Review
Siyu Li, Yangyang Wang, Xiao Liang, Yu Li
Autophagy intersection: Unraveling the role of the SNARE complex in lysosomal fusion in Alzheimer’s disease
Abstract: Autophagy is a fundamental cellular process critical for maintaining neuronal health, particularly in the context of neurodegenerative diseases such as Alzheimer’s disease (AD). This review explores the intricate role of the SNARE complex in the fusion of autophagosomes with lysosomes, a crucial step in autophagic flux. Disruptions in this fusion process, often resulting from aberrant SNARE complex function or impaired lysosomal acidification, contribute to the pathological accumulation of autophagosomes and lysosomes observed in AD. We examine the composition, regulation, and interacting molecules of the SNARE complex, emphasizing its central role in autophagosome-lysosome fusion. Furthermore, we discuss the potential impact of specific SNARE protein mutations and the broader implications for neuronal health and disease progression. By elucidating the molecular mechanisms underlying SNARE-mediated autophagic fusion, we aim to highlight therapeutic targets that could restore autophagic function and mitigate the neurodegenerative processes characteristic of AD.
Review
Fengqing Xu, Jingshan Shi
Insulin signaling and oxidative stress: Bridging the gap between type 2 diabetes mellitus and Alzheimer's disease
Abstract: Background: Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are two prevalent chronic diseases that pose significant global health challenges. Increasing evidence suggests a complex bidirectional relationship between these conditions, where T2D elevates the risk of AD, and AD exacerbates glucose metabolism abnormalities in T2D. Objective: This review explores the molecular mechanisms linking T2D and AD, focusing on the role of insulin signaling pathways and oxidative stress. Methods: A comprehensive literature search from PubMed, Web of Science, and other relevant databases was conducted and analyzed. Results: Insulin resistance in T2D leads to impaired insulin signaling in the brain, contributing to cognitive decline and the development of AD. Hyperglycemia-induced oxidative stress exacerbates neuronal damage, promoting the formation of amyloid-β plaques and neurofibrillary tangles characteristic of AD. Clinically antidiabetic drugs such as metformin show potential against AD in preclinical studies; Many natural products such as Dendrobium nobile Lindl. have anti-T2D efficacy and are also effective against AD in various in vivo and in vitro models. Conclusions: Improving insulin resistance and reducing oxidative stress are important strategies in the treatment of T2D and AD. To understand the bridging role of insulin singling and oxidative stress in T2D and AD will provide insights and broader applications in alleviating T2D and AD.
Short Communication
Paula Theobald, Fabian Herold, Thomas Gronwald, Notger G. Müller
Subjective motoric cognitive risk syndrome: Preliminary prevalence from an online survey of a German cohort aged 50+
Abstract: The motoric cognitive risk syndrome (MCR) is a novel and clinically relevant pre-dementia syndrome indicating a higher dementia risk (e.g., for Alzheimer's disease). Given that MCR prevalence is unknown in Germany, we conducted a cross-sectional study, in which 208 participants from Germany aged 50 and 82 years answered an online survey including questions to assess subjective MCR (sMCR). The adjusted sMCR prevalence was 25.3%. Adults with sMCR reported more diseases and showed negative associations with physical activity, sedentary behavior, and sleep, suggesting that lifestyle modifications can play a significant role in MCR prevention. Further research is required to complement our preliminary findings on sMCR prevalence in Germany.
Commentary
Dorothee Horstkötter (Handling Editor: Allyson Rosen)
Alzheimer’s disease prediction and prevention in a public health perspective: Ethical considerations and collaborations beyond the biomedical paradigm
Abstract: The prevention of dementia is increasingly a task for public health promotion and aims at the general public. This likewise holds for potentially modifiable lifestyle risk factors and biomarkers indicating susceptibility. This commentary argues that from a public health ethical perspective, there is a significant overlap between the implications and requirements of the biomedical domain and lifestyle approaches. What’s more, once public awareness of Alzheimer’s disease prevention or risk reduction is further established, the public will likely intermix options and advice. Public health ethical recommendations should pro-actively reflect on upcoming questions, concerns, and remedies, combine but not separate both domains and anticipate their conceivable interactions.
Gro Gujord Tangen, Knut Engedal, Karin Persson, Geir Selbæk, Shams Dakhil, Riona McArdle, Marit Mjørud, Janne Røsvik, Anne Marit Mengshoel, Anne Brita Knapskog (Handling Associate Editor: Martin Vyhnalek)
Validation of Spatial Orientation Screening questionnaire for use in memory clinic patients
Abstract: Background: Spatial orientation is required for independent mobility in society. Deficits in spatial orientation can be an early symptom of Alzheimer’s disease and other dementias, and there is a need for brief assessment tools to identify impairments. Objective: The aim of this study was to evaluate the construct and known-group validity of our newly developed Spatial Orientation Screening (SOS) questionnaire. Methods: We included 132 patients with subjective cognitive decline (n=16), mild cognitive impairment (n=32), or all-cause dementia (n=84) from a memory clinic and a reference group of cognitively unimpaired older adults (n=108). The patients and their next-of-kin answered the self- and proxy-rated versions of the 4-item SOS (0–8 points) and the 10-item Questionnaire of Everyday Navigational Ability (QuENA, 0–30 points). The patients also performed the Floor Maze Test (FMT) for performance-based spatial abilities. Results: Mean ages (SD) of the patient and reference groups were 68.6 (±7.6) years and 73.7 (±6.7) years, respectively. Construct validity between self-rated versions of the SOS and QuENA was satisfactory with rs=0.66, between the proxy-rated versions rs=0.61, and between the proxy-reported SOS and FMT rs=0.49 (all p<0.001). Known-group validity was also acceptable, with significantly higher median (IQR) SOS self-reported scores in patients 1.0 (2.0) compared to the reference group 0.2 (0.5) points, (p<0.001). Informants reported more severe impairments compared to the patients’ self-reports on both SOS and QuENA (both p<0.001). Conclusions: The SOS had satisfactory validity for use as a screening instrument for assessment of spatial orientation in memory clinic patients.
Ze-Hu Sheng, Jia-Yao Liu, Jun-Yi Ma, Yin-Chu Mi, Hao Wang, Fan Guo, Ling-Zhi Ma, Lan Tan, Alzheimer’s Disease Neuroimaging Initiative
Frailty increases the risk of Alzheimer’s disease in non-demented individuals: A longitudinal cohort study
Abstract: Background: Frailty, which is considered a potential modifiable risk factor for dementia, continues to generate debate when it comes to Alzheimer's disease (AD). Furthermore, the underlying pathological mechanisms linking frailty to AD remain uncertain. Objective: We aimed to investigate the relationship between frailty and the risk of AD while elucidating the connections between frailty, AD biomarkers, and cognitive function. Methods: Total of 829 non-frail (261 robust, 568 pre-frail) and 94 frail individuals from the Alzheimer’s Disease Neuroimaging Initiative database were recruited. Kaplan–Meier analysis and Cox regression assessed AD risk across diverse frail statuses in 923 non-demented individuals. Multiple linear regression, mixed effects models and causal mediation analyses bootstrapped 10,000 iterations were conducted to examined underlying associations. Results: The frail group had a 67.7% increased risk of AD than non-frail group (HR=1.677; 95%CI, 1.179-2.385; p=0.004), a 61.8% increased risk of AD than pre-frail group (HR=1.618; 95%CI, 1.131-2.316; p=0.009) and a far higher risk of AD than robust group (HR=2.011; 95%CI, 1.263-3.202; p=0.003). Frailty was associated with cognitive decline (global cognition, memory and executive function), whole brain and hippocampus atrophy, and ventricle dilation. Higher frail degree predicted faster cognitive decline, brain atrophy and ventricle dilation. Frailty’s association with cognition was partially mediated by volume of whole brain (29.54%-30.17% of total effect), hippocampus (18.21%-24.55% of total effect), and ventricle (baseline, 7.62%-10.87% of total effect; change rate, 13.30%-24.33% of total effect). Conclusions: Frailty as a potential risk factor for AD, further mechanisms investigation is warranted; mitigating frailty could potentially contribute to AD prevention.
Julie Vignolo, Jean-Pierre Jacus, Thierry Darnaud, Christine Vanessa Cuervo-Lombard
Exploratory study of French healthcare workers’ experiences of anosognosia in Alzheimer’s disease and related disorders
Abstract: Background: Anosognosia or lack of insight is a common feature of Alzheimer’s disease (AD) and associated disorders. It is an impairment in the ability to recognize the disease and related symptoms. Anosognosia is associated among patients with poor compensatory strategies, behavioral disorders, apathy and caregiver burden. Therefore, its early identification by healthcare workers is a major challenge in order to provide support for both patients and caregivers. Objective: To explore the knowledge, attitudes and experiences of French healthcare workers relating to anosognosia in AD and related disorders. Methods: An online self-completed questionnaire was created for the study. It was anonymous and divided into three dimensions: general knowledge, confidence, and subjective experiences of anosognosia. One hundred and eleven healthcare workers completed the questionnaire. Mann Whitney and Kruskal Wallis tests were used to determine the variables associated with the total knowledge and confidence scores. Ordinal logistic regressions were performed to explore the associations between subjective experiences and demographics. Results: The participants had moderate knowledge. Knowledge scores were influenced by their experience in the geriatric field, type of profession, workplaces and training. The areas where knowledge was poorest were anosognosia assessment and management. The participants with the lowest knowledge levels were those interacting the most with patients, especially at home. Overall, they identified difficulties related to anosognosia and did not seem confident about their ability to deal with this condition. Conclusions: This study determines specific areas for training on anosognosia, such as identification, assessment and management of this condition.
Junyong Du, Shabei Xu, Wenhao Zhu
Structure-function coupling alterations in cognitively normal individuals with white matter hyperintensities
Abstract: Background: White matter hyperintensities (WMH) are prominent neuroimaging markers of cerebral small vessel disease (CSVD) linked to cognitive decline. Nevertheless, the pathophysiological mechanisms underlying WMH remain unclear. Objective: This study aimed to assess the structural decoupling index (SDI) as a novel metric for quantifying the brain’s hierarchical organization associated with WMH in cognitively normal older adults. Methods: We analyzed data from 112 cognitively normal individuals with varying WMH burdens (43 high WMH burden and 69 low WMH burden). Neuroimaging data were used to calculate SDI, and gene enrichment analysis was conducted to explore related molecular pathways. Results: An increased spatial gradient of SDI from the sensory-motor cortex to the associative cortex was observed. Compared to the low WMH burden group, the high WMH group exhibited elevated SDI in the right superior frontal gyrus, bilateral orbital gyrus, bilateral precentral gyrus, bilateral cingulate gyrus, bilateral thalamus, and bilateral striatum. In the high WMH burden group, SDI in the left thalamus and right cingulate gyrus negatively correlated with memory, while SDI in the right orbital gyrus and left precentral gyrus positively correlated with processing speed. Gene enrichment analysis highlighted associations with pathways involved in neural system function, potassium ion transmembrane transport, synaptic signaling, neuron projection development, and cell secretion regulation. Conclusions: The findings suggest SDI alterations as a potential mechanistic pathway in WMH, which is associated with significant molecular pathways and cognitive impairments. This study provides a theoretical framework for understanding the pathophysiology of WMH progression and subsequent cognitive deficits.
Min Wei#, Xianfeng Yu#, Shimin Hu#, Wenjing Hu, Rong Shi, Min Wang, Jiayi Zhong, Qi Zhang, Ying Zhang, Chenyang Li, Ziyan Song, Jiehui Jiang, Ying Han #These authors contributed equally to this work.
Differences of longitudinal plasma biomarkers between single memory domain and multidomain subject cognitive decline: Evidence from SILCODE
Abstract: Background: Plasma biomarkers demonstrated potential in identifying amyloid pathology in early Alzheimer's disease. Different subtypes of subjective cognitive decline (SCD) may lead to different cognitive impairment conversion risks. Objective: To investigate the differences of plasma biomarkers in SCD subtypes individuals, which were unclear. Methods: The 347 individuals were involved, including 93 normal control (NC), 76 single memory domain SCD (sd-SCD), 79 multidomain SCD (md-SCD), 55 mild cognitive impairment and 44 dementia. We investigated plasma biomarkers (Aβ42/40, p-tau181, p-tau217, NfL, and GFAP) and neuropsychological scales in the baseline and follow-up. The Kaplan-Meier survival analysis and cox proportional hazards model were performed to investigate the risk of cognitive decline conversion. The t-test, Mann-Whitney U and multiple linear regression analysis were employed to evaluate the rate of change and correlation between PET-SUVR and plasma biomarker change. Results: In cognitively normal subjects, md-SCD exhibits lower Aβ42/40 and higher p-tau181 and p-tau217 levels. Kaplan-Meier survival analysis revealed that md-SCD group exhibited a higher risk of cognitive decline conversion compared to NC and sd-SCD. Within SCD subgroups, those with positive GFAP status showed higher conversion risk than negative. In cox model, the risk of conversion in the md-SCD group was 2.77 times higher than sd-SCD. The md-SCD group demonstrated a faster rate of Aβ42/40 decline than sd-SCD. Conclusions: The study utilized plasma biomarkers to highlight the significance of staging in SCD. In cognitively normal subjects, md-SCD presents a higher risk of cognitive decline than sd-SCD, providing a valuable reference and convenient tool for early identification of individuals at risk for AD.
Stephanie Van Asbroeck, Sophie CPM Wimmers, Martin PJ van Boxtel, Rob BM Groot Zwaaftink, Vera Otten, Dinant Bekkenkamp, Sebastian Köhler, Kay Deckers (Handling Associate Editor: Mariagnese Barbera)
Development and evaluation of a free e-learning program on dementia risk reduction for the general public: A pre-post study
Abstract: Background: There is consistent evidence for the contribution of modifiable risk factors to dementia risk, offering opportunities for primary prevention. Yet, most individuals are unaware of these opportunities. Objective: To investigate whether online education about dementia risk reduction may be a low-level means to increase knowledge and support self-management of modifiable dementia risk factors. Methods: A pre-post study was conducted with Dutch community-dwelling individuals who registered for a free e-learning course called “Keep your brain healthy”. The e-learning covers seven themes delivered week-by-week covering cognitive and physical activity, diet, and cardiovascular health, amongst others. Participants completed an online survey before starting the e-learning, immediately afterwards, and three months later. The survey covered user experience, knowledge on dementia risk reduction, motivation for, and engagement in, health behaviors. Results: Of the 477 participants (70.9% women, mean age=63 years), 339 (71.1%) completed the survey immediately after the e-learning, and 241 (50.5%) completed the three-month follow-up survey. User experiences were positive with weekly themes receiving average ratings between 7.9-8.1 out of 10. Improvements over time were seen in knowledge of dementia risk reduction, Mediterranean diet adherence, social contact satisfaction, and motivation for physical activity. Cognitive activity levels and alcohol consumption improved over time in women. Moreover, improvements in knowledge and Mediterranean diet adherence remained present three months after course completion. Conclusions: This e-learning program was positively perceived, increased knowledge of dementia risk reduction, and promoted engagement in brain-healthy lifestyles. The program can easily be implemented as a stand-alone tool or as part of larger dementia risk reduction initiatives.
Yayu Ma#, Chao Tang#, Xiaoyang Lei, Li Wang, Dian He #These authors contributed equally to this work. (Handling Associate Editor: Yi Tang)
Clinical characteristics of semantic variant of primary progressive aphasia with TDP-43- and tau-related gene variants
Abstract: Background: Semantic variant primary progressive aphasia (svPPA) can be inheritable. There is a predictable relationship between the pathological substrate and genetic variants in this condition. Objective: To report a case with svPPA who carried a MAPT gene mutation and to explore clinical differences between svPPA with TDP-43 pathology-related genes and svPPA with tau pathology-related genes. Methods: Studies reporting svPPA patients with MAPT, TARDBP, GRN, C9orf72, or TBK1 gene mutations were selected from PubMed and China National Knowledge Infrastructure (CNKI). Of the 109 articles from the literature, 31 reports involving 75 cases provided the outcomes of interest. Results: Along with the new case, 76 patients (43 males and 33 females) were included in this study. Among them, 34 carried MAPT mutations, 15 with TARDBP mutations, 13 with GRN mutations, 8 with C9orf72 expansions, and 6 with TBK1 mutations. The analysis results revealed that the mean age of onset in the tau pathology-related gene mutation group (50.56±7.46 years) was younger than that in the TDP-43 pathology-related gene mutation group (58.19±7.66 years) (p < 0.001). MAPT and TARDBP mutations were more prevalent in the study population, accounting for 44.7% and 19.7%, respectively. Within the MAPT gene mutation population, P301L accounted for 41.2%, while IVS10+16C>T accounted for 38.2%. Among the TARDBP gene mutation carriers, I383V accounted for 73.3%. Conclusions: The onset age in svPPA patients with tau pathology-related gene mutations is younger than in those with TDP-43 pathology-related gene mutations. MAPT variants, specifically P301L and IVS10+16C>T, as well as TARDBP I383V variant, may have higher mutation frequency in svPPA.
Ying Wang#, Liangying Zhu#，Kun He#, Liang Cui, Fengfeng Pan, Yihui Guan, Rongqiao He, Fang Xie, Qihao Guo #These authors contributed equally to this work.
Urinary formic acid is associated with cerebral amyloid deposition and glucose metabolism in memory clinic patients
Abstract: Background: Urinary formic acid (FA) has been reported to be a biomarker for Alzheimer's disease (AD). However, the association between FA and pathological changes in memory clinic patients is currently unclear. Objective: This study aims to investigate associations between FA and pathological changes across different cognitive statuses in memory clinic patients. Methods: A cohort of patients with mild cognitive impairment (MCI-Aβ- n=37, MCI-Aβ+ n=33), AD dementia (n=39), and cognitively normal subjects (CN-Aβ- n=98, CN-Aβ+ n=50) were included. Comprehensive neuropsychological assessment, urinary FA, AD-related plasma biomarkers, MRI scans, [18F]-flurbetapir and [18F]-FDG PET scan data were collected from all participants. Results: Urinary FA levels were higher in patients with MCI and AD than in CN subjects and higher in Aβ+ (CN- Aβ+, MCI-Aβ+, AD dementia) subjects than in Aβ-subjects (CN- Aβ-, MCI-Aβ-). Urinary FA was positively associated with cerebral Aβ deposition and negatively associated with glucose metabolism, both at the global level and in multiple regions of interest cortical regions in participants with different cognitive statuses. Additionally, urinary FA levels were positively correlated with the severity of white matter hyperintensities and hippocampal atrophy. Urinary FA combined with age, Mini-Mental State Examination, plasma p-tau181, and neurofilament light chain could be used to predict Aβ deposition in the brain. Conclusions: Urinary FA is associated with brain pathological changes in memory clinic patients, including cerebral Aβ deposition, glucose metabolism, white matter hyperintensities, and hippocampal atrophy. It could be used as a biomarker for the early diagnosis of AD and predicting Aβ deposition.
Hang Xing, Shawn Kant, Meghamsh Kanuparthy, Dwight Harris, Christopher Stone, Mark Broadwin, Zhiqi Zhang, Elena Pearson, Jiayu Hu, Ava Sauer, Amy Princiotto, Elizabeth O Harrington, Suzanne M de la Monte, Frank Sellke, Jun Feng
Impaired cerebral microvascular reactivity and endothelial SK channel activity in a streptozotocin-treated mouse model of Alzheimer’s disease
Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease marked by increased amyloid-β (Aβ) deposition, tau hyperphosphorylation, impaired energy metabolism, and chronic ischemia-type injury. Cerebral microvascular dysfunction likely contributes to AD pathology, but its precise pathogenic role has been poorly defined. Objective: To examine microvascular reactivity to endothelium-dependent vasodilators and small conductance calcium-activated potassium (SK) channel activity in an intracerebral streptozotocin (STZ)-induced AD mouse model. Methods: Control and STZ-AD mice underwent Morris Water Maze and Barnes testing, after which cerebral microvascular and brain microvascular endothelial cells (MBMECs) were dissected to assess microvascular reactivity, responses to SK channel activator NS309, and ion-channel current recordings using whole-cell patch clamp methodology. Control mouse cerebral microvascular and human brain microvascular endothelial cells (HBMECs) were treated with soluble Aβ1-42 peptide to characterize microvascular reactivity and endothelial potassium currents. Results: STZ-AD mice exhibited impaired performance vs control mice in behavioral testing. STZ-AD mice also exhibited diminished cerebral microvascular responsiveness and MBMECs potassium current augmentation in response to NS309 compared with control mice. Incubation of control mouse cerebral micro-vessels and HBMECs with soluble Aβ (1 µM) for 2 h attenuated relaxation responses to NS309 and diminished NS309-sensitive endothelial potassium currents. Conclusions: STZ-AD mice exhibited impaired microvascular relaxation responses to endothelium-dependent vasodilators; SK/IK channel dysfunction may be involved in the mechanism of this impairment. Acute treatment with Aβ produced dysregulated cerebrovascular endothelial SK/IK channels. Further elucidation of the role of microvascular dysfunction in AD is needed to prevent the chronic ischemia-type injury that contributes to cognitive decline.
Hao Yang#, Yuye Ning#, Meilin Chen#, Jianping Jia #These authors contributed equally to this work.
SGLT2 inhibition, circulating biomarkers, and Alzheimer’s disease: A Mendelian randomization study
Abstract: Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors is a novel category of medications for diabetes, exhibiting neuroprotective potential. However, evidence regarding whether the use of SGLT2 inhibitors effectively reduces the risk of Alzheimer's disease (AD) remains unclear. Objective: Our study employed Mendelian randomization (MR) analysis to investigate potential causal relationships between SGLT2 inhibition, metabolites, and AD. Methods: In our research, we used a two-sample MR method to explore the link between SGLT2 inhibitor use and AD, addressing both its late-onset and early-onset forms. Furthermore, we executed a two-step MR analysis to explore how circulating metabolites, primarily endogenous in nature due to SGLT2 inhibition, mediate the relationship between SGLT2 inhibition and AD. The genetic instruments for SGLT2 inhibition were pinpointed through their association with SLC5A2 gene expression and the decreased glycated hemoglobin (HbA1c) levels. Results: Genetic analysis indicated that SGLT2 inhibition, which effectively reduces HbA1c by enhancing renal glucose excretion and improving glycemic control, was associated with a lower likelihood of developing AD for every 1 SD decrease in HbA1c (OR = 0.48, [0.36, 0.63], p < 0.001). Our MR analysis revealed that SGLT2 inhibition significantly affected 27 of the 123 metabolites examined, adhering to a Bonferroni correction threshold (p < 4.06 × 10-4). Among these 27 significant metabolites, citrate was also associated with AD, showing a significant association (0.81 [0.79, 0.83], p < 0.001). Conclusions: The study provides strong evidence linking SGLT2 inhibition with a lower AD risk, highlighting citrate's potential mediating role for subsequent clinical research.
Chunxin Lu, Jiechao Zhou
Analysis of the causal relationship between five chosen factors and early-onset Alzheimer’s disease: A Mendelian randomization study
Abstract: Background: This study aims to explore the causal relationship between five selected factors—lysosome, migrasomes, macrophage, fibroblast, and endothelium cell—and early-onset Alzheimer’s disease (EOAD) through related genes, providing clues for EOAD research. Methods: Using genes related to the five selected factors as exposure variables and EOAD as the disease outcome, significant genes were screened through Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method, based on the OpenGWAS database. The selected genes were intersected with genes related to the exposure factors to assess the causal relationships between the five factors and EOAD. Results: MR analysis identified 13 genes in total. Six of these genes were protective factors for EOAD, with LYST being the most significant (OR=0.4259, 95% CI: 0.2218–0.8178, p=0.0103). Seven genes were risk factors for EOAD, with NCF4 being the most significant (OR=2.7207, 95% CI: 1.0229–7.2362, p=0.0449). A total of 1,925 genes related to lysosome, migrasomes, macrophage, fibroblast, and endothelium cell were analyzed. After intersection, 10 lysosome-related genes (NCF4, VIPAS39, LYST, SORT1, ARSB, EPDR1, SYNGR1, ANXA11, PYGB, CLN5) and 3 endothelium cell -related genes (ADM, NFIB, NKTR) were found to have significant causal relationships with EOAD. Conclusions: There are genes related to lysosome and endothelium cell that have significant relationships with EOAD, while no causal relationships were found between migrasomes, macrophage, fibroblast, and EOAD. This study provides an important basis for further EOAD research.
Andrew J Petkus, Anup N Sonti, Lucy Montoya, Bryan Rowe, Abhay Sagare, John M Ringman
Sequence of decline on the NIH-toolbox cognitive battery in a predominantly Latino sample with autosomal dominant Alzheimer’s disease
Abstract: Background: Understanding the sequential progression of cognitive decline in autosomal dominant Alzheimer’s disease (ADAD) in the Latino population is crucial for enhancing early identification for targeted interventions. Given the tablet-based administration and increasing frequency of use in epidemiological research, validating this progression within the NIH Toolbox cognitive battery (NIHTB-CB) is important. Objective: The first aim was to utilize an innovative Event-Based Modeling (EBM) analytic approach to estimate the sequence of cognitive declines in persons at risk for ADAD enriched for being of Latino origin. The second aim was to examine associations between EBM-derived estimates of cognitive disease severity and independent cognitive outcomes within carriers and noncarriers. Methods: This cross-sectional observational study (N=30) included 16 ADAD mutation carriers and 14 noncarriers who completed the NIHTB-CB in their primary language (n=8 Spanish; n=22 English). An EBM was constructed to compare ADAD mutation carriers and noncarriers on NIHTB-CB performance. We utilized linear regression to examine the associations between the EBM-derived cognitive-decline disease stage and independent outcomes (e.g., performance on the Cognitive Abilities Screening Instrument (CASI) and estimated years to dementia diagnosis). Results: The EBM estimated that tests assessing episodic memory were the first to become abnormal in the sequence of ADAD-related cognitive decline. Each higher estimated cognitive-decline disease stage was associated with approximately a three-point decline in the CASI and two years closer to dementia diagnosis. Conclusions: Findings support the EBM applied to the tablet-based NIHTB-CB to estimate the likely progression of cognitive decline in Latinos with ADAD.
George P Prigatano, Lucia W Braga, Molly McElvogue, Katelyn Coddaire, Lori Steffes, Anna Burke, Ashley M Stokes
Motor correlates of finger tapping variability in subjective memory complaints, mild cognitive impairment and probable Alzheimer’s disease
Abstract: Background: Variability of finger tapping speeds, especially in the non-dominant hand, has been reported in individuals with amnestic mild cognitive impairment (MCI-A) and dementia of the Alzheimer’s type (AD). An explanation of this finding, however, has not appeared. Objective: The aim of this study was to investigate possible motor correlates of finger tapping variability in normal older healthy controls (HC), persons with subjective memory complaints (SMC), MCI-A and probable AD. Methods: Using a modified version of the Halstead Finger Tapping Test (HFTT), individual finger tapping movements were classified as “valid” (i.e., advanced the number on a mechanical counter) or “invalid” (i.e., did not advance the number). Failures at selective motor inhibition and learning and fatigue effects were also measured. Results: Finger tapping variability was significantly greater in the non-dominant hand in probable AD patients compared to HC and SMC patients. MCI-A and probable AD patients did not differ on this measure. Finger tapping variability was significantly correlated (ρ = +0.65) with the number of invalid tapping responses but not with selective motor inhibition failures. A small but significant correlation of dominant hand learning effect with finger tapping variability was found. Invalid tapping responses were significantly greater in MCI and probable AD groups compared to HC and SMC groups. Conclusions: Frequency of invalid tapping responses strongly correlated with finger tapping variability. The number of invalid tapping responses may have diagnostic and prognostic significance when evaluating older individuals with known or suspected memory impairment of a neurodegenerative type.
Shu-Fen Chu, Cheng-Hua Ni, Kuo-Hsing Liao, Ya-Ting Wen (Handling Associate Editor: I-Shiang Tzeng)
Dementia and epilepsy without traumatic brain injury among subjects middle-aged females: a population-based case-control study
Abstract: Background: Although the association between dementia such as Alzheimer's disease and traumatic brain injury (TBI) is well established, there are significant knowledge gaps with respect to the perspective of dementia and epilepsy without TBI. Objective: We aimed to investigate the relationship between dementia and epilepsy in a population-based study of patients without history of TBI. Methods: This study included a random sample of 30,715 patients with no history of TBI, including 6143 with epilepsy as the study cohort and 24,572 without epilepsy as the comparison cohort. Stratified Cox proportional hazard regression was used to calculate the adjusted hazard ratio (HR), with 95% confidence interval, for the risk of developing dementia in the two cohorts. Results: Patients with epilepsy but no history of TBI had increased risk of dementia (adjusted HR = 1.84). For patients aged 55-64 years, the adjusted HR for dementia was 4.5-fold higher among females in the study cohort than among males. Additionally, this study revealed that risk of dementia among above 75-year population lowest than other age subgroups (adjusted HR= 1.45). Conclusions: The study demonstrated an association between dementia and epilepsy in the patients who had no history of TBI. The effect was pronounced in patients aged 55-64 years, especially in the female population, suggesting that epilepsy needs to be more intensively prevented and controlled in this age group.
Max A Thorwald, Naomi S Sta Maria, Ararat Chakhoyan, Peggy A O’Day, Russell E Jacobs, Berislav Zlokovic, Caleb E Finch
Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins
Abstract: Background: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimer’s disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO and other chelators do enter the brain despite some contrary reports. Objective: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid-β protein precursor (AβPP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. Methods: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and AβPP processing by western blot. Results: DFO decreased brain iron 18% (p<0.01) estimated by R2 MRI and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. AβPP and secretase enzymes also decreased by 30%. Conclusions: WT mice respond to DFO with decreased AβPP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered AβPP and secretase enzymes.
Isreal Ayobami Onifade, Haruna Isiyaku Umar, Abdullahi Tunde Aborode, Aeshah A. Awaji, Ifeoluwapo Deborah Jegede, Bunmi Helen Adeleye, Dorcas Oladayo Fatoba
In silico study of selected alkaloids as dual inhibitors of β- and γ-secretases for Alzheimer’s disease
Abstract: Background: Alzheimer's disease (AD) has become common as the number of aged people increases making it as a socioeconomic problem lately. To date, no success is recorded for disease-modifying therapies for AD but only drugs for symptomatic relief exist. Research has been centered on the role of amyloid-β on the pathogenesis of AD, which has led to the development of drugs that target Aβ (β- and γ-secretase inhibitors) to reduce the amount of Aβ formed. However, the existing β and γ-secretase inhibitors were associated with harmful side effects, low efficacy, and inability to cross the blood-brain barrier. Objective: This study therefore used in silico approach to predict the inhibitory properties of alkaloids as potential drug targets against AD. Methods: Thus, in this current study, 54 alkaloids from the PhytoHub server (phytohub.eu), and two approved drugs were docked against β-secretases. Additionally, galantamine and 5 alkaloids with the utmost binding potential with β-secretase were subjected to pharmacokinetics evaluation and docked against γ-secretase. Results: From the result, 5 compounds displayed for both docking periods, with demissidine, solasodine, tomatidine, and solanidine having better BE than the control drugs. Based on the pharmacokinetics evaluation, 4 compounds possessed good pharmacokinetic evaluation and biological activities than galantamine. Conclusions: This study suggests that demissidine, solasodine, tomatidine, and solanidine are promising dual inhibitors against β- and γ-secretase proteins in silico. However, there is an urgent need to carry out in vitro and in vivo experiments on these new leads to validate the findings of this study.
Philip S Crooke, 3rd, John T Tossberg, Thomas M Aune
Increased unedited Alu RNA patterns found in cortex extracellular vesicles in Alzheimer’s disease resemble hippocampus vasculature Alu RNA editing patterns but not cortex Alu RNA editing patterns
Abstract: Background: Endogenous Alu RNAs form double-stranded RNAs recognized by double-stranded RNA sensors and activate IRF and NF-kB transcriptional paths and innate immunity. Deamination of adenosines to inosines by the ADAR family of enzymes, a process termed A-to-I editing, disrupts double-stranded RNA structure and prevents innate immune activation. Innate immune activation is observed in Alzheimer’s disease, the most common form of dementia. We have previously reported loss of A-to-I editing in hippocampus vasculature, but no change in cortex or cortex vasculature, associated with Alzheimer’s disease. Objective: Here, we investigated the status of Alu RNA A-to-I editing in cortex extracellular vesicles in Alzheimer’s disease. Methods: We used existing RNA-seq data sets and the SPRINT software package to determine levels of Alu RNA A-to-I editing in cortex extracellular vesicles in Alzheimer’s disease and control groups and compared these editing profiles to those found in both total cortex and hippocampus vasculature. Results: We find substantial loss of Alu A-to-I editing in cortex extracellular vesicles in Alzheimer’s disease. By measuring editing patterns on a gene-by-gene basis, we determined that editing patterns in cortex extracellular vesicles resemble editing patterns in hippocampus vasculature rather than total cortex. Conclusions: We conclude that hippocampus vasculature unedited Alu RNAs are packaged in extracellular vesicles, travel to the cortex, deliver their cargo and stimulate innate immunity and alter other basic biological processes contributing to Alzheimer’s disease progression.
Mohammad Taufeeq, Arunabh Choudhury, Afzal Hussain, Mohamed F Alajmi, Taj Mohammad, Anas Shamsi, Md Imtaiyaz Hassan (Handling Associate Editor: Rekha Khandia)
Discovering potential ERK1 inhibitors from natural products for therapeutic targeting of Alzheimer’s disease
Abstract: Background: Extracellular signal-regulated kinase 1 (ERK1) belongs to mitogen-activated protein kinases, which are essential for memory formation, cognitive function, and synaptic plasticity. During Alzheimer’s disease (AD), ERK1 phosphorylates tau at 15 phosphorylation sites, leading to the formation of neurofibrillary tangles. The overactivation of ERK1 in microglia promotes the release of pro-inflammatory cytokines, which results in neuroinflammation. Additionally, elevated oxidative stress during AD stimulates the ERK1 pathway, leading to neuronal loss. Objective: Because ERK1 signaling plays a significant role in tau phosphorylation, targeting ERK1 may be therapeutically beneficial by either preventing excessive activation of the signaling pathway or altering its pathway to enhance neuroprotective effects during AD. Methods: This study employed structure-based virtual screening of phytoconstituents from the IMPPAT library. Subsequently, in-depth docking and molecular dynamics (MD) simulation studies were implemented to identify potential ERK1 inhibitors with desirable pharmacological properties. Results: Silandrin and Hydroxytuberosone were found to be potential ERK1 inhibitors with higher affinity and specificity than the control molecule Tizaterkib. These compounds specifically bind to the ERK1 substrate binding pocket and interact with crucial residues. Finally, the elucidated compounds with ERK1 were evaluated using an all-atom molecular MD simulation to analyze structural dynamics, structural compactness, hydrogen bond dynamics, principal component analysis, and free energy landscape. Conclusions: The study suggested that Silandrin and Hydroxytuberosone can further be exploited as potential lead molecules for therapeutic development against ERK1-mediated AD.
Huaying Cai#, Nan Zhang#, Yun Jiang, Qianwen Wu, Linhui Ni, Guocan Han, Jiaao Liaocheng, Dan Wu, Zhiyong Zhao #These authors contributed equally to this work.
State-dependent functional network connectivity alterations in post-stroke dementia with subcortical lesions
Abstract: Background: Recent studies have revealed disrupted dynamic functional network connectivity (dFNC) in stroke or dementia brains. However, it remains unclear how the dFNC was altered in post-stroke dementia (PSD). Objective: This study aimed to explore PSD-specific alterations in the dFNC and their association with clinical assessments. Methods: We included 19 normal controls (NC), 16 PSD, and 20 post-stroke non-dementia (PSND) patients who underwent resting-state functional MRI scan. Independent component analysis, combined with a sliding-window approach, was employed to calculate dFNC. The cognitive performance was assessed by both Mini-Mental State Examination and MiniCog assessments, which were subsequently used for multiple regression analysis to investigate the relationships with dFNC. Results: We identified 13 meaningful resting-state networks, and the dFNC among them derived four states exhibiting different connection patterns. In state III with strong connections within high-order networks, PSD and PSND both showed increased connectivity between visual network (VN) and high-order networks relative to NC; in state I with weak connections among all networks, PSD showed weaker connectivity between default mode network (DMN) and executive control network and between VN and DMN compared to PSND. Moreover, the dFNC measures showed significant correlations with cognitive assessments of patients. Conclusions: Our findings suggest that PSD-specific FNC alterations are state-dependent, and dFNC reveals a coexistence mechanism of functional impairment and compensation in large-scale brain networks, which is not observed in static FNC. This offers a new perspective to understand the neural mechanisms of PSD.
Ashley Gillman, Pierrick Bourgeat, Timothy Cox, Victor L Villemagne, Jurgen Fripp, Kun Huang, Rob Williams, Rosita Shishegar, Graeme O’Keefe, Shenpeng Li, Natasha Krishnadas, Azadeh Feizpour, Svetlana Bozinovski, Christopher C Rowe, Vincent Doré
Digital detector PET/CT increases Centiloid measures of amyloid in Alzheimer’s disease: A head-to-head comparison of cameras
Abstract: Background: The introduction of therapeutics for Alzheimer’s disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent PET hardware innovations including digital detectors have led to superior resolution and sensitivity, improving quantitative accuracy. However, the effect of PET scanner on Centiloid remains relatively unexplored and is assumed to be minimized by harmonizing PET resolutions. Objective: To quantify the differences in Centiloid between scanners in a paired cohort. Methods: 36 participants from the AIBL cohort were scanned within a year on two scanners. Each participant underwent 18F-NAV4694 imaging on two of the three scanners investigated, the Siemens Vision, the Siemens mCT and the Philips Gemini. We compared Aβ Centiloid quantification between scanners and assessed the effectiveness of post-reconstruction PET resolution harmonization. We further compared the scanner differences in target sub-regions and with different reference regions to assess spatial variability. Results: Centiloid from the Vision camera was found to be significantly higher compared to the Gemini and mCT; the difference was greater at high-Centiloid levels. Post-reconstruction resolution harmonization only accounted for and corrected ~20% of the CL difference between scanners. We further demonstrated that residual differences have effects that vary spatially between different subregions of the Centiloid mask. Conclusions: We have demonstrated that the type of PET scanner that a participant is scanned on affects Centiloid quantification, even when scanner resolution is harmonized. We conclude by highlighting the need for further investigation into harmonization techniques that consider scanner differences.
Chang Hyun Park, Hyunji Lee, Young-Min Lee, Byung-Dae Lee, Eunsoo Moon, Hwagyu Suh, Kyungwon Kim, Hak-Jin Kim, Hwanwook Shim, Kyoungjune Pak, Kyung-Un Choi, Chang-Seok Kim
Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period
Abstract: Background: Hippocampal atrophy is implicated in the early onset of Alzheimer's disease (AD). It is closely associated with rapid cognitive decline and serves as a critical predictor for conversion from mild cognitive impairment (MCI) to AD. Consequently, with growing interest in utilizing hippocampal volume (HV) as an outcome measure in clinical trials, elucidating the neurobiological mechanisms underlying hippocampal atrophy is essential for early diagnosing AD and predicting its progression. Objective: The risk of AD associated with the apolipoprotein E ε4 (APOE4) allele is higher in females than in males. However, the presence of sex-specific effects of the APOE4 genotype on longitudinal hippocampal atrophy (ΔHV) remains unclear. We aimed to examine the effects of the interaction between the APOE4 genotype and sex on ΔHV in amnestic mild cognitive impairment (aMCI). Methods: This hospital-based prospective longitudinal study included 73 patients with aMCI. ΔHV, the major outcome measure, was assessed using magnetic resonance imaging performed at a baseline date and 2 years after the baseline evaluation. A two-way analysis of variance was conducted to examine the effects of the interaction between the APOE4 genotype and sex on ΔHV over the 2-year period. Results: A significant interaction was observed between APOE4 and sex concerning ΔHV (p = 0.036). In females, ΔHV significantly correlated with the APOE4 status. Female APOE4 carriers (ε3/ε4) exhibited 2.3 times higher ΔHV compared with female non-carriers (ε3/ε3) (−0.51 ± 0.28 versus −0.22 ± 0.26, p<0.001). In contrast, ΔHV was not linked to the APOE4 status in males (p = 0.599). Conclusions: We identified that the APOE4 genotype affected ΔHV in females. Our findings suggest that female APOE4 carriers, unlike males, may be more susceptible than non-carriers to the underlying pathophysiological mechanisms of hippocampal atrophy in aMCI.
Erdong Zhang#, Fengqiu Dai#, Ling Tao, Yanqin Chen, Tingting Chen, Xiangchun Shen #These authors contributed equally to this work.
Immune cells: Mediators in the metabolites and Alzheimer’s disease
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly individuals across the globe. While genetic, environmental, and lifestyle factors are known to influence the onset of AD, the underlying mechanisms remain unclear. Objective: To elucidate the intricate interplay between metabolites and immune cell activation in the ethology of AD, and to determine their collective impact on AD risk. Methods: We conducted a comprehensive analysis of genome-wide association studies data to examine the relationships between metabolites, immune cell phenotypes, and the risk of AD. Our study encompassed a comprehensive examination involving 731 distinct immune cell types, 1400 metabolites, and a large cohort comprising10,520 AD cases with 401,661 controls. We employed univariate Mendelian randomization to assess bidirectional relationships between metabolites and AD, metabolites and immune cells, as well as immune cells and AD. Subsequently, multivariate Mendelian randomization was then applied to evaluate the potential mediating role of immune cells on the relationship between metabolites and AD. Results: Specific metabolites, the histidine/pyruvate ratio and homoarginine, were positively associated with the risk of AD, mediated by immune cells. Conversely, 4-hydroxycoumarin and glycolithocholate sulfate showed protective associations against AD. Immune cell markers, CD64 on monocytes and HLA DR on CD14+ CD16- monocytes were linked to higher AD risk, while CD33dim HLA DR+ CD11b- myeloid cells and HLA DR on CD8+ T cells were protective. Conclusions: This study highlights the critical role of immune cells in the pathogenesis of AD, demonstrating how their interaction with specific metabolites influences disease risk.
