Journal of Alzheimer's Disease - Volume 96, issue 2

Authors: Li, Yintong | Bian, Jinghua | Li, Yongna

Article Type: Research Article

Abstract: Background: Attention is an essential cognitive ability that is necessary in other cognitive processes. Only few studies have focused on decline in specific functions of attention in older adults with cognitive decline. No research explores the difference in the proactive and reactive mode of control between the healthy control (HC) and older adults with subjective cognitive decline (SCD). Objective: The current work investigated whether there was any decline in alerting, orienting, and executive control in SCD. Particularly, the present study further explored the impairment of the proactive and reactive control in SCD. Methods: We recruited 25 …HC and 26 SCD. All participants first finished a set of neuropsychological assessments. They then completed an Attention Network Test for measuring the alerting, orienting, and executive control, the List-wide and the Item-specific Proportion Congruency Effect task for measuring the proactive and reactive mode of control, respectively. Results: No difference was found in alerting, orienting, and executive control measured by the ANT between SCD and HC. The results also indicated no difference in the reactive control between SCD and HC. However, older adults with SCD performed worse in the proactive control as compared to HC. Conclusion: Older adults with SCD showed an impairment in the proactive control. The current findings help us better understand objective decline in cognitive domains other than memory and shed light on early assessment and prevention of AD. Show more

Keywords: Alzheimer’s disease, attention, attention network test, proactive control, reactive control, subjective cognitive decline

DOI: 10.3233/JAD-230037

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 551-561, 2023

Authors: Buchman, Aron S. | Leurgans, Sue E. | Kim, Namhee | Agrawal, Sonal | Oveisgharan, Shahram | Zammit, Andrea R. | VanderHorst, Veronique | Nag, Sukrit | Bennett, David A.

Article Type: Research Article

Abstract: Background: Assessments of Alzheimer’s disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. Objective: Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. Methods: Autopsies were obtained in decedents with cognitive testing (n  = 300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n  = 14), brainstem (n  = 5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases. Results: Age at death …was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. Conclusion: Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum. Show more

Keywords: Alzheimer’s disease dementia, amyloid-β, PHF tau-tangles

DOI: 10.3233/JAD-230223

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 563-578, 2023

Authors: Heser, Kathrin | Kleineidam, Luca | Wagner, Michael | Luppa, Melanie | Löbner, Margrit | Wiese, Birgitt | Oey, Anke | König, Hans-Helmut | Brettschneider, Christian | van der Leeden, Carolin | van den Bussche, Hendrik | Fuchs, Angela | Pentzek, Michael | Weyerer, Siegfried | Werle, Jochen | Bickel, Horst | Scherer, Martin | Maier, Wolfgang | Ramirez, Alfredo | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: Subjective memory complaints and family history of dementia are possibly intertwined risk factors for the own subsequent dementia risk and Alzheimer’s disease. However, their interaction has rarely been studied. Objective: To study the association between subjective memory complaints and family history of dementia with regard to the own subsequent risk of dementia. Methods: Cross-sectional and longitudinal analyses over a follow-up period of up to 13 years were conducted in a population sample of participants without dementia at baseline (n = 3,256, mean age = 79.62 years), using group comparisons and Cox proportional hazards models. …Results: Cross-sectionally, participants with subjective memory complaints were significantly more likely to report family history of dementia. Longitudinally, family history of dementia (FH) was significantly associated with subsequent dementia in the subjective memory complaints (SMC) group, but not in those without SMC. A relative excess risk due to interaction analysis confirmed a significant FHxSMC-interaction. Conclusions: Family history of dementia was a predictor of incident dementia in those with SMC, which can serve as an additional, clinically relevant criterion to gauge the risk of dementia in older-aged subjects with SMC with and without objective cognitive impairment. Show more

Keywords: Aging, Alzheimer’s disease, cognitive complaints, dementia, family history of dementia, memory complaints, mild cognitive impairment, subjective cognitive decline, subjective cognitive impairment

DOI: 10.3233/JAD-230410

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 579-589, 2023

Authors: Roach, Jared C. | Rapozo, Molly K. | Hara, Junko | Glusman, Gwênlyn | Lovejoy, Jennifer | Shankle, William R. | Hood, Leroy | Atthara, Mouna | Baloni, Priyanka | Dill, Lauren | Edens, Lance E. | Fischer, Dan | Fortier, Dennis | Fridman, Deborah | Funk, Cory C. | Glusman, Gwênlyn | Hara, Junko | Hood, Leroy | Jade, Kathleen | Lovejoy, Jennifer C. | Magis, Andrew | Markewych, Daria R. | Price, Nathan | Rapozo, Molly K. | Roach, Jared C. | Shankle, William R.

Article Type: Research Article

Abstract: Background: Comprehensive treatment of Alzheimer’s disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer’s disease (AD). Objective: The Coaching for Cognition in Alzheimer’s (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. Methods: Participants with early-stage AD were randomized into two arms. Arm 1 (N  = 24) received standard of care. Arm 2 (N  = 31) …additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. Results: The intervention arm ameliorated 2.1 [1.0 ] MPI points (mean [SD], p  = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. Conclusion: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic. Show more

Keywords: Alzheimer’s disease and related disorders, cognitive decline, cognitive impairment, cognitive training, diet, lifestyle, exercise, multimodal interventions, personalized 34 coaching, remote coaching

DOI: 10.3233/JAD-230403

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 591-607, 2023

Authors: Bian, Zhihong | Hu, Xinran | Liu, Xia | Yu, Haibo | Bian, Yuting | Sun, Hongming | Fukui, Yusuke | Morihara, Ryuta | Ishiura, Hiroyuki | Yamashita, Toru

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by cognitive dysfunction and memory loss that is accompanied by pathological changes to white matter. Some clinical and animal research revealed that AD combined with chronic cerebral hypoperfusion (CCH) exacerbates AD progression by inducing blood-brain barrier dysfunction and fibrinogen deposition. Rivaroxaban, an anticoagulant, has been shown to reduce the rates of dementia in atrial fibrillation patients, but its effects on white matter and the underlying mechanisms are unclear. Objective: The main purpose of this study was to explore the therapeutic effect of rivaroxaban on the white matter of AD+CCH mice. …Methods: In this study, the therapeutic effects of rivaroxaban on white matter in a mouse AD+CCH model were investigated to explore the potential mechanisms involving fibrinogen deposition, inflammation, and oxidative stress on remyelination in white matter. Results: The results indicate that rivaroxaban significantly attenuated fibrinogen deposition, fibrinogen-related microglia activation, oxidative stress, and enhanced demyelination in AD+CCH mice, leading to improved white matter integrity, reduced axonal damage, and restored myelin loss. Conclusions: These findings suggest that long-term administration of rivaroxaban might reduce the risk of dementia. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, chronic cerebral hypoperfusion, rivaroxaban, white matter

DOI: 10.3233/JAD-230413

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 609-622, 2023

Authors: Xia, Siqi | Chen, Huaijun | Tang, Tianchi

Article Type: Research Article

Abstract: Background: No study has compared the risk of Alzheimer’s disease (AD) in patients with brain tumors, gliomas, or glioblastomas with the risk in patients with other tumors. Objective: To determine whether, compared with other tumors, brain tumors, gliomas, and glioblastomas increase the risk of AD. Methods: This study identified a case group of 24,441 patients from the Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed with only one primary tumor at age > 20 years in 1975–2019 and died from AD at age > 65 years as case group. The control group comprised 122,205 subjects from the SEER …database who died from causes other than AD but otherwise had the same conditions as those in the case group. Results: There was a significantly lower prevalence of glioma (0.074% versus 0.14%, p  = 0.007) and glioblastoma (0.0082% versus 0.074%, p  = 0.001) in patients who died from AD than in those who died from other causes, while brain tumors were not significantly associated with AD death (p  = 0.227). When adjusted for factors including age at death, sex, race, tumor behavior, radiation therapy and tumor-directed surgery, glioblastoma was related to a significantly lower AD risk than other tumors (odds ratio: 0.19, 95% CI: 0.05–0.77). Additionally, patients who were older, female, American Indian/Alaska Native, had a benign tumor, radiation therapy and tumor-directed surgery had a significantly higher risk of dying from AD. Conclusion: Gliomas and glioblastomas were associated with a significantly lower risk of death from AD than other tumors. Show more

Keywords: Alzheimer’s disease, brain tumor, cancer, glioblastoma, glioma, risk, tumor

DOI: 10.3233/JAD-230554

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 623-631, 2023

Authors: Kim, Minjae | Yi, Dahyun | Byun, Min Soo | Ahn, Hyejin | Jung, Joon Hyung | Kong, Nayeong | Chang, Yoonyoung | Choi, Hyeji | Choi, Jungmin | Kim, Kyungtae | Jung, Gijung | Lee, Dong Young

Article Type: Research Article

Abstract: Background: As tracking subtle cognitive declines in the preclinical stage of Alzheimer’s disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. Objective: We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults. Methods: A total 225 cognitively normal elderly individuals from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease, were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composites. Three …candidate composites including Consortium to Establish a Registry for Alzheimer’s Disease Word list recall (WLR), Logical memory (LM) II, and Mini-Mental status examination (MMSE) in common, and Letter fluency test (LF), category fluency test, or Stroop color and word test, were selected. Results: Student t -tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two-year follow-up period between Aβ positive and negative group (p  = 0.03). Linear mixed model analyses also showed that the Aβ x time interaction effect was significant only for Composite 1 (p  = 0.025). Based on the results, Composite 1 was chosen as the final cognitive composite for preclinical Alzheimer’s disease (CPAD). Conclusions: CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in Korean older adults. It also may be used for monitoring progression or treatment benefits in clinical practices. Show more

Keywords: Alzheimer’s disease, cognitive composite, cognitively normal, preclinical Alzheimer’s disease

DOI: 10.3233/JAD-230263

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 633-641, 2023

Authors: Li, Anqi | Du, Jing | Cai, Yue | Chen, Xuhui | Sun, Kun | Guo, Tengfei

Article Type: Research Article

Abstract: Background: Body mass index (BMI) changes may be related to Alzheimer’s disease (AD) alterations, but it is unclear how the apolipoprotein E ɛ4 (APOE ɛ4) allele affects their association. Objective: To explore the association of BMI changes with AD pathologies in APOE ɛ4 carriers and non-carriers. Methods: In 862 non-demented ADNI participants with≥2 BMI measurements, we investigated the relationships between BMI slopes and longitudinal changes in amyloid-β (Aβ) accumulation, neurodegeneration and cognition, and follow-up tau deposition in different Aβ and APOE ɛ4 statuses. Results: In Aβ+ APOE ɛ4 non-carriers, faster …BMI declines were associated with faster rates of Aβ accumulation (standardized β (βstd ) = –0.29, p  = 0.001), AD meta regions of interest (metaROI) hypometabolism (βstd  = 0.23, p  = 0.026), memory declines (βstd  = 0.17, p  = 0.029), executive function declines (βstd  = 0.19, p  = 0.011), and marginally faster Temporal-metaROI cortical thinning (βstd  = 0.15, p  = 0.067) and higher follow-up Temporal-metaROI tau deposition (βstd  = –0.17, p  = 0.059). Among Aβ- individuals, faster BMI decreases were related to faster Aβ accumulation (βstd  = –0.25, p  = 0.023) in APOE ɛ4 carriers, whereas predicted faster declines in memory and executive function in both APOE ɛ4 carriers (βstd  = 0.25, p  = 0.008; βstd  = 0.32, p  = 0.001) and APOE ɛ4 non-carriers (βstd  = 0.11, p  = 0.030; βstd  = 0.12, p  = 0.026). Conclusions: This study highlights the significance of tracking BMI data in older adults by providing novel insights into how body weight fluctuations and APOE ɛ4 interact with AD pathology and cognitive decline. Show more

Keywords: Alzheimer’s disease, apolipoprotein E ɛ4, body mass index, cognitive decline, neurodegeneration

DOI: 10.3233/JAD-230446

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 643-655, 2023

Authors: Han, Xiaolei | Song, Lin | Li, Yuanjing | Dong, Yi | Liu, Rui | Han, Qi | Wang, Xiaojie | Mao, Ming | Cong, Lin | Tang, Shi | Hou, Tingting | Zhang, Qinghua | Liu, Cuicui | Han, Xiaodong | Shi, Lin | Nyberg, Lars | Launer, Lenore J. | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Sedentary behavior is associated with cognitive impairment, but the neuropathological mechanisms underlying their associations are poorly understood. Objective: To investigate the associations of accelerometer-measured sedentary behavior patterns with brain structure and cognition, and further to explore the potential mechanisms. Methods: This community-based study included 2,019 older adults (age≥60 years, 59% women) without dementia derived from participants in the baseline examination of MIND-China (2018–2020). We assessed sedentary parameters using an accelerometer and cognitive function using a neuropsychological test battery. Structural brain markers were assessed on the structural brain MRI scans in a subsample (n  = 1,009). Data …were analyzed using the general linear, isotemporal substitution, and mediation models. Results: In the total sample (n  = 2,019), adjusting for multiple covariates and moderate-to-vigorous-intensity physical activity, longer mean sedentary bout duration was linearly related with lower z- scores of global cognition, verbal fluency, and memory (ptrend  < 0.05), whereas greater total sedentary time was linearly associated with lower z-scores of global cognition, verbal fluency, and memory only among individuals with long sedentary time (>10 h/day) (ptrend  < 0.05); Breaking up sedentary time with same amount of light-intensity physical activity was significantly associated with higher verbal fluency and memory z- scores (p  < 0.05). In the MRI subsample (n  = 1,009), separately entering structural brain MRI markers into the mediation models substantially attenuated the associations of mean sedentary bout duration with global cognition, verbal fluency, and memory z- scores. Conclusion: Prolonged uninterrupted sedentary time is associated with poor global cognition, memory, and verbal fluency among rural older adults, and structural brain markers could partially mediate the association. Show more

Keywords: Accelerometer, Alzheimer’s disease, brain aging, cognition, magnetic resonance imaging, population-based study, sedentary behavior patterns

DOI: 10.3233/JAD-230575

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 657-668, 2023

Authors: Jiang, Jiwei | Hong, Yin | Li, Wenyi | Wang, Anxin | Jiang, Shirui | Jiang, Tianlin | Wang, Yanli | Wang, Linlin | Yang, Shiyi | Ren, Qiwei | Zou, Xinying | Xu, Jun

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE ) is the most recognized risk gene for cognitive decline and clinical progression of late-onset Alzheimer’s disease (AD); nonetheless, its association with neuropsychiatric symptoms (NPSs) remains inconclusive. Objective: To investigate the association of APOE ɛ4 with NPSs and explore nutritional status and cognition as joint mediators of this association. Methods: Between June 2021 and October 2022, patients with amnestic mild cognitive impairment (aMCI) or AD were recruited from the Chinese Imaging, Biomarkers, and Lifestyle Study. NPSs were assessed using the Neuropsychiatric Inventory, while global cognition and nutritional status were evaluated using …the Mini-Mental State Examination (MMSE) and Mini-Nutritional Assessment (MNA), respectively. Simple mediation and multiple chain mediation models were developed to examine the mediating effects of the MNA and MMSE scores on the relationship between APOE ɛ4 and specific neuropsychiatric symptom. Results: Among 310 patients, 229 (73.87%) had NPSs, and 110 (35.48%) carried APOE ɛ4. Patients with APOE ɛ4 were more likely to have hallucinations (p  = 0.014), apathy (p  = 0.008), and aberrant motor activity (p  = 0.018). MNA and MMSE scores mediated the association between APOE ɛ4 and hallucinations (17.97% and 37.13%, respectively), APOE ɛ4 and apathy (30.73% and 57.72%, respectively), and APOE ɛ4 and aberrant motor activity (17.82% and 34.24%), respectively. Chain-mediating effects of MNA and MMSE scores on the association of APOE ɛ4 with hallucinations, apathy, and aberrant motor activity after adjusting for confounding factors were 6.84%, 11.54%, and 6.19%, respectively. Conclusion: Nutritional status and cognition jointly mediate the association between APOE ɛ4 and neuropsychiatric symptoms in patients with aMCI or AD. Show more

Keywords: Alzheimer’s disease, cognition, mediation analysis, mild cognitive impairment, neuropsychiatric symptoms, nutrition

DOI: 10.3233/JAD-230577

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 669-681, 2023

Authors: Bahrani, Ahmed A. | Abner, Erin L. | DeCarli, Charles S. | Barber, Justin M. | Sutton, Abigail C. | Maillard, Pauline | Sandoval, Francisco | Arfanakis, Konstantinos | Yang, Yung-Chuan | Evia, Arnold M. | Schneider, Julie A. | Habes, Mohamad | Franklin, Crystal G. | Seshadri, Sudha | Satizabal, Claudia L. | Caprihan, Arvind | Thompson, Jeffrey F. | Rosenberg, Gary A. | Wang, Danny J.J. | Jann, Kay | Zhao, Chenyang | Lu, Hanzhang | Rosenberg, Paul B. | Albert, Marilyn S. | Ali, Doaa G. | Singh, Herpreet | Schwab, Kristin | Greenberg, Steven M. | Helmer, Karl G. | Powel, David K. | Gold, Brian T. | Goldstein, Larry B. | Wilcock, Donna M. | Jicha, Gregory A.

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer’s Disease. Objective: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. Methods: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were …analyzed in relation to WMH changes to explore its construct validity. Results: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. Conclusions: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression. Show more

Keywords: Aging, Alzheimer’s disease, cerebrovascular disease, dementia, longitudinal, MarkVCID, small vessel ischemic disease, white matter hyperintensity

DOI: 10.3233/JAD-230629

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 683-693, 2023

Authors: Kravatz, Nigel L. | Adhikari, Dristi | Ayers, Emmeline | Verghese, Joe

Article Type: Research Article

Abstract: Background: Motoric cognitive risk syndrome (MCR), a pre-dementia syndrome characterized by subjective cognitive complaints and slow gait, is associated with disability in instrumental activities of daily living. It is unknown whether these functional limitations occur even before this pre-dementia syndrome is diagnosed. Objective: To assess profiles of complex and instrumental activities of daily living in the prodromal stages of MCR. Methods: We examined functional profiles in 46 older adults (mean age 79 years, 59% women) living in the community with normal cognition at baseline who developed MCR over follow-up (‘pre-MCR’) with 264 older adults (mean age …75 years, 57% women) who remained cognitively intact over the follow-up period. Results: Pre-MCR individuals had more limitations on complex everyday function at baseline compared to normal controls in multivariable logistic regression models (odds ratio 1.21). Pre-MCR cases at baseline had limitations in handling finances (odds ratio 3.0) and performing hobbies (odds ratio 5.5) as compared to normal controls. Pre-MCR cases had a greater difference in the number of complex functional limitations from baseline to MCR compared to the difference from baseline to final visit for the controls (1.2±3.0 versus 0.5±2.2, p  < 0.001). Conclusions: Limitations in complex everyday tasks arise in the prodromal stages of MCR and can assist in risk prognostication. Show more

Keywords: Activities of daily living, Alzheimer’s disease, functional status, motoric cognitive risk syndrome

DOI: 10.3233/JAD-230579

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 695-704, 2023

Authors: Xue, Weiqi | He, Weifeng | Yan, Mengyuan | Zhao, Huanyi | Pi, Jianbin

Article Type: Research Article

Abstract: Background: Patients are at increased risk of dementia, including Alzheimer’s disease (AD), after myocardial infarction (MI), but the biological link between MI and AD is unclear. Objective: To understand the association between the pathogenesis of MI and AD and identify common biomarkers of both diseases. Methods: Using public databases, we identified common biomarkers of MI and AD. Least absolute shrinkage and selection operator (LASSO) regression and protein-protein interaction (PPI) network were performed to further screen hub biomarkers. Functional enrichment analyses were performed on the hub biomarkers. Single-cell/nucleus analysis was utilized to further analyze the hub biomarkers …at the cellular level in carotid atherosclerosis and AD datasets. Motif enrichment analysis was used to screen key transcription factors. Results: 26 common differentially expressed genes were screened between MI and AD. Function enrichment analyses showed that these differentially expressed genes were mainly associated with inflammatory pathways. A key gene, Regulator of G-protein Signaling 1 (RGS1), was obtained by LASSO regression and PPI network. RGS1 was confirmed to mainly express in macrophages and microglia according to single-cell/nucleus analysis. The difference in expression of RGS1 in macrophages and microglia between disease groups and controls was statistically significant (p  < 0.0001). The expression of RGS1 in the disease groups was upregulated with the differentiation of macrophages and microglia. RelA was a key transcription factor regulating RGS1. Conclusion: Macrophages and microglia are involved in the inflammatory response of MI and AD. RGS1 may be a key biomarker in this process. Show more

Keywords: Alzheimer’s disease, bioinformatics, myocardial infarction, single-cell RNA sequencing, single-nucleus RNA sequencing

DOI: 10.3233/JAD-230559

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 705-723, 2023

Authors: He, Qiang | Wang, Wenjing | Li, Hao | Xiong, Yang | Tao, Chuanyuan | Ma, Lu | You, Chao

Article Type: Research Article

Abstract: Background: The role of metabolic syndrome (MetS) on dementia is disputed. Objective: We conducted a Mendelian randomization to clarify whether the genetically predicted MetS and its components are casually associated with the risk of different dementia types. Methods: The genetic predictors of MetS and its five components (waist circumference, hypertension, fasting blood glucose, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) come from comprehensive public genome-wide association studies (GWAS). Different dementia types are collected from the GWAS in the European population. Inverse variance weighting is utilized as the main method, complemented by several sensitivity approaches to verify the …robustness of the results. Results: Genetically predicted MetS and its five components are not causally associated with the increasing risk of dementia (all p  > 0.05). In addition, no significant association between MetS and its components and Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and dementia due to Parkinson’s disease (all p  > 0.05), except the association between HDL-C and dementia with Lewy bodies. HDL-C may play a protective role in dementia with Lewy bodies (OR: 0.81, 95% CI: 0.72–0.92, p  = 0.0010). Conclusions: From the perspective of genetic variants, our study provides novel evidence that MetS and its components are not associated with different dementia types. Show more

Keywords: Alzheimer’s disease, causal association, components, dementia, Mendelian randomization, metabolic syndrome, types

DOI: 10.3233/JAD-230623

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 725-743, 2023

Authors: Lee, Alina | Shan, Di | Castle, David | Rajji, Tarek K. | Ma, Clement

Article Type: Research Article

Abstract: Background: Drug development in Alzheimer’s disease (AD) over the past two decades has had high rates of failure. Novel trial designs, such as adaptive designs, have the potential to improve the efficiency of drug development in AD. Objective: To evaluate the design characteristics, temporal trends, and differences in design between sponsor types in phase II trials of investigational agents in AD. Methods: Phase I/II, II, and II/III trials for AD with drug or other biological interventions registered from December 1996 to December 2021 in ClinicalTrials.gov were included. Descriptive statistics were used to summarize trial characteristics. Linear, …logistic, and multinomial regression models assessed temporal trends and differences between sponsor types in design characteristics. Results: Of N  = 474 trials identified, randomized parallel group design was the most common design (72%). Only 12 trials (2.5%) used an adaptive design; adaptive features included early stopping rules, model-based dose-finding, adaptive treatment arm selection, and response adaptive randomization. The use of non-randomized parallel-group and open-label single arm designs increased over time. No temporal trend in the use of adaptive design was identified. Trials sponsored by industry only were more likely to use a randomized parallel-group design and have a larger estimated sample size than trials with other sponsor types. Conclusion: Our systematic review showed that very few phase II trials in AD used an adaptive trial design. Innovation and implementation of novel trial designs in AD trials can accelerate the drug development process. Show more

Keywords: Adaptive designs, Alzheimer’s disease, novel trial designs, phase II trials, systematic review

DOI: 10.3233/JAD-230660

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 745-757, 2023

Authors: Alkon, Daniel L. | Sun, Miao-Kun | Tuchman, Alan J. | Thompson, Richard E.

Article Type: Research Article

Abstract: Background: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. Objective: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. Methods: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. Results: With no safety events noted …by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p  < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p  < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p  = 0.409, NS), treatment versus placebo p  < 0.007. The Moderate Cohort patients showed no significant benefit. Conclusions: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients’ decline of -12.8 SIB points. Show more

Keywords: Alzheimer’s disease, Bryostatin, moderately severe AD patients, prevention, safety

DOI: 10.3233/JAD-230868

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 759-766, 2023

Authors: Ingannato, Assunta | Bessi, Valentina | Chiari, Annalisa | Salvatori, Davide | Bagnoli, Silvia | Bedin, Roberta | Ferrari, Camilla | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer ’s disease (AD) patients. Objective: Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2 , and APP ). In addition, …Microtubule-associated protein tau (MAPT ) gene was studied too. All patients underwent an extensive neuropsychological battery. Methods: Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records. Results: Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect. Conclusions: Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD. Show more

Keywords: Alzheimer’s disease, genetic variants, GRN , Progranulin

DOI: 10.3233/JAD-230689

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 767-775, 2023

Authors: Larsson, Liss Elin | Wang, Rui | Cederholm, Tommy | Wiggenraad, Fleur | Rydén, Marie | Hagman, Göran | Hellénius, Mai-Lis | Kivipelto, Miia | Thunborg, Charlotta

Article Type: Research Article

Abstract: Background: Sarcopenia and cognitive impairment are two leading causes of disabilities. Objective: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients. Methods: 368 patients were included (age 59.0±7.25 years, women: 58.7%), displaying three clinical phenotypes of cognitive impairments, i.e., subjective cognitive impairment (SCI, 57%), mild cognitive impairment (MCI, 26%), and Alzheimer’s disease (AD, 17%). Sarcopenia was defined according to diagnostic algorithm recommended by the European Working Group on Sarcopenia in Older People. Components …of sarcopenia were grip strength, bioelectrical impedance analysis, and gait speed. They were further aggregated into a score (0–3 points) by counting the numbers of limited components. Multi-nominal logistic regression was applied. Results: Probable sarcopenia (i.e., reduced grip strength) was observed in 9.6% of the patients, and 3.5% were diagnosed with sarcopenia. Patients with faster gait speed showed less likelihood of MCI (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.06–0.90) and AD (OR: 0.12, 95% CI: 0.03–0.60). One or more limited sarcopenia components was associated with worse cognitive function. After adjusting for potential confounders, the association remained significant only for AD (OR 4.29, 95% CI 1.45–11.92). Conclusion: The results indicate a connection between the sarcopenia components and cognitive impairments. Limitations in the sarcopenia measures, especially slow walking speed, were related to poorer cognitive outcomes. More investigationsare required to further verify the causal relationship between sarcopenia and cognitive outcomes. Show more

Keywords: Alzheimer’s disease, body composition, cognitive function, gait speed, hand grip strength, outpatients, sarcopenia

DOI: 10.3233/JAD-221186

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 777-788, 2023

Authors: Hoang, Minh Tuan | Kåreholt, Ingemar | Schön, Pär | von Koch, Lena | Xu, Hong | Tan, Edwin C.K | Johnell, Kristina | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Long-term care improves independence and quality of life of persons with dementia (PWD). The influence of socioeconomic status on access to long-term care was understudied. Objective: To explore the socioeconomic disparity in long-term care for PWD. Methods: This registry-based study included 14,786 PWD, registered in the Swedish registry for cognitive and dementia disorders (2014–2016). Education and income, two traditional socioeconomic indicators, were the main exposure. Outcomes were any kind of long-term care, specific types of long-term care (home care, institutional care), and the monthly average hours of home care. The association between outcomes and socioeconomic …status was examined with zero-inflated negative binomial regression and binary logistic regression. Results: PWD with compulsory education had lower likelihood of receiving any kind of long-term care (OR 0.80, 95% CI 0.68–0.93), or home care (OR 0.83, 95% CI 0.70–0.97), compared to individuals with university degrees. Their monthly average hours of home care were 0.70 times (95% CI 0.59–0.82) lower than those of persons with university degrees. There was no significant association between education and the receipt of institutional care. Stratifying on persons with Alzheimer’s disease showed significant association between lower education and any kind of long-term care, and between income and the hours of home care. Conclusions: Socioeconomic inequalities in long-term care existed in this study population. Lower-educated PWD were less likely to acquire general long-term care, home care and had lower hours of home care, compared to their higher-educated counterparts. Income was not significantly associated with the receipt of long-term care. Show more

Keywords: KeywordsAlzheimer’s disease, aged care, dementia, disparity, education, home care, income, inequality, institutional care, long-term care

DOI: 10.3233/JAD-230388

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 789-800, 2023

Authors: Li, Jing | Weiss, Jordan | Rajadhyaksha, Ashish | Acosta, Daisy | Harrati, Amal | Jiménez Velázquez, Ivonne Z. | Liu, Mao-Mei | Guerra, Jorge J. Llibre | Rodriguez, Juan de Jesús Llibre | Dow, William H.

Article Type: Research Article

Abstract: Background: Despite the high burden of Alzheimer’s disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region. Objective: This study examines healthcare utilization associated with Alzheimer’s disease and other dementias among older adults in the Caribbean as compared to the US. Methods: We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined …changes in hospital nights and physician visits in response to incident and ongoing dementias. Results: Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean. Conclusions: The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean. Show more

Keywords: Alzheimer’s disease, Caribbean, dementia, healthcare utilization, Hispanics

DOI: 10.3233/JAD-230505

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 801-811, 2023

Authors: Ben Khedher, Mohamed Raâfet | Haddad, Mohamed | Fulop, Tamas | Laurin, Danielle | Ramassamy, Charles

Article Type: Research Article

Abstract: Background: The perplex interrelation between circulating extracellular vesicles (cEVs) and amyloid-β (Aβ) deposits in the context of Alzheimer’s disease (AD) is poorly understood. Objective: This study aims to 1) analyze the possible cross-linkage of the neurotoxic amyloid-β oligomers (oAβ) to the human cEVs, 2) identify cEVs corona proteins associated with oAβ binding, and 3) analyze the distribution and expression of targeted cEVs proteins in preclinical participants converted to AD 5 years later (Pre-AD). Methods: cEVs were isolated from 15 Pre-AD participants and 15 healthy controls selected from the Canadian Study of Health and Aging. Biochemical, clinical, …lipid, and inflammatory profiles were measured. oAβ and cEVs interaction was determined by nanoparticle tracking analysis and proteinase K digestion. cEVs bound proteins were determined by ELISA. Results: oAβ were trapped by cEVs and were topologically bound to their external surface. We identified surface-exposed proteins functionally able to conjugate oAβ including apolipoprotein J (apoJ), apoE and RAGE, with apoJ being 30- to 130-fold higher than RAGE and apoE, respectively. The expression of cEVs apoJ was significantly lower in Pre-AD up to 5 years before AD onset. Conclusion: Our findings suggest that cEVs might participate in oAβ clearance and that early dysregulation of cEVs could increase the risk of conversion to AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, apolipoprotein J, extracellular vesicles

DOI: 10.3233/JAD-230823

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 813-825, 2023

Authors: Alrouji, Mohammed | Majrashi, Taghreed A. | Alhumaydhi, Fahad A. | Zari, Ali | Zari, Talal A. | Al Abdulmonem, Waleed | Sharaf, Sharaf E. | Shahwan, Moyad | Anwar, Saleha | Shamsi, Anas | Atiya, Akhtar

Article Type: Research Article

Abstract: Background: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery. Objective: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn. Methods: Through a comprehensive approach involving molecular docking, drug likeliness filters, and …molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity. Results: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes. Conclusion: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies. Show more

Keywords: Alzheimer’s disease, drug discovery, molecular dynamics simulations, phytochemicals, tyrosine-protein kinase Fyn, virtual screening

DOI: 10.3233/JAD-230828

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 827-844, 2023

Authors: Dong, Yi | Hou, Tingting | Li, Yuanjing | Liu, Rui | Cong, Lin | Liu, Keke | Liu, Cuicui | Han, Xiaolei | Ren, Yifei | Tang, Shi | Winblad, Bengt | Blennow, Kaj | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. Methods: This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. …Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Results: Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42 /Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. Conclusions: In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum. Show more

Keywords: Alzheimer’s disease, diagnostic accuracy, mild cognitive impairment, plasma biomarkers, population-based study

DOI: 10.3233/JAD-230932

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 845-858, 2023

Article Type: Correction

DOI: 10.3233/JAD-239011

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 859-860, 2023