It is a well-established fact that Alzheimer's Disease (AD) is a growing public health challenge worldwide, with increasing prevalence among older adults. Cardiometabolic multimorbidity (CMM) and various sociodemographic and lifestyle factors are acknowledged to influence AD risk. This study aimed to estimate the prevalence of AD and investigate its association with CMM and related sociodemographic and behavioral factors in older adults aged 60 years and above in Türkiye.

This study was conducted using secondary data obtained from the Türkiye Health Survey, provided by the Turkish Statistical Institute (TÜİK). Data were derived from 4630 individuals (weighted sample of 11,331,239) aged 60 years and older. AD prevalence, CMM (hypertension, coronary heart disease, stroke, diabetes, hyperlipidemia), and relevant covariates were evaluated. Multivariable binary logistic regression models were used to identify independent predictors of AD.

The overall prevalence of AD was 3.8% (95% CI: 3.6-4.9%), slightly higher in females (4.1%, 95% CI: 3.8-5.7%) than males (3.5%, 95% CI: 2.8-4.7%). AD was more common among individuals who were single/divorced (6.4%), had lower education (4.1%), presented with CMM (5.9%), or led sedentary lifestyles (4.9%). In the model adjusted for age, sex, educational status, and marital status, the presence of CMM was significantly associated with increased odds of AD (aOR = 2.081; 95% CI: 1.522-2.844). In the further adjusted model for BMI, tobacco use, alcohol use, and activity during the day, CMM remained a significant predictor of AD (aOR = 1.975, 95% CI: 1.446-2.698).

This large-scale study highlights a substantial burden of AD among older adults in Türkiye, strongly linked to CMM and modifiable social and behavioral factors. The findings of this study highlight the importance of integrated prevention strategies targeting vascular health, education, social support, and physical activity to reduce AD risk.

Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimer's disease. While most studies examine the role of APOE4 in aging, APOE4 causes persistent changes in brain structure as early as infancy and is associated with altered functional connectivity that extends beyond adolescence. Here, we used human induced pluripotent stem cell-derived cortical and ganglionic eminence organoids (COs and GEOs) to examine APOE4's influence during the development of cortical excitatory and inhibitory neurons. We show that APOE4 reduces cortical neurons and increases glia by promoting gliogenic transcriptional programs. In contrast, APOE4 increases proliferation and differentiation of GABAergic progenitors resulting in early and persistent increases in GABAergic neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupts neural network function resulting in heightened excitability and synchronicity. Together, our data provide new insights on how APOE4 influences cortical neurodevelopmental processes and the establishment of functional networks.

A major challenge in the development of more effective therapeutic strategies for Alzheimer's disease (AD) is the identification of molecular mechanisms linked to specific pathophysiological features of the disease. Importantly AD has a two-fold higher incidence in women than men and a protracted prodromal phase characterized by amnestic mild-cognitive impairment (aMCI) suggesting that biological processes occurring early can initiate vulnerability to AD. Here, we used a sample of 125 subjects from two independent study cohorts to determine the levels in plasma (the most accessible specimen) of two essential mitochondrial markers acetyl-L-carnitine (LAC) and its derivative free-carnitine motivated by a mechanistic model in rodents in which targeting mitochondrial metabolism of LAC leads to the amelioration of cognitive function and boosts epigenetic mechanisms of gene expression. We report a sex-specific deficiency in free-carnitine levels in women with aMCI and early-AD compared to cognitively healthy controls; no change was observed in men. We also replicated the prior finding of decreased LAC levels in both women and men with AD, supporting the robustness of the study samples assayed in our new study. The magnitude of the sex-specific free-carnitine deficiency reflected the severity of cognitive dysfunction and held in two study cohorts. Furthermore, patients with the lower free-carnitine levels showed higher β-amyloid(Aβ) accumulation and t-Tau levels assayed in cerebrospinal fluid (CSF). Computational analyses showed that the mitochondrial markers assayed in plasma are at least as accurate as CSF measures to classify disease status. Together with the mechanistic platform in rodents, these translational findings lay the groundwork to create preventive individualized treatments targeting sex-specific changes in mitochondrial metabolism that may be subtle to early cognitive dysfunction of AD risk.

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition distinguished by the occurrence of memory impairment, cognitive deterioration, and neuronal impairment. Despite extensive research efforts, conventional treatment strategies primarily focus on symptom management, highlighting the need for innovative therapeutic approaches. This review explores the challenges of AD treatment and the integration of computational methodologies to advance therapeutic interventions. A comprehensive analysis of recent literature was conducted to elucidate the broad scope of Alzheimer's etiology and the limitations of conventional drug discovery approaches. Our findings underscore the critical role of computational models in elucidating disease mechanisms, identifying therapeutic targets, and expediting drug discovery. Through computational simulations, researchers can predict drug efficacy, optimize lead compounds, and facilitate personalized medicine approaches. Moreover, machine learning algorithms enhance early diagnosis and enable precision medicine strategies by analyzing multi-modal datasets. Case studies highlight the application of computational techniques in AD therapeutics, including the suppression of crucial proteins implicated in disease progression and the repurposing of existing drugs for AD management. Computational models elucidate the interplay between oxidative stress and neurodegeneration, offering insights into potential therapeutic interventions. Collaborative efforts between computational biologists, pharmacologists, and clinicians are essential to translate computational insights into clinically actionable interventions, ultimately improving patient outcomes and addressing the unmet medical needs of individuals affected by AD. Overall, integrating computational methodologies represents a promising paradigm shift in AD therapeutics, offering innovative solutions to overcome existing challenges and transform the landscape of AD treatment.

Recent research has established a strong link between metabolic abnormalities and an increased risk of dementia. In parallel, there is growing epidemiological evidence supporting the neuroprotective effects of antidiabetic medications against cognitive impairments. Among these, sodium-glucose co-transporter (SGLT2) inhibitors have emerged as pharmacological candidates with promising potential in alleviating the burden of age-related diseases, particularly neurodegenerative diseases (NDD). SGLT2 inhibitor therapies are FDA-approved medications routinely prescribed to manage diabetes. This novel class was initially developed to address cardiovascular disorders and to reduce the risk of hypoglycemia associated with insulin-secretagogue agents. It subsequently attracted growing interest for its beneficial effects on central nervous system (CNS) disorders. However, the molecular mechanisms through which these glucose-lowering therapies mitigate cognitive decline and limit the progression of certain brain degenerative diseases remain largely unexplored. Consequently, the neuroscientific community needs further studies that gather, analyze, and critically discuss the available mechanistic evidence regarding the neuroprotective effects of SGLT2 inhibitors. This review aims to critically examine the most relevant published findings, both in vitro and in vivo, as well as human studies evaluating the impact of SGLT2 inhibitors exposure on Alzheimer's disease (AD). It seeks to integrate the current understanding of their beneficial effects at the molecular level and their role in addressing the pathophysiology and neuropathology of AD. These insights will help extend our knowledge of how SGLT2 inhibitor therapies are associated with reduced risk of dementia and thus shed light on the link between diabetes and AD.

In addition to dementia, Alzheimer's patients suffer from sleep impairments and aberrations in sleep-dependent brain rhythms. Deficits in inhibitory GABAergic interneuron function disrupt one of those rhythms, slow oscillation in particular, and actively contribute to Alzheimer's progression. We tested the degree to which transplantation of healthy donor interneuron progenitors would restore slow oscillation rhythm in young APP mice. We harvested medial ganglionic eminence (MGE) progenitors from mouse embryos and transplanted them into host APP mutant cortices. 3D light-sheet and structured illumination microscopy revealed that transplanted MGE progenitors survived and matured into healthy interneurons. In vivo multiphoton calcium imaging and voltage-sensitive dye imaging showed functional integration and slow oscillation rescue in absence or presence of optogenetic stimulation. Our work provides proof-of-concept evidence that stem cell therapy may serve as a viable strategy to rescue functional impairments in cortical circuits of APP mice and potentially those of Alzheimer's patients.

Neuraminidase in humans is studied to see how well repurposed oseltamivir works for treating Alzheimer's disease (AD) using methods like molecular docking, molecular dynamic (MD) simulation, and gene expression analysis. Gene enrichment analysis was also studied to understand the behaviour of neuraminidases in humans.

Molecular docking was done using oseltamivir and the neuraminidase proteins with the PyRx tool, and the results were analysed using BIOVIA Discovery Studio. MD simulation (50 ns) of the oseltamivir and neuraminidase complex was performed using GROMACS tools. The gene expression analysis and gene enrichment study were done using GEO2R, which showed the results as log FC and significant values. Enricher tool-based gene enrichment analysis was done to determine the gene behaviour related to the AD.

The molecular docking showed a strong connection between oseltamivir and neuraminidase (-6.5 kcal/mol), acetylcholinesterase (-7.9 kcal/mol), CDKs (-6.5 kcal/mol), and GSKs (-6.6 kcal/mol), interacting with different amino acids in the protein sequences. MD simulations showed a strong interaction between the ligand and neuraminidase, with stable measurements indicating that both the protein and ligand remained consistent in size and energy, which is better explained through the results of MM_PBSA and MM_GBSA analysis of the complex, resulting in the ΔE_vdW, ΔE_elec, ΔG_polar, ΔG_nonpolar, ΔG_gas, (ΔE_vdW + ΔEEL), ΔG_solvation: (ΔG_polar + ΔG_nonpolar) and ΔG_bind: total energies suggesting the complex stayed stable in conditions similar to those resembling natural cell. The gene expression analysis expressed TUBB3 (formation of beta-tubulin), FABP3 (regulates alpha-synuclein uptake in dopaminergic neurons), and CALM1 (calcium signal transduction pathway) to be highly upregulated in the given conditions with kinase binding (p = 0.0006541) and protein phosphatase regulatory activity (p = 0.001357) were highly upregulated, implicating their importance in the AD.

The study ends on a hopeful note for using oseltamivir to treat neurological diseases, but it suggests that future research should include a solid cell line study, an in vitro study, and a clinical study.

Serotonin (5-HT) is a neurotransmitter that also plays an important role in the regulation of vascular tone and angiogenesis. This review focuses on the involvement of the 5-HT system in pathological processes leading to the development of Alzheimer's disease (AD). There is evidence that damage or dysfunction of the 5-HT system contributes to the development of AD, and different subtypes of 5-HT receptors are a potential target for the treatment of AD. A link has been established between AD, depression, stress, and 5-HT deficiency in the brain. There are new data on the role of circadian rhythms in modulating stress, depression, and the 5-HT system; amyloid β (Aβ) plaque clearance; and AD progression. Circadian disruption inhibits Aβ plaque clearance and modulates AD progression. The properties and functions of 5-HT, its receptors, and serotonergic neurons are presented. Special attention is paid to the central role of 5-HT in brain development, including neurite outgrowth, regulation of somatic morphology, motility, synaptogenesis, control of dendritic spine shape and density, neuronal plasticity determining its role in network regeneration, and changes in innervation after brain damage. The results of different studies indicate that the interaction of amyloid β oligomers (AβO) with mitochondria is a sufficient trigger for AD-related neurodegeneration. The action of 5-HT leads to an improvement in mitochondrial quality and the restoration of brain areas after traumatic brain injury, chronic stress, or developmental disorders in AD. The role of a healthy lifestyle and drugs acting on serotonin receptors in the prevention and treatment of AD is discussed.

Previous studies have found that sodium benzoate (the pivotal D-amino acid oxidase [DAO] inhibitor) improved cognitive function in patients with mild Alzheimer disease; however, its efficacy for mild cognitive impairment (MCI) (especially its core feature, impaired short-term memory) remains uncertain. The aim of this study was to evaluate the efficacy and safety of sodium benzoate in treating amnestic MCI (aMCI).

This study was a randomized, double-blind, placebo-controlled clinical trial conducted in a major medical center in Taiwan. Eighty-two patients with aMCI were recruited for 24-week treatment of 250 to 1500 mg/day of sodium benzoate or placebo. Overall, cognitive function was measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and short-term memory was evaluated by the 'recall of test instructions' item in the ADAS-cog. The generalized estimating equation was applied to compare the two groups in efficacy.

Compared with placebo, sodium benzoate therapy, displayed a trend, albeit statistically insignificant, in improving overall cognitive function (P = 0.082), and significantly improved short-term memory (P = 0.044). Both benzoate and placebo were well tolerated and benzoate therapy produced no additional side effect.

With the moderate sample size of the current study, treatment using sodium benzoate, a DAO inhibitor, showed promise in improving cognition, especially short-term memory, in patients with aMCI. Of note, while the ADAS-cog total score has been regarded as insensitive in measuring aMCI, its 'recall of test instructions' item may be a more sensitive and clinically feasible tool. Further larger studies are warranted to confirm the preliminary finding.

ClinicalTrials.gov Identifier. NCT04736355.

A hallmark of Alzheimer's disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of Aβ plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (AMPARs) mediate rapid excitatory synaptic transmission in the mammalian brain, primarily driven by the neurotransmitter glutamate. The modulation of AMPAR activity, particularly calcium-permeable AMPARs (CP-AMPARs), is crucially influenced by various auxiliary subunits. These subunits are integral membrane proteins that bind to the receptor's core and modify its functional properties, including ion channel kinetics and receptor trafficking. This review comprehensively catalogs all known AMPAR auxiliary proteins, providing vital insights into the biochemical mechanisms governing synaptic modulation and the specific impact of CP-AMPARs compared to their calcium-impermeable AMPA receptor (CI-AMPARs). Understanding the complex interplay between AMPARs and their auxiliary subunits in different brain regions is essential for elucidating their roles in cognitive functions such as learning and memory. Importantly, alterations in these auxiliary proteins' expression, function or interactions have been implicated in various neurological disorders. Aberrant signaling through CP-AMPARs, in particular, is associated with severe synaptic dysfunctions across neurodevelopmental, neurodegenerative and psychiatric conditions. Targeting the distinct properties of AMPAR-auxiliary subunit complexes, especially those involving CP-AMPARs, could disclose new therapeutic strategies, potentially allowing for more precise interventions in treating complex neuronal disorders.

BackgroundGamma oscillation modulation has emerged as a potential non-invasive treatment to counteract cognitive impairment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Non-invasive brain stimulation techniques like transcranial alternating current stimulation (tACS), gamma sensory stimulation (GSS), and transcranial magnetic stimulation (TMS) show promise in supporting specific cognitive functions.ObjectiveTo review and evaluate the efficacy of gamma oscillation modulation techniques in benefiting cognitive functions among individuals with AD and MCI.MethodsA systematic review was conducted, analyzing studies from 2015 to 2023 across databases such as PubMed, Web of Science, and Scopus. Inclusion criteria focused on studies involving tACS, GSS, or TMS applied to older adults with MCI or AD. A total of 438 articles were screened, of which 10 met the eligibility criteria.ResultsFindings suggest that gamma tACS, especially targeting the precuneus and dorsolateral prefrontal cortex, benefits episodic memory and cognitive performance. GSS also showed potential in supporting memory and attention, while TMS exhibited inconsistent but promising results when applied to the angular gyrus. However, heterogeneity in study designs and small sample sizes limit the generalizability of these outcomes.ConclusionsGamma oscillation modulation offers potential cognitive benefits for patients with AD and MCI, particularly in memory support. Further studies with larger samples and well-designed protocols are needed to confirm its therapeutic efficacy and optimize intervention parameters.

Alzheimer's disease (AD) is a neurodegenerative disorder with a higher risk incidence in females than in males, and there are also differences in AD pathophysiology between sexes. The role of sex in the pathogenesis of AD may be crucial, yet the cellular and molecular basis remains unclear. Here, we performed a comprehensive analysis using four public transcriptome datasets of AD patients and age-matched control individuals in prefrontal cortex, including bulk transcriptome (295 females and 402 males) and single-nucleus RNA sequencing (snRNA-seq) data (224 females and 219 males). We found that the transcriptomic profile in female control was similar to those in AD. To characterize the key features associated with both the pathogenesis of AD and sex difference, we identified a co-expressed gene module that positively correlated with AD, sex, and aging, and was also enriched with immune-associated pathways. Using snRNA-seq datasets, we found that microglia (MG), a resident immune cell in the brain, demonstrated substantial differences in several aspects between sexes, such as an elevated proportion of activated MG, altered transcriptomic profile and cell-cell interaction between MG and other brain cell types in female control. Additionally, genes upregulated in female MG, such as TLR2, MERTK, SPP1, SLA, ACSL1, and FKBP5, had high confidence to be identified as biomarkers to distinguish AD status, and these genes also interacted with some approved drugs for treatment of AD. These findings underscore the altered immune response in female is associated with sex difference in susceptibility to AD, and the necessity of considering sex factors when developing AD biomarkers and therapeutic strategies, providing a scientific basis for further in-depth studies on sex differences in AD.

A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.

Autophagy disruption is important in Alzheimer's disease (AD) as it prevents misfolded proteins from being removed, which leads to the accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Restoring autophagy improves neuronal survival and cognitive function, according to experimental models. In AD models, mTOR inhibition and AMPK activation enhance synaptic plasticity and lessen learning deficits. Inhibitors of phosphodiesterase-4 (PDE4) improve cognition and reduce neuroinflammation via altering cyclic adenosine monophosphate (cAMP) transmission. Furthermore, autophagic-lysosomal clearance is encouraged by upregulating transcription factor EB (TFEB), which lessens the pathogenic damage linked to AD. These results point to autophagy modification as a promising therapeutic approach, with the mTOR, AMPK, cAMP, and TFEB pathways being possible targets for drugs. Though much evidence is based on animal studies, these findings provide valuable insights into autophagy's role in AD pathology, offering promising directions for future research and drug development.

Alzheimer's disease (AD) is predominantly the most recurring and devastating neurological condition among the elderly population, characterized by the accumulation of amyloid-β (Aβ) and phosphorylated tau proteins, and is accompanied by progressive decline of learning and memory. Due to its complex and multifactorial etiology, a wide variety of therapeutic interventions have been developed. Despite constant advancements in the field, effective treatments that ameliorate the severity of Alzheimer's symptoms or cease their progression are still insufficient. Mounting evidence suggests that synaptic dysfunction could be an essential component of AD pathogenesis as synapse signaling is impaired in the aging brain, which contributes to synaptic decline. Therefore, improving neuroplasticity such as synaptic plasticity or neurogenesis could be a promising therapeutic approach for alleviating the effects of AD. This article reviews the cellular and molecular threads of neuroplasticity as well as targets that restore neuronal survival and plasticity to provide functional recoveries, including receptors, downstream signaling pathways, ion channels, transporters, enzymes, and neurotrophic factors.

Alzheimer's disease (AD) presents significant challenges in drug discovery and development due to its complex and poorly understood pathology and etiology. Digital twins (DTs) are recently developed virtual real-time representations of physical entities that enable rapid assessment of the bidirectional interaction between the virtual and physical domains. With recent advances in artificial intelligence (AI) and the growing accumulation of multi-omics and clinical data, application of DTs in healthcare is gaining traction. Digital twin technology, in the form of multiscale virtual models of patients or organ systems, can track health status in real time with continuous feedback, thereby driving model updates that enhance clinical decision-making. Here, we posit an additional role for DTs in drug discovery, with particular utility for complex diseases like AD. In this review, we discuss salient challenges in AD drug development, including complex disease pathology and comorbidities, difficulty in early diagnosis, and the current high failure rate of clinical trials. We also review DTs and discuss potential applications for predicting AD progression, discovering biomarkers, identifying new drug targets and opportunities for drug repurposing, facilitating clinical trials, and advancing precision medicine. Despite significant hurdles in this area, such as integration and standardization of dynamic medical data and issues of data security and privacy, DTs represent a promising approach for revolutionizing drug discovery in AD.

Gastrodia elata BI., which is an edible plant, has been reported in previous studies to possess a strong capacity for alleviating the symptoms of Alzheimer's disease (AD). This study focuses on ginger-processed and fermented Gastrodia elata BI. (FGGE) to investigate its effects on behaviour, brain neuroregulation, and the gut microbiota in an AlCl3-induced AD rat model, and to explore the underlying mechanisms. Results indicate that FGGE significantly improved novel object recognition and the correct alternation rate in the Y-maze test for AD rats. In addition, FGGE alleviated brain oxidative stress and restored the anti-inflammatory response, cholinergic function, and tissue morphology in the hippocampus. Furthermore, FGGE activated the cAMP response element-binding protein/brain-derived neurotrophic factor signalling pathway, reversing neural network abnormalities and enhancing neural regulation. FGGE also promoted the proliferation of bacteria negatively associated with AD, such as Methanosphaera and Lactobacillus, thereby restoring gut microbiota balance. The mechanisms by which FGGE alleviates AD may involve the modulation of the gut-brain axis, ultimately mitigating AD symptoms. FGGE represents an innovative functional food with significant therapeutic potential and promising application prospects.

Alzheimer disease (AD) therapy may benefit from optimized approaches to inhibit neuroinflammation. Small-molecule inhibitors of the proinflammatory molecule double-stranded RNA (dsRNA)-activated protein kinase R (PKR) have efficacy in AD models but their utility is compromised by adverse side effects. Here, we target PKR in two mouse models of AD using circular RNAs containing short double-stranded regions (ds-cRNAs), which are structurally similar to what we used previously to target PKR in psoriasis models. We show that the intrahippocampal injection of ds-cRNAs to neurons and microglia by adeno-associated virus (AAV) effectively dampens excessive PKR activity with minimal toxicity, accompanied by reduced neuroinflammation and amyloid-β plaques. We also deliver ds-cRNAs to the whole brain through intravenous injection of AAV-PHP.eB, which crosses the blood-brain barrier, resulting in neuroprotection and enhanced capability of spatial learning and memory in AD mouse models. The delivery of ds-cRNAs at different progressive stages of AD alleviates disease phenotypes, with therapeutic effects sustained for at least 6 months after a single administration.

Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive memory loss and cognitive decline. Recent evidence indicates that inflammation plays a central role in AD pathogenesis, with elevated inflammatory markers and risk genes linked to innate immune functions. Glial cell dysfunction, particularly in astrocytes and microglia, is crucial to the neuroinflammatory process, contributing to oxidative stress, synaptic dysfunction, neuronal death, and impaired neurogenesis. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analogue, on microglial morphology, inflammation, and oxidative stress parameters in a sporadic Alzheimer-like disease model induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days significantly reduced inflammation in the hippocampus and provided protection against oxidative damage in the entorhinal cortex by activating the Nrf-2 pathway and enhancing the expression of antioxidant enzymes such as SOD1 and CAT. These findings suggest that BFT exerts neuroprotective effects in AD, particularly impacting glial cell function and redox homeostasis.

Alzheimer's Disease (AD) is a neurodegenerative disorder classified as the leading form of dementia in the elderly. Classical hallmarks of AD pathology believed to cause AD include Amyloid-beta (Aβ) plaques as well as neurofibrillary tau tangles (NTT). However, research into these classical hallmarks has failed to account for a causative link or therapeutic success. More recently, metabolic hallmarks of AD pathology have become a popular avenue of research. Elevated urea and ammonia detected in cases of AD point towards a dysfunctional urea cycle involved in AD. This review covers the expansive body of literature surrounding the work of researchers deciphering the role of the urea cycle in AD pathology through the study of urea cycle enzymes, metabolites, and transporters in the AD brain. Urea cycle enzymes of interest in AD pathology include OTC, NOS isoforms, ARG1, ARG2, MAOB, and ODC, which all present as promising therapeutic targets. Urea metabolites indicated in AD pathology have varying concentrations across the regions of the brain and the different cell types (neurons, microglia, astrocytes). Finally, the role of UT-B as a clearance modulator presents this protein as a key target for research in the role of the urea cycle in the AD brain. In the future, these key enzymes, pathways, and proteins relating to the urea cycle in AD should be further investigated to better understand the cell-specific urea cycle profiles in the AD brain and uncover their therapeutic potential.

To assess the relationship of subtle preclinical cognitive changes with white matter microstructure and cortical volume in middle-aged adults at high AD risk due to a parental history.

Participants (n = 278) were AD patients' offspring from the Israel Registry for Alzheimer's Prevention study. Cognitively unimpaired-decliners (CU-D) were based on a linear regression model. In a subsample with MRI (n = 220), we examined relationships of CU-D with white matter (WM) microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) and cortical volume in brain regions commonly affected in AD.

CU-D participants had lower FA in the superior longitudinal fasciculus (SLF) (p = < 0.001) and higher MD in the SLF (p = < 0.001), and cingulum adjacent to the corpus callosum (p = < 0.001) and genu (p = 0.006) compared to cognitively unimpaired-stable (CU-S) participants. The groups did not differ in cortical brain volumes.

CU-D participants had poorer WM microstructure in brain tracts affected early in AD. Early interventions can target individuals that fit the CU-D criteria.

Alzheimer's disease (AD) is characterized by progressive cognition and behavior impairments. Diagnosing AD early is important for clinicians to slow down AD progression and preserve brain function. Biomarkers such as tau protein and amyloid-β peptide (Aβ) are used to aid diagnosis as clinical diagnosis often lags. Additionally, biomarkers can be used to monitor AD status and evaluate AD treatment. Clinicians detect these AD biomarkers in the brain using positron emission tomography/computed tomography or in the cerebrospinal fluid using a lumbar puncture. However, these methods are expensive and invasive. In contrast, saliva collection is simple, inexpensive, non-invasive, stress-free, and repeatable. Moreover, damage to the brain parenchyma can impact the oral cavity and some pathogenic molecules could travel back and forth from the brain to the mouth. This has prompted researchers to explore biomarkers in the saliva. Therefore, this study provides an overview of the main finding of salivary biomarkers for AD diagnosis. Based on these available studies, Aβ, tau, cholinesterase enzyme activity, lactoferrin, melatonin, cortisol, proteomics, metabolomics, exosomes, and the microbiome were changed in AD patients' saliva when compared to controls. However, well-designed studies are essential to confirm the reliability and validity of these biomarkers in diagnosing and monitoring AD.

Alzheimer's disease (AD) is the most prevalent cause of dementia and a significant contributor to health issues and mortality among older individuals. This condition involves a progressive deterioration in cognitive function and the onset of dementia. Recent advancements suggest that the development of AD is more intricate than its underlying brain abnormalities alone. In addition, Alzheimer's disease, metabolic syndrome, and oxidative stress are all intricately linked to one another. Increased concentrations of circulating lipids and disturbances in glucose homeostasis contribute to the intensification of lipid oxidation, leading to a gradual depletion of the body's antioxidant defenses. This heightened oxidative metabolism adversely impacts cell integrity, resulting in neuronal damage. Pathways commonly acknowledged as contributors to AD pathogenesis include alterations in synaptic plasticity, disorganization of neurons, and cell death. Abnormal metabolism of some membrane proteins is thought to cause the creation of amyloid (Aβ) oligomers, which are extremely hazardous to neurotransmission pathways, especially those involving acetylcholine. The interaction between Aβ oligomers and these neurotransmitter systems is thought to induce cellular dysfunction, an imbalance in neurotransmitter signaling, and, ultimately, the manifestation of neurological symptoms. Antioxidants have a significant impact on human health since they may improve the aging process by combating free radicals. Neurodegenerative diseases are currently incurable; however, they may be effectively managed. An appealing alternative is the utilization of natural antioxidants, such as polyphenols, through diet or dietary supplements, which offer numerous advantages. Within this framework, we have extensively examined the importance of oxidative stress in the advancement of Alzheimer's disease, as well as the potential influence of antioxidants in mitigating its effects.

Microglia, the resident immune cells of the central nervous system, continuously monitor the brain's microenvironment through their array of specific receptors. Once brain function is altered, microglia are recruited to specific sites to perform their immune functions, including phagocytosis of misfolded proteins, cellular debris, and apoptotic cells to maintain homeostasis. When toxic substances are overproduced, microglia are over-activated to produce large amounts of pro-inflammatory cytokines, which induce chronic inflammatory responses and lead to neurotoxicity. Additionally, microglia can also monitor and protect neuronal function through microglia-neuron crosstalk. Microglia receptors are important mediators for microglia to receive external stimuli, regulate the functional state of microglia, and transmit signals between cells. In this paper, we first review the role of microglia-expressed receptors in the pathogenesis and treatment of Alzheimer's disease; moreover, we emphasize the complexity of targeting microglia for therapeutic interventions in neurodegenerative disorders to inform the discovery of new biomarkers and the development of innovative therapeutics.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated in vitro and in vivo. In vitro studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while in vivo effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression in vitro and decreased cortical BACE1 expression in 3xTg-AD mice. In vivo treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.

Changes in population demographics indicate that the elderly population will reach 2.1 billion worldwide by 2050. In parallel, there will be an increase in neurodegenerative diseases such as Alzheimer's and Parkinson's. This review explores dysbiosis occurring in these pathologies and how virulence factors contribute to the worsening or development of clinical conditions, and it summarizes existing and potential ways to combat microorganisms related to these diseases. Microbiota imbalances can contribute to the progression of neurodegenerative diseases by increasing intestinal permeability, exchanging information through innervation, and even acting as a Trojan horse affecting immune cells. The microorganisms of the microbiota produce virulence factors to protect themselves from host defenses, many of which contribute to neurodegenerative diseases. These virulence factors are expressed according to the genetic composition of each microorganism, leading to a wide range of factors to be considered. Among the main virulence factors are LPS, urease, curli proteins, amyloidogenic proteins, VacA, and CagA. These factors can also be packed into bacterial outer membrane vesicles, which transport proteins, RNA, and DNA, enabling distal communication that impacts various diseases, including Alzheimer's and Parkinson's.

Ketamine has received growing attention for its effects on neuroplasticity and neuroinflammation, and as a treatment for depression and other mental health disorders. Recent evidence suggests that early sensory and behavioral deficits in Alzheimer's disease could be caused by synaptic disruption that occurs before irreversible neuropathology. This raises the possibility that ketamine could slow down or prevent network disruption and the ensuing sensory and behavioral deficits in Alzheimer's. Here we tested this idea in the 5XFAD mouse model of Alzheimer's, using either an acute single injection of ketamine, or chronic daily injections over 15 weeks. We tested the effects of ketamine on both amyloid plaque load and on a behavioral auditory gap detection task that is an early Alzheimer's biomarker in both mice and humans. We found that ketamine had no effect on plaque load, nor any effect on gap detection, for either acute or chronic dosing. Chronic ketamine facilitated startle responses specifically in 5XFAD mice, but this could simply be related to experience-dependent effects on stress or habituation rather than any rescue effect of ketamine on Alzheimer's-related deficits. We did find robust correlations between gap detection deficits and plaque load in auditory cortex and in the caudal pontine reticular nucleus, demonstrating that the behavioral deficits seen in 5XFAD mice are directly related to amyloid accumulation in these brain regions, and confirming the validity of gap detection as an early biomarker of Alzheimer's. Ketamine, however, had no effect on the strength of these correlations. We conclude that ketamine has no beneficial effect on the development of behavioral gap detection deficits or plaque load in the 5XFAD Alzheimer's mouse model, following either an acute single dose or a chronic daily dose regimen.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-β and Tau protein depositions, with treatments focusing on single proteins have shown limited success due to the complexity of pathways involved. This study explored the potential of chronokines -proteins that modulate aging-related processes- as an alternative therapeutic approach. Specifically, we focused on a novel pleiotropic chimeric protein named HEBE, combining s-KL, sTREM2 and TIMP2, guided by bioinformatic analyses to ensure the preservation of each protein's conformation, crucial for their functions. In vitro studies confirmed HEBE's stability and enzymatic activities, even suggesting it has different activities compared to the individual chronokines. In vivo experiments on APP/Tau mice revealed improved learning and memory functions with HEBE treatment, along with decreased levels of phosphorylated Tau and minor effects on amyloid-β levels. These findings suggest that HEBE is as a promising therapeutic candidate for ameliorating memory deficits and reducing pTau in an AD mouse model.

The World Health Organization has identified Alzheimer's disease (AD), the leading cause of dementia globally, as a public health priority. However, the complex multifactorial pathology of AD means that its etiology remains incompletely understood. Despite being recognized a century ago, incomplete knowledge has hindered the development of effective treatments for AD. Recent scientific advancements, particularly in induced pluripotent stem cell (iPSC) technology, show great promise in elucidating the fundamental mechanisms of AD. iPSCs play a dual role in regenerating damaged cells for therapeutic purposes and creating disease models to understand AD pathology and aid in drug screening. Nevertheless, as an emerging field, iPSC technology requires further technological advancement to develop effective AD treatments in the future. Thus, this review summarizes recent advances in stem cell therapies, specifically iPSCs, aimed at understanding AD pathology and developing treatments.

Due to a continuous increase in life expectancy and the progress made in specialized healthcare, the incidence of Alzheimer's disease (AD) has dramatically increased to the point that it has become one of the main challenges of contemporary medicine. Despite a huge scientific and clinical effort, current treatments manage just a temporary alleviation of symptomatology but offer no cure. Modern trials involving cell transplantation in experimental animals require the involvement of neurosurgeons in the treatment protocol. CSF shunting, intraventricular infusions, or DBS for symptoms relief have been an integral part of the therapeutic arsenal from the very beginning. The development of stereotactic surgery has facilitated the experimental potential of cell transplantation in the hippocampus for Alzheimer's disease. We conducted a narrative review of the literature in the top three medical databases (PubMed, Science Direct, and Google Scholar) using the keywords "Alzheimer's disease", "hippocampus", and "transplant". After eliminating duplicates, 241 papers were selected and screened by title and abstract. Two reviewers independently analyzed the 88 papers and chose 32 experiments that involved stereotactic hippocampal transplantation of cells in experimental animals with AD. The stereotactic transplantation of cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), induced pluripotent cells (iPSCs), astrocytes, and derivates from stem cells was analyzed. The experiments used either a chemically induced or transgenic AD model and observed the impact of the stereotactic transplantation with behavioral testing, MRS spectroscopy, and biochemical analysis. The stereotaxic method delivers minimal invasive treatment option by cell transplantation at the hippocampus. The results showed that amyloid deposits were lower after transplantation, showing a positive impact. Other impactful results involve proliferation of neurogenesis, downregulation of anti-inflammatory response, and increased neuronal plasticity. The increased precision with which the stereotaxic method manages to target deep structures of the brain and the results of the reviewed papers could represent an argument for future human trials. More studies are needed to confirm the viability of the transplanted cells and the long-term effects.

Biomedical research requires sophisticated understanding and reasoning across multiple specializations. While large language models (LLMs) show promise in scientific applications, their capability to safely and accurately support complex biomedical research remains uncertain.

We present CARDBiomedBench, a novel question-and-answer benchmark for evaluating LLMs in biomedical research. For our pilot implementation, we focus on neurodegenerative diseases (NDDs), a domain requiring integration of genetic, molecular, and clinical knowledge. The benchmark combines expert-annotated question-answer (Q/A) pairs with semi-automated data augmentation, drawing from authoritative public resources including drug development data, genome-wide association studies (GWAS), and Summary-data based Mendelian Randomization (SMR) analyses. We evaluated seven private and open-source LLMs across ten biological categories and nine reasoning skills, using novel metrics to assess both response quality and safety.

Our benchmark comprises over 68,000 Q/A pairs, enabling robust evaluation of LLM performance. Current state-of-the-art models show significant limitations: models like Claude-3.5-Sonnet demonstrates excessive caution (Response Quality Rate: 25% [95% CI: 25% ± 1], Safety Rate: 76% ± 1), while others like ChatGPT-4o exhibits both poor accuracy and unsafe behavior (Response Quality Rate: 37% ± 1, Safety Rate: 31% ± 1). These findings reveal fundamental gaps in LLMs' ability to handle complex biomedical information.

CARDBiomedBench establishes a rigorous standard for assessing LLM capabilities in biomedical research. Our pilot evaluation in the NDD domain reveals critical limitations in current models' ability to safely and accurately process complex scientific information. Future iterations will expand to other biomedical domains, supporting the development of more reliable AI systems for accelerating scientific discovery.

Alzheimer's disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) is emerging as a promising target for AD therapy. In this study, by combining a PDE9 inhibitor C33 with the antioxidant melatonin, we designed and discovered a series of pyrazolopyrimidinone derivatives that simultaneously inhibit PDE9 and possess antioxidant activities. Molecular docking, together with dynamics simulations, were applied to accelerate compound design and reduce synthetic work. Four out of the 14 compounds were validated as effective PDE9 inhibitors with comparable antioxidant activity. Notably, compounds 17b and 17d demonstrated IC50 values of 91 and 89 nM against PDE9, respectively, with good antioxidant activities (ORAC (Trolox) of 2.00 and 2.60). This work provides a new approach for designing MTDLs for the treatment of AD and offers insights for further structural modifications of PDE9 inhibitors with antioxidant capacities.

Among the many changes associated with aging, inflammation in the central nervous system (CNS) and throughout the body likely contributes to the constellation of health-related maladies associated with aging. Genetics, lifestyle factors, and environmental experiences shape the trajectory of aging-associated inflammation, including the developmental timing, frequency, and intensity of alcohol consumption. This chapter posits that neuroinflammatory processes form a critical link between alcohol exposure and the trajectory of healthy aging, at least in part through direct or indirect interactions with cholinergic circuits that are crucial to cognitive integrity. In this chapter, we begin with a discussion of how inflammation changes from early development through late aging; discuss the role of inflammation and alcohol in the emergence of mild cognitive impairment (MCI); elaborate on critical findings on the contribution of alcohol-related thiamine deficiency to the loss of cholinergic function and subsequent development of Wernicke-Korsakoff syndrome (WKS); and present emerging findings at the intersection of alcohol and Alzheimer's disease and related dementias (ADRD). In doing so, our analysis points toward inflammation-mediated compromise of basal forebrain cholinergic function as a key culprit in cognitive dysfunction associated with chronic alcohol exposure, effects that may be rescuable through either pharmacological or behavioral approaches. Furthermore, our chapter reveals an interesting dichotomy in the effects of alcohol on neuropathological markers of ADRD that depend upon both biological sex and genetic vulnerability.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, which is characterized by a progressive loss of cognitive functions. The high prevalence, chronicity, and multimorbidity are very common in AD, which significantly impair the quality of life and functioning of patients. Early detection and accurate diagnosis of Alzheimer's disease (AD) can stop the illness from progressing thereby postponing its symptoms. Therefore, for the early diagnosis and monitoring of AD, more sensitive, noninvasive, straightforward, and affordable screening tools are needed.

This review summarizes the importance of early detection methods and novel techniques for Alzheimer's disease diagnosis that can be used by healthcare professionals.

Early diagnosis assists the patient and caregivers to understand the problem establishing reasonable goals and making future plans together. Early diagnosis techniques not only help in monitoring disease progression but also provide crucial information for the development of novel therapeutic targets. Researchers can plan to potentially alleviate symptoms or slow down the progression of Alzheimer's disease by identifying early molecular changes and targeting altered pathways.