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