Journal of Alzheimer's Disease - Volume 98, issue 2

Authors: García-Alberca, José María | de Rojas, Itziar | Sanchez-Mejias, Elisabeth | Garrido-Martín, Diego | Gonzalez-Palma, Laura | Jimenez, Sebastian | Pino-Angeles, Almudena | Cruz-Gamero, Jose Manuel | Mendoza, Silvia | Alarcón-Martín, Emilio | Muñoz-Castro, Clara | Real, Luis Miguel | Tena, Juan Jesus | Polvillo, Rocio | Govantes, Fernando | Lopez, Aroa | Royo-Aguado, Jose Luis | Navarro, Victoria | Gonzalez, Irene | Ruiz, Maximiliano | Reyes-Engel, Armando | Gris, Esther | Bravo, Maria Jose | Lopez-Gutierrez, Lidia | Mejias-Ortega, Marina | De la Guía, Paz | López de la Rica, María | Ocejo, Olga | Torrecilla, Javier | Zafra, Carmen | Nieto, María Dolores | Urbano, Concepción | Jiménez-Sánchez, Rocío | Pareja, Nuria | Luque, Macarena | García-Peralta, María | Carrillejo, Rosario | Furniet, María del Carmen | Rueda, Lourdes | Sánchez-Fernández, Ana | Mancilla, Tomás | Peña, Isabel | García-Casares, Natalia | Moreno-Grau, Sonia | Hernández, Isabel | Montrreal, Laura | Quintela, Inés | González-Pérez, Antonio | Calero, Miguel | Franco-Macías, Emilio | Macías, Juan | Menéndez-González, Manuel | Frank-García, Ana | Huerto Vilas, Raquel | Diez-Fairen, Mónica | Lage, Carmen | García-Madrona, Sebastián | García-González, Pablo | Valero, Sergi | Sotolongo-Grau, Oscar | Pérez-Cordón, Alba | Rábano, Alberto | Arias Pastor, Alfonso | Pastor, Ana Belén | Espinosa, Ana | Corma-Gómez, Anaïs | Martín Montes, Ángel | Sanabria, Ángela | Martínez Rodríguez, Carmen | Buiza-Rueda, Dolores | Rodriguez-Rodriguez, Eloy | Ortega, Gemma | Alvarez, Ignacio | Rosas Allende, Irene | Pineda, Juan A. | Rosende-Roca, Maitée | Bernal Sánchez-Arjona, María | Fernández-Fuertes, Marta | Alegret, Montserrat | Roberto, Natalia | del Ser, Teodoro | Garcia-Ribas, Guillermo | Sánchez-Juan, Pascual | Pastor, Pau | Piñol-Ripoll, Gerard | Bullido, María José | Álvarez, Victoria | Mir, Pablo | Medina, Miguel | Marquié, Marta | Sáez, María Eugenia | Carracedo, Ángel | Laplana, Marina | Tomas-Gallardo, Laura | Orellana, Adelina | Tárraga, Lluís | Boada, Mercè | Fibla Palazon, Joan | Vitorica, Javier | Ruiz, Agustín | Guigo, Roderic | Gutierrez, Antonia | Royo, Jose Luis

Article Type: Research Article

Abstract: Background: Microglial dysfunction plays a causative role in Alzheimer’s disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to …bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p  = 0.018) and a higher risk to develop AD (OR = 1.678, p  = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p  < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p  = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway. Show more

Keywords: Alzheimer’s disease, copy-number variant, DAP12, microglia, SIRPβ1, TREM2, TYROBP

DOI: 10.3233/JAD-231150

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 601-618, 2024

Authors: Chenoweth, Lynn | Burley, Claire | Cook, Jacquelene | Cheah, Seong-Leang | Reyes, Patricia | Maiden, Genevieve | McGuire, Jane | McCade, Donna | Brodaty, Henry | Sukhapure, Mayouri | Harrison, Fleur | Williams, Anna

Article Type: Research Article

Abstract: Background: Person-centered care is considered beneficial for persons with dementia. Objective: To evaluate the impact of a person-centered knowledge translation intervention on the quality of healthcare and outcomes for persons with dementia. Methods: Over nine months, sub-acute hospital nursing, allied health, and medical staff (n  = 90) participated in online and/or face-to-face person-centered education and were supported by senior nursing, allied health, and medical staff champions (n  = 8) to implement person-centered healthcare. The quality of healthcare service, ward climate and care delivery were evaluated pre/post study intervention. In the week following hospital admission (Time 1) and week …of discharge (Time 3), agitation incidence (co-primary outcome) was assessed in participants with dementia (n  = 80). Participant delirium (co-primary outcome), accidents/injuries, psychotropic medicines, length of stay, readmission and discharge destination (secondary outcomes) were compared with a retrospective group (n  = 77) matched on demographics, cognition and function in activities of daily living. Results: Improvements occurred post-intervention in service quality by 17.5% (p  = 0.369, phi = 0.08), ward climate by 18.1% (p  = 0.291, phi = 0.08), and care quality by 50% (p  = 0.000, phi = 0.37). Participant agitation did not change from Time 1 to Time 3 (p  = 0.223). Relative to the retrospective group, significant reductions occurred in participant delirium (p  = 0.000, phi = 0.73), incidents/injuries (p  = 0.000, phi = 0.99), psychotropic medicine use (p  = 0.030, phi = 0.09), and hospital readmissions within 30 days (p  = 0.002, phi = 0.25), but not in discharge to home (p  = 0.171). Conclusions: When person-centered healthcare knowledge is translated through staff education and practice support, persons with dementia can experience improved healthcare services and clinical outcomes, while healthcare services can benefit through reductions in unplanned service use. Show more

Keywords: Alzheimer’s disease, clinical outcomes, healthcare quality, person-centered care champion, sub-acute hospital

DOI: 10.3233/JAD-231056

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 619-628, 2024

Authors: Chi, Hao-Chen | Ma, Ling-Zhi | Wang, Zhi-Bo | Sheng, Ze-Hu | Liu, Jia-Yao | Mi, Yin-Chu | Fu, Yan | Huang, Yi-Ming | Han, Shuang-Ling | Gao, Pei-Yang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer’s disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation …analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative database, frailty, modified frailty index, neuropsychiatric symptoms

DOI: 10.3233/JAD-231111

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 629-642, 2024

Authors: Gohel, Dhruv | Zhang, Pengyue | Gupta, Amit Kumar | Li, Yichen | Chiang, Chien-Wei | Li, Lang | Hou, Yuan | Pieper, Andrew A. | Cummings, Jeffrey | Cheng, Feixiong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. Objective: To investigate the potential therapeutic benefit of sildenafil on AD. Methods: We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil’s mechanism-of-action. Results: …We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32– 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49– 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. Conclusions: These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD. Show more

Keywords: KeywordsAlzheimer’s disease, induced pluripotent stem cells, phosphodiesterase-5 (PDE5), real-world patient data, RNA-sequencing, sildenafil, tau phosphorylation

DOI: 10.3233/JAD-231391

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 643-657, 2024

Authors: Shimada, Hiroyuki | Doi, Takehiko | Tsutsumimoto, Kota | Makino, Keitaro | Harada, Kenji | Tomida, Kouki | Arai, Hidenori

Article Type: Research Article

Abstract: Background: Social networks and social participation have protective effects on cognitive function maintenance and Alzheimer’s disease and general dementia development. Objective: We aimed to investigate the association between conversations and dementia incidence in older adults. Methods: This longitudinal prospective cohort study used population data from the National Center for Geriatric and Gerontology–Study of Geriatric Syndromes (NCGG–SGS) from September 2015 to February 2017. The database included 4,167 individuals in Japan aged ≥60 years who were generally healthy and without major cognitive impairment. Participants were classified into two groups according to six daily conversation measures at baseline. The …conversation index was calculated as a composite score for these measures. Participants were tracked monthly over 60 months for new-onset dementia. Results: Data from 2,531 participants were analyzed (72.7±6.7 years; range: 60–96 years). Dementia incidence per 1,000 person-years was 15.7 (95% confidence interval, 13.6–18.1). The Youden index determined the cut-off point for dementia incidence, with a conversation index of 16/17 points. The low conversation group included more participants with new-onset dementia. Cox proportional hazards regression crude models showed remarkable relationships between dementia onset and specific conversation measurements, including conversation index. According to the Cox regression adjusted model, the cut-off point of the conversation index showed only a remarkable relationship with dementia onset. Conclusions: Dementia risk was extensively associated with low daily conversation statuses. The assessment of conversational factors may be useful as a risk indicator for the development of Alzheimer’s disease and general dementia. Show more

Keywords: Alzheimer’s disease, dementia, social interaction, social isolation, social participation

DOI: 10.3233/JAD-231420

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 659-669, 2024

Authors: Kavoosi, Sakine | Shahraki, Ali | Sheervalilou, Roghayeh

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent neurological disorder worldwide, affecting approximately 24 million individuals. Despite more than a century of research on AD, its pathophysiology is still not fully understood. Objective: Recently, genetic studies of AD have focused on analyzing the general expression profile by employing high-throughput genomic techniques such as microarrays. Current research has leveraged bioinformatics advancements in genetic science to build upon previous efforts. Methods: Data from the GSE118553 dataset used in this investigation, and the analyses carried out using programs such as Limma and BioBase. Differentially expressed genes (DEGs) and differentially …expressed microRNAs (DEmiRs) associated with AD identified in the studied areas of the brain. Target genes of the DEmiRs identified using the MultiMiR package. Gene ontology (GO) completed using the Enrichr website, and the protein-protein interaction (PPI) network for these genes drawn using STRING and Cytoscape software. Results: The findings introduced DEGs including CTNNB1, PAK2, MAP2K1, PNPLA6, IGF1R, FOXL2, DKK3, LAMA4, PABPN1, and GDPD5, and DEmiRs linked to AD (miR-106A, miR-1826, miR-1253, miR-10B, miR-18B, miR-101-2, miR-761, miR-199A1, miR-379 and miR-668), (miR-720, miR-218-2, miR-25, miR-602, miR-1226, miR-548K, miR-H1, miR-410, miR-548F2, miR-181A2), (miR-1470, miR-651, miR-544, miR-1826, miR-195, miR-610, miR-599, miR-323, miR-587 and miR-340), and (miR-1282, miR-1914, miR-642, miR-1323, miR-373, miR-323, miR-1322, miR-612, miR-606 and miR-758) in cerebellum, frontal cortex, temporal cortex, and entorhinal cortex, respectively. Conclusions: The majority of the genes and miRNAs identified by our findings may be employed as biomarkers for prediction, diagnosis, or therapy response monitoring. Show more

Keywords: Alzheimer’s disease, bioinformatics, microRNA (miRNA or miR)-mRNA regulatory network, nanoparticles, protein-protein interaction

DOI: 10.3233/JAD-230966

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 671-689, 2024

Authors: Olavarría, Loreto | Caramelli, Paulo | Lema, José | Andrade, Caíssa Bezerra de | Pinto, Alejandra | Azevedo, Lílian Viana dos Santos | Thumala, Daniela | Vieira, Maria Carolina Santos | Rossetti, Adriana Peredo | Generoso, Alana Barroso | Carmona, Karoline Carvalho | Sepúlveda-Loyola, Walter | Pinto, Ludmilla Aparecida Cardoso | Barbosa, Maira Tonidandel | Slachevsky, Andrea

Article Type: Research Article

Abstract: Background: Previous studies reported the negative impact of social isolation on mental health in people with dementia (PwD) and their caregivers, butlongitudinal studies seem scarcer. Objective: To describe a one-year follow-up impact of the COVID-19 pandemic on PwD and their caregivers in both Brazil and Chile. Methods: This study analyzed the impact of the pandemic on the psychological and physical health of PwD and their family caregivers after one year of follow-up in three outpatient clinics in Brazil (n  = 68) and Chile (n  = 61). Results: In both countries, PwD reduced their functional capacity after …one year of follow-up (p  = 0.017 and p  = 0.009; respectively) and caregivers reported worse physical and mental health (p  = 0.028 and p  = 0.039). Only in Chile, caregivers reported more sadness associated with care (p  = 0.001), and reduced time sleeping (p  = 0.07). Conclusions: In conclusion, the COVID-19 pandemic appears to have had a long-lasting impact on PwD and their caregivers. However, it is essential to acknowledge that the inherent progression of dementia itself may also influence changes observed over a year. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, caregiver, COVID-19, dementia, follow-up studies

DOI: 10.3233/JAD-231310

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 691-698, 2024

Authors: Kumari, Sakshi | Kaur, Priyajit | Singh, Abhinay Kumar | Ashar, Mohd Suhail | Pradhan, Rashmita | Rao, Abhijit | Haldar, Partha | Chakrawarty, Avinash | Chatterjee, Prasun | Dey, Sharmistha

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and symptoms develop gradually over many years. The current direction for medication development in AD is focused on neuro-inflammation and oxidative stress. Amyloid-β (Aβ) deposition activates microglia leading to neuro-inflammation and neurodegeneration induced by activation of COX-2 via NFκB p50 in glioblastoma cells. Objective: The study aimed to evaluate the concentration of COX-2 and NFκB p50 in serum of AD, mild cognitive impairment (MCI), and geriatric control (GC) and to establish a blood-based biomarker for early diagnosis and its therapeutic implications. Methods: Proteins and their mRNA level …in blood of study groups were measured by surface plasmon resonance (SPR) and quantitative polymerase chain reaction (qPCR), respectively. The level of protein was further validated by western blot. The binding study of designed peptide against COX-2 by molecular docking was verified by SPR. The rescue of neurotoxicity by peptide was also checked by MTT assay on SH-SY5Y cells (neuroblastoma cell line). Results: Proteins and mRNA were highly expressed in AD and MCI compared to GC. However, COX-2 decreases with disease duration. The peptide showed binding affinity with COX-2 with low dissociation constant in SPR and rescued the neurotoxicity of SH-SY5Y cells by decreasing the level of Aβ, tau, and pTau proteins. Conclusions: It can be concluded that COX-2 protein can serve as a potential blood-based biomarker for early detection and can be a good platform for therapeutic intervention for AD. Show more

Keywords: Alzheimer’s disease, blood-based biomarker, COX-2, inhibitor, SPR

DOI: 10.3233/JAD-231445

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 699-713, 2024

Authors: Verwaerde, Philippe | Estrella, Cecilia | Burlet, Stéphane | Barrier, Mathieu | Marotte, Andrée-Anne | Clincke, Gilbert

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are major neurodegenerative conditions with tau pathology in common but distinct symptoms—AD involves cognitive decline while PSP affects balance and eye movement. Progranulin (PGRN) is a growth factor implicated in neurodegenerative diseases, including AD and PSP. AZP2006, a synthetic compound, targets tauopathies by stabilizing PGRN levels and reducing tau aggregation and neuroinflammation. Objective: Evaluate the safety, tolerability, and pharmacokinetics of AZP2006. Methods: A first-in-Human phase 1 study comprised a single ascending dose (SAD) and a multiple ascending dose study (MAD). The SAD study included 64 healthy male …volunteers and tested singles oral doses of 3 to 500 mg of AZP2006 free base equivalent or placebo. In the MAD study, 24 healthy male volunteers were administered oral doses of 30, 60, and 120 mg per day of AZP2006 or placebo for 10 days. Results: No serious adverse events were observed. Clinical, biological, and electrocardiogram findings were non-relevant. Nineteen minor adverse events resolved before study completion. The safety profile indicated no specific risks. The multiple ascending dose study was halted, and the optional dose level of 180 mg was not performed due to high levels of M2 metabolite in plasma that necessitated additional preclinical evaluation of M2. Both AZP2006 and its M2 metabolite were quickly absorbed and widely distributed in tissues. Exposure increased more than proportionally with dose. Conclusions: AZP2006 had a favorable safety profile and was rapidly absorbed. Elevated M2 metabolite levels necessitated further studies to clarify excretion and metabolism mechanisms. Show more

Keywords: Alzheimer’s disease, AZP2006, ezeprogind, multiple ascending dose, neurologic degenerative diseases, progranulin, progressive supranuclear palsy, single ascending dose, small-molecule drug, tauopathies

DOI: 10.3233/JAD-220883

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 715-727, 2024

Authors: Lu, Thuy V. | Grill, Joshua D. | Gillen, Daniel L.

Article Type: Research Article

Abstract: Background: In randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer’s disease (AD) RCTs require participants to enroll with a study partner. Objective: We examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type. Methods: We estimated AE reporting rates using placebo data from seven independent RCTs conducted by the Alzheimer’s Disease Cooperative Study. We assessed the heterogeneity of reporting rates as a function of visits using generalized estimating equations. In the primary analysis, we tested the hypotheses that the rates of reporting differed …by study partner type and time they spent with the participant weekly using Poisson regression with robust variance estimation. In all regression models, log-transformed total patient years was included. Results: The estimated reporting rates were 2.83 (95% CI: 2.66, 3.02), 1.18 (95% CI: 1.09, 1.28), 0.23 (95% CI: 0.19, 0.27), and 0.28 (95% CI: 0.24, 0.33) events per participant year for grade 1–3 AEs and SAEs, respectively. We estimated that greater number of visits per year was associated with increased reporting for grade 1–2 AEs and SAEs. We did not find evidence to suggest that AE reporting differed by study partner type or by time the study partner spent with the participant. Conclusions: Study partner type and time the study partner spent with the participant did not appear to impact AE reporting. Estimated reporting rates may be useful to evaluate safety in future studies, particularly those with no control arm and similar visit frequencies. Show more

Keywords: Adverse event, Alzheimer’s disease, clinical trials, study partner

DOI: 10.3233/JAD-231283

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 729-738, 2024