Journal of Alzheimer's Disease - Volume 88, issue 4

Authors: Bleakley, Amy | Maloney, Erin K. | Harkins, Kristin | Nelson, Maria N. | Akpek, Eda | Langbaum, Jessica B.

Article Type: Research Article

Abstract: Background: There is a lack of racial, ethnic, and sex diversity in recruitment research registries and Alzheimer’s disease (AD) research studies and trials. Theory-based recruitment messages may provide an opportunity to increase study participant diversity in AD research studies and trials. Objective: To identify behavioral, normative, and control beliefs that are associated with joining an AD-focused recruitment registry among historically underrepresented groups. Method: Using a Reasoned Action Approach, we conducted 60 semi-structured phone interviews in 2020 among White, Black, and Hispanic adults ages 49–79 years in Philadelphia, PA. Underlying beliefs were elicited for the target behavior …of “signing up to be on a registry for brain health research studies in the next month.” Percentages based on counts are reported for the overall sample and by race and ethnicity and sex. Results: Participants were most concerned that if they were to sign up for a registry, they would be asked to participate in experimental studies. Advancing science to help others was a commonly reported positive belief about signing up. Participants’ children and friends/neighbors were important from a normative perspective. Barriers to enrollment focused on logistical concerns and inconvenient sign-up processes, including using a computer. Results show generally few racial and ethnic or sex group differences. Conclusion: The elicited beliefs from underrepresented groups offer a basis for understanding the behavior of signing up for research registries. However, there were few differences between the groups. Implications for outreach and recruitment are discussed. Show more

Keywords: Alzheimer’s disease, attitudes, health behavior, health communication, research participant recruitment

DOI: 10.3233/JAD-220196

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1499-1509, 2022

Authors: Rahja, Miia | Air, Tracy | Ahern, Susannah | Ward, Stephanie A. | Caughey, Gillian E. | Sluggett, Janet K. | Cations, Monica | Lin, Xiaoping | Wallis, Kasey | Crotty, Maria | Inacio, Maria C.

Article Type: Research Article

Abstract: Background: Studies related to clinical quality indicators (CQIs) in dementia have focused on hospitalizations, medication management, and safety. Less attention has been paid to indicators related to primary and secondary care. Objective: To evaluate the incidence of primary and secondary care CQIs for Australians with dementia using government-subsidized aged care. The examined CQIs were: comprehensive medication reviews, 75+ health assessments, comprehensive geriatric assessments, chronic disease management plans, general practitioner (GP) mental health treatment plans, and psychiatrist attendances. Methods: Retrospective cohort study (2011–2016) of 255,458 individuals. National trend analyses estimated incidence rates and 95% confidence intervals (CI) …using Poisson or negative binomial regression. Associations were assessed using backward stepwise multivariate Poisson or negative binomial regression model, as appropriate. Funnel plots examined geographic and permanent residential aged care (PRAC) facility variation. Results: CQI incidence increased in all CQIs but medication reviews. For the overall cohort, 75+ health assessments increased from 1.07/1000 person-days to 1.16/1000 person-days (adjusted incidence rate ratio (aIRR) = 1.03, 95% CI 1.02–1.03).Comprehensive geriatric assessments increased from 0.24 to 0.37/1000 person-days (aIRR = 1.12, 95% CI 1.10–1.14). GP mental health treatment plans increased from 0.04 to 0.07/1000 person-days (aIRR = 1.13, 95% CI 1.12–1.15). Psychiatric attendances increased from 0.09 to 0.11/1000 person-days (aIRR = 1.05, 95% CI 1.03–1.07). Being female, older, having fewer comorbidities, and living outside a major city were associated with lower likelihood of using the services. Large geographical and PRAC facility variation was observed (0–92%). Conclusion: Better use of primary and secondary care services to address needs of individuals with dementia is urgently needed. Show more

Keywords: Dementia, health care, health services for the aged, primary health care, quality indicators, secondary care

DOI: 10.3233/JAD-220336

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1511-1522, 2022

Authors: Sun, Wenhao | Wu, Qiuyan | Chen, Huifeng | Yu, Lechang | Yin, Jie | Liu, Fang | Tian, Rui | Song, Bingbing | Qu, Bingqian | Xing, Mengya | Zhang, Nan

Article Type: Research Article

Abstract: Background: The Hong Kong Brief Cognitive Test (HKBC), a brief instrument designed to screen for cognitive impairment in older adults, has been validated in Cantonese-speaking populations and has shown better performance than the Mini-Mental State Examination (MMSE) in detecting both mild and major neurocognitive disorder (NCD). Objective: This study aimed to validate the HKBC for detecting patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) in a Mandarin-speaking Chinese population. Methods: Two hundred forty-eight patients with aMCI, 67 patients with mild AD and 306 healthy controls (HCs) were recruited for this study and completed …both the HKBC and the MMSE. The performance of the HKBC and MMSE in distinguishing patients with aMCI from HCs and distinguishing patients with AD from patients with aMCI was compared in the whole population and in age- and education-stratified subgroups. Results: The optimal HKBC cutoff score for distinguishing patients with aMCI from HCs was 23, and the optimal cutoff score for distinguishing patients with AD from patients with aMCI was 17. The HKBC significantly outperformed the MMSE at differentiating patients with aMCI from HCs in the whole population (z  = 12.38, p  < 0.01) and all subgroups stratified by age or education. Regarding the discrimination of patients with AD from patients with aMCI, the HKBC showed better performance than the MMSE in the oldest subgroup (z  = 2.18, p  = 0.03). Conclusion: The HKBC is a sensitive and specific screening tool for detecting aMCI and AD in the Chinese population across age groups and educational levels. Show more

Keywords: Alzheimer’s disease, cognitive test, mild cognitive impairment, Mini-Mental State Examination

DOI: 10.3233/JAD-220417

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1523-1532, 2022

Authors: Motazedi, Ehsan | Cheng, Weiqiu | Thomassen, Jesper Q. | Frei, Oleksandr | Rongve, Arvid | Athanasiu, Lavinia | Bahrami, Shahram | Shadrin, Alexey | Ulstein, Ingun | Stordal, Eystein | Brækhus, Anne | Saltvedt, Ingvild | Sando, Sigrid B. | O’Connell, Kevin S. | Hindley, Guy | van der Meer, Dennis | Bergh, Sverre | Nordestgaard, Børge G. | Tybjærg-Hansen, Anne | Bråthen, Geir | Pihlstrøm, Lasse | Djurovic, Srdjan | Frikke-Schmidt, Ruth | Fladby, Tormod | Aarsland, Dag | Selbæk, Geir | Seibert, Tyler M. | Dale, Anders M. | Fan, Chun C. | Andreassen, Ole A.

Article Type: Research Article

Abstract: Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian …DemGene cohort (n  = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n  = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n  = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations. Show more

Keywords: Age at onset, Alzheimer’s disease, Nordic ancestry, polygenic hazard score

DOI: 10.3233/JAD-220174

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1533-1544, 2022

Authors: Boujelbane, Mohamed Ali | Trabelsi, Khaled | Boukhris, Omar | Kacem, Faten Hadj | Ammar, Achraf | Charfi, Ichrak | Turki, Mouna | Charfeddine, Salma | Bouaziz, Bassem | Hakim, Ahmed | Frikha, Hamdi | Chabchoub, Mohamed Amine | Chtourou, Hamdi | Glenn, Jordan M. | Myers, Jennifer Rae

Article Type: Research Article

Abstract: Background: There has been increasing evidence and support for the use of digital technology in the cognitive health field. Despite the growing use of innovative digital technology to assess cognitive function, such technology remains scarce in Arabic countries, particularly in Tunisia. Objective: To investigate the effectiveness of a digitally delivered cognitive assessment battery in differentiating varying degrees of cognitive function in older Tunisian adults. Methods: One hundred fifty-five Tunisian older adults (age: 62.24±7.52 years) were assigned to one of four groups: healthy controls (HC), at-risk (AR), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Participants completed …a translated version of the Neurotrack digital cognitive battery. Results: The AD group performed significantly lower on the associative learning (p  = 0.01) and associative memory assessments (p  = 0.002), than the HC and AR groups. The AD group also performed worse on the inhibition measure (p  = 0.008) than the HC, AR, and MCI groups. For recognition memory, the was a significant difference between all four groups (p  < 0.0005), with AD having the lowest scores followed by the MCI, AR, and HC groups, respectively. There were no significant differences observed on attention, executive function and processing speed performance between the four groups (p  > 0.05). Conclusion: The use of digital technology appears to be a viable solution to current cognitive assessment challenges for assessing cognitive function in a Tunisian population. These findings provide further support for the use of digital technology in cognitive assessment, particularly in understudied populations. Show more

Keywords: Aging, cognitive decline, dementia, digital technology, eye-tracking movement

DOI: 10.3233/JAD-220398

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1545-1552, 2022

Authors: Howard, Erica | Ballinger, Samantha | Kinney, Nikolas G. | Balgenorth, Yvonne | Ehrhardt, Annabess | Phillips, Jeffrey S. | Irwin, David J. | Grossman, Murray | Cousins, Katheryn A.Q.

Article Type: Research Article

Abstract: Background: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS. Objective: To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD). Methods: Fifty-six patients (LBSD = 35; PSP = 21) …completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman’s and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls. Results: PSP had worse complex numbers performance than LBSD (F  = 6.06, p  = 0.02) but similar basic numbers performance (F  = 0.38, p  > 0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p  = 0.01) but not JOLO (rho = 0.23, p  > 0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance. Conclusion: PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy. Show more

Keywords: Cognitive decline, executive function, frontal lobe, neurodegenerative diseases, Parkinsonian disorders, progressive supranuclear palsy

DOI: 10.3233/JAD-215327

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1553-1566, 2022

Authors: Chia, Sook Yoong | Vipin, Ashwati | Ng, Kok Pin | Tu, Haitao | Bommakanti, Ananth | Wang, Brian Zhiyang | Tan, Yi Jayne | Zailan, Fatin Zahra | Ng, Adeline Su Lyn | Ling, Shuo-Chien | Okamura, Katsutomo | Tan, Eng-King | Kandiah, Nagaendran | Zeng, Li

Article Type: Research Article

Abstract: Background: There is an urgent need for noninvasive, cost-effective biomarkers for Alzheimer’s disease (AD), such as blood-based biomarkers. They will not only support the clinical diagnosis of dementia but also allow for timely pharmacological and nonpharmacological interventions and evaluations. Objective: To identify and validate a novel blood-based microRNA biomarker for dementia of the Alzheimer’s type (DAT). Methods: We conducted microRNA sequencing using peripheral blood mononuclear cells isolated from a discovery cohort and validated the identified miRNAs in an independent cohort and AD postmortem tissues. miRNA correlations with AD pathology and AD clinical-radiological imaging were conducted. We …also performed bioinformatics and cell-based assay to identify miRNA target genes. Results: We found that miR-150-5p expression was significantly upregulated in DAT compared to mild cognitive impairment and healthy subjects. Upregulation of miR-150-5p was observed in AD hippocampus. We further found that higher miR-150-5p levels were correlated with the clinical measures of DAT, including lower global cognitive scores, lower CSF Aβ42 , and higher CSF total tau. Interestingly, we observed that higher miR-150-5p levels were associated with MRI brain volumes within the default mode and executive control networks, two key networks implicated in AD. Furthermore, pathway analysis identified the targets of miR-150-5p to be enriched in the Wnt signaling pathway, including programmed cell death 4 (PDCD4 ). We found that PDCD4 was downregulated in DAT blood and was downregulated by miR-150-5p at both the transcriptional and protein levels Conclusion: Our findings demonstrated that miR-150-5p is a promising clinical blood-based biomarker for DAT Show more

Keywords: Alzheimer’s dementia, biomarker, cerebrospinal fluid, MRI, microRNA

DOI: 10.3233/JAD-220116

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1567-1584, 2022

Authors: Nabirotchkin, Serguei | Bouaziz, Jan | Glibert, Fabrice | Mandel, Jonas | Foucquier, Julie | Hajj, Rodolphe | Callizot, Noëlle | Cholet, Nathalie | Guedj, Mickaël | Cohen, Daniel

Article Type: Research Article

Abstract: Background: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. Objective: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations …of repurposed drugs for treatment of common human diseases. Methods: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. Results: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. Conclusion: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer’s disease. Show more

Keywords: Drug combination, drug repurposing, genetics, networks, neurodegeneration, pathways, systems biology

DOI: 10.3233/JAD-220120

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1585-1603, 2022

Authors: Camino, Julieta | Khondoker, Mizanur | Trucco, Ana Paula | Backhouse, Tamara | Kishita, Naoko | Mioshi, Eneida

Article Type: Research Article

Abstract: Background: The identification and understanding of the discrepancy between caregivers’ reports of people with dementia’s (PwD) performance of activities of daily living (ADLs) and observed performance, could clarify what kind of support a PwD effectively needs when completing tasks. Strategies used by caregivers have not been included in the investigation of this discrepancy. Objective: To (1) investigate if caregivers’ report of PwD’s ADL performance are consistent with PwD’s observed performance; (2) explore if caregiver management styles, depression, and anxiety, contribute to this discrepancy. Methods: PwD (n  = 64) were assessed with standardized performance-based (Assessment of Motor and …Process Skills, AMPS) and informant-based (Disability Assessment for Dementia, DAD) ADL assessments. Caregivers completed depression (PHQ-9), anxiety (GAD-7), and dementia management style (DMSS: criticism, active-management, and encouragement) questionnaires. Cohen’s kappa determined agreement/disagreement in ADL performance. To investigate the potential discrepancy between the DAD and AMPS, a continuous variable was generated: comparative ADL score. Multiple linear regression analysis explored whether caregivers’ management styles, depression or anxiety could explain the ADL discrepancy. Results: Poor level of agreement between observed and reported ADL performance [k  = –0.025 (95% CI –0.123 –0.073)] was identified, with most caregivers underestimating ADL performance. The combined model explained 18% (R2  = 0.18, F (5,55)   = 2.52, p ≤0.05) of the variance of the comparative ADL score . Active-management (β= –0.037, t  (60)   = –3.363, p  = 0.001) and encouragement (β= 0.025, t  (60)   = 2.018, p  = 0.05) styles made the largest and statistically significant contribution to the model. Conclusion: Encouragement style could be advised for caregivers who underestimate ADL performance, while active management style for those who overestimate it. Findings have scope to increase caregivers’ abilities to support PwD activity engagement in daily life. Show more

Keywords: Activities of daily living, caregiver management styles, anxiety, depression

DOI: 10.3233/JAD-220155

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1605-1614, 2022

Authors: Ramanan, Vijay K. | Heckman, Michael G. | Przybelski, Scott A. | Lesnick, Timothy G. | Lowe, Val J. | Graff-Radford, Jonathan | Mielke, M. | Jack Jr. , Clifford R. | Knopman, David S. | Petersen, Ronald C. | Ross, Owen A. | Vemuri, Prashanthi

Article Type: Research Article

Abstract: Background: Brain accumulation of amyloid-β is a hallmark event in Alzheimer’s disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. Objective: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer’s Disease …Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. Results: Known AD risk variants in APOE , PICALM , CR1 , and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p  = 1.51×10–50 ) and ADNI (p  = 3.21×10–64 ). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels. Conclusion: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity. Show more

Keywords: Alzheimer’s disease, amyloid, Apolipoprotein E, polygenic risk scores, positron emission tomography

DOI: 10.3233/JAD-220164

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1615-1625, 2022