours) was associated with increased dementia risk, with the “8 hours” group (adjusted HR = 1.30, 95% CI:0.99–1.73) and “≥9 hours” group (adjusted HR = 1.46, 95% CI:1.00–2.15) having an increased risk (marginally significant) relative to the reference group. Early bedtime was associated with increased dementia risk (adjusted p for trend = 0.0010), with the “21 : 00 or earlier” group (adjusted HR = 1.61, 95% CI:1.14–2.28) having an increased risk relative to the reference (“23 : 00”). Conclusions: A long self-reported sleep duration and early bedtime are both associated with increased dementia risk in middle-aged and older people Show more
Keywords: Alzheimer’s disease, bedtime, cohort study, dementia, sleep duration
DOI: 10.3233/JAD-231104
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Liu, Jiaqi | Sun, Sirui | Chen, Yongjie
Article Type: Research Article
Abstract: Background: Numerous studies have investigated the correlation between malondialdehyde (MDA) and cognitive decline. However, limited research has explored the interplay between superoxide dismutase (SOD), C-reactive protein (CRP), and MDA. Objective: This study aims to scrutinize the association between MDA and cognitive function in older adults, while also elucidating the roles of SOD and CRP within this relationship. Methods: Utilizing data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) spanning 2008–2009, 2011–2012, and 2014, this study included 2,696 eligible subjects. Cognitive function was evaluated using the Chinese version of the Mini-Mental State Examination (MMSE). Linear mixed-effects models …were employed to examine the links between MDA, SOD, CRP, and their interactions with cognitive function. Results: Elevated serum levels of MDA and CRP, as well as decreased serum SOD levels, were related to decreased cognitive function (β= –0.220 and –0.346, 95% CI: –0.399, –0.041 and –0.526, –0.167 for MDA and CRP; β= 0.384, 95% CI: 0.204, 0.564 for SOD). Notably, a significant interaction between MDA and SOD was detected (p = 0.001). An increase per standard deviation in serum MDA levels was significantly associated with a 0.347-point lower MMSE score only in participants with normal cognitive function and high SOD levels (β= –0.347, 95% CI: –0.497, –0.197; p < 0.001). Conclusions: Elevated serum MDA levels in the normal population with high SOD levels suggested diminished cognitive performance. Combining MDA with SOD could be pivotal in identifying older adults at risk of cognitive decline in clinical settings. Show more
Keywords: Alzheimer’s disease, cognitive decline, C-reactive protein malondialdehyde, mini-mental state examination score, superoxide dismutase
DOI: 10.3233/JAD-231278
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Lissek, Vanessa J. | Orth, Stefan | Suchan, Boris
Article Type: Research Article
Abstract: Background: Cognitive training and physical exercise show positive effects on cognitive decline in subjects with mild cognitive impairment (MCI). Multimodal interventions for MCI patients, combining physical and cognitive training in a social context seem to slow down cognitive decline. Objective: Based on a previous study, a new mobile gamification tool (go4cognition; https://www.ontaris.de/go4cognition) has been developed to train cognitive and physical functions simultaneously in a group setting. It involves tasks targeting various cognitive functions (short-term memory, working memory, executive functions). The computer-based setup allows for individual performance analysis. This study evaluated the effects of this tool. Methods: …30 participants with MCI, as defined by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) cut-off-score, aged between 66 and 89 years, trained for one hour two days a week for twelve weeks. Additionally, standard neuropsychological assessment of memory and attention was carried out before and after the intervention. Results: The go4cognition device is highly effective in improving various cognitive functions. A significant improvement in the CERAD total score resulting in re-classification of 70% of former MCI patients into non-MCI patients was found. Additionally, an improvement of verbal fluency, verbal memory, spatial memory, and attention was observed. Furthermore, the CERAD total score was significantly correlated with performance in the go4cognition tool. Conclusions: The results of the intervention support the idea of the effectiveness of a combined cognitive and motor intervention by incorporating neuropsychological paradigms in a group setting and suggest a close relation between combined cognitive and physical exercise and cognitive performance. Show more
Keywords: Alzheimer’s disease, CERAD total score, cognitive training, gamification, mild cognitive impairment, multimodal intervention, physiological intervention, simultaneous stimulation of cognitive and physical abilities, social contact
DOI: 10.3233/JAD-230802
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Thunell, Johanna A. | Joyce, Geoffrey F. | Ferido, Patricia M. | Chen, Yi | Guadamuz, Jenny S. | Qato, Dima M. | Zissimopoulos, Julie M.
Article Type: Research Article
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) and prescribed central nervous system (CNS) active drugs to treat them are prevalent among persons living with Alzheimer’s disease and related dementias (PLWD) and lead to negative outcomes for PLWD and their caregivers. Yet, little is known about racial/ethnic disparities in diagnosis and use of drugs to treat BPSD. Objective: Quantify racial/ethnic disparities in BPSD diagnoses and CNS-active drug use among community-dwelling PLWD. Methods: We used a retrospective cohort of community-dwelling Medicare Fee-for-Service beneficiaries with dementia, continuously enrolled in Parts A, B and D, 2017–2019. Multivariate logistic models …estimated rates of BPSD diagnosis and, conditional on diagnosis, CNS-active drug use. Results: Among PLWD, 67.1% had diagnoses of an affective, psychosis or hyperactivity symptom. White (68.3%) and Hispanic (63.9%) PLWD were most likely, Blacks (56.6%) and Asians (52.7%) least likely, to have diagnoses. Among PLWD with BPSD diagnoses, 78.6% took a CNS-active drug. Use was highest among whites (79.3%) and Hispanics (76.2%) and lowest among Blacks (70.8%) and Asians (69.3%). Racial/ethnic differences in affective disorders were pronounced, 56.8% of white PLWD diagnosed; Asians had the lowest rates (37.8%). Similar differences were found in use of antidepressants. Conclusions: BPSD diagnoses and CNS-active drug use were common in our study. Lower rates of BPSD diagnoses in non-white compared to white populations may indicate underdiagnosis in clinical settings of treatable conditions. Clinicians’ review of prescriptions in this population to reduce poor outcomes is important as is informing care partners on the risks/benefits of using CNS-active drugs. Show more
Keywords: Alzheimer’s disease, antidepressants, antipsychotics, behavioral and psychological symptoms of dementia, dementia
DOI: 10.3233/JAD-231266
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Elghanam, Yomna | Purja, Sujata | Kim, Eun Young
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. Objective: This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. Methods: In this retrospective study, trials were collected by searching clinicaltrials.gov using the term “Alzheimer”. Primary and …secondary outcomes were analyzed separately for each phase. Results: Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials (p = 0.001) and secondary endpoints in phase 3 trials (p = 0.001). Conclusions: The growing recognition of the importance of biomarkers in AD trial’ design and drug development is evident by the significant steady increase in biomarkers’ utilization in phases 2 and 3. Show more
Keywords: Alzheimer’s disease, amyloid, biomarkers, clinical trials, drug development, endpoint, tau
DOI: 10.3233/JAD-240008
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Cressot, Coralie | Vrillon, Agathe | Lilamand, Matthieu | Francisque, Hélène | Méauzoone, Aurélie | Hourregue, Claire | Dumurgier, Julien | Marlinge, Emeline | Paquet, Claire | Cognat, Emmanuel
Article Type: Systematic Review
Abstract: Background: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer’s disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. Objective: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. Methods: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). Results: Psychosis is a frequently …observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6–78.3%) and visual hallucinations (50–69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, respectively (9.1–60.3% and 3.10–41.5%). Limited data were found regarding psychosis in the early stages of these disorders. Conclusions: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues. Show more
Keywords: Alzheimer’s disease, delusion, dementia, dementia with Lewy bodies, frontotemporal degeneration, hallucinations, neurodegenerative disease, psychosis
DOI: 10.3233/JAD-231363
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Article Type: Correction
DOI: 10.3233/JAD-249008
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2024
Authors: Memon, Ashar | Moore, Jasmine A. | Kang, Chris | Ismail, Zahinoor | Forkert , Nils D.
Article Type: Research Article
Abstract: Background: While various biomarkers of Alzheimer’s disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. Objective: To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. Methods: Data from participants (N = 1,460) in the Alzheimer’s Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination …(MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. Results: MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aβ1–42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. Conclusions: Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition. Show more
Keywords: Alzheimer’s disease, biomarkers, dementia, MRI, neuroimaging, visual processing
DOI: 10.3233/JAD-231084
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Xu, Feifan | Xu, Jiajie | Wang, Qiong | Gao, Feng | Fu, Jiayu | Yan, Tingmeng | Dong, Qiang | Su, Ya | Cheng, Xin
Article Type: Research Article
Abstract: Background: Neuroinflammation is a major cause of secondary brain injury in intracerebral hemorrhage (ICH). To date, the prognostic value of YKL-40 (chitinase-3-like-1 protein), a biomarker of neuroinflammation, in cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-ICH) remains undiscovered. Objective: To evaluate the relationships between serum YKL-40 and CAA-ICH recurrence. Methods: Clinical and imaging information of 68 first-onset probable CAA-ICH cases and 95 controls were collected at baseline. Serum YKL-40 was measured by Luminex assay. Cox proportional hazards model was used to analyze the associations between YKL-40 level and CAA-ICH recurrence. Results: Serum YKL-40 level was significantly …higher in CAA-ICH cases than healthy controls (median [interquartile range, IQR], 46.1 [19.8, 93.4] versus 24.4 [13.9, 59.0] ng/mL, p = 0.004). Higher level of YKL-40 predicted increased risk of CAA-ICH recurrence adjusted for age, ICH volume and enlarged perivascular space score (ePVS) (above versus below 115.5 ng/ml, adjusted hazard ratios 4.721, 95% confidence intervals 1.829–12.189, p = 0.001) within a median follow-up period of 2.4 years. Adding YKL-40 to a model of only MRI imaging markers including ICH volume and ePVS score improved the discriminatory power (concordance index from 0.707 to 0.772, p = 0.001) and the reclassification power (net reclassification improvement 28.4%; integrated discrimination index 11.0%). Conclusions: Serum YKL-40 level might be a candidate prognostic biomarker for CAA-ICH recurrence. Show more
Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, intracerebral hemorrhage, recurrence, YKL-40
DOI: 10.3233/JAD-231125
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
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