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

Authors: Cotton, Quinton D. | Albers, Elle | Ingvalson, Steph | Skalla, Emily | Bailey, Dionne | Marx, Katie | Anderson, Keith | Dabelko-Schoeny, Holly | Parker, Lauren | Gitlin, Laura N. | Gaugler, Joseph E.

Article Type: Research Article

Abstract: Background: Adult day services (ADS) are an important and often underutilized support resource for older adults. For persons living with dementia (PLWD), ADS is an optimal access point to not only receive therapeutic and rehabilitative activities, but as a vehicle for respite/relief for dementia caregivers. Yet, there is currently a lack of research on integrating caregiver interventions into home and community-based services such as ADS. Objective: This paper reports on qualitative findings from the Improving Outcomes for Family Caregivers of Older Adults with Complex Conditions: The Adult Day Plus (ADS Plus) Program Trial. Methods: Drawing from …semi-structured interviews conducted with family caregivers and ADS site staff, we conducted a thematic analysis to examine the implementation process of ADS Plus. Results: Themes address the relational nature of the intervention, learning, influence of the administrative infrastructure, and receptivity of ADS Plus. Conclusions: Our analysis determined that implementation of ADS Plus was feasible and accepted by site staff and dementia caregivers but also calls for additional evaluation of embedded caregiver support interventions across different contexts (e.g., staff size, limited technology environments) to further identify and test implementation mechanisms across settings. Show more

Keywords: Adult day services, Alzheimer’s disease, caregiver support, respite care

DOI: 10.3233/JAD-230787

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 445-463, 2024

Authors: Rapos Pereira, Filipa | George, Nathalie | Dalla Barba, Gianfranco | Dubois, Bruno | La Corte, Valentina

Article Type: Research Article

Abstract: Background: The asymptomatic at-risk phase might be the optimal time-window to establish clinically meaningful endpoints in Alzheimer’s disease (AD). Objective: We investigated whether, compared with the Free and Cued Selective Reminding Test (FCSRT), the Memory Binding Test (MBT) can anticipate the diagnosis of emergent subtle episodic memory (EM) deficits to an at-risk phase. Methods: Five-year longitudinal FCSRT and MBT scores from 45 individuals matched for age, education, and gender, were divided into 3 groups of 15 subjects: Aβ-/controls, Aβ+/stable, and Aβ+/progressors (preclinical-AD). The MBT adds an associative memory component (binding), particularly sensitive to subtle EM decline. …Results: In the MBT, EM decline started in the Aβ+/progressors (preclinical-AD) up to 4 years prior to diagnosis in delayed free recall (FR), followed by decline in binding-associated scores 1 year later. Conversely, in the FCSRT, EM-decline began later, up to 3 years prior to diagnosis, in the same group on both immediate and delayed versions of FR, while on total recall (TR) and intrusions decline started only 1 year prior to diagnosis. Conclusions: The MBT seems more sensitive than the FCSRT for early EM-decline detection, regarding the year of diagnosis and the number of scores showing AD-linked EM deficits (associated with the AD-characteristic amnesic hippocampal syndrome). Considering the MBT as a detection tool of early subtle EM-decline in an asymptomatic at-risk phase, and the FCSRT as a classification tool of stages of EM-decline from a preclinical phase, these tests ought to potentially become complementary diagnostic tools that can foster therapies to delay cognitive decline. Clinical trial registration title: Electrophysiological markers of the progression to clinical Alzheimer disease in asymptomatic at-risk individuals: a longitudinal event-related potential study of episodic memory in the INSIGHT pre-AD cohort (acronym: ePARAD). Show more

Keywords: Alzheimer’s disease, amyloid-β, at-risk, episodic memory, free and cued selective reminding test, memory binding test, preclinical Alzheimer’s disease

DOI: 10.3233/JAD-230921

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 465-479, 2024

Authors: Li, Sha | Lan, Xiaoyong | Liu, Yumei | Zhou, Junhong | Pei, Zian | Su, Xiaolin | Guo, Yi

Article Type: Research Article

Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is an advanced and noninvasive technology that uses pulse stimulation to treat cognitive impairment. However, its specific effects have always been mixed with those of cognitive training, and the optimal parameter for Alzheimer’s disease (AD) intervention is still ambiguous. Objective: This study aimed to summarize the therapeutic effects of pure rTMS on AD, excluding the influence of cognitive training, and to develop a preliminary rTMS treatment plan. Methods: Between 1 January 2010 and 28 February 2023, we screened randomized controlled clinical trials from five databases (PubMed, Web of Science, Embase, …Cochrane, and ClinicalTrials. gov). We conducted a meta-analysis and systematic review of treatment outcomes and rTMS treatment parameters. Result: A total of 4,606 articles were retrieved. After applying the inclusion and exclusion criteria, 16 articles, comprising 655 participants (308 males and 337 females), were included in the final analysis. The findings revealed that rTMS significantly enhances both global cognitive ability (p  = 0.0002, SMD = 0.43, 95% CI = 0.20–0.66) and memory (p  = 0.009, SMD = 0.37, 95% CI = 0.09–0.65). Based on follow-up periods of at least 6 weeks, the following stimulation protocols have demonstrated efficacy for AD: stimulation sites (single or multiple targets), frequency (20 Hz), stimulation time (1–2 s), interval (20–30 s), single pulses (≤2500), total pulses (>20000), duration (≥3 weeks), and sessions (≥20). Conclusions: This study suggests that rTMS may be an effective treatment option for patients with AD, and its potential therapeutic capabilities should be further developed in the future. Show more

Keywords: Alzheimer’s disease, meta-analysis, repetitive transcranial magnetic stimulation, systematic review

DOI: 10.3233/JAD-231031

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 481-503, 2024

Authors: Wang, YuanYing | Wang, ShiHao | Wu, JiaXin | Liu, XinLian | Zhang, LuShun

Article Type: Research Article

Abstract: Background: The link between allergic diseases and dementia remains controversial, and the genetic causality of this link is unclear. Objective: This study investigated the causal relationship between allergic diseases and dementia using univariate and multivariate Mendelian randomization (MR) methods. Methods: We selected genome-wide association studies including 66,645 patients with allergic diseases and 12,281 patients with dementia, with statistical datasets derived from the FinnGen Consortium of European origin. After a rigorous screening process for single nucleotide polymorphisms to eliminate confounding effects, MR estimation was performed mainly using the inverse variance weighting method and the MR-Egger method. Sensitivity …analyses were performed using Cochran’s Q test, MR-PRESSO test, MR Pleiotropy residuals and leave-one-out analysis. Results: Univariate and multivariate MR together demonstrated a causal relationship between atopic dermatitis and reduced vascular dementia (VaD) risk (OR = 0.89, 95% CI: 0.81–0.99, p  = 0.031; OR = 0.85, 95% CI: 0.76–0.95, p  = 0.003). MVMR confirmed asthma was associated with a reduction in the risk of Alzheimer’s disease (AD) (OR = 0.82, 95% CI: 0.71–0.94, p  = 0.005) and may be associated with a reduction in the risk of VaD (OR = 0.80, 95% CI: 0.65–0.99, p  = 0.042); allergic rhinitis may be causally associated with an increased risk of AD (OR = 1.16, 95% CI: 1.00–1.35, p  = 0.046) and VaD (OR = 1.29, 95% CI: 1.03–1.62, p  = 0.027). In sensitivity analyses, these findings were reliable. Conclusions: MR methods have only demonstrated that allergic rhinitis dementia is associated with an increased risk of developing dementia. Previously observed associations between other allergic diseases and dementia may be influenced by comorbidities and confounding factors rather than causality. Show more

Keywords: Alzheimer’s disease, allergic rhinitis, asthma, atopic dermatitis, dementia, Mendelian randomization

DOI: 10.3233/JAD-231091

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 505-517, 2024

Authors: Wang, Jing | Leong, I Tek | Johnson, Min Kyoung | Pei, Yaolin | Lee, Kyung Hee | Mittelman, Mary S. | Epstein, Cynthia | Cho, Soyeon | Wu, Bei

Article Type: Research Article

Abstract: Background: Chinese and Korean Americans are among the fastest-growing minority groups in the US but face disparities in income and limited English proficiency, leading to health inequities in Alzheimer’s disease and related dementias (ADRD) care. Objective: This study aims to understand cultural influences in ADRD care from the perspectives of Chinese and Korean American caregivers to inform culturally sensitive support for caregivers in Asian immigrant populations. Methods: We conducted a study that was part of a broader project aimed at informing the cultural adaptation of the NYU Caregiver Intervention-Enhanced Support (NYUCI-ES) program specifically for Chinese and …Korean American caregivers managing multiple chronic conditions. In our interviews with 14 Chinese American and 11 Korean American caregivers, we focused on how their roles as primary caregivers were influenced by cultural and family expectations, the impact of caregiving on their personal and emotional well-being, and the specific barriers they face in accessing healthcare for themselves and their relatives with dementia. Results: Cultural beliefs and values significantly influenced the perceptions and utilization of support systems among Chinese and Korean American caregivers. Family stigma and adherence to cultural norms impacted their caregiving experiences. The study also highlighted the added burden during the pandemic and the potential benefits of telehealth and information technology in ADRD care. Conclusions: Developing culturally tailored, person-centered programs is crucial to meeting the unique needs of Chinese and Korean American caregivers. This research contributes to understanding and supporting this vulnerable population, promoting healthcare equity for ADRD patients and caregivers. Show more

Keywords: Alzheimer’s disease, COVID-19, culture, ethnicity, self care, social stigma

DOI: 10.3233/JAD-231140

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 519-538, 2024

Authors: Kameyama, Hiroshi | Tagai, Kenji | Takasaki, Emi | Kashibayashi, Tetsuo | Takahashi, Ryuichi | Kanemoto, Hideki | Ishii, Kazunari | Ikeda, Manabu | Shigeta, Masatoshi | Shinagawa, Shunichiro | Kazui, Hiroaki

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) in patients with dementia lead to caregiver burdens and worsen the patient’s prognosis. Although many neuroimaging studies have been conducted, the etiology of NPS remains complex. We hypothesize that brain structural asymmetry could play a role in the appearance of NPS. Objective: This study explores the relationship between NPS and brain asymmetry in patients with Alzheimer’s disease (AD). Methods: Demographic and MRI data for 121 mild AD cases were extracted from a multicenter Japanese database. Brain asymmetry was assessed by comparing the volumes of gray matter in the left and right brain …regions. NPS was evaluated using the Neuropsychiatric Inventory (NPI). Subsequently, a comprehensive assessment of the correlation between brain asymmetry and NPS was conducted. Results: Among each NPS, aggressive NPS showed a significant correlation with asymmetry in the frontal lobe, indicative of right-side atrophy (r  = 0.235, p  = 0.009). This correlation remained statistically significant even after adjustments for multiple comparisons (p  < 0.01). Post-hoc analysis further confirmed this association (p  < 0.05). In contrast, no significant correlations were found for other NPS subtypes, including affective and apathetic symptoms. Conclusions: The study suggests frontal lobe asymmetry, particularly relative atrophy in the right hemisphere, may be linked to aggressive behaviors in early AD. These findings shed light on the neurobiological underpinnings of NPS, contributing to the development of potential interventions. Show more

Keywords: Alzheimer’s disease, asymmetry, behavioral and psychological symptoms of dementia, neuroimaging

DOI: 10.3233/JAD-231306

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 539-547, 2024

Authors: Vera, Robert | Hong, Nicholas | Jiang, Bailin | Liang, Ge | Eckenhoff, Maryellen F. | Kincaid, Halle J. | Browne, Veron | Chellaraj, Vinolia | Gisewhite, Douglas | Greenberg, Michael | Ranjan, Sudhir | Zhu, Gaozhong | Wei, Huafeng

Article Type: Research Article

Abstract: Background: Repurposing dantrolene to treat Alzheimer’s disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 and 9–11-month-old C57BL/6J mice. Blood and brain samples were collected 20 minutes after a single ERFR dose, and the plasma and brain concentrations were analyzed. Baseline behavior was assessed …in untreated PS19 tau transgenic mice at 6 and 9 months of age. PS19 mice were treated with intranasal ERFR, with or without acrolein (to potentiate cognitive dysfunction), for 3 months, beginning at 2 months of age. Animal behavior was examined, including cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: The dantrolene concentration in the blood and brain decreased with age, with the decrease greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction, or motor function in the PS19 mice compared to controls after chronic treatment with intranasal ERFR, even with acrolein. Conclusions: Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, calcium, cognition, dantrolene, pharmacokinetics, PS19 mice, ryanodine receptor, tau protein, therapeutics

DOI: 10.3233/JAD-231337

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 549-562, 2024

Authors: Wang, Carol Sheei-Meei | Chen, Po See | Tsai, Tsung-Yu | Hou, Nien-Tsen | Tang, Chia-Hung | Chen, Pai-Lien | Huang, Ying-Che | Cheng, Kuo-Sheng

Article Type: Research Article

Abstract: Background: Transcranial direct current stimulation (tDCS) is considered a potential therapeutic instrument for Alzheimer’s disease (AD) because it affects long-term synaptic plasticity through the processes of long-term potentiation and long-term depression, thereby improving cognitive ability. Nevertheless, the efficacy of tDCS in treating AD is still debated. Dorsal lateral prefrontal cortex is the main role in executive functions. Objective: We investigate the cognitive effects of tDCS on AD patients. Methods: Thirty mild AD patients aged 66–86 years (mean = 75.6) were included in a double-blind, randomized, sham-controlled crossover study. They were randomly assigned to receive 10 consecutive daily sessions …of active tDCS (2 mA for 30 min) or a sham intervention and switched conditions 3 months later. The anodal and cathodal electrodes were placed on the left dorsal lateral prefrontal cortex and the right supraorbital area, respectively. Subjects underwent various neuropsychological assessments before and after the interventions. Results: The results showed that tDCS significantly improved Cognitive Abilities Screening Instrument scores, especially on the items of “concentration and calculation”, “orientation”, “language ability”, and “categorical verbal fluency”. Mini-Mental State Examination and Wisconsin Card Sorting Test scores in all domains of “concept formation”, “abstract thinking”, “cognitive flexibility”, and “accuracy” also improved significantly after tDCS. For the sham condition, no difference was found between the baseline scores and the after-intervention scores on any of the neuropsychological tests. Conclusion: >: Using tDCS improves the cognition of AD patients. Further large size clinical trials are necessary to validate the data. Show more

Keywords: Alzheimer’s disease, cognitive function, effect, left dorsal lateral prefrontal cortex, transcranial direct currentstimulation

DOI: 10.3233/JAD-240002

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 563-577, 2024

Authors: Njomboro, Progress | Lekhutlile, Tlholego

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. Its initially characterized by progressive short-term memory loss followed by cross-domain cognitive decline in later stages resulting in significant functional deficits and loss of activities of daily living (ADLs) independence. Apathy and depression are frequent neuropsychiatric sequelae in AD, but their contribution to functional deficits is poorly understood. Objective: We aimed to quantitatively investigate if apathy and depressive symptoms predict ADLs in AD. We also wanted to fractionate apathy dimensions by factor-analyzing the apathy evaluation scale (AES) and then investigate the dimensions’ relation to ADLs. …Methods: We recruited a sample of 115 patients with probable or possible AD and assessed them for depression, apathy, and ADLs alongside other measures. We hypothesized that apathy and depressive symptoms would predict ADLs and that AES items will load into cognitive, behavioral, and affective factors that would differentially relate to ADLs. Results: Our results indicated that apathy symptoms predict ADLs deficits. The AES items resolved into a three-factor solution but the manner of clustering diverged from that proposed by AES authors. When these factors were regressed simultaneously, only behavioral apathy predicted global ADLs. Distinguishing basic from instrumental ADLs showed that behavioral and cognitive apathy symptoms associate with ADLs deficits while affective symptoms do not. Conclusions: Our results highlight the influence of apathy on ADLs in AD. This has important implications for patient care considering the high prevalence of apathy in AD and other dementing illnesses. Show more

Keywords: Activities of daily living, Alzheimer’s disease, apathy, depression

DOI: 10.3233/JAD-230426

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 579-591, 2024

Authors: Parker, Daniel C. | Whitson, Heather E. | Smith, Patrick J. | Kraus, Virginia B. | Huebner, Janet L. | North, Rebecca | Kraus, William E. | Cohen, Harvey Jay | Huffman, Kim M.

Article Type: Research Article

Abstract: Background: Some human studies have identified infection with cytomegalovirus (CMV), a member of the alpha herpesvirus family, as a risk factor for Alzheimer’s disease and related dementias (ADRD). To our knowledge, no studies have evaluated associations of CMV seropositivity with plasma biomarkers of ADRD risk in middle-aged adults. Objective: In participants recruited for an exercise study, we evaluated cross-sectional associations of CMV seropositivity with: Aβ42 /Aβ40 ratio, a low ratio suggestive of central nervous system Aβ accumulation; glial fibrillary acidic protein (GFAP), a measure of neuroinflammation; and neurofilament light (NfL), a measure of neurodegeneration. Methods: …Anti-CMV IgG was quantified by ELISA. Plasma ADRD biomarkers were quantified using the ultrasensitive SIMOA assay. We used linear regression to evaluate associations of CMV seropositivity with the ADRD biomarkers, adjusting for age, sex, and race (n  = 303; Age = 55.7±9.2 years). For ADRD biomarkers significantly associated with CMV seropositivity, we evaluated continuous associations of anti-CMV IgG levels with the ADRD biomarkers, excluding CMV seronegative participants. Results: 53% of participants were CMV seropositive. CMV seropositivity was associated with a lesser Aβ42 /Aβ40 ratio (β=–3.02e–03 95% CI [–5.97e–03, –7.18e–05]; p  = 0.045). In CMV seropositive participants, greater anti-CMV IgG levels were associated with a lesser Aβ42 /Aβ40 ratio (β=–4.85e–05 95% CI[–8.45e–05, –1.25e–05]; p  = 0.009). CMV seropositivity was not associated with plasma GFAP or NfL in adjusted analyses. Conclusions: CMV seropositivity was associated with a lesser plasma Aβ42 /Aβ40 ratio. This association may be direct and causally related to CMV neuro-cytotoxicity or may be indirect and mediated by inflammatory factors resulting from CMV infection burden and/or the immune response. Show more

Keywords: Alzheimer’s disease and related dementias, biomarkers, cytomegalovirus, herpesviruses

DOI: 10.3233/JAD-230220

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 593-600, 2024

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

Article Type: Correction

DOI: 10.3233/JAD-249006

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 739-739, 2024