Journal of Alzheimer's Disease - Volume 100, issue 4

Authors: Mace, Ryan A. | Lyons, Christopher | Cohen, Joshua E. | Ritchie, Christine | Bartels, Stephen | Okereke, Olivia I. | Hoeppner, Bettina B. | Brewer, Judson A. | Vranceanu, Ana-Maria

Article Type: Research Article

Abstract: Background: Interventions that promote healthy lifestyles are critical for the prevention of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). However, knowledge of the best practices for implementing AD/ADRD prevention in healthcare settings remains limited. Objective: We aimed to qualitatively identify barriers and facilitators to implementing a clinical trial of a novel lifestyle intervention (My Healthy Brain ) in our medical center for older patients with subjective cognitive decline who are at-risk for AD/ADRD. Methods: We conducted focus groups with 26 healthcare professionals (e.g., physicians, psychology, nursing) from 5 clinics that treat older patients (e.g., memory …care, psychiatry). Our qualitative analysis integrated two implementation frameworks to systematically capture barriers and facilitators to AD/ADRD prevention (Consolidated Framework for Implementation Science Research) that impact implementation outcomes of acceptability, appropriateness, and feasibility (Proctor’s framework). Results: We found widespread support for an RCT of My Healthy Brain and AD/ADRD prevention. Participants identified barriers related to patients (stigma, technological skills), providers (dismissiveness of “worried well,” doubting capacity for behavior change), clinics (limited time and resources), and the larger healthcare system (underemphasis on prevention). Implementation strategies guided by Expert Recommendations for Implementing Change (ERIC) included: developing tailored materials, training staff, obtaining buy-in from leadership, addressing stigmatized language and practices, identifying “champions,” and integrating with workflows and resources. Conclusions: The results will inform our recruitment, enrollment, and retention procedures to implement the first randomized clinical trial of My Healthy Brain . Our study provides a blueprint for addressing multi-level barriers to the implementation of AD/ADRD prevention for older patients in medical settings. Show more

Keywords: Alzheimer’s disease, brain health, dementia, implementation, prevention, qualitative

DOI: 10.3233/JAD-240365

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1237-1259, 2024

Authors: Wang, Hongqi | Li, Jilai | Tu, Wenjun | Wang, Zhiqun | Zhang, Yiming | Chang, Lirong | Wu, Yan | Zhang, Xia

Article Type: Research Article

Abstract: Background: Blood biomarkers are crucial for the diagnosis and therapy of Alzheimer’s disease (AD). Energy metabolism disturbances are closely related to AD. However, research on blood biomarkers related to energy metabolism is still insufficient. Objective: This study aims to explore the diagnostic and therapeutic significance of energy metabolism-related genes in AD. Methods: AD cohorts were obtained from GEO database and single center. Machine learning algorithms were used to identify key genes. GSEA was used for functional analysis. Six algorithms were utilized to establish and evaluate diagnostic models. Key gene-related drugs were screened through network pharmacology. …Results: We identified 4 energy metabolism genes, NDUFA1 , MECOM , RPL26 , and RPS27 . These genes have been confirmed to be closely related to multiple energy metabolic pathways and different types of T cell immune infiltration. Additionally, the transcription factors INSM2 and 4 lncRNAs were involved in regulating 4 genes. Further analysis showed that all biomarkers were downregulated in the AD cohorts and not affected by aging and gender. More importantly, we constructed a diagnostic prediction model of 4 biomarkers, which has been validated by various algorithms for its diagnostic performance. Furthermore, we found that valproic acid mainly interacted with these biomarkers through hydrogen bonding, salt bonding, and hydrophobic interaction. Conclusions: We constructed a predictive model based on 4 energy metabolism genes, which may be helpful for the diagnosis of AD. The 4 validated genes could serve as promising blood biomarkers for AD. Their interaction with valproic acid may play a crucial role in the therapy of AD. Show more

Keywords: Alzheimer’s disease, diagnostic biomarkers, drug prediction, energy metabolism, machine learning

DOI: 10.3233/JAD-240301

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1261-1287, 2024

Authors: van den Kieboom, Robin | Snaphaan, Liselore | Mark, Ruth | van Assen, Marcel | Bongers, Inge

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms are a robust risk factor for caregiver burden in family dementia caregivers. By grouping these symptoms, clinical interpretations regarding neuropsychiatric symptoms may facilitated because different groups of symptoms may require a different approach for intervention, thereby reducing caregiver burden. Objective: As clustering of neuropsychiatric symptoms could be clinically relevant, we aimed to explore the effects of these clusters on burden in family dementia caregivers. Methods: 152 family dementia caregivers were included. Caregiver burden was measured using the Ervaren Druk door Informele Zorg (EDIZ)/Self-Perceived Pressure from Informal Care, a Dutch questionnaire. Caregivers also reported …the neuropsychiatric symptoms and functional impairments in daily activities of the people with dementia they cared for. Multiple regression analyses were used in this cross-sectional study. Results: Adjusted for functional impairments and sociodemographic variables, neuropsychiatric symptoms were associated with more caregiver burden (p  < 0.001). However, this association did not differ between the three neuropsychiatric symptom clusters (p  = 0.745). Conclusions: Neuropsychiatric symptoms were associated with more family caregiver burden, but no conclusive evidence was found that this association differed for the three clusters. Clustering of neuropsychiatric symptoms is, however, worth exploring further in future studies with more participants. If specific links are found, these could be targeted in clinical practice in order to prevent, reduce and/or postpone caregiver burden. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, carers, community care, dementia

DOI: 10.3233/JAD-230972

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1289-1298, 2024

Authors: Wang, Wan | Gong, Zhenping | Wang, Yadan | Zhao, Ying | Lu, Yaru | Sun, Ruihua | Zhang, Haohan | Shang, Junkui | Zhang, Jiewen

Article Type: Research Article

Abstract: Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic …kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy. Show more

Keywords: Alzheimer’s disease, autophagy, CADASIL, mitochondrial dysfunction, NOTCH3ECD mutation, mitophagy

DOI: 10.3233/JAD-240273

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1299-1314, 2024

Authors: Brar, Manjot | Mc Ardle, Ríona | Hagan, Alexander | Al-Oraibi, Amani | Hanjari, Matilda | Stephan, Blossom | Brayne, Carol | Lafortune, Louise | Bains, Manpreet | Qureshi, Nadeem | Robinson, Louise

Article Type: Research Article

Abstract: Background: Increased understanding of dementia risk-reduction and early detection of Alzheimer’s disease and related disorders has spurred interest in the identification of risks for dementia, underlying putative biologies, or dementia itself. Implementation of such approaches require acceptability to the public. Research prior to 2012 indicated limited acceptability for population dementia screening. The changing landscape of dementia prevention research may influence recent perceptions. Additionally, perspectives from underserved populations, such as ethnic minorities and low socio-economic groups, are lacking. Objective: In this systematic review, we sought published studies since 2012 on attitudes and preferences of people with dementia, carers and …the general public from ethnic minorities and low socio-economic groups regarding dementia screening. Methods: This review was preregistered on PROSPERO (CRD42023384115) and followed PRISMA guidelines. Key search terms were entered into five databases. Articles were included if they focused on population or risk screening for dementia via primary/community care-based assessments, and which included majority ethnic minority or low socio-economic groups or discretely considered these groups in data analysis. Data were synthesized narratively. Results: Seven studies reported perspectives of ethnic minorities regarding dementia screening; one study included people from low socio-economic groups. Results indicated that participants from ethnic minorities were willing to undergo dementia screening. Predictors of willingness included belief in benefits, desire to boost diversity, and to implement lifestyle changes. Unwillingness was associated with anxiety regarding results. Conclusions: Although there seems to be high acceptability for screening in the studied groups, more research is necessary to explore the practical considerations for screening such as cultural and economic barriers, trust, and post-screening actions. Show more

Keywords: Alzheimer’s disease, attitudes, dementia, ethnic minorities, low socioeconomic status, preferences, screening

DOI: 10.3233/JAD-240315

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1315-1331, 2024

Authors: Han, Bao-Lin | Ma, Ling-Zhi | Han, Shuang-Ling | Mi, Yin-Chu | Liu, Jia-Yao | Sheng, Ze-Hu | Wang, Hui-Fu | Tan, Lan

Article Type: Research Article

Abstract: Background: The relationship between Alzheimer’s disease (AD)-related pathology and cognition was not exactly consistent. Objective: To explore whether the association between AD pathology and cognition can be moderated by frailty. Methods: We included 1711 participants from the Alzheimer’s Disease Neuroimaging Initiative database. Levels of cerebrospinal fluid amyloid-β, p-tau, and t-tau were identified for AD-related pathology based on the amyloid-β/tau/neurodegeneration (AT[N]) framework. Frailty was measured using a modified Frailty Index-11 (mFI-11). Regression and interaction models were utilized to assess the relationship among frailty, AT(N) profiles, and cognition. Moderation models analyzed the correlation between AT(N) profiles and cognition …across three frailty levels. All analyses were corrected for age, sex, education, and APOE ɛ 4 status. Results: In this study, frailty (odds ratio [OR] = 1.71, p  < 0.001) and AT(N) profiles (OR = 2.00, p  < 0.001) were independently associated with cognitive status. The model fit was improved when frailty was added to the model examining the relationship between AT(N) profiles and cognition (p  < 0.001). There was a significant interaction between frailty and AT(N) profiles in relation to cognitive status (OR = 1.12, pinteraction  = 0.028). Comparable results were obtained when Mini-Mental State Examination scores were utilized as the measure of cognitive performance. The association between AT(N) profiles and cognition was stronger with the levels of frailty. Conclusions: Frailty may diminish patients’ resilience to AD pathology and accelerate cognitive decline resulting from abnormal AD-related pathology. In summary, frailty contributes to elucidating the relationship between AD-related pathology and cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid/tau/neurodegeneration (AT[N]) framework, cognition, frailty

DOI: 10.3233/JAD-231489

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1333-1343, 2024

Authors: Esiaka, Darlingtina | Odo, Obinna | Luth, Elizabeth

Article Type: Research Article

Abstract: Background: Research suggests that the neighborhood in which people live can be a risk or protective factor for various health outcomes, including cognitive decline to Alzheimer’s disease. Similar to the impact of neighborhood on health outcomes, sleep difficulties have been linked to cognitive function in older adults. However, few studies have examined how neighborhood physical disorders moderate the effects of sleep on subjective cognitive decline (SCD). Objective: The study examined the moderating effect of neighborhood factors on the relationship between sleep difficulties and SCD. Methods: Data were obtained from 2,494 respondents (1,065 males and 1,429 females) …from Wave 11 of the National Health and Aging Trends (NHATS) data. Sleep difficulties were operationalized as the presence of difficulties in falling and staying asleep. Neighborhood physical disorder (e.g., vandalism, graffiti) was based on interviewer observations of respondents’ neighborhoods. SCD was operationalized as subjective reports of increasing or worse memory loss in the past 12 months and present memory rating. We utilized Linear regression to test neighborhood physical disorder as a moderator of the relationship between sleep difficulties and SCD. Results: We found a significant interaction between sleep difficulties and neighborhood physical disorder on SCD (β=0.046, p = 0.031, 95% CI[0.00,0.51], p < 0.001). Participants who reported higher average sleep difficulties and higher levels of neighborhood physical disorder were more likely to report SCD. Conclusions: Our findings add to inform future health interventions and policy recommendations that address modifiable sources of cognitive decline and risk of Alzheimer’s disease. Show more

Keywords: ADRD risk, Alzheimer’s disease, cognitive decline, dementia, neighborhood, sleep

DOI: 10.3233/JAD-240142

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1345-1354, 2024

Authors: Syrjanen, Jeremy A. | Krell-Roesch, Janina | Kremers, Walter K. | Fields, Julie A. | Scharf, Eugene L. | Knopman, David S. | Petersen, Ronald C. | Vassilaki, Maria | Geda, Yonas E.

Article Type: Research Article

Abstract: Background: Studies that assess cognition prospectively and study in detail anxiety history in the participants’ medical records within the context of brain aging and Alzheimer’s disease are limited. Objective: To examine the associations of anxiety and unspecified emotional distress (UED) acquired throughout a person’s life with prospectively collected cognitive outcomes. Methods: Mayo Clinic Study of Aging participants who were cognitively unimpaired at baseline were included. Anxiety and UED data were abstracted from the medical record using the Rochester Epidemiology Project (REP) resources and were run separately as predictors in our models. The data were analyzed using …Cox proportional hazards models for the outcomes of incident mild cognitive impairment (MCI) and dementia and using linear mixed effects models for the outcomes of global and domain specific cognitive z-scores and included key covariates. Results: The study sample (n  = 1,808) had a mean (standard deviation) age of 74.5 (7.3) years and 51.4% were male. Anxiety was associated with increased risk of MCI and dementia and was associated with lower baseline cognitive z-scores and accelerated decline over time in the global, memory, and attention domains. UED was associated with faster decline in all domains except visuospatial but did not show evidence of association with incident cognitive outcomes. These results varied by medication use and timing of anxiety. Conclusions: Anxiety and UED both showed inverse associations with cognition. Utilization of anxiety and UED data from across the life course, as available, from the REP system adds robustness to our results. Show more

Keywords: Alzheimer’s disease, anxiety, cognition, dementia, mild cognitive impairment, neuropsychiatric symptoms

DOI: 10.3233/JAD-240213

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1355-1364, 2024

Authors: Wang, Ruo-Tong | Sun, Zhen | Tan, Chen-Chen | Tan, Lan | Xu, Wei

Article Type: Research Article

Abstract: Background: The causal relationships of late-life body mass index (BMI) with Alzheimer’s disease (AD) remains debated. Objective: We aimed to assess the associations of dynamic BMI features (ΔBMIs) with cognitive trajectories, AD biomarkers, and incident AD risk. Methods: We analyzed an 8-year cohort of 542 non-demented individuals who were aged ≥65 years at baseline and had BMI measurements over the first 4 years. ΔBMIs were defined as changing extent (change ≤ or >5%), variability (standard deviation), and trajectories over the first 4 years measured using latent class trajectory modeling. Linear mixed-effect models were utilized to examine …the influence of ΔBMIs on changing rates of AD pathology biomarkers, hippocampus volume, and cognitive functions. Cox proportional hazards models were used to test the associations with AD risk. Stratified analyzes were conducted by the baseline BMI group and age. Results: Over the 4-year period, compared to those with stable BMI, individuals who experienced BMI decreases demonstrated accelerated declined memory function (p  = 0.006) and amyloid-β deposition (p  = 0.034) while BMI increases were associated with accelerated hippocampal atrophy (p  = 0.036). Three BMI dynamic features, including stable BMI, low BMI variability, and persistently high BMI, were associated with lower risk of incident AD (p  < 0.005). The associations were validated over the 8-year period after excluding incident AD over the first 4 years. No stratified effects were revealed by the BMI group and age. Conclusions: High and stable BMI in late life could predict better cognitive trajectory and lower risk of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, body mass index, cognitive, late life, trajectory

DOI: 10.3233/JAD-240292

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1365-1378, 2024

Authors: Yu, Jian | Tang, Wenyu | Sulaiman, Zubaidan | Ma, Xin | Wang, Jiayi | Shi, Zhongyong | Liu, Qidong | Xie, Zhongcong | Shen, Yuan

Article Type: Research Article

Abstract: Background: Surgery may be associated with postoperative cognitive impairment in elder participants, yet the extent of its association with mild cognitive impairment (MCI) remains undetermined. Objective: To determine the relationship between surgery and MCI. Methods: The data of participants from the Alzheimer’s Disease Neuroimaging Initiative were analyzed, including individuals with MCI or normal cognition. We focused on surgeries conducted after the age of 45, categorized by the number of surgeries, surgical risk, and the age at which surgeries occurred. Multivariable logistic regression was employed to determine the association between surgery and the development of MCI. …Results: The study is comprised of 387 individuals with MCI and 578 cognitively normal individuals. The overall surgery exposure (adjusted OR = 1.14, [95% CI 0.83, 1.56], p  = 0.43) and the number of surgeries (adjusted OR = 0.92  [0.62, 1.36], p  = 0.67 for single exposure, adjusted OR = 1.12 [0.71, 1.78], p  = 0.63 for two exposures, adjusted OR = 1.38 [0.95, 2.01], p  = 0.09 for three or more exposures compared to no exposure as the reference) were not associated with the development of MCI. However, high-risk surgeries (adjusted OR = 1.79 [1.00, 3.21], p  = 0.049) or surgeries occurring after the age of 75 (adjusted OR = 2.01 [1.03, 3.90], p  = 0.041) were associated with a greater risk of developing MCI. Conclusions: High risk surgeries occurring at an older age contribute to the development of MCI, indicating a complex of mechanistic insights for the development of postoperative cognitive impairment. Show more

Keywords: Aging, Alzheimer’s disease, elderly, geriatric, mild cognitive impairment, surgery

DOI: 10.3233/JAD-240467

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1379-1388, 2024