Current Alzheimer research最新文献

Introduction: Alzheimer's Disease (AD) is the most common neurodegenerative disease, and timely and effective diagnosis is essential for the prevention and treatment of AD. Peripheral blood is readily available, inexpensive, and non-invasive, making it an ideal substrate for screening diagnostic biomarkers.

Method: The Notch signaling pathway is closely related to AD, so genes related to the Notch signaling pathway may be candidate diagnostic biomarkers for AD. Here, we have performed an integrated analysis of peripheral blood cells transcriptomics from two AD cohorts (GSE63060: Ctrl = 104, MCI = 80, AD = 145; GSE63061: Ctrl = 134, MCI = 109, AD = 139) to reveal the expression levels of 16 Notch signals involving 100 genes.

Result: The results have shown the changes in Notch signaling-related genes to be highly consistent in both AD cohorts. Bioinformatics analysis has found Differentially Expressed Genes (DEGs) related to Notch signaling to mainly play important roles in Alzheimer's disease, the Notch signaling pathway, and the C-type lectin receptor signaling pathway. Multiple machine learning analyses have revealed IKBKB, HDAC2, and PIK3R1 to exhibit good diagnostic value in both AD cohorts and that they may be ideal biomarkers for early diagnosis of AD.

Conclusion: This study has provided a comprehensive description of the molecular signatures of the Notch signaling pathway in AD peripheral blood and a potential diagnostic model for AD clinical screening.

Alzheimer's Disease (AD) is characterized by synapse loss and neurodegeneration, which leads to cognitive and psychiatric symptoms. Researchers worldwide have been studying therapeutic approaches aiming to induce plasticity and neuroprotection once AD has no cure and the existing treatments are limited. Environmental Enrichment (EE) is a change in housing conditions that promotes increased cognitive stimulus. Studies have demonstrated that EE acts as a plasticity modulator in several conditions and experimental models. In this review, we analyze and discuss the potential role of EE on plasticity modulation in different animal models but primarily on AD models. The data were extracted from the PubMed and ScienceDirect databases. The EE was shown to induce plasticity. LTP and behavior were enhanced in animals under different conditions, such as the AD model. The mechanisms were related to the glutamatergic system and excitatory/ inhibitory balance. Moreover, many studies have evidenced that EE promotes the upregulation of BDNF and the synaptic proteins SYN and PSD95. These data also suggest a neuroprotective function performed by EE in different contexts, such as aging and AD. Therefore, an enriched environment can be a target of new therapeutic approaches that aim to induce neuroplasticity and neuroprotection against AD.

Background: The association between physical activity (PA) and cognitive function remains controversial, and the impact of gender on this association remains underexplored. Therefore, this study aimed to investigate the association between PA and cognitive function and to explore whether this association was modified by gender among older adults.

Methods: In 2016, a cluster sampling method was used to select community-dwelling older adults aged 65 and above. PA was assessed using the International Physical Activity Questionnaire-Short Form and classified as low, middle, and high. Cognitive function was assessed using the revised Chinese version of the Wechsler Adult Intelligence Scale. The multiple linear regression model was used to explore the association between PA and cognitive function and to assess whether this association differs by gender.

Results: A total of 676 participants with a mean age of 73.63 ± 6.39 were included. The multiple linear regression analysis showed that higher PA was significantly statistically associated with higher Full Intelligence Quotient (FIQ), Performance Intelligence Quotient (PIQ), and verbal Intelligence Quotient (VIQ) scores (P<0.05). Among the WAIS-RC subtests, higher PA was significantly statistically associated with higher scores of the similarity subtest, picture completion subtest, and picture arrangement subtest (P<0.05). In the gender subgroup analysis, higher PA was significantly statistically associated with higher FIQ and PIQ scores (P<0.05), but no significant association was found with VIQ scores (P>0.05) in the male group, while in the female group, there was no significant statistical association between higher PA and FIQ, PIQ, or VIQ scores (P>0.05).

Conclusion: Higher PA was significantly statistically associated with better cognitive function (P<0.05). In the male group, PA was significantly statistically associated with cognitive function, whereas no comparable association was found in the female group.

Object: The study aims to determine whether multimorbidity status is associated with cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders.

Methods: A total of 827 patients were enrolled from the Parkinson's Progression Markers Initiative (PPMI) database, including 638 patients with early-stage Parkinson's disease (PD) and 189 healthy controls (HCs). Multimorbidity status was evaluated based on the count of long-term conditions (LTCs) and the multimorbidity pattern. Using linear regression models, cross-sectional and longitudinal analyses were conducted to assess the associations of multimorbidity status with CSF biomarkers for neurodegenerative disorders, including α-synuclein (αSyn), amyloid-β₄₂ (Aβ₄₂), total tau (t-tau), phosphorylated tau (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL).

Results: At baseline, the CSF t-tau (p = 0.010), p-tau (p = 0.034), and NfL (p = 0.049) levels showed significant differences across the three categories of LTC counts. In the longitudinal analysis, the presence of LTCs was associated with lower Aβ₄₂ (β < -0.001, p = 0.020), and higher t-tau (β = 0.007, p = 0.026), GFAP (β = 0.013, p = 0.022) and NfL (β = 0.020, p = 0.012); Participants with tumor/musculoskeletal/mental disorders showed higher CSF levels of t-tau (β = 0.016, p = 0.011) and p-tau (β = 0.032, p = 0.044) than those without multimorbidity.

Conclusion: Multimorbidity, especially severe multimorbidity and the pattern of mental/musculoskeletal/ tumor disorders, was associated with CSF biomarkers for neurodegenerative disorders in early-stage PD patients, suggesting that multimorbidity might play a crucial role in aggravating neuronal damage in neurodegenerative diseases.

Background: Mild Cognitive Impairment (MCI) usually precedes the symptomatic phase of dementia and constitutes a window of opportunities for preventive therapies.

Objectives: The objective of this study was to predict the time an MCI patient has left to reach dementia and obtain the most likely natural history in the progression of MCI towards dementia.

Methods: This study was conducted on 633 MCI patients and 145 subjects with dementia through 4726 visits over 15 years from Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. A combination of data from AT(N) profiles at baseline and longitudinal predictive modeling was applied. A data-driven approach was proposed for categorical diagnosis prediction and timeline estimation of cognitive decline progression, which combined supervised and unsupervised learning techniques.

Results: A reduced vector of only neuropsychological measures was selected for training the models. At baseline, this approach had high performance in detecting subjects at high risk of converting from MCI to dementia in the coming years. Furthermore, a Disease Progression Model (DPM) was built and also verified using three metrics. As a result of the DPM focused on the studied population, it was inferred that amyloid pathology (A+) appears about 7 years before dementia, and tau pathology (T+) and neurodegeneration (N+) occur almost simultaneously, between 3 and 4 years before dementia. In addition, MCI-A+ subjects were shown to progress more rapidly to dementia compared to MCI-A- subjects.

Conclusion: Based on proposed natural histories and cross-sectional and longitudinal analysis of AD markers, the results indicated that only a single cerebrospinal fluid sample is necessary during the prodromal phase of AD. Prediction from MCI into dementia and its timeline can be achieved exclusively through neuropsychological measures.

Background: Cannabis consumption has rapidly increased in the United States due to more states legalizing non-medical and medical use. There is limited research, however, investigating whether cannabis may be associated with cognitive function, particularly across multiple dimensions of cannabis use.

Objective: The objective of this study was to examine whether cannabis consumption reason, frequency, and method are associated with subjective cognitive decline (SCD).

Methods: Data were obtained from 4,744 U.S. adults aged 45 and older in the 2021 Behavioral Risk Factor Surveillance System (BRFSS). SCD was a self-reported increase in confusion or memory loss in the past year. Odds of SCD by cannabis use reason, frequency, and methods (e.g., smoke, eat, vaporize) were examined using multiple logistic regression after imputing missing data, applying sampling weights, and adjusting for sociodemographic, health, and substance use covariates.

Results: Compared to non-users, non-medical cannabis use was significantly associated with 96% decreased odds of SCD (aOR=0.04, 95% CI=0.01-0.44, p<.01). Medical (aOR=0.46, 95% CI=0.06-3.61, p=.46) and dual medical and non-medical use (aOR=0.30, 95% CI=0.03-2.92, p=.30) were also associated with decreased odds of SCD, although not significant. Cannabis consumption frequency and method were not significantly associated with SCD.

Conclusion: The reason for cannabis use, but not frequency and method, is associated with SCD. Further research is needed to investigate the mechanisms that may contribute to the observed associations between non-medical cannabis use and decreased odds of SCD.

Introduction: Suicide has been described in patients with Alzheimer's disease. Some promising medications for treating Alzheimer's disease have had their studies suspended because they increase the risk of suicide. Understanding the correlations between suicide and Alzheimer's disease is essential in an aging world.

Methods: A search was carried out on electronic websites (PubMed and Scielo) using the MeSH Terms "suicide" and "Alzheimer" (1986-2023). Of a total of 115 articles, 26 were included in this review.

Results: Depression and the allele ε4 of Apolipoprotein (APOE4) were demonstrated to be the main risk factors for suicide in patients with Alzheimer's disease.

Conclusion: Adequately delineating which elderly people are vulnerable to suicide is important so that new treatments for Alzheimer's disease can be successful. This review showed a need for new studies to investigate the interface between Alzheimer's disease and suicide.

The prevalence of Alzheimer's disease (AD) is increasing as the elderly population, which hurts elderly people's cognition and capacity for self-care. The process of mitophagy involves the selective clearance of ageing and impaired mitochondria, which is required to preserve intracellular homeostasis and energy metabolism. Currently, it has been discovered that mitophagy abnormalities are intimately linked to the beginning and progression of AD. This article discusses the mechanism of mitophagy, abnormal mitophagy, and therapeutic effects in AD. The purpose is to offer fresh perspectives on the causes and remedies of AD.

Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-β plaques and tau protein-rich neurofibrillary tangles. Amyloid-β also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.

Background: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized by cognitive and behavioral impairments significantly hindering social and occupational functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between these medications and Bmal1 remains insufficiently explored.

Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1, this research explores the potential synergistic efficacy of combining these pharmaceutical agents with melatonin for AD treatment.

Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles.

Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate notably similar binding energy values to melatonin, interacting within the Bmal1 binding site through analogous amino acid residues and functional groups.

Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects.