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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: Jehu, Deborah A. | Pottayil, Faheem | Dong, Yanbin | Zhu, Haidong | Sams, Richard | Young, Lufei
Article Type: Research Article
Abstract: Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition : Montreal Cognitive Assessment; executive function : Trail-Making Test, Digit Span Forward Test; perception and orientation : Benton Judgement of Line Orientation Test; …language : Boston Naming Test; learning and memory : Rey Auditory Verbal Learning Test; complex attention : Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer’s disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (p s < 0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes. Show more
Keywords: Accelerometry, actigraphy, Alzheimer’s disease, cognition, cognitive domains, dementia, physical activity
DOI: 10.3233/JAD-230594
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Guo, Ze-Xin | Liu, Fang | Wang, Fang-Yuan | Ou, Ya-Nan | Huang, Liang-Yu | Hu, Hao | Wang, Zhi-Bo | Fu, Yan | Gao, Pei-Yang | Tan, Lan | Yu, Jin-Tai
Article Type: Research Article
Abstract: Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual’s risk of dementia. However, studies on the link of the CAIDE score to Alzheimer’s disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. …Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p < 0.001), tTau (p < 0.001), as well as tTau/Aβ42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p < 0.001) as well as MoCA score (p < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2% . Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration. Show more
Keywords: Alzheimer’s disease, CAIDE dementia risk score, cerebrospinal fluid biomarkers, cognition, neurodegeneration
DOI: 10.3233/JAD-240005
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Nakaya, Moto | Sato, Noriko | Matsuda, Hiroshi | Maikusa, Norihide | Ota, Miho | Shigemoto, Yoko | Sone, Daichi | Yamao, Tensho | Kimura, Yukio | Tsukamoto, Tadashi | Yokoi, Yuma | Sakata, Masuhiro | Abe, Osamu
Article Type: Research Article
Abstract: Background: Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer’s disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics. Objective: The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics. Methods: Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11 C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the …AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics. Results: Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology. Conclusions: This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter. Show more
Keywords: Alzheimer’s disease, 11C-Pittsburgh compound B PET, diffusion tensor imaging, free water imaging, gray matter-based spatial statistics, voxel-based morphometry
DOI: 10.3233/JAD-231416
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Thyrian, Jochen René | Boekholt, Melanie | Biernetzky, Olga | Blotenberg, Iris | Teipel, Stefan | Killimann, Ingo | Hoffmann, Wolfgang
Article Type: Research Article
Abstract: Background: Caregivers of people with dementia living at home (CPwDh) are likely to be affected by a range of health problems. However, CPwDh are often regarded as accompanying persons and receive less attention in research and care. Little is known about this population and their needs in Germany. However, better knowledge of CPwDH is needed to design effective interventions. Objective: The objective of this report is to describe the situation of CPwDh and highlight differences based on sex and living situation. Methods: This was a cross-sectional analysis of the psychosocial characteristics of participants in the GAIN …trial, a cluster-randomized, controlled intervention trial investigating the effectiveness of a care management program. A total of n = 192 CPwDh were recruited in GP offices, memory clinics or through public campaigns in the German federal state of Mecklenburg-Western Pomerania. The inclusion criteria were an age of 18 years or above, being a CPwDh, written informed consent. In a comprehensive digital assessment, psychosocial variables, burden, and care needs were assessed. Results: Partners, women, and people living in the same household represented the majority of caregivers, and their mean number of needs was 8.7. Overall, participants indicated a mild to moderate burden. There are differences in burden based on sex and living situation, with caregivers living with people with dementia showing less burden and different psychosocial demographics. Conclusions: There is a need for interventions to reduce caregivers’ unmet needs in the CPwDh. Such interventions should consider differences in sex and living situation to better address individual caregiver needs. Show more
Keywords: Alzheimer’s disease, caregiver, dementia, intervention, primary care, unmet needs
DOI: 10.3233/JAD-231055
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2024
Authors: Pluta, Ryszard | Bogucka-Kocka, Anna | Bogucki, Jacek | Kocki, Janusz | Czuczwar, Stanisław J.
Article Type: Research Article
Abstract: Background: Currently, no evidence exists on the expression of apoptosis (CASP3 ), autophagy (BECN1 ), and mitophagy (BNIP3 ) genes in the CA3 area after ischemia with long-term survival. Objective: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6–24 months. Methods: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer’s disease. Results: First time, we demonstrated overexpression of the CASP3 gene …in CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. Conclusions: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3 . This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia. Show more
Keywords: Alzheimer’s disease, apoptosis, autophagy, brain ischemia, CA3 area, genes, hippocampus, long-term survival, mitophagy, neurodegeneration
DOI: 10.3233/JAD-240401
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Van Asbroeck, Stephanie | Köhler, Sebastian | Wimmers, Sophie C.P.M. | Muris, Jean W.M. | van Boxtel, Martin P.J. | Deckers, Kay
Article Type: Research Article
Abstract: Background: Dementia risk reduction is a public health priority, but interventions that can be easily implemented in routine care are scarce. Objective: To evaluate the feasibility of integrating dementia risk reduction in regular consultations in primary care and the added value of a dedicated smartphone app (‘MyBraincoach’). Methods: 188 participants (40–60 years), with modifiable dementia risk factors were included from ten Dutch general practices in a cluster-randomized trial (NL9773, 06/10/2021). Practices were randomly allocated (1 : 1) to provide a risk-reduction consultation only or to additionally provide the app. During the consultation, participants learned about dementia risk reduction …and how to improve their risk profile. The app group received daily microteaching-notifications about their personally relevant risk factors. Feasibility was evaluated after 3 months using questionnaires assessing knowledge on dementia risk reduction and health behavior change. The primary outcome was change in the validated “LIfestyle for BRAin health” (LIBRA) score. In-depth interviews were conducted with participants and primary care providers (PCPs). Results: The interventions were positively perceived, with 72.0% finding the consultation informative and 69.2% considering the app useful. Drop-out was low (6.9%). LIBRA improved similarly in both groups, as did Mediterranean diet adherence and body mass index. Knowledge of dementia risk reduction increased, but more in the app group. Interviews provided insight in participants’ and PCPs’ needs and wishes. Conclusions: Integrating dementia risk reduction in primary care, supported by a smartphone app, is a viable approach towards dementia risk reduction. Larger trials are needed to establish (cost-)effectiveness. Show more
Keywords: Alzheimer’s disease, dementia, health behavior, lifestyle, prevention and control, primary health care, risk factors, telemedicine
DOI: 10.3233/JAD-240229
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Stam, Cornelis Jan | de Haan, Willem
Article Type: Research Article
Abstract: Background: There is increasing evidence from animal and clinical studies that network hyperexcitability (NH) may be an important pathophysiological process and potential target for treatment in early Alzheimer’s disease (AD). Measures of functional connectivity (FC) have been proposed as promising biomarkers for NH, but it is unknown which measure has the highest sensitivity for early-stage changes in the excitation/inhibition balance. Objective: We aim to test the performance of different FC measures in detecting NH at the earliest stage using a computational approach. Methods: We use a whole brain computational model of activity dependent …degeneration to simulate progressive AD pathology and NH. We investigate if and at what stage four measures of FC (amplitude envelope correlation corrected [AECc], phase lag index [PLI], joint permutation entropy [JPE] and a new measure: phase lag time [PLT]) can detect early-stage AD pathophysiology. Results: The activity dependent degeneration model replicates spectral changes in line with clinical data and demonstrates increasing NH. Compared to relative theta power as a gold standard the AECc and PLI are shown to be less sensitive in detecting early-stage NH and AD-related neurophysiological abnormalities, while the JPE and the PLT show more sensitivity with excellent test characteristics. Conclusions: Novel FC measures, which are better in detecting rapid fluctuations in neural activity and connectivity, may be superior to well-known measures such as the AECc and PLI in detecting early phase neurophysiological abnormalities and in particular NH in AD. These markers could improve early diagnosis and treatment target identification. Show more
Keywords: Activity dependent degeneration, Alzheimer’s disease, biomarkers, computational model, functional connectivity, network hyperexcitability, whole brain
DOI: 10.3233/JAD-230825
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Xiong, Rui | Li, Binrui | Yu, Haitao | Fan, Tianceng | Yu, Huiling | Yang, Ying | Wang, Jian-Zhi | Pi, Guilin | Yang, Xifei
Article Type: Research Article
Abstract: Background: Anxiety and social withdrawal are highly prevalent among patients with Alzheimer’s disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. Objective: This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. Methods: We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. Results: In 5xFAD mice, we observed significant amyloid-β (Aβ) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice …displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aβ accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. Conclusions: The aBLA-vCA1 circuit is a vulnerable pathway in response to Aβ accumulation during the progression of AD and plays a crucial role in Aβ-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aβ-impaired social ability. Show more
Keywords: Alzheimer’s disease, amyloid-β , anxiety, aBLA-vCA1 circuit, urolithin A
DOI: 10.3233/JAD-240298
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Slachevsky, Andrea | Grandi, Fabrissio | Thumala, Daniela | Baez, Sandra | Santamaria-García, Hernando | Schmitter-Edgecombe, Maureen | Parra, Mario A.
Article Type: Research Article
Abstract: Dementia is a syndrome characterized by cognitive and neuropsychiatric symptoms associated with progressive functional decline (FD). FD is a core diagnostic criterion for dementia, setting the threshold between its prodromal stages and the full-blown disease. The operationalization of FD continues to generate a great deal of controversy. For instance, the threshold of FD for the diagnosis of dementia varies across diagnostic criteria, supporting the need for standardization of this construct. Moreover, there is a need to reconsider how we are measuring FD to set boundaries between normal aging, mild cognitive impairment, and dementia. In this paper, we propose a multidimensional …framework that addresses outstanding issues in the assessment of FD: i) What activities of daily living (ADLs) are necessary to sustain an independent living in aging? ii) How to assess FD in individuals with suspected neurocognitive disorders? iii) To whom is the assessment directed? and iv) How much does FD differentiate healthy aging from mild and major neurocognitive disorders? Importantly, the To Whom Question introduces a person-centered approach that regards patients and caregivers as active agents in the assessment process of FD. Thus, once impaired ADLs have been identified, patients can indicate how significant such impairments are for them in daily life. We envisage that this new framework will guide future strategies to enhance functional assessment and treatment of patients with dementia and their caregivers. Show more
Keywords: Activities of daily living, Alzheimer’s disease, dementia, disability, functional dependence, functional independence, functional status, person-center care, functional ability
DOI: 10.3233/JAD-230376
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2024
Authors: Zeng, Baoqi | Tang, Chunbian | Wang, Junjian | Yang, Qingqing | Ren, Qingcuo | Liu, Xiaozhi
Article Type: Research Article
Abstract: Background: Early intervention is essential for meaningful disease modification in Alzheimer’s disease (AD). Objective: We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence. …Results: Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments— ranging from low to high certainty— showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] –0.239, 95% confidence interval [CI] –0.343 to –0.134) and lecanemab (SMD –0.194, 95% CI –0.279 to –0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo. Conclusions: Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD. Show more
Keywords: Alzheimer’s disease, meta-analysis, pharmacology, randomized controlled trial, systematic review, treatment efficacy
DOI: 10.3233/JAD-240161
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
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