Journal of Alzheimer's Disease - Volume 99, issue 4

Authors: Guo, Ze-Xin | Liu, Fang | Wang, Fang-Yuan | Ou, Ya-Nan | Huang, Liang-Yu | Hu, Hao | Wang, Zhi-Bo | Fu, Yan | Gao, Pei-Yang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual’s risk of dementia. However, studies on the link of the CAIDE score to Alzheimer’s disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. …Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p  < 0.001), tTau (p  < 0.001), as well as tTau/Aβ42 (p  = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p  < 0.001) as well as MoCA score (p  < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2%. Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration. Show more

Keywords: Alzheimer’s disease, CAIDE dementia risk score, cerebrospinal fluid biomarkers, cognition, neurodegeneration

DOI: 10.3233/JAD-240005

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1273-1283, 2024

Authors: Suganuma, Takaya | Hatori, Sena | Chen, Chung-Kuan | Hori, Satoshi | Kanuka, Mika | Liu, Chih-Yao | Tatsuzawa, Chika | Yanagisawa, Masashi | Hayashi, Yu

Article Type: Research Article

Abstract: Background: Caffeoylquinic acid (CQA), which is abundant in coffee beans and Centella asiatica , reportedly improves cognitive function in Alzheimer’s disease (AD) model mice, but its effects on neuroinflammation, neuronal loss, and the amyloid-β (Aβ) plaque burden have remained unclear. Objective: To assess the effects of a 16-week treatment with CQA on recognition memory, working memory, Aβ levels, neuronal loss, neuroinflammation, and gene expression in the brains of 5XFAD mice, a commonly used mouse model of familial AD. Methods: 5XFAD mice at 7 weeks of age were fed a 0.8% CQA-containing diet for 4 months and …then underwent novel object recognition (NOR) and Y-maze tests. The Aβ levels and plaque burden were analyzed by enzyme-linked immunosorbent assay and immunofluorescent staining, respectively. Immunostaining of markers of mature neurons, synapses, and glial cells was analyzed. AmpliSeq transcriptome analysis and quantitative reverse-transcription-polymerase chain reaction were performed to assess the effect of CQA on gene expression levels in the cerebral cortex of the 5XFAD mice. Results: CQA treatment for 4 months improved recognition memory and ameliorated the reduction of mature neurons and synaptic function-related gene mRNAs. The Aβ levels, plaque burden, and glial markers of neuroinflammation seemed unaffected. Conclusions: These findings suggest that CQA treatment mitigates neuronal loss and improves cognitive function without reducing Aβ levels or neuroinflammation. Thus, CQA is a potential therapeutic compound for AD, improving cognitive function via as-yet unknown mechanisms independent of reductions in Aβ or neuroinflammation. Show more

Keywords: Alzheimer’s disease, amyloid-β , caffeoylquinic acid, chlorogenic acid, coffee, cognition, DeepLabCut

DOI: 10.3233/JAD-240033

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1285-1301, 2024

Authors: Xiong, Rui | Li, Binrui | Yu, Haitao | Fan, Tianceng | Yu, Huiling | Yang, Ying | Wang, Jian-Zhi | Pi, Guilin | Yang, Xifei

Article Type: Research Article

Abstract: Background: Anxiety and social withdrawal are highly prevalent among patients with Alzheimer’s disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. Objective: This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. Methods: We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. Results: In 5xFAD mice, we observed significant amyloid-β (Aβ) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice …displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aβ accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. Conclusions: The aBLA-vCA1 circuit is a vulnerable pathway in response to Aβ accumulation during the progression of AD and plays a crucial role in Aβ-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aβ-impaired social ability. Show more

Keywords: Alzheimer’s disease, amyloid-β, anxiety, aBLA-vCA1 circuit, urolithin A

DOI: 10.3233/JAD-240298

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1303-1316, 2024

Authors: Chai, Yuek Ling | Strohm, Lea | Zhu, Yanan | Chia, Rachel S.L. | Chong, Joyce Ruifen | Suresh, Danesha Devini | Zhou, Li Han | Too, Heng Phon | Hilal, Saima | Radivoyevitch, Tomas | Koo, Edward H. | Chen, Christopher P. | Poplawski, Gunnar Heiko Dirk

Article Type: Research Article

Abstract: Background: Emerging diagnostic modalities suggest that miRNA profiles within extracellular vesicles (EVs) isolated from peripheral blood specimens may provide a non-invasive diagnostic alternative for dementia and neurodegenerative disorders. Given that EVs confer a protective environment against miRNA enzymatic degradation, the miRNAs enriched in the EV fraction of blood samples could serve as more stable and clinically relevant biomarkers compared to those obtained from serum. Objective: To compare miRNAs isolated from EVs versus serum in blood taken from Alzheimer’s disease (AD) dementia patients and control cohorts. Methods: We compared 25 AD patients to 34 individuals who exhibited …no cognitive impairments (NCI). Subjects were Singapore residents with Chinese heritage. miRNAs purified from serum versus blood-derived EVs were analyzed for associations with AD dementia and medial temporal atrophy detected by magnetic resonance imaging. Results: Compared to serum-miRNAs, we identified almost twice as many EV-miRNAs associated with AD dementia, and they also correlated more significantly with medial temporal atrophy, a neuroimaging marker of AD-brain pathology. We further developed combination panels of serum-miRNAs and EV-miRNAs with improved performance in identifying AD dementia. Dominant in both panels was miRNA-1290. Conclusions: This data indicates that miRNA profiling from EVs offers diagnostic superiority. This underscores the role of EVs as vectors harboring prognostic biomarkers for neurodegenerative disorders and suggests their potential in yielding novel biomarkers for AD diagnosis. Show more

Keywords: Alzheimer’s disease, blood biomarker, dementia, diagnosis, extracellular vesicle, medial temporal atrophy, microRNA

DOI: 10.3233/JAD-230572

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1317-1331, 2024

Authors: Stam, Cornelis Jan | de Haan, Willem

Article Type: Research Article

Abstract: Background: There is increasing evidence from animal and clinical studies that network hyperexcitability (NH) may be an important pathophysiological process and potential target for treatment in early Alzheimer’s disease (AD). Measures of functional connectivity (FC) have been proposed as promising biomarkers for NH, but it is unknown which measure has the highest sensitivity for early-stage changes in the excitation/inhibition balance. Objective: We aim to test the performance of different FC measures in detecting NH at the earliest stage using a computational approach. Methods: We use a whole brain computational model of activity dependent degeneration to simulate …progressive AD pathology and NH. We investigate if and at what stage four measures of FC (amplitude envelope correlation corrected [AECc], phase lag index [PLI], joint permutation entropy [JPE] and a new measure: phase lag time [PLT]) can detect early-stage AD pathophysiology. Results: The activity dependent degeneration model replicates spectral changes in line with clinical data and demonstrates increasing NH. Compared to relative theta power as a gold standard the AECc and PLI are shown to be less sensitive in detecting early-stage NH and AD-related neurophysiological abnormalities, while the JPE and the PLT show more sensitivity with excellent test characteristics. Conclusions: Novel FC measures, which are better in detecting rapid fluctuations in neural activity and connectivity, may be superior to well-known measures such as the AECc and PLI in detecting early phase neurophysiological abnormalities and in particular NH in AD. These markers could improve early diagnosis and treatment target identification. Show more

Keywords: Activity dependent degeneration, Alzheimer’s disease, biomarkers, computational model, functional connectivity, network hyperexcitability, whole brain

DOI: 10.3233/JAD-230825

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1333-1348, 2024

Authors: Geng, Zhi | Wu, Yue | Liu, Jiaqiu | Zhan, Yuqian | Yan, Yibing | Yang, Chaoyi | Pang, Xuerui | Ji, Yi | Gao, Manman | Zhou, Shanshan | Wei, Ling | Hu, Panpan | Wu, Xingqi | Tian, Yanghua | Wang, Kai

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by brain network dysfunction. Few studies have investigated whether the functional connections between executive control networks (ECN) and other brain regions can predict the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS). Objective: The purpose of this study is to examine the relationship between the functional connectivity (FC) within ECN networks and the efficacy of rTMS. Methods: We recruited AD patients for rTMS treatment. We established an ECN using baseline period fMRI data and conducted an analysis of the ECN’s FC throughout the brain. Concurrently, the support …vector regression (SVR) method was employed to project post-rTMS cognitive scores, utilizing the connectional attributes of the ECN as predictive markers. Results: The average age of the patients was 66.86±8.44 years, with 8 males and 13 females. Significant improvement on most cognitive measures. We use ECN connectivity and brain region functions in baseline patients as features for SVR model training and fitting. The SVR model could demonstrate significant predictability for changes in Montreal Cognitive Assessment scores among AD patients after rTMS treatment. The brain regions that contributed most to the prediction of the model (the top 10% of weights) were located in the medial temporal lobe, middle temporal gyrus, frontal lobe, parietal lobe and occipital lobe. Conclusions: The stronger the antagonism between ECN and parieto-occipital lobe function, the better the prediction of cognitive improvement; the stronger the synergy between ECN and fronto-temporal lobe function, the better the prediction of cognitive improvement. Show more

Keywords: Alzheimer’s disease, executive control network, functional connectivity, repetitive transcranial magnetic stimulation, support vector regression

DOI: 10.3233/JAD-231449

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1349-1359, 2024

Authors: Wang, Wenxiao | Yang, Yiru | Sang, Feng | Chen, Yaojing | Li, Xin | Chen, Kewei | Wang, Jun | Zhang, Zhanjun

Article Type: Research Article

Abstract: Background: The aging population and high rates of Alzheimer’s disease (AD) create significant medical burdens, prompting a need for early prevention. Targeting modifiable risk factors like vascular risk factors (VRFs), closely linked to AD, may provide a promising strategy for intervention. Objective: This study investigates how VRFs influence cognitive performance and brain structures in a community-based cohort. Methods: In this cross-sectional study, 4,667 participants over 50 years old, drawn from the Beijing Ageing Brain Rejuvenation Initiative project, were meticulously examined. Cognitive function and VRFs (diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking), were comprehensively assessed through one-to-one …interviews. Additionally, a subset of participants (n  = 719) underwent MRI, encompassing T1-weighted and diffusion-weighted scans, to elucidate gray matter volume and white matter structural network organization. Results: The findings unveil diabetes as a potent detriment to memory, manifesting in atrophy within the right supramarginal gyrus and diminished nodal efficiency and degree centrality in the right inferior parietal lobe. Hypertension solely impaired memory without significant structural changes. Intriguingly, individuals with comorbid diabetes and hypertension exhibited the most pronounced deficits in both brain structure and cognitive performance. Remarkably, hyperlipidemia emerged as a factor associated with enhanced cognition, and preservation of brain structure. Conclusions: This study illuminates the intricate associations between VRFs and the varied patterns of cognitive and brain structural damage. Notably, the synergistic effect of diabetes and hypertension emerges as particularly deleterious. These findings underscore the imperative to tailor interventions for patients with distinct VRF comorbidities, especially when addressing cognitive decline and structural brain changes. Show more

Keywords: Aging cohort, Alzheimer’s disease, brain structural, cognitive performance, vascular risk factors

DOI: 10.3233/JAD-240240

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1361-1374, 2024

Authors: Pluta, Ryszard | Bogucka-Kocka, Anna | Bogucki, Jacek | Kocki, Janusz | Czuczwar, Stanisław J.

Article Type: Research Article

Abstract: Background: Currently, no evidence exists on the expression of apoptosis (CASP3 ), autophagy (BECN1 ), and mitophagy (BNIP3 ) genes in the CA3 area after ischemia with long-term survival. Objective: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6–24 months. Methods: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer’s disease. Results: First time, we demonstrated overexpression of the CASP3 gene in …CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. Conclusions: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3 . This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia. Show more

Keywords: Alzheimer’s disease, apoptosis, autophagy, brain ischemia, CA3 area, genes, hippocampus, long-term survival, mitophagy, neurodegeneration

DOI: 10.3233/JAD-240401

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1375-1383, 2024

Authors: Wang, Tao | Zhang, Wei | Maclin, Joshua M.A. | Xu, Hua | Hong, Bo | Yan, Feng | Liu, Yuanyuan | He, Haining | Liang, Huafeng | Li, Chunbo | Fang, Yiru | Xiao, Shifu

Article Type: Research Article

Abstract: Background: Long noncoding RNAs (lncRNAs) regulate the pathogenesis of Alzheimer’s disease (AD). Objective: To identify lncRNAs in the peripheral blood as potential diagnostic biomarkers for amnestic mild cognitive impairment. Methods: In the discovery group, a microarray was used to screen for significant differences in lncRNA expression between patients with mild cognitive impairment (MCI) caused by AD and normal controls (NCs) (n  = 10; MCI, 5; NC, 5). Furthermore, two analytic groups were assessed (analytic group 1: n  = 10; amnestic MCI (aMCI), 5; NC, 5; analytic group 2: n  = 30; AD, 10; aMCI, 10; NC, 10) and finalized …in the validation group (n  = 150; AD, 50; aMCI, 50; NC, 50). In the analytic and validation groups, real-time quantitative reverse-transcription polymerase chain reaction was used to identify differentially expressed lncRNAs between the aMCI and NC groups. Results: We identified 67 upregulated and 220 downregulated lncRNAs among the expression profiles. The panel with lncRNAs T324988 , NR_024049 , ENST00000567919 , and ENST00000549762 displayed the highest discrimination ability between patients with aMCI and NCs. The area under the receiver operating characteristic curve of this combined model was 0.941, with a sensitivity of 92.00% and specificity of 84.00%. Conclusions: This study reports on a panel of four lncRNAs as promising biomarkers to diagnose aMCIs. Show more

Keywords: Alzheimer’s disease, biomarkers, classification, cognitive dysfunction, diagnosis, long noncoding, RNA

DOI: 10.3233/JAD-231446

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1385-1396, 2024

Authors: Galvin, Angéline | Pedersen, Jacob Krabbe | Arbeev, Konstantin G. | Feitosa, Mary F. | Ukraintseva, Svetlana | Yao, Shanshan | Newman, Anne B. | Christensen, Kaare

Article Type: Research Article

Abstract: Background: Better physical robustness and resilience of long-lived siblings compared to sporadic long-livers has been demonstrated in several studies. However, it is unknown whether long-lived siblings also end their lives better. Objective: To investigate end-of-life (EoL) events (dementia diagnosis, medication, hospitalizations in the last 5 years of life), causes of death, and location of death in long-lived siblings compared to matched sporadic long-livers from the Danish population. Methods: Long-lived siblings were identified through three nationwide Danish studies in which the inclusion criteria varied, but 99.5% of the families had at least two siblings surviving to age …90 + . Those who died between 2006 and 2018 were included, and randomly matched with sex, year-of-birth and age-at-death controls (i.e., sporadic long-lived controls) from the Danish population. Results: A total of 5,262 long-lived individuals were included (1,754 long-lived siblings, 3,508 controls; 63% women; median age at death 96.1). Long-lived siblings had a significantly lower risk of being diagnosed with dementia in the last years of life (p  = 0.027). There was no significant difference regarding the number of prescribed drugs, hospital stays, days in hospital, and location of death. Compared to controls, long-lived siblings presented a lower risk of dying from dementia (p  = 0.020) and ill-defined conditions (p  = 0.030). Conclusions: In many aspects long-lived siblings end their lives similar to sporadic long-livers, with the important exception of lower dementia risk during the last 5 years of life. These results suggest that long-lived siblings are excellent candidates for identifying environmental and genetic protective factors of dementia. Show more

Keywords: Aging, Alzheimer’s disease, causes of death, dementia, end of life events, familial longevity

DOI: 10.3233/JAD-231204

Citation: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1397-1407, 2024