Journal of Alzheimer's Disease - Volume 99, issue 3

Authors: Khandia, Rekha | Gurjar, Pankaj | Romashchenko, Victoria | Al-Hussain, Sami A. | Alexiou, Athanasios | Zouganelis, George | Zaki, Magdi E.A.

Article Type: Research Article

Abstract: Background: Autophagy and apoptosis are cellular processes that maintain cellular homeostasis and remove damaged or aged organelles or aggregated and misfolded proteins. Stress factors initiate the signaling pathways common to autophagy and apoptosis. An imbalance in the autophagy and apoptosis, led by cascade of molecular mechanism prior to both processes culminate into neurodegeneration. Objective: In present study, we urge to investigate the codon usage pattern of genes which are common before initiating autophagy and apoptosis. Methods: In the present study, we took up eleven genes (DAPK1, BECN1, PIK3C3 (VPS34 ), BCL2, MAPK8, …BNIP3  L (NIX ), PMAIP1 , BAD, BID, BBC3, MCL1 ) that are part of molecular signaling mechanism prior to autophagy and apoptosis. We analyzed dinucleotide odds ratio, codon bias, usage, context, and rare codon analysis. Results: CpC and GpG dinucleotides were abundant, with the dominance of G/C ending codons as preferred codons. Clustering analysis revealed that MAPK8 had a distinct codon usage pattern compared to other envisaged genes. Both positive and negative contexts were observed, and GAG-GAG followed by CTG-GCC was the most abundant codon pair. Of the six synonymous arginine codons, two codons CGT and CGA were the rarest. Conclusions: The information presented in the study may be used to manipulate the process of autophagy and apoptosis and to check the pathophysiology associated with their dysregulation. Show more

Keywords: Alzheimer’s disease, apoptosis, autophagy, codon context, codon pairs, rare codons, relative synonymous codon usage

DOI: 10.3233/JAD-240158

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 927-939, 2024

Authors: Bruinsma, Jeroen | Loukas, Vasileios S. | Kassiotis, Thomas | Heger, Irene | Rosenberg, Anna | Visser, Leonie N. C. | Mangialasche, Francesca | Fotiadis, Dimitrios I. | Hanke, Sten | Crutzen, Rik

Article Type: Research Article

Abstract: Background: Unhealthy behavior increases the risk of dementia. Various socio-cognitive determinants influence whether individuals persist in or alter these unhealthy behaviors. Objective: This study identifies relevant determinants of behavior associated to dementia risk. Methods: 4,104 Dutch individuals (40–79 years) completed a screening questionnaire exploring lifestyle behaviors associated with dementia risk. Subsequently, 3,065 respondents who engaged in one or more unhealthy behaviors completed a follow-up questionnaire investigating socio-cognitive determinants of these behaviors. Cross-tables were used to assess the accuracy of participants’ perceptions regarding their behavior compared to recommendations. Confidence Interval-Based Estimation of Relevance (CIBER) …was used to identify the most relevant determinants of behavior based on visual inspection and interpretation. Results: Among the respondents, 91.3% reported at least one, while 65% reported two or more unhealthy lifestyle behaviors associated to dementia risk. Many of them were not aware they did not adhere to lifestyle recommendations. The most relevant determinants identified include attitudes (i.e., lacking a passion for cooking and finding pleasure in drinking alcohol or smoking), misperceptions on social comparisons (i.e., overestimating healthy diet intake and underestimating alcohol intake), and low perceived behavioral control (i.e., regarding changing physical inactivity, altering diet patterns, and smoking cessation). Conclusions: Individual-level interventions that encourage lifestyle change should focus on enhancing accurate perceptions of behaviors compared to recommendations, while strengthening perceived control towards behavior change. Given the high prevalence of dementia risk factors, combining interventions at both individual and environmental levels are likely to be the most effective strategy to reduce dementia on a population scale. Show more

Keywords: Alzheimer’s disease, behavioral medicine, dementia, health promotion, health risk behaviors, prevention, public health

DOI: 10.3233/JAD-231369

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 941-952, 2024

Authors: Sato, Kenichiro | Niimi, Yoshiki | Ihara, Ryoko | Suzuki, Kazushi | Iwata, Atsushi | Iwatsubo, Takeshi

Article Type: Research Article

Abstract: Background: Primary outcome measure in the clinical trials of disease modifying therapy (DMT) drugs for Alzheimer’s disease (AD) has often been evaluated by Clinical Dementia Rating sum of boxes (CDRSB). However, CDR testing requires specialized training and 30–50 minutes to complete, not being suitable for daily clinical practice. Objective: Herein, we proposed a machine-learning method to estimate CDRSB changes using simpler cognitive/functional batteries (Mini-Mental State Examination [MMSE] and Functional Activities Questionnaire [FAQ]), to replace CDR testing. Methods: Baseline data from 944 ADNI and 171 J-ADNI amyloid-positive participants were used to build machine-learning models …predicting annualized CDRSB changes between visits, based on MMSE and FAQ scores. Prediction performance was evaluated with mean absolute error (MAE) and R2 comparing predicted to actual rmDeltaCDRSB/rmDeltayear. We further assessed whether decline in cognitive function surpassing particular thresholds could be identified using the predicted rmDeltaCDRSB/rmDeltayear. RESULTS: The models achieved the minimum required prediction errors (MAE < 1.0) and satisfactory prediction accuracy (R2 >0.5) for mild cognitive impairment (MCI) patients for changes in CDRSB over periods of 18 months or longer. Predictions of annualized CDRSB progression>0.5, >1.0, or >1.5 demonstrated a consistent performance (i.e., Matthews correlation coefficient>0.5). These results were largely replicated in the J-ADNI case predictions. CONCLUSIONS: Our method effectively predicted MCI patient deterioration in the CDRSB based solely on MMSE and FAQ scores. It may aid routine practice for disease-modifying therapy drug efficacy evaluation, without necessitating CDR testing at every visit. Show more

Keywords: Alzheimer’s disease, clinical dementia rating, disease-modifying therapy, efficacy assessment, machine-learning, prediction

DOI: 10.3233/JAD-231426

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 953-963, 2024

Authors: Chong, Joanna Su Xian | Tan, Yi Jayne | Koh, Amelia Jialing | Ting, Simon Kang Seng | Kandiah, Nagaendran | Ng, Adeline Su Lyn | Zhou, Juan Helen

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) show differential vulnerability to large-scale brain functional networks. Plasma neurofilament light (NfL), a promising biomarker of neurodegeneration, has been linked in AD patients to glucose metabolism changes in AD-related regions. However, it is unknown whether plasma NfL would be similarly associated with disease-specific functional connectivity changes in AD and bvFTD. Objective: Our study examined the associations between plasma NfL and functional connectivity of the default mode and salience networks in patients with AD and bvFTD. Methods: Plasma NfL and neuroimaging data from patients …with bvFTD (n  = 16) and AD or mild cognitive impairment (n  = 38; AD + MCI) were analyzed. Seed-based functional connectivity maps of key regions within the default mode and salience networks were obtained and associated with plasma NfL in these patients. RESULTS: We demonstrated divergent associations between NfL and functional connectivity in AD + MCI and bvFTD patients. Specifically, AD + MCI patients showed lower default mode network functional connectivity with higher plasma NfL, while bvFTD patients showed lower salience network functional connectivity with higher plasma NfL. Further, lower NfL-related default mode network connectivity in AD + MCI patients was associated with lower Montreal Cognitive Assessment scores and higher Clinical Dementia Rating sum-of-boxes scores, although NfL-related salience network connectivity in bvFTD patients was not associated with Neuropsychiatric Inventory Questionnaire scores. CONCLUSIONS: Our findings indicate that plasma NfL is differentially associated with brain functional connectivity changes in AD and bvFTD. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, plasma neurofilament light, resting state functional connectivity

DOI: 10.3233/JAD-231251

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 965-980, 2024

Authors: Jaen, Jocelyn | Grodstein, Francine | Lajous, Martín | Bello-Chavolla, Omar Yaxmehen | Gómez-Flores-Ramos, Liliana | Yang, Jingyun | Bennett, David A. | Marquez, David X. | Lamar, Melissa

Article Type: Research Article

Abstract: Background: US-based Latinos have lower education and income combined with higher health risks than non-Latino whites, but often ‘paradoxically’ evidence better health-related outcomes. Less work has investigated this paradox for cognitive-related outcomes despite nativity diversity. Objective: We evaluated cognitive aging within older Latinos of diverse nativity currently living in the US and participating in Rush Alzheimer’s Disease Center studies. Methods: Participants without baseline dementia, who completed annual neuropsychological assessments (in English or Spanish) were grouped by US-born (n  = 117), Mexico-born (n  = 173), and born in other Latin American regions (LAr-born = 128). Separate regression models examined associations between …nativity and levels of (N  = 418) or change in (n  = 371; maximum follow-up ∼16 years) global and domain-specific cognition. Results: Demographically-adjusted linear regression models indicated that foreign-born nativity was associated with lower levels of global cognition and select cognitive domains compared to US-born Latinos. No associations of nativity with cognitive decline emerged from demographically-adjusted mixed-effects models; however, Mexico-born nativity appeared associated with slower declines in working memory compared to other nativity groups (p -values ≥ 0.051). Mexico-born Latinos had relatively higher vascular burden and lower education levels than other nativity groups; however, this did not alter results. Conclusions: Nativity differences in baseline cognition may be due, in part, to accumulated stressors related to immigration and acculturation experienced by foreign-born Latinos which may hasten meeting criteria for dementia later in life. In contrast, Mexico-born participants’ slower working memory declines, taken in the context of other participant characteristics including vascular burden, suggests the Hispanic Paradox may relate to factors with the potential to affect cognition Show more

Keywords: Alzheimer’s disease, Hispanic Paradox, Latinos, nativity, working memory

DOI: 10.3233/JAD-231358

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 981-991, 2024

Authors: Wang, Linlin | Zhang, Xuezhen | Wang, Lei | Guo, Miaomiao | Yang, Qihang | Chen, Xiaogang | Sha, Hong

Article Type: Research Article

Abstract: Background: Early recognition of dementia like Alzheimer’s disease is crucial for disease diagnosis and treatment, and existing objective tools for early screening of cognitive impairment are limited. Objective: To investigate age-related behavioral indicators of dual-task cognitive performance and gait parameters and to explore potential objective markers of early cognitive decline. Methods: The community-based cognitive screening data was analyzed. Hierarchical cluster analysis and Pearson correlation analysis were performed on the 9-item subjective cognitive decline (SCD-9) scores, walking-cognitive dual-task performance, walking speed, and gait parameters of 152 participants. The significant differences of indicators that may related to cognitive …decline were statistically analyzed across six age groups. A mathematical model with age as the independent variable and motor cognition composite score as the dependent variable was established to observe the trend of motor cognition dual-task performance with age. Results: Strong correlation was found between motor cognitive scores and SCD and age. Gait parameters like the mean value of ankle angle, the left-right difference rate of ankle angle and knee angle and the coefficient of variation of gait cycle showed an excellent correlation with age. Motor cognition scores showed a decreasing trend with age. The slope of motor cognition scores with age after 50 years (k  = –1.06) was six times higher than that before 50 years (k  = –0.18). Conclusions: Cognitive performance and gait parameters in the walking-cognitive dual-task state are promising objective markers that could characterize age-related cognitive decline. Show more

Keywords: Age, Alzheimer’s disease, cognitive decline, motor cognitive assessment, objective markers, walking-cognitive dual task

DOI: 10.3233/JAD-240066

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 993-1004, 2024

Authors: Wu, Can | Ruan, Tingting | Yuan, Yalan | Xu, Chunshuang | Du, Lijuan | Wang, Fang | Xu, Shujun

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegeneration disease. Physical activity is one of the most promising modifiable lifestyles that can be effective in slowing down the progression of AD at an early stage. Objective: Explore the molecular processes impaired in AD that were conversely preserved and enhanced by physical activity. Methods: Integrated transcriptomic analyses were performed in datasets that contain AD patients and elders with different degrees of physical activity. The changes of the hub genes were validated through analyzing another two datasets. The expression of the hub genes was further detected …in the hippocampus and cortexes of APP/PS1 transgenic mice with or without physical activity by Quantitative polymerase chain reaction (qPCR). Results: Cross-comparison highlighted 195 DEGs displaying opposed regulation patterns between AD and high physical activity (HPA). The common DEGs were predominantly involved in synaptic vesicle recycling and synaptic transmission, largely downregulated in AD patients but upregulated in the elders with HPA. Two key modules and four hub genes that were related to synaptic vesicle turnover were obtained from the PPI network. The expression of these hub genes (SYT1, SYT4, SH3GL2, and AP2M1 ) was significantly decreased in AD transgenic mice and was reversed by HPA training. Conclusions: HPA may reverse AD pathology by upregulating a range of synaptic vesicle transport related proteins which might improve the efficiency of synaptic vesicle turnover and facilitate inter-neuronal information transfer. The study provides novel insights into the mechanisms underlining the protective effects of HPA on AD. Show more

Keywords: Alzheimer’s disease, physical activity, synaptic connectivity, synaptic transmission, synaptic vesicle cycling, transcriptomic analysis

DOI: 10.3233/JAD-240123

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 1005-1022, 2024

Authors: Youssef, Hossam | Gatto, Rodolfo G. | Pham, Nha Trang Thu | Petersen, Ronald C. | Machulda, Mary M. | Reichard, R. Ross | Dickson, Dennis W. | Jack, Clifford R. | Whitwell, Jennifer L. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment …of the distribution of Aβ (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n  = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body. Show more

Keywords: Alzheimer’s disease, Cornu Ammonis 1, LATE-NC, primary age-related tauopathy, TAR DNA binding Protein 43, type-alpha

DOI: 10.3233/JAD-240136

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 1023-1032, 2024

Authors: Rolandsson, Olov | Tornevi, Andreas | Steneberg, Pär | Edlund, Helena | Olsson, Tommy | Andreasson, Ulf | Zetterberg, Henrik | Blennow, Kaj

Article Type: Research Article

Abstract: Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer’s disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1–40 and Aβ1–42 concentrations in individuals with T2D and matched controls. Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66–72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in …a randomized order, each lasting 4 hours. Aβ1–40 , Aβ1–42 , and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1–40 and Aβ1–42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results: At baseline, Aβ1–40 and Aβ1–42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1–40 : p  = 0.034, Aβ1–42 : p  = 0.020), IDE increased (p  = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognition, endocrinology and metabolism specialty, hyperglycemia, type 2 diabetes

DOI: 10.3233/JAD-230628

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 1033-1046, 2024

Authors: Estrella, Mayra L. | Tarraf, Wassim | Kuwayama, Sayaka | Gallo, Linda C. | Salazar, Christian R. | Stickel, Ariana M. | Mattei, Josiemer | Vásquez, Priscilla M. | Eldeirawi, Kamal M. | Perreira, Krista M. | Penedo, Frank J. | Isasi, Carmen R. | Cai, Jianwen | Zeng, Donglin | González, Hector M. | Daviglus, Martha L. | Lamar, Melissa

Article Type: Research Article

Abstract: Background: Higher allostatic load (AL), a multi-system measure of physiological dysregulation considered a proxy for chronic stress exposure, is associated with poorer global cognition (GC) in older non-Hispanic white adults. However, evidence of these associations in middle-aged and older US-based Hispanic/Latino adults is limited. Objective: To examine associations of AL with level of cognition, performance in cognition 7 years later, and change in cognition over 7 years among middle-aged and older US-based Hispanic/Latino adults. Methods: We used data (n  = 5,799, 45–74 years at baseline) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation of …Neurocognitive Aging (SOL-INCA). The AL score comprised 16 biomarkers representing cardiometabolic, glucose, cardiopulmonary, parasympathetic, and inflammatory systems (higher scores = greater dysregulation). Cognitive outcomes included GC and individual tests of verbal learning and memory, world fluency (WF), Digit Symbol Substitution (DSS), and Trail Making (Parts A & B). Survey-linear regressions assessed associations of AL with performance in cognition at baseline, 7 years later, and via 7-year cognitive change scores adjusting for sociodemographic characteristics, lifestyle factors, and depressive symptoms. Results: Higher AL was associated with lower baseline performance in GC and WF; and lower 7-year follow-up performance in these same measures plus DSS and Trail Making Parts A & B. Higher AL was associated with more pronounced 7-year change (reduction) in GC and on WF and DSS tests. Conclusions: Findings extend previous evidence in predominantly older non-Hispanic white cohorts to show that AL is related to level of and change in GC (as well as WF and DSS) among middle-aged and older US-based Hispanic/Latino adults. Show more

Keywords: Allostatic load, Alzheimer’s disease, cognitive function, Hispanic/Latino

DOI: 10.3233/JAD-230796

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 1047-1064, 2024