Journal of Alzheimer's Disease - Volume 91, issue 4

Authors: Zhu, Min | Tang, Minglu | Du, Yifeng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) brings heavy burden to society and family. There is an urgent need to find effective methods for disease diagnosis and treatment. The robust rank aggregation (RRA) approach that could aggregate the resulting gene lists has been widely utilized in genomic data analysis. Objective: To identify hub genes using RRA approach in AD. Methods: Seven microarray datasets in frontal cortex from GEO database were used to identify differential expressed genes (DEGs) in AD patients using RRA approach. STRING was performed to explore the protein-to-protein interaction (PPI). Gene Ontology enrichment and Kyoto Encyclopedia of …Genes and Genomes pathway analyses were utilized for enrichment analysis. Human Gene Connectome and Gene Set Enrichment Analysis were used for functional annotation. Finally, the expression levels of hub genes were validated in the cortex of 5xFAD mice by quantitative real-time polymerase chain reaction. Results: After RRA analysis, 473 DEGs (216 upregulated and 257 downregulated) were identified in AD samples. PPI showed that DEGs had a total of 416 nodes and 2750 edges. These genes were divided into 17 clusters, each of which contains at least three genes. After functional annotation and enrichment analysis, TAC1 is identified as the hub gene and may be related to synaptic function and inflammation. In addition, Tac1 was found downregulated in cortices of 5xFAD mice. Conclusion: In the current study, TAC1 is identified as a key gene in the frontal cortex of AD, providing insight into the possible pathogenesis and potential therapeutic targets for this disease. Show more

Keywords: Alzheimer’s disease, bioinformatics, synaptic function, tachykinins

DOI: 10.3233/JAD-220950

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1339-1349, 2023

Authors: Wang, Jian | Yu, Neng-Wei | Wang, Duo-Zi | Guo, Lei | Yang, Shu | Zheng, Bo | Guo, Fu-Qiang | Wang, Jian-Hong

Article Type: Research Article

Abstract: Background: Previous cross-sectional studies have identified a possible link between Helicobacter pylori (H. pylori ) infection and dementia. However, the association of H. pylori infection with longitudinal cognitive decline has rarely been investigated. Objective: This cohort study aims to demonstrate the effects of H. pylori infection on longitudinal cognitive decline. Methods: This cohort study recruited 268 subjects with memory complaints. Among these subjects, 72 had a history of H. pylori infection, and the rest 196 subjects had no H. pylori infection. These subjects were followed up for 24 months and received …cognitive assessment in fixed intervals of 12 months. Results: At baseline, H. pylori infected, and uninfected participants had no difference in MMSE scores. At 2 years of follow-up, H. pylori infected participants had lower MMSE scores than uninfected participants. H. pylori infection was associated with an increased risk of longitudinal cognitive decline, as defined by a decrease of MMSE of 3 points or more during follow-up, adjusting for age, sex, education, APOE ɛ 4 genotype, hypertension, diabetes, hyperlipidemia, and smoking history (HR: 2.701; 95% CI: 1.392 to 5.242). H. pylori infection was associated with larger cognitive decline during follow-up, adjusting for the above covariates (standardized coefficient: 0.282, p  < 0.001). Furthermore, H. pylori infected subjects had significantly higher speed of cognitive decline than uninfected subjects during follow-up, adjusting for the above covariates. Conclusion: H. pylori infection increases the risk of longitudinal cognitive decline in older subjects with memory complaints. This study is helpful for further understanding the association between infection and dementia. Show more

Keywords: Alzheimer’s disease, cognitive decline, Helicobacter pylori , infection

DOI: 10.3233/JAD-221112

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1351-1358, 2023

Authors: Janse, André | van de Rest, Ondine | de Groot, Lisette C.P.G.M. | Witkamp, Renger F.

Article Type: Research Article

Abstract: Background: Vitamin D deficiency is associated with all-cause dementia and Alzheimer’s disease (AD). At the same time, this knowledge is limited specifically for vascular dementia (VaD), while data regarding other subtypes of dementia are even more limited. Objective: To investigate the association of 25-hydroxy vitamin D (25(OH)D) status with dementia subtypes in an outpatient geriatric population. Methods: In a cross-sectional design, we analyzed data from 1,758 patients of an outpatient memory clinic in The Netherlands. Cognitive disorders were diagnosed by a multidisciplinary team according to international clinical standards. At each first-visit 25(OH)D levels were measured. Data …were analyzed using ANCOVA in four models with age, gender, BMI, education, alcohol, smoking, season, polypharmacy, calcium, eGFR, and glucose as co-variates. 25(OH)D was treated as a continuous square rooted (sqr) variable. Results: In the fully adjusted model, reduced 25(OH)D serum levels (sqr) were found in AD (estimated mean 7.77±0.11 CI95% 7.55-7.99): and in VaD (estimated mean 7.60±0.16 CI95% 7.28-7.92) patients compared to no-dementia (ND) patients (estimated mean 8.27±0.09 CI95% 8.10-8.45) (ND-AD: p  = 0.006, CI95% 0.08-0.92.; ND-VaD p  = 0.004 CI95% 0.13-1.22). We did not find differences in 25(OH)D levels of mild cognitive impairment (MCI) or other dementia patients compared to ND patients, nor differences in comparing dementia subtypes. Conclusion: We observed significantly lower 25(OH)D serum levels in both AD and VaD patients compared to no-dementia patients, but no significant differences between MCI and Lewy body and mixed dementia subtypes in this cross-sectional study of a geriatric outpatient clinic population. Show more

Keywords: 25(OH)D, Alzheimer’s disease, cognition, dementia, Lewy body dementia, mild cognitive impairment, vascular dementia, vitamin D

DOI: 10.3233/JAD-220732

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1359-1369, 2023

Authors: Hays Weeks, Chelsea C. | Zlatar, Zvinka Z. | Meloy, M.J. | Shin, David D. | Thomas, Liu | Wierenga, Christina E.

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele confers risk for age and Alzheimer’s disease related cognitive decline but the mechanistic link remains poorly understood. Blood oxygenation level dependent (BOLD) response in the fusiform gyrus (FG) during object naming appears greater among APOE ɛ 4 carriers even in the face of equivalent cognitive performance, suggesting neural compensation. However, BOLD is susceptible to known age and APOE -related vascular changes that could confound its interpretation. Objective: To address this limitation, we used calibrated fMRI during an object naming task and a hypercapnic challenge to obtain a more …direct measure of neural function – percent change cerebral metabolic rate of oxygen consumption (%ΔCMRO2 ). Methods: Participants were 45 older adults without dementia (28 ɛ 4–, 17 ɛ 4+) between the ages of 65 and 85. We examined APOE -related differences in %ΔCMRO2 in the FG during object naming and the extent to which APOE modified associations between FG %ΔCMRO2 and object naming accuracy. Exploratory analyses also tested the hypothesis that %ΔCMRO2 is less susceptible to vascular compromise than are measures of %ΔCBF and %ΔBOLD. Results: We observed a modifying role of APOE on associations between FG %ΔCMRO2 and cognition, with ɛ 4 carriers (but not non-carriers) demonstrating a positive association between right FG %ΔCMRO2 and object naming accuracy. Conclusion: Results suggest that the relationship between neural function and cognition is altered among older adult APOE ɛ 4 carriers prior to the onset of dementia, implicating CMRO2 response as a potential mechanism to support cognition in APOE -related AD risk. Show more

Keywords: Aging, Alzheimer’s disease, APOE ɛ4, calibrated fMRI, cerebral blood flow, cognition, cognitive decline, metabolism

DOI: 10.3233/JAD-220749

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1371-1383, 2023

Authors: Sacripante, Riccardo | Girtler, Nicola | Doglione, Elisa | Nobili, Flavio | Della Sala, Sergio

Article Type: Research Article

Abstract: Background: Some authors report steeper slopes of forgetting in early Alzheimer’s disease (AD), while others do not. Contrasting findings are thought to be due to methodological inconsistencies or variety of testing methods, yet they also emerge when people are assessed on the same testing procedure. Objective: We aimed to assess if forgetting slopes of people with mild cognitive impairment due to AD (MCI-AD) are different from age-matched healthy controls (HC) by using a prose paradigm. Methods: Twenty-nine people with MCI-AD and twenty-six HC listened to a short prose passage and were asked to freely recall it …after delays of 1 h and 24 h. Results: Generalized linear mixed modelling revealed that, compared to HC, people with MCI-AD showed poorer encoding at immediate recall and steeper forgetting up to 1 h in prose memory as assessed by free recall and with repeated testing of the same material. Forgetting rates between groups did not differ from 1 h to 24 h. Conclusion: The differences observed in MCI-AD could be due to a post-encoding deficit. These findings could be accounted either by a differential benefit from retrieval practice, whereby people with MCI-AD benefit less than HC, or by a working memory deficit in people with MCI-AD, which fails to support their memory performance from immediate recall to 1 h. Show more

Keywords: Alzheimer’s disease, episodic memory, forgetting, mild cognitive impairment, repeated testing

DOI: 10.3233/JAD-220803

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1385-1394, 2023

Authors: Mascarenhas Fonseca, Luciana | Sage Chaytor, Naomi | Olufadi, Yunusa | Buchwald, Dedra | Galvin, James E. | Schmitter-Edgecombe, Maureen | Suchy-Dicey, Astrid

Article Type: Research Article

Abstract: Background: American Indians have high prevalence of risk factors for Alzheimer’s disease and related dementias (ADRD) compared to the general population, yet dementia onset and frequency in this population are understudied. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, may be a novel, noninvasive biomarker of neurodegeneration and early dementia. Objective: To characterize the cross-sectional associations between IICV and hippocampal, total brain volume, and white matter disease measured by magnetic resonance imaging (MRI) among older American Indians. Methods: IICV measures for memory, executive function, and …processing speed, and multidomain cognition were calculated for 746 American Indians (aged 64–95) who underwent MRI. Regression models were used to examine the associations of IICV score with hippocampal volume, total brain volume, and graded white matter disease, adjusting for age, sex, education, body mass index, intracranial volume, diabetes, stroke, hypertension, hypercholesterolemia, alcohol use, and smoking. Results: Higher memory IICV measure was associated with lower hippocampal volume (Beta = –0.076; 95% CI –0.499, –0.023; p  = 0.031). After adjustment for Bonferroni or IICV mean scores in the same tests, the associations were no longer significant. No IICV measures were associated with white matter disease or total brain volume. Conclusion: These findings suggest that the IICV measures used in this research cannot be robustly associated with cross-sectional neuroimaging features; nonetheless, the results encourage future studies investigating the associations between IICV and other brain regions, as well as its utility in the prediction of neurodegeneration and dementia in American Indians. Show more

Keywords: Alzheimer’s disease, American Indians, cognitive variability, dementia, dispersion, indigenous, magnetic resonance imaging, Native Americans, neurodegeneration

DOI: 10.3233/JAD-220825

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1395-1407, 2023

Authors: Chenoweth, Lynn | Williams, Anna | McGuire, Jane | Reyes, Patricia | Maiden, Genevieve | Brodaty, Henry | Liu, Zhixin | Cook, Jacquelene | McCade, Donna | Taylor-Rubin, Cathleen | Freeman, Matilda | Burley, Claire

Article Type: Research Article

Abstract: Background: While Australian guidelines promote person-centered healthcare (PCC) for persons with dementia, healthcare systems, routines, rules, and workplace cultures can pose challenges in the provision of PCC. Objective: To present a knowledge translation protocol of the PCC model in a sub-acute rehabilitation hospital. Methods: The two-year pre/post/follow-up translation project will include (n  = 80) persons with dementia, (n  = 80) adult family/carers of patient participants, (n  = 60) healthcare staff (medical, nursing, allied health), and (n  = 8) PCC staff champions. Champions will complete six half-days’ training in PCC. Medical, nursing, and allied health staff will be provided with PCC …learning manuals, complete six hours of online PCC education and attend six face-to-face PCC education sessions. Champions will provide ongoing support to staff in PCC practice. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework will be used to evaluate: i) outcomes for prospective patients provided with PCC, compared with a matched sample of retrospective patients (primary outcomes agitation incidence and severity); 2) champion and staff PCC knowledge, confidence, engagement, and practice quality; 3) person, family/carer, champion, and staff satisfaction with PCC; 4) PCC costs and benefits; and 5) organizational structures, systems and policies required to implement and maintain PCC in sub-acute healthcare. Results: We will identify if PCC benefits persons with dementia, staff, and healthcare services, and we will generate evidence on the educational and organizational resources required to embed PCC in practice. Conclusion: Project findings will inform tailored PCC education applications for dissemination in healthcare and produce evidence-based PCC practice guidelines to improve healthcare for persons with dementia. Show more

Keywords: Delirium, dementia, health personnel, hospitals, patient-centered care, quality of healthcare

DOI: 10.3233/JAD-220882

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1409-1421, 2023

Authors: Nicolazzo, Jessica | Cavuoto, Marina | Rowsthorn, Ella | Cribb, Lachlan | Bransby, Lisa | Gibson, Madeline | Wall, Prudence | Velakoulis, Dennis | Eratne, Dhamidhu | Buckley, Rachel | Yassi, Nawaf | Yiallourou, Stephanie | Brodtmann, Amy | Hamilton, Garun S. | Naughton, Matthew T. | Lim, Yen Ying | Pase, Matthew P.

Article Type: Research Article

Abstract: Background: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer’s disease remains equivocal. Objective: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a cognitively unimpaired middle-aged community sample. Methods: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia’s core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number …of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42 , phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOE ɛ 4 genotype. Results: Higher ISI score was associated with greater average levels of CSF Aβ42 (per point: 30.7 pg/mL, 95% CI: 4.17–57.3, p  = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48–223, p  = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55–192, p  < 0.001). Difficulty initiating sleep was not associated with CSF Aβ42 , nor were insomnia features associated with p-tau181, total-tau, or NfL levels. Conclusion: Insomnia symptoms were associated with higher CSF Aβ42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, insomnia, sleep

DOI: 10.3233/JAD-220924

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1423-1434, 2023

Authors: Tang, Xingyao | Wang, Ying | Simó, Rafael | Stehouwer, Coen D.A. | Zhou, Jian-Bo

Article Type: Research Article

Abstract: Background: Diabetes is a risk factor for cognitive impairment, and disease duration is associated with geriatric decline and functional disabilities. Objective: This study aimed to examine the association of diabetes duration with domain-specific cognitive impairment in elderly. Methods: A total of 3,142 participants from the National Health and Nutrition Examination Survey (NHANES) from the period between 2011 and 2014 were included. We assessed cognitive function using the Digit Symbol Substitution Test (DSST), the CERAD Word Learning (CERAD-WL) test, the CERAD Delayed Recall (CERAD-DR) test and animal fluency (AF) test. Results: After adjusting for age, …sex, race/ethnicity, education level, and annual household income, we found that diabetes with a duration longer than 20 years were at 3.32-fold increased risk of DSST impairment (OR = 3.32, 95% CI: 1.95 to 5.67), 1.72-fold increased risk of CERAD-WL impairment (OR = 1.72, 95% CI: 1.13 to 2.62), and 1.76-fold increased risk of AF impairment (OR = 1.76, 95% CI: 1.23 to 2.53), compared with those with no diabetes. Associations were generally stronger in women than in men. Participants with diabetes, who were diagnosed at 50–59 years old were at increased risk of DSST impairment, CERAD-WL impairment, CERAD-DR impairment, and AF impairment per 5 years longer duration of diabetes. Conclusion: Longer diabetes duration was associated with the increased risk of cognitive impairment, especially in processing speed and attention. The presence of chronic kidney disease was associated with the increased risk of DSST impairment. Show more

Keywords: Age of onset, cognitive impairment, diabetes duration

DOI: 10.3233/JAD-220972

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1435-1446, 2023

Authors: Igarashi, Ataru | Sakata, Yukinori | Azuma-Kasai, Mie | Kamiyama, Harue | Kawaguchi, Mika | Tomita, Kiyoyuki | Ishii, Mika | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: The need for a cognition bolt-on version of the EQ-5D, which would capture cognitive impairment by adding a dimension to the generic instrument assessing health status, has been increasing in Japan. Objective: To develop a cognition bolt-on version of the 5-level EQ-5D (EQ-5D-5L+C), we linguistically validated a cognition dimension and psychometrically validated the EQ-5D-5L+C. Methods: Following linguistic validation of the cognition dimension, psychometric validation of the EQ-5D-5L+C proxy version utilized anonymized data collected from nursing home residents between October 2021 to April 2022. The validity, reliability, and sensitivity to change were evaluated. Results: …Data from 254 participants, including the finalized Japanese EQ-5D-5L+C proxy version, were analyzed for the psychometric validation. Mean (±standard deviation) age and Mini-Mental State Examination (MMSE) scores were 87.14±7.29 years and 15.76±8.46, respectively. The correlation was strongest between the cognition dimension and MMSE scores (r s  = –0.640). Test-retest reliability was good in the cognition dimension in both baseline and two-time points (3 months: k  = 0.644; 6 months: k  = 0.656). Although a correlation between changes in the cognition dimension and those in the MMSE score from baseline was weak (3 months: r s  = –0.191; 6 months: r s  = –0.267), a correlation with changes in the MMSE score was higher when the cognition dimension was added compared to the EQ-5D alone (3 months: r s  = –0.142 versus r s  = –0.074). Conclusion: The Japanese EQ-5D-5L+C proxy version developed is a valid tool that captures health status including cognitive function, with a consideration for an over-time assessment. The benefits in adding the cognition dimension to the EQ-5D-5L to assess health state were suggested. Show more

Keywords: Cognition, health status, quality of life, psychometrics, public health

DOI: 10.3233/JAD-221080

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1447-1458, 2023