Journal of Alzheimer's Disease - Volume 101, issue 3

Authors: Seligmann, Bruce | Camiolo, Salvatore | Hernandez, Monica | Yeakley, Joanne M. | Sahagian, Gregory | McComb, Joel

Article Type: Research Article

Abstract: Background: There is no molecular test for Alzheimer’s disease (AD) using self-collected samples, nor is there a definitive molecular test for AD. We demonstrate an accurate and potentially definitive TempO-Seq® gene expression test for AD using fingerstick blood spotted and dried on filter paper, a sample that can be collected in any doctor’s office or can be self-collected. Objective: Demonstrate the feasibility of developing an accurate test for the classification of persons with AD from a minimally invasive sample of fingerstick blood spotted on filter paper which can be obtained in any doctor’s office or self-collected to …address health disparities. Methods: Fingerstick blood samples from patients clinically diagnosed with AD, Parkinson’s disease (PD), or asymptomatic controls were spotted onto filter paper in the doctor’s office, dried, and shipped to BioSpyder for testing. Three independent patient cohorts were used for training/retraining and testing/retesting AD and PD classification algorithms. Results: After initially identifying a 770 gene classification signature, a minimum set of 68 genes was identified providing classification test areas under the ROC curve of 0.9 for classifying patients as having AD, and 0.94 for classifying patients as having PD. Conclusions: These data demonstrate the potential to develop a screening and/or definitive, minimally invasive, molecular diagnostic test for AD and PD using dried fingerstick blood spot samples that are collected in a doctor’s office or clinic, or self-collected, and thus, can address health disparities. Whether the test can classify patients with AD earlier then possible with cognitive testing remains to be determined. Show more

Keywords: Alzheimer’s disease, dementia, diagnostic classifier, fingerstick blood, gene expression signature, health disparity, Parkinson’s disease, self-test, TempO-Seq, whole blood

DOI: 10.3233/JAD-240174

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 813-822, 2024

Authors: Utyro, Olga | Włoczkowska-Łapińska, Olga | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Background: Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer’s disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4’s association with AD was unknown. Objective: To assess GLOD4’s role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh –/– 5xFAD mouse AD model of AD. Methods: GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. …Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4, Aβ precursor protein (Aβpp), Atg5, p62, and Lc3 proteins and mRNAs were quantified. Results: GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh –/– 5xFAD mice compared to Blmh +/+ 5xFAD sibling controls, but not in Blmh –/– mice without the 5xFAD transgene compared to Blmh +/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh –/– mice of both sexes and in Blmh +/+ males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh –/– 5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5 , p62 , and Lc3 genes. Conclusions: These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, autophagy, bleomycin hydrolase, Blmh–/–5xFAD mouse, GLOD4, N2a-APPswe mouse neuroblastoma cells

DOI: 10.3233/JAD-240512

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 823-834, 2024

Authors: Zhao, Huimin | Yang, Changlin | Xing, Fangkai

Article Type: Research Article

Abstract: Background: The relationship between serum fatty acids and cognitive function has been the subject of extensive study. Objective: To analyze the relationship between serum fatty acids composition and cognitive function by NHANES database and multivariate Mendelian randomization (MR) analysis. Methods: A sub-cohort of 1,339 individuals with serum fatty acids and Digit Symbol Substitution Test (DSST) examinations from the 2011–2014 wave of the NHANES were analyzed using fully adjusted multiple linear regression models for associations between serum hydrolyzed fatty acid levels and cognitive function. Univariable and multivariable MR was used to analyze the correlation between 98 exposures …related to serum fatty acids and cognitive function. Results from different database sources were combined using meta-analysis. Results: The fully adjusted regression analysis showed that linoleic acid (LA), Omega 6, fatty acids (FAs), and LA/FAs were positively correlated with DSST. 27 exposures were included for univariate MR analysis. Ultimately, only 2 traits had IVW test p -values ranging between 0.0019 and 0.05, both of which were LA/FAs. The meta-analysis of univariate MR revealed that LA/FAs was positively associated with cognitive function (β: 0.040, 95% CI = 0.013–0.067, p  = 0.0041). In multivariate MR analysis, after adjusting for education, ischemic stroke, and age, LA/FAs was positively independently associated with cognitive function (IVW β: 0.049, 95% CI = 0.021–0.077, p  = 0.0006). The results of MVMR are well in line with the univariate results. Conclusions: Both the Cross-sectional observational analyses and MR-based studies supported a suggestive causal relationship between the serum ratio of Linoleic acid in fatty acids and cognitive function. Show more

Keywords: Alzheimer’s disease, cognitive function, fatty acids, linoleic acid, Mendelian randomization, NHANES

DOI: 10.3233/JAD-240715

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 835-845, 2024

Authors: Sang, Xian-Zheng | Chen, Wen | Hou, Xiao-Xiang | Wang, Chun-Hui | Zhang, Dan-Feng | Hou, Li-Jun

Article Type: Review Article

Abstract: Background: Emerging evidence suggests the potential of hydroxymethylglutaryl-coenzyme A (HMG-CoA, statins) as a therapeutic option for dementia. Objective: The primary objective of this study is to assess the current state of research on statins use in dementia, with a focus on identifying pivotal questions within the field. Methods: A systemic search for publications on statin use in dementia between 2007 and 2023 was conducted, utilizing the Web of Science Core Collection. The scientific output was analyzed from various perspectives through VOSviewer, CiteSpace, and the bibliometrics website (https://bibliometric.com/ ). Results: 560 articles authored by 2,977 …individuals and 999 institutions across 58 countries were included, which were published in 295 periodicals and cited 21,176 references from 16,424 authors. The annual publication output remained steady, while the number of citations increased consistently. The U.S. and Mayo Clinic emerged as the most significant country and institution, respectively. B. McGuinness and D.L. Sparks were the most eminent authors. Journal of Alzheimer ’s Disease was the most influential journal. Three sets of keywords and the top 10 references were identified, suggesting pivotal questions within the field. Conclusions: While statins show promising potential as a treatment option for dementia, their use remains uncertain due to the reported short-term cognitive impairment events and questionable long-term protective effects against dementia. The pivotal question is to ascertain the association between statins and cognition. The mechanisms underlying the effects of statins on cognition are multifaceted. This study provides insights into the current status within the field of statin use in dementia. Show more

Keywords: Alzheimer’s disease, association, bibliometrics, dementia, hydroxymethylglutaryl-CoA reductase inhibitors, mechanism, statins, vascular dementia

DOI: 10.3233/JAD-240270

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 847-876, 2024

Authors: Méndez-Barrio, Carlota | Medina-Rodríguez, Manuel | Mendoza-Vázquez, Gonzalo | García-Roldán, Ernesto | Rodrigo-Herrero, Silvia | Luque-Tirado, Andrea | Almodóvar-Sierra, Ángela | Franco-Macías, Emilio

Article Type: Research Article

Abstract: Background: Predicting which patients with prodromal AD (pAD) will imminently convert to dementia may be paramount in a memory clinical setting, especially with potential disease-modifying therapies on the horizon. Objective: To explore a practical tool for this prediction, combining cognitive tests and cerebrospinal fluid (CSF) biomarkers. Methods: We designed a longitudinal prospective, observational, and multicenter study, enrolling patients with pAD. Inclusion criteria comprised memory complaints, Mini-Mental State Examination (MMSE) score of≥22, memory impairment as indicated by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) and/or TMA-93, Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, …and positive CSF Aβ42 /Aβ40 ratio (<0.095, Euroimmun). The primary outcome was the conversion to dementia (CDR-GS≥1) within the first year of follow-up, referred to as “short-term conversion”. A multiple regression logistic model was adopted to design the “Predict Short-Term Conversion” (PSTC) score. Results: Between 2020 and 2022, 83 patients were recruited. The median age was 74, with 49.4% being women. Twenty-five (30.1%) patients were classified as short-term converters. The PSTC score incorporated baseline scores on MMSE ( ≤24 = 3, >24 = 0) and FCSRT + IR Total Recall ( ≤14 = 4, >14 = 0), and CSF neurofilament light chains (NfLs) concentrations (β=0.001299). The PSTC score demonstrated an area under the curve of 0.78 (95% CI: 0.67-0.90, p < 0.001), with a cutoff value of 5.14 presenting 76% sensitivity and 80% specificity. Conclusions: The PSTC score, comprising two relatively brief cognitive test scores and NfLs CSF concentrations, could be useful for predicting short-term converters among patients diagnosed with pAD. Show more

Keywords: Alzheimer’s disease, conversion to dementia, Free and Cued Selective Reminding Test, global cognition, Mini-Mental State Examination, neurofilament light chains

DOI: 10.3233/JAD-240689

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 877-887, 2024

Authors: Liu, Shu | Maruff, Paul | Fedyashov, Victor | Masters, Colin L. | Goudey, Benjamin

Article Type: Research Article

Abstract: Background: Integrating scores from multiple cognitive tests into a single cognitive composite has been shown to improve sensitivity to detect AD-related cognitive impairment. However, existing composites have little sensitivity to amyloid-β status (Aβ +/–) in preclinical AD. Objective: Evaluate whether a data-driven approach for deriving cognitive composites can improve the sensitivity to detect Aβ status among cognitively unimpaired (CU) individuals compared to existing cognitive composites. Methods: Based on the data from the Anti-Amyloid Treatment in the Asymptomatic Alzheimer’s Disease (A4) study, a novel composite, the Data-driven Preclinical Alzheimer’s Cognitive Composite (D-PACC), was developed based on test …scores and response durations selected using a machine learning algorithm from the Cogstate Brief Battery (CBB). The D-PACC was then compared with conventional composites in the follow-up A4 visits and in individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Result: The D-PACC showed a comparable or significantly higher ability to discriminate Aβ status [median Cohen’s d = 0.172] than existing composites at the A4 baseline visit, with similar results at the second visit. The D-PACC demonstrated the most consistent sensitivity to Aβ status in both A4 and ADNI datasets. Conclusions: The D-PACC showed similar or improved sensitivity when screening for Aβ+ in CU populations compared to existing composites but with higher consistency across studies. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, machine learning, neuropsychological tests

DOI: 10.3233/JAD-231319

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 889-899, 2024

Authors: Wang, Tao | Yan, Shaozhen | Shan, Yi | Xing, Yi | Bi, Sheng | Chen, Zhigeng | Xi, Hanyu | Xue, Hanxiao | Qi, Zhigang | Tang, Yi | Lu, Jie

Article Type: Research Article

Abstract: Background: Transcranial alternating current stimulation (tACS) could improve cognition in patients with Alzheimer’s disease (AD). However, the effects of tACS on brain activity remain unclear. Objective: The purpose is to investigate the change in regional neuronal activity after tACS in AD patients employing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: A total of 46 patients with mild AD were enrolled. Each patient received 30 one-hour sessions of real or sham tACS for three weeks (clinical trial: NCT03920826). The fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) measured by rs-fMRI were calculated to evaluate …the regional brain activity. Results: Compared to baseline, AD patients in the real group exhibited increased fALFF in the left middle frontal gyrus-orbital part and right inferior frontal gyrus-orbital part, as well as increased ReHo in the left precentral gyrus and right middle frontal gyrus at the end of intervention. At the 3-month follow-up, fALFF increased in the left superior parietal lobule and right inferior temporal gyrus, as well as ReHo, in the left middle frontal gyrus and right superior medial frontal gyrus. A higher fALFF in the right lingual gyrus and ReHo in the right parahippocampal gyrus were observed in the response group than in the nonresponse group. Conclusions: The findings demonstrated the beneficial effects of tACS on the neuronal activity of the prefrontal cortex and even more extensive regions and provided a neuroimaging biomarker of treatment response in AD patients. Show more

Keywords: Alzheimer’s disease, functional magnetic resonance imaging, transcranial alternating current stimulation

DOI: 10.3233/JAD-240400

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 901-912, 2024

Authors: Manakkadan, Anoop | Krishnan, Dolly | Rui Xia Ang, Sheila | Sajikumar, Sreedharan

Article Type: Research Article

Abstract: Background: Impairment of synaptic plasticity along with the formation of amyloid-β (Aβ) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer’s disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2 S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2 S in AD conditions using rat hippocampal …slices and the organic molecule GYY4137, a slow releasing H2 S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aβ42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aβ42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro . Conclusions: GYY4137, with its slow release of H2 S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD. Show more

Keywords: Alzheimer’s disease, gaseous neurotransmitter, hippocampus, H2S, long term potentiation, synaptic plasticity, synaptic tagging and capture

DOI: 10.3233/JAD-240456

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 913-921, 2024

Authors: Guo, Hongxiu | Sun, Shangqi | Yang, Yang | Ma, Rong | Wang, Cailin | Zheng, Siyi | Wang, Xiufeng | Li, Gang

Article Type: Research Article

Abstract: Background: Identifying high-risk individuals with mild cognitive impairment (MCI) who are likely to progress to Alzheimer’s disease (AD) is crucial for early intervention. Objective: This study aimed to develop and validate a novel clinical score for personalized estimation of MCI-to-AD conversion. Methods: The data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study were analyzed. Two-thirds of the MCI patients were randomly assigned to a training cohort (n  = 478), and the remaining one-third formed the validation cohort (n  = 239). Multivariable logistic regression was performed to identify factors associated with MCI-to-AD progression within 4 years. A prediction score …was developed based on the regression coefficients derived from the logistic model and tested in the validation cohort. Results: A lipidomics-signature was obtained that showed a significant association with disease progression. The MCI conversion scoring system (ranged from 0 to 14 points), consisting of the lipidomics-signature and five other significant variables (Apolipoprotein ɛ 4, Rey Auditory Verbal Learning Test immediate and delayed recall, Alzheimer’s Disease Assessment Scale delayed recall test, Functional Activities Questionnaire, and cortical thickness of the AD signature), was constructed. Higher conversion scores were associated with a higher proportion of patients converting to AD. The scoring system demonstrated good discrimination and calibration in both the training cohort (AUC = 0.879, p of Hosmer-Lemeshow test = 0.597) and the validation cohort (AUC = 0.915, p of Hosmer-Lemeshow test = 0.991). The risk classification achieved excellent sensitivity (0.84) and specificity (0.75). Conclusions: The MCI-to-AD conversion score is a reliable tool for predicting the risk of disease progression in individuals with MCI. Show more

Keywords: Alzheimer’s disease, conversion score, individual prediction, lipid metabolism, noninvasive biomarkers, progression

DOI: 10.3233/JAD-240532

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 923-936, 2024

Authors: Zhang, Xiaohong | Wang, Mingzhen | Chen, Kaiyue | Shi, Na | Cui, Xia | Yang, Zhicheng | Chen, Feifei | Lin, Xingfeng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) are progressive conditions. Family caregivers of patients, especially those caring for patients with ADRD exhibiting behavioral and psychological symptoms of dementia (BPSD), undergo significant physical and mental changes during long-term care. While most researchers have focused on the specific needs of family caregivers, the comprehensive understanding of these needs is limited. In this study, Alderfer’s existence, relatedness, and growth theory was used to develop an interview framework to systematically and comprehensively understand the needs of family caregivers of individuals with ADRD. Objective: The objective of this study was to understand family …caregivers’ needs in coping with BPSD in individuals with ADRD, aiming to alleviate caregivers’ stress and promote their overall well-being. Methods: This study used a hermeneutic–phenomenological interview research design. Data were collected via remote conferences involving interviews with 17 participants selected via maximum variation sampling. The Colaizzi seven-step method was utilized, and the interview contents were analyzed using NVivo 12.0 software. Results: The needs of family caregivers in coping with the BPSD of individuals with ADRD could be summarized into three themes, namely existence needs, relatedness needs, and growth needs, and 10 sub-themes. Conclusions: The study findings provide new insights into the needs of family caregivers in coping with patients exhibiting BPSD. Family caregivers experience significant negative emotions, poor caregiving experiences, heavy caregiving burdens, and a desire for professional assistance and policy support. Show more

Keywords: Alzheimer’s disease, family caregivers, hermeneutic phenomenology, needs assessment, nonprofessional home care

DOI: 10.3233/JAD-240629

Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 937-950, 2024