Alzheimer's Disease Process Research Articles

Brain inflammation co-localizes highly with tau in mild cognitive impairment due to early-onset Alzheimer's disease.

Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease (AD) and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) positron emission tomography (PET), but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, [11C]ER176, that has a high binding potential and a more favorable metabolite profile than other TSPO tracers currently available. We applied [11C]ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset AD. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated Aβ and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 women) and 23 healthy controls (average age 65 ± 6.0 years, 12 women), both groups with a similar proportion of all three TSPO-binding affinities. [11C]ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n=23), and tau PET (n=21). For Aβ and tau tracers, standard uptake value ratios (SUVRs) were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset AD, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r= 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r= 0.55±0.25) and of inflammation with Aβ (0.43±0.22). Inflammation co-localized least with atrophy (-0.29±0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in AD-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the AD process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.

The Downregulation of ITGAX Exacerbates Amyloid-β Plaque Deposition in Alzheimer's Disease by Increasing Polarization of M1 Microglia.

Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-β (Aβ) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aβ plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction.

Efficacy and safety of acupuncture for cognitive impairment in Alzheimer's disease: a systematic review and meta-analysis.

To systematically evaluate the efficacy of acupuncture in the treatment of cognitive impairment in Alzheimer's disease (AD) by meta-analysis, in order to provide evidence-based evidence for the application of acupuncture therapy in the clinical process of AD. From the establishment of the database to December 31, 2022, China Biomedical Literature Database (CBM), China National Knowledge Network (CNKI), VIP database, WanFang Database, Pubmed, Embase and Cochrane Library Database were systematically searched. To collect published randomized controlled clinical trials (RCTS) of acupuncture in the treatment of cognitive impairment in AD. The subjects in the intervention group were given acupuncture alone or combined with other treatments the same as the control group; the control group received conventional Western medicine treatment. The main outcome indicators of the study were cognitive function assessment of subjects, including: Simple Mental State Examination Scale (MMSE), Assessment of daily Living Ability Scale (ADL), Alzheimer's Disease Cognitive Function Assessment Scale (ADAS-Cog), TCM syndrome score (SDSD), Montreal Cognitive Test (MoCA), Secondary outcome indicators were the occurrence of adverse reactions. Literature screening, data extraction, and quality evaluation of the included literature were performed independently by two researchers, according to bias risk assessment tools recommended in the Cochrane manual. Data were analyzed by RevMan5.3 software. Dichotomous variables were represented by risk ratio (OR) and 95% CI, and continuity variables were represented by mean difference (MD) and 95% CI. For heterogeneity analysis, when P > 0.1 and I 2 ≤ 50%, fixed effect model was applied. When P ≤ 0.1 and I 2 > 50%, the random effects model is applied. A total of 1,172 eligible subjects were included in 18 RCTS, including 595 in the intervention group and 577 in the control group. The results of meta-analysis are as follows: acupuncture intervention group improved MMSE [MD = 1.67, 95% CI (0.94, 2.41), P < 0.00001], ADL [MD = -1.18, 95% CI (-3.09, 0.72), P = 0.22], ADAS-Cog [MD = 3.31, 95% CI (5.84, 0.78), P = 0.01], SDSD [MD = 2.40, 95% CI (3.53, 1.26), P < 0.0001], MoCA [MD = 4.80, 95% CI (3.74, 5.86), P = 0.04] were better than the control group. No serious adverse reactions related to acupuncture were observed in the intervention group, and the incidence and severity of adverse reactions were lower than those in the control group, with statistical significance [OR = 0.17, 95% CI (0.04, 0.67), P = 0.01]. Existing data show that acupuncture therapy has certain advantages in improving cognitive dysfunction and improving self-care ability of patients with Alzheimer's disease. However, due to the small number of RCTS and cases evaluating the efficacy of acupuncture, and the possibility of measurement bias and selectivity bias in included studies, it is still unable to conduct high-intensity demonstration on its effectiveness. Further large-scale, high-quality randomized, double-blind controlled trials are needed to evaluate its efficacy. https://inplasy.com/inplasy-2021-12-0125/, identifier: INPLASY2021120125.

Microglial purinergic signaling in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of β-amyloid (Aβ) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y2, P2Y6, P2Y12, and P2Y13. The adenosine P1 receptors expressed in microglia include A1R, A2AR, and A2BR. Among them, the activation of P2X4, P2X7, and adenosine A1, A2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y2, P2Y6, P2Y12, and P2Y13 receptors expressed by microglia can induce neuroprotective effects. However, A1R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aβ production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.

Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer's Disease.

Alzheimer's disease (AD) manifests as a complex systems pathology with intricate interplay among various genes and biological processes. Traditional differential gene expression (DEG) analysis, while commonly employed to characterize AD-driven perturbations, does not sufficiently capture the full spectrum of underlying biological processes. Utilizing single-nucleus RNA-sequencing data from postmortem brain samples across key regions-middle temporal gyrus, superior frontal gyrus, and entorhinal cortex-we provide a comprehensive systematic analysis of disrupted processes in AD. We go beyond the DEG-centric analysis by integrating pathway activity analysis with weighted gene co-expression patterns to comprehensively map gene interconnectivity, identifying region- and cell-type-specific drivers of biological processes associated with AD. Our analysis reveals profound modular heterogeneity in neurons and glia as well as extensive AD-related functional disruptions. Co-expression networks highlighted the extended involvement of astrocytes and microglia in biological processes beyond neuroinflammation, such as calcium homeostasis, glutamate regulation, lipid metabolism, vesicle-mediated transport, and TOR signaling. We find limited representation of DEGs within dysregulated pathways across neurons and glial cells, suggesting that differential gene expression alone may not adequately represent the disease complexity. Further dissection of inferred gene modules revealed distinct dynamics of hub DEGs in neurons versus glia, suggesting that DEGs exert more impact on neurons compared to glial cells in driving modular dysregulations underlying perturbed biological processes. Interestingly, we observe an overall downregulation of astrocyte and microglia modules across all brain regions in AD, indicating a prevailing trend of functional repression in glial cells across these regions. Notable genes from the CALM and HSP90 families emerged as hub genes across neuronal modules in all brain regions, suggesting conserved roles as drivers of synaptic dysfunction in AD. Our findings demonstrate the importance of an integrated, systems-oriented approach combining pathway and network analysis to comprehensively understand the cell-type-specific roles of genes in AD-related biological processes.

Exploring the Potential Role of Oligodendrocyte-Associated PIP4K2A in Alzheimer's Disease Complicated with Type 2 Diabetes Mellitus via Multi-Omic Analysis.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two common diseases that affect the elderly population worldwide. The identification of common genes associated with AD and T2DM holds promise for potential biomarkers and intriguing pathogenesis of these two complicated diseases. This study utilized a comprehensive approach by integrating transcriptome data from multiple cohorts, encompassing both AD and T2DM. The analysis incorporated various data types, including blood and tissue samples as well as single-cell datasets, allowing for a detailed assessment of gene expression patterns. From the brain region-specific single-cell analysis, PIP4K2A, which encodes phosphatidylinositol-5-phosphate 4-kinase type 2 alpha, was found to be expressed mainly in oligodendrocytes compared to other cell types. Elevated levels of PIP4K2A in AD and T2DM patients' blood were found to be associated with key cellular processes such as vesicle-mediated transport, negative regulation of autophagosome assembly, and cytosolic transport. The identification of PIP4K2A's potential roles in the cellular processes of AD and T2DM offers valuable insights into the development of biomarkers for diagnosis and therapy, especially in the complication of these two diseases.

Rodent Models of Alzheimer's Disease: Past Misconceptions and Future Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson's disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, 'the isodendritic core', which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies.

Unraveling Alzheimer's Disease: Investigating Dynamic Functional Connectivity in the Default Mode Network through DCC-GARCH Modeling.

Alzheimer's disease (AD) has a prolonged latent phase. Sensitive biomarkers of amyloid beta ( ), in the absence of clinical symptoms, offer opportunities for early detection and identification of patients at risk. Current biomarkers, such as CSF and PET biomarkers, are effective but face practical limitations due to high cost and limited availability. Recent blood plasma biomarkers, though accessible, still incur high costs and lack physiological significance in the Alzheimer's process. This study explores the potential of brain functional connectivity (FC) alterations associated with AD pathology as a non-invasive avenue for detection. While current stationary FC measurements lack sensitivity at the single-subject level, our investigation focuses on dynamic FC using resting-state functional MRI (rs-fMRI) and introduces the Generalized Auto-Regressive Conditional Heteroscedastic Dynamic Conditional Correlation (DCC-GARCH) model. Our findings demonstrate the superior sensitivity of DCC-GARCH to CSF status, and offer key insights into dynamic functional connectivity analysis in AD.

Development and Validation of Paradigms Based on the Global-First Topological Approach for Alzheimer's Disease Severity Staging.

Conventional methods like patient history, neuropsychological testing, cerebrospinal fluid examination, and magnetic resonance imaging are widely used to diagnose cases in the current clinical setting but are limited in classifying Alzheimer's disease (AD) stages. Patients with AD exhibit visual perception deficits, which may be a potential target to assess the severity of the disease according to visual paradigms. However, owing to the inconsistent forms of perceived objects, the defects of current visual processing paradigms often lead to inconsistent results and a lack of sensitivity and specificity. We develop two paradigms based on global-first topological approach of visual perception, which avoids inconsistent results and lack of sensitivity and specificity owing to the inconsistent forms of perceived objects in traditional paradigms, delineate a unique detection strategy from perception organization (Experiment 1) and visual working memory (VWM) (Experiment 2). Except for the significant differences of the reaction times (RTs) between groups, significant differences were found when AD subjects recognize small figures due to the consistency of global and local figures in similarity test. The difference of RTs between recognizing global and local figures can be recognized in AD and mild cognitive impairment (MCI) group compared to healthy elderly (HE) in similarity test (Experiment 1). The memory capacity of AD patients was significantly lower than MCI group. Topological interference effect was observed in MCI and HE group, whereas MCI patients may have a greater difference trend in non-topological and topological changes than HE (Experiment 2). Our paradigms provide a new strategy, which can assist clinical severity staging and linking topological approach of visual perception with pathophysiological processes in AD.

Cytotoxic Effect of Amyloid-β1-42 Oligomers on Endoplasmic Reticulum and Golgi Apparatus Arrangement in SH-SY5Y Neuroblastoma Cells.

Amyloid-β oligomers are a cytotoxic structure that is key for the establishment of the beginning stages of Alzheimer's disease (AD). These structures promote subcellular alterations that cause synaptic dysfunction, loss of cell communication, and even cell death, generating cognitive deficits. The aim of this study was to investigate the cytotoxic effects of amyloid-β1-42 oligomers (AβOs) on the membranous organelles involved in protein processing: the endoplasmic reticulum (ER) and Golgi apparatus (GA). The results obtained with 10 μM AβOs in SH-SY5Y neuroblastoma cells showed that oligomeric structures are more toxic than monomers because they cause cell viability to decrease as exposure time increases. Survivor cells were analyzed to further understand the toxic effects of AβOs on intracellular organelles. Survivor cells showed morphological alterations associated with abnormal cytoskeleton modification 72-96 h after exposure to AβOs. Moreover, the ER and GA presented rearrangement throughout the cytoplasmic space, which could be attributed to a lack of constitutive protein processing or to previous abnormal cytoskeleton modification. Interestingly, the disorganization of both ER and GA organelles exposed to AβOs is likely an early pathological alteration that could be related to aberrant protein processing and accumulation in AD.

Generating real-world evidence in Alzheimer's disease: Considerations for establishing a core dataset.

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real-world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real-world settings.

Mitochondria-targeting near-infrared fluorescence/afterglow sensing assay for the rapid detection of HClO and its application in the early detection of Alzheimer's disease

Hypochloric acid (HClO) in living organisms is generated by the catalysis of myeloperoxidase (MPO). As an inflammatory signaling molecule, it can lead to neuronal cell death in the process of neuroinflammation, which is closely related to the etiology of Alzheimer’s disease (AD). Therefore, it is of great significance to develop effective tools for the localization of HClO in the early pathological process of AD. Therefore, a near-infrared (NIR) fluorescent probe HCy-1 targeting mitochondria for brain HClO detection was developed in this work. The reaction time between HCy-1 and HClO is short (within in 10 minutes), and the rapid detection of hypochlorous acid can be realized by naked eyes. HCy-1 also shows high selectivity and sensitivity to HClO with a detection limit of 34.5 nM, and the fluorescence intensity of HCy-1 at 715 nm is increased over 38 times after the incubation of HClO. HCy-1 can be used to detect both exogenous and endogenous HClO in PC-12 nerve cells and RAW 264.7 cells, and it can also be used for oxidative stress imaging analysis in AD cell model. For in vivo experiments, HCy-1 showed a strong ability to penetrate the blood-brain barrier, and the fluctuation of HClO could be detected in AD mice. More importantly, the special structure of hemicyanine was used to perform afterglow imaging under in vitro light irradiation, which proved that HCy-1 could detect the early onset of AD in a lower background.

Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.

APOE4 is widely recognized as a genetic risk factor for Alzheimer's disease (AD), implicated in 60-80% of all AD cases. Recent research suggests that microglia carrying the APOE4 genotype display abnormal lipid metabolism and accumulate lipid droplets, which may exacerbate the pathology of AD. Microglia play a critical role in immune surveillance within the central nervous system and are responsible for removing harmful particles and preserving neuronal function. The APOE4 genotype causes abnormal lipid metabolism in microglia, resulting in excessive accumulation of lipid droplets. This accumulation not only impairs the phagocytic and clearance capabilities of microglia but also disrupts their interactions with neurons, resulting in disorganization and neurodegenerative alterations at the neuronal network level. In addition, the presence of APOE4 modifies the metabolic landscape of microglia, particularly affecting purinergic signaling and lipid metabolism, thereby exacerbating the pathological processes of AD. In conclusion, the accumulation of lipid droplets and abnormal lipid metabolism may be critical mechanisms in the progression of AD in microglia carrying the APOE4 genotype.

FoxG1 as a Potential Therapeutic Target for Alzheimer’s Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway

An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer’s disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aβ peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aβ25–35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aβ25–35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aβ25–35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aβ25–35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aβ25–35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.

Specific Binding of Alzheimer's Aβ Peptides to Extracellular Vesicles.

Alzheimer's disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as AD progresses, less Aβ42 is detectable in the plasma, a phenomenon thought to result from Aβ becoming more aggregated in the brain and less Aβ42 and Aβ40 being transported from the brain to the plasma via the CSF. We propose that extracellular vesicles (EVs) play a role in this transport. EVs are found in bodily fluids such as blood, urine, and cerebrospinal fluid and carry diverse "cargos" of bioactive molecules (e.g., proteins, nucleic acids, lipids, metabolites) that dynamically reflect changes in the cells from which they are secreted. While Aβ42 and Aβ40 have been reported to be present in EVs, it is not known whether this interaction is specific for these peptides and thus whether amyloid-carrying EVs play a role in AD and/or serve as brain-specific biomarkers of the AD process. To determine if there is a specific interaction between Aβ and EVs, we used isothermal titration calorimetry (ITC) and discovered that Aβ42 and Aβ40 bind to EVs in a manner that is sequence specific, saturable, and endothermic. In addition, Aβ incubation with EVs overnight yielded larger amounts of bound Aβ peptide that was fibrillar in structure. These findings point to a specific amyloid-EV interaction, a potential role for EVs in the transport of amyloid from the brain to the blood, and a role for this amyloid pool in the AD process.

Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies

Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aβ) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aβ42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (β 0.11; 95% CI: 0.05-0.17). Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

Okadaik Asitle İndüklenen Alzheimer Sıçan Modelinde Betulin Tedavisi ile Çoklu Organ Hasarının COX Aracılığıyla Düzenlenmesi

Objective: Alzheimer's Disease (AD) is a progressive neurodegenerative disease. Cyclooxygenases (COXs) are essential in the inflammatory and regenerative processes of AD. This study aims to show that Betulin, a natural phytochemical (triterpene), is a candidate for COX-mediated correction of multiple organ damage of AD.&#x0D; Materials and Methods: In this study, the effects and treatment potential of Betulin were investigated in the kidney, heart, and small intestine tissue in genetic, and histological contexts in an okadaic acid-induced rat AD model. A total of 36 Wistar albino male rats were included in the study. Cyclooxygenase 1 (COX-1) and Cyclooxygenase 2 (COX2) gene expressions were investigated by quantitative real-time PCR (qRT-PCR) in kidney, heart, and small intestine tissues. COX-1 and COX-2 proteins in tissues were analyzed by immunohistochemistry.&#x0D; Results: COX-1 and COX-2 genes were detected to be overexpressed in the AD model. The expression of both genes was increased in the AD model and decreased after betulin treatment. Histological scores showed a strong positive effect of Betulin on the kidney, while it was relatively less effective on the heart and small intestine tissue. &#x0D; Conclusion: In treating organ damage in AD, COXs can be inhibited by Betulin and may be effective in functional recovery.

Novel Development and Prospects in Pathogenesis, Diagnosis, and Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with cognitive decline and behavioral dysfunction. AD will become a global public health concern due to its increasing prevalence brought on by the severity of global aging. It is critical to understand the pathogenic mechanisms of AD and investigate or pursue a viable therapy strategy in clinic. Amyloid-β (Aβ) accumulation and abnormally hyperphosphorylated tau protein are the main regulating variables in the pathological phase of AD. And neuroinflammation brought on by activated microglia was found to be one risk factor contributing to changes in Aβ and tau pathology. It is important to investigate the unique biomarkers of early diagnosis and advanced stage, which may help to elucidate the specific pathological process of AD and provide potential novel therapeutic targets or preventative measures.

TNF-α Levels Are Increased in Patients with Subjective Cognitive Impairment and Are Negatively Correlated with β Amyloid-42.

The role of tumor necrosis factor-α (TNF-α) in Alzheimer's disease (AD) has recently become a topic of debate. TNF-α levels increase in the blood of patients with AD, and amyloid beta (Aβ) plaques contain TNF-α deposits. The therapeutic efficacy of blocking TNF-α in patients with AD remains controversial as it is mostly based on preclinical studies. Thus, whether and how TNF-α contributes to amyloidogenic processes in AD is still an open question to be addressed. We analyzed plasma TNF-α and Aβ42 levels in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, and in healthy volunteers (HLT). In addition, we performed correlation analysis to evaluate whether changes in plasma TNF-α levels correlate with cognitive decline, Aβ42 levels, age, and BMI, which are all factors considered to contribute to or predispose individuals to AD. We found that TNF-α and Aβ42 plasma levels were higher in patients with AD than in HLT individuals. High TNF-α levels were also observed in patients with SCI, in whom TNF-α and Aβ42 levels were negatively correlated. Notably, TNF-α did not affect the amyloidogenic pathway in human microglial cultures exposed to 48 h of incubation, although it did trigger neuroinflammatory processes. These results imply that high TNF-α levels are more likely to be a clinical condition linked to AD than are direct contributors. Nonetheless, elevated levels of TNF-α in early-stage patients, like those with SCI and MCI, may provide a distinguishing feature for identifying clinical profiles that are at risk of having a poorer outcome in AD and could benefit from tailored therapies.

Adaptive 3DCNN-based Interpretable Ensemble Model for Early Diagnosis of Alzheimer's Disease.

Adaptive interpretable ensemble model based on three-dimensional Convolutional Neural Network (3DCNN) and Genetic Algorithm (GA), i.e., 3DCNN+EL+GA, was proposed to differentiate the subjects with Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) and further identify the discriminative brain regions significantly contributing to the classifications in a data-driven way. Plus, the discriminative brain sub-regions at a voxel level were further located in these achieved brain regions, with a gradient-based attribution method designed for CNN. Besides disclosing the discriminative brain sub-regions, the testing results on the datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Open Access Series of Imaging Studies (OASIS) indicated that 3DCNN+EL+GA outperformed other state-of-the-art deep learning algorithms and that the achieved discriminative brain regions (e.g., the rostral hippocampus, caudal hippocampus, and medial amygdala) were linked to emotion, memory, language, and other essential brain functions impaired early in the AD process. Future research is needed to examine the generalizability of the proposed method and ideas to discern discriminative brain regions for other brain disorders, such as severe depression, schizophrenia, autism, and cerebrovascular diseases, using neuroimaging.