Current Alzheimer Research

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and risk of Alzheimer’s disease (AD). In this manuscript, we first summarize the study design and methods. Then, we present data on: 1) the relation of motor function to cognition, disability, and death; 2) the relation of risk factors to cognitive and motor outcomes, disability and death; 3) the relation of neuropathologic indices to cognitive outcomes; 4) the relation of risk factors to neuropathologic indices; and 5) additional study findings. The findings are discussed and contextualized. Keywords: Dementia, Alzheimer's disease, cognitive function, epidemiology, clinical-pathologic study, Catholic clergy, spinal cord, congestive heart failure

UNLABELLED: The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer's disease (AD). In this manuscript, we summarize the study methods including the study design and describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected postmortem data. THE RESULTS: (1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; (2) examine the relation of risk factors to clinical outcomes; (3) examine the relation of risk factors to measures of neuropathology; and (4) summarize additional study findings. We then discuss and contextualize the study findings.

Cognitive reserve explains why those with higher IQ, education, occupational attainment, or participation in leisure activities evidence less severe clinical or cognitive changes in the presence of age-related or Alzheimer's disease pathology. Specifically, the cognitive reserve hypothesis is that individual differences in how tasks are processed provide reserve against brain pathology. Cognitive reserve may allow for more flexible strategy usage, an ability thought to be captured by executive functions tasks. Additionally, cognitive reserve allows individuals greater neural efficiency, greater neural capacity, and the ability for compensation via the recruitment of additional brain regions. Taking cognitive reserve into account may allow for earlier detection and better characterization of age-related cognitive changes and Alzheimer's disease. Importantly, cognitive reserve is not fixed but continues to evolve across the lifespan. Thus, even late-stage interventions hold promise to boost cognitive reserve and thus reduce the prevalence of Alzheimer's disease and other age-related problems.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multi-center study assessing neuroimaging in diagnosis and longitudinal monitoring. Amnestic Mild Cognitive Impairment (MCI) often represents a prodromal form of dementia, conferring a 10-15% annual risk of converting to probable AD. We analyzed baseline 1.5T MRI scans in 693 participants from the ADNI cohort divided into four groups by baseline diagnosis and one year MCI to probable AD conversion status to identify neuroimaging phenotypes associated with MCI and AD and potential predictive markers of imminent conversion. MP-RAGE scans were analyzed using publicly available voxel-based morphometry (VBM) and automated parcellation methods. Measures included global and hippocampal grey matter (GM) density, hippocampal and amygdalar volumes, and cortical thickness values from entorhinal cortex and other temporal and parietal lobe regions. The overall pattern of structural MRI changes in MCI (n=339) and AD (n=148) compared to healthy controls (HC, n=206) was similar to prior findings in smaller samples. MCI-Converters (n=62) demonstrated a very similar pattern of atrophic changes to the AD group up to a year before meeting clinical criteria for AD. Finally, a comparison of effect sizes for contrasts between the MCI-Converters and MCI-Stable (n=277) groups on MRI metrics indicated that degree of neurodegeneration of medial temporal structures was the best antecedent MRI marker of imminent conversion, with decreased hippocampal volume (left > right) being the most robust. Validation of imaging biomarkers is important as they can help enrich clinical trials of disease modifying agents by identifying individuals at highest risk for progression to AD.

There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer's disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.

This paper reviews recent progress in the diagnosis of Alzheimer's disease (AD) from electroencephalograms (EEG). Three major effects of AD on EEG have been observed: slowing of the EEG, reduced complexity of the EEG signals, and perturbations in EEG synchrony. In recent years, a variety of sophisticated computational approaches has been proposed to detect those subtle perturbations in the EEG of AD patients. The paper first describes methods that try to detect slowing of the EEG. Next the paper deals with several measures for EEG complexity, and explains how those measures have been used to study fluctuations in EEG complexity in AD patients. Then various measures of EEG synchrony are considered in the context of AD diagnosis. Also the issue of EEG pre-processing is briefly addressed. Before one can analyze EEG, it is necessary to remove artifacts due to for example head and eye movement or interference from electronic equipment. Pre-processing of EEG has in recent years received much attention. In this paper, several state-of-the-art pre-processing tech- niques are outlined, for example, based on blind source separation and other non-linear filtering paradigms. In addition, the paper outlines opportunities and limitations of computational approaches for diagnosing AD based on EEG. At last, future challenges and open problems are discussed.

Insulin modulates cognition and other aspects of normal brain function. Insulin resistance is characterized by chronic peripheral insulin elevations, and it is accompanied by reduced brain insulin levels and insulin activity. Obesity, type 2 diabetes mellitus and hypertension are strongly associated with insulin resistance. In addition, insulin resistance increases the risk of age-related memory impairment and Alzheimer's disease. Possible mechanisms through which these risks are increased include the effects of peripheral hyperinsulinemia on memory, CNS inflammation, and regulation of the beta-amyloid peptide. We have shown that raising plasma insulin in humans to levels that characterize patients with insulin resistance increases the levels of Abeta and inflammatory agents in brain. These convergent effects may impair memory and induce AD pathology. Therapeutic strategies focused on preventing or correcting insulin abnormalities may thus benefit a subset of adults with age-related memory impairment and AD.

Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > or = 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > or = 25 and <30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD.

INTRODUCTION/BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, significantly reduces amyloid markers and slows clinical decline in early Alzheimer's disease (AD) clinical trials. We assessed our single-center experience with lecanemab, including evaluating efficacy and safety data as well as patient-reported outcomes of individuals from our single center treated with intravenous or subcutaneous lecanemab. MATERIALS AND METHODS: We conducted a single-center, nested cohort study of early AD subjects on lecanemab (intravenous or subcutaneous) at our center. Participants had been initiated on lecanemab therapy as part of lecanemab Study 201 or Clarity AD, and then continued lecanemab treatment in our center. Data collection included patient demographic characteristics, efficacy (eg, CDR-SB), safety, and patient-reported outcomes from surveys. RESULTS: At our center, 136 people were randomized to receive either lecanemab or placebo in either lecanemab Study 201 (lecanemab:53; placebo:16) or Clarity AD (lecanemab:37; placebo:30). Patients receiving lecanemab were more likely to have higher rates of stable or improved disease across efficacy assessments relative to placebo. There were no new long-term safety signals, and the most common adverse events for lecanemab patients were infusion-related reactions (36.2%), ARIA-H (25.9%), and ARIA-E (13.8%). Survey responses demonstrated high satisfaction with the subcutaneous lecanemab administration, including with treatment satisfaction (97%) and convenience (97%). All patients preferred subcutaneous over IV dosing, citing quickness, ease, and comfort. DISCUSSION: Our single-center experience with long-term lecanemab treatment was similar to that observed in clinical trials. CONCLUSION: The subcutaneous lecanemab formulation was highly preferred by patients and care partners, with feedback highlighting reduced treatment burden and strong acceptability.

INTRODUCTION: Research has found that the disinfection byproduct Tetrachloro-1,4- Benzoquinone (TCBQ) in drinking water increases the risk of Alzheimer's Disease (AD). However, the mechanism by which TCBQ increases the risk of AD remains unclear. METHODS: This study employs a comprehensive approach that includes network toxicology (PPI network, hub genes, KEGG analysis), Mendelian randomization, computational simulations (molecular docking and dynamics), and cellular experiments to systematically elucidate the neurotoxic mechanisms of TCBQ. RESULTS: Key findings indicate that TCBQ induces neurotoxicity by activating the Toll-like receptor signaling pathway, AD, and the apoptosis pathway. All ligand-receptor docking energies are recorded at ≤ -1.8 kcal/mol, suggesting that TCBQ demonstrates a stable interaction with the targets. Molecular simulations confirm that TCBQ tightly binds to targets such as Caspase3 and TLR4. Mendelian randomization found that XDH, FABP3, IMPDH1, ACBD7, and CASP3 are common targets and play a potential role in AD. Immunofluorescence experiments revealed that APP expression increased after TCBQ treatment. Cellular experiments verified that TCBQ significantly upregulates the expression of inflammation- and apoptosis-related proteins, including IL-1B, MyD88, NFκB, TLR4, Cleaved-Caspase3, and Cyt C, leading to neuronal cell death. Notably, the TLR4 inhibitor effectively reversed the expression of these proteins and alleviated cell death. DISCUSSION: The discussion indicates that TCBQ induces neurotoxicity by activating the TLR4 pathway and apoptotic signals, and Caspase3 is a potential co-target. TLR4 inhibitors can reverse protein alterations and cell death, suggesting that intervention in this pathway may alleviate TCBQrelated nerve damage. CONCLUSION: Our research provides a theoretical basis for the clinical assessment of potential neurotoxicity risks in populations exposed to TCBQ.

INTRODUCTION: To conduct the first systematic bibliometric analysis of global research on the relationship between Alzheimer's disease (AD) and apoptosis from 2007 to 2025. METHODS: This study utilized the Web of Science Core Collection (WoSCC) and Scopus to retrieve literature from 2007 to 2025 concerning the role of apoptosis in Alzheimer's disease. Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, SCImago Graphica, and Bibliometrix R software packages. RESULTS: China produced the most papers (n=823), though co-authorship led to duplicate counting. Leading institutions included China Medical University and Huazhong University of Science and Technology; Harvard University had the highest academic impact. The Journal of Biochemistry was the most active and cited journal. Dr. Zhang Y was the most prolific author, and Dr. Wang H the most cited. DISCUSSION: China and the United States are dominant contributors, but Chinese research remains domestically oriented with lower international citation impact. The Journal of Alzheimer's Disease serves as a key dissemination platform. Major research themes include Aβ-induced mitochondrial dysfunction, oxidative stress, tau hyperphosphorylation synergizing with apoptosis, and emerging multi-target therapies. Recent attention has shifted towards inflammation, synaptic impairment, and combined strategies. The vicious cycles between Aβ and oxidative stress, and between tau pathology and apoptosis, warrant further mechanistic investigation. CONCLUSIONS: This study provides a systematic summary of research on AD and apoptosis. β- amyloid (Aβ) and abnormal Tau phosphorylation are likely to remain central areas of focus for future research.

BACKGROUND: Recent studies have suggested cathepsins, lysosomal cysteine proteases, are associated with Alzheimer's DISEASE (AD). This study conducted Mendelian Randomization (MR) analysis to systematically assess the causal effect of genetically predicted plasma cathepsins levels on AD and AD endophenotypes (cognition and brain structure). METHOD: Recent large-scale Genome-Wide Association Studies (GWAS) in Europe provided summary statistics on plasma cathepsins, AD, cognition, and brain structure. The primary statistical estimate was employed by Inverse Variance Weighting (IVW). Various sensitivity analysis was performed to draw robust results, including Cochran's Q test, MR-Egger intercept test, and MR PRESSO. RESULTS: Genetically predicted plasma cathepsin levels were not significantly associated with AD risk. Higher genetically predicted cathepsin L2 levels were associated with better fluid intelligence (β = 0.081, 95% CI 0.029 to 0.133, P = 0.00230, adjusted P = 0.0207). The associations of cathepsin L2 with general cognitive function (β = 0.081, 95% CI 0.010 to 0.152, P = 0.0247, adjusted P = 0.2226) and white matter hyperintensity volume (WMH, β = -0.068, 95% CI -0.134 to -0.002, P = 0.0433, adjusted P = 0.3898) were considered exploratory. Cathepsin L2 was also associated with monocyte count after correction across the three evaluated immune-cell traits (nominal P = 0.0133, FDR-adjusted P = 0.0285); the estimated indirect effect through monocyte count was -0.0016. DISCUSSION: These findings identify cathepsin L2 as the most consistently associated candidate with fluid intelligence and additional exploratory signals across cognitive, neuroimaging, and peripheral immune-cell phenotypes. The association with monocyte count raises a testable hypothesis regarding a peripheral immune-related pathway. Further studies using larger protein GWAS datasets, stronger genetic instruments, and independent populations are required to validate these findings. CONCLUSION: Genetically predicted plasma cathepsin L2 levels were associated with fluid intelligence after multiple comparisons. Although the immune-cell analyses raised the possibility of a monocyte-related peripheral pathway, the present findings did not establish a statistically supported mediating effect or a direct protective effect of cathepsin L2 against AD.

A recent article by Siddique et al. published in Current Alzheimer's Research suggests that vitamin C may have a neuroprotective effect in Alzheimer's disease, which inspired us to write this commentary. In this commentary, we focus on the effects of vitamin C treatment on amyloid in a transgenic Drosophila melanogaster model of Alzheimer's disease. It should be noted that some of the information presented in this article raises more questions than it answers. The article does not provide a clear answer to the question posed in the title. We note that the authors demonstrated, to a very limited extent, the ameliorative effects of vitamin C on oxidative stress, cholinergic function, improved behavior, and prolonged lifespan, yet their enthusiasm for the therapeutic potential of vitamin C in Alzheimer's disease has not faded. In conclusion, the work contains controversial and speculative statements; therefore, drawing far-reaching conclusions and applying vitamin C to Alzheimer's disease are not justified by the available evidence.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder of the Central Nervous System (CNS), characterized by amyloid-β (Aβ) deposition and Neurofibrillary Tangles (NFTs) caused by the hyperphosphorylation of tau protein. Neuroinflammation is an increasingly recognized feature of AD, playing a critical role in disrupting the immune microenvironment within the brain parenchyma. High levels of various inflammatory mediators have been documented in both AD patients and experimental AD models. Similarly, multiple immune cells have been found to accumulate in the brain parenchyma, the meninges, and the choroid plexus. Therefore, antiinflammatory therapies, including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and immune regulatory strategies hold promise as potential novel approaches for the prevention and treatment of AD. Currently, a variety of anti-inflammatory agents and immunotherapies have demonstrated efficacy in AD animal models, and several clinical trials of immunotherapeutic interventions have been completed or are underway. This review systematically summarizes the core pathophysiological mechanisms by which inflammatory and immune dysfunctions contribute to AD pathogenesis and explores potential therapeutic interventions targeting these mechanisms, thereby providing theoretical insights for clinical translational research on AD treatment.

INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Its characteristic pathological features include Aβ plaque deposition and abnormal tau protein aggregation. Biomarker testing has improved AD diagnosis. However, current treatments are primarily symptomatic, and no effective therapies are available to slow disease progression. MATERIALS AND METHODS: In this review, PubMed, CNKI, Wanfang Data, and the Chinese Medical Journal Full-text Database were searched using core terms including lymphatic system, Alzheimer's disease, and deep cervical lymphatic-venous anastomosis with supplementary synonyms. After deduplication and two-round screening, irrelevant, duplicate, low-quality, and non-full-text articles were excluded, and eligible literature was systematically summarized. RESULTS: The proposal of the glymphatic system has refined the theory of cerebral fluid circulation and waste clearance. Its dysfunction is closely associated with neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), providing a novel target for AD treatment. Deep cervical Lymphatic-Venous Anastomosis (LVA), as an emerging surgical approach with potential to alleviate AD symptoms, has been initially validated for its short-term efficacy. However, it is still in the early stage of clinical exploration, and further systematic research is required for its successful clinical translation. DISCUSSION: The glymphatic system mediates brain fluid circulation and waste clearance, providing new insights into AD pathogenesis and treatment. Building on this understanding, deep cervical Lymphatic-Venous Anastomosis (LVA) has emerged as a promising surgical intervention to alleviate AD pathology. Nevertheless, the considerable technical demands and incompletely elucidated mechanism of LVA severely limit its clinical translation, rendering these challenges a central research priority. CONCLUSION: Breakthroughs in the central lymphatic system have provided an important direction for exploring the pathological mechanisms of AD and developing innovative therapeutic strategies. Clarifying the theoretical basis and technical evolution of LVA surgery, as well as addressing relevant controversial issues, constitutes a key focus to advance the basic research and clinical translation of AD treatment.

INTRODUCTION/OBJECTIVE: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, making its inhibition a promising therapeutic strategy. This study evaluated the effects of two phenylalanine derivatives on Aβ aggregation and associated neurotoxicity. METHODS: Interactions between Aβ monomer and two compounds (12a and 5g) were explored by molecular docking. The inhibitory effects of the compounds on Aβ aggregation were evaluated using a thioflavin-T (ThT) assay, transmission electron microscopy (TEM), and dot blot. The neuroprotective ability of the two compounds was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. RESULTS: Docking analysis revealed that compounds 12a and 5g can bind to monomeric Aβ and identified the amino acids responsible for the interactions. The two compounds significantly reduced ThT fluorescence during the 48-hour incubation at all concentrations in ThT kinetics assays. The inhibitory effects were further confirmed in TEM. Both compounds suppressed Aβ oligomerization (reductions to 42.72% and 35.90% of the untreated control group, respectively). Furthermore, compound 5g, with a new structure, showed remarkable protection (cell viability increased to 97.86% of the control) against Aβ oligomer-treated human neuroblastoma SH-SY5Y cells, while having no intrinsic effect on cell viability. DISCUSSION: Compounds 12a and 5g act as more specific Aβ oligomerization inhibitors than traditional polyphenols such as (-)-epigallocatechin-3-gallate (EGCG). The results may provide molecular insights for the rational design of potent Aβ aggregation inhibitors for AD therapy. CONCLUSION: This study demonstrates that phenylalanine derivatives hold great promise as novel AD therapeutic leads.

Introduction: The study aimed to compare plasma Epoxyeicosatrienoic Acid (EET) isomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) in patients with advanced-stage late-onset Alzheimer’s Disease (AS-LOAD) versus healthy controls matched by age and sex. materials and methods: 2. Materials and Methods 2.1. Study Population This study included 60 participants: 30 patients with AS-LOAD who were being followed at the Community Mental Health Center of the Nigde Training and Research Hospital, and 30 age- and sex-matched cognitively healthy volunteers recruited from the hospital’s outpatient clinics. The diagnosis of AD in the patient group was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), based on clinical psychiatric evaluation. The control group consisted of individuals without any psychiatric disorders, as confirmed by DSM-V criteria and clinical examination, who volunteered to participate in the study. All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. This study was approved by the Nigde Omer Halisdemir University Non-Interventional Clinical Research Ethics Committee (Approval No: 2025/70). 2.2. Collection of Blood Samples Participants and their guardians were informed about the study, and written informed consent was obtained before blood collection. Five mL of blood was collected from each participant into sterile EDTA tubes. The blood samples were centrifuged at 3000 rpm for 10 minutes to separate plasma. Plasma samples were stored at -80°C until EET level analyses were performed. 2.3. Determination of Plasma EET Levels Before the LC-MS/MS experiment, standards for all compounds were purchased from Cayman Chemicals (Ann Arbor, MI). The formic acid, Millipore water, dichloromethane, methanol (MeOH), and ammonium formate used were LC-grade and were obtained from Merck (Darmstadt, Germany). Quantification of plasma EET levels was performed by a validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method in the research and development laboratory of Bome Trivitron Industry Products Foreign Trade Inc., as previously described by Duflot et al.[19]. LC-MS/MS analysis was conducted using a Shimadzu 8040 LC-MS/MS system (Shimadzu, Japan) equipped with an electrospray ionization (ESI) source operating in positive ion mode. This system was coupled with a Shimadzu Prominence UFLC system (Shimadzu, Kyoto, Japan), which included a DGU-20A3 degasser, a Nexera-X2 pump, a SIL-20ACHT temperature-controlled autosampler, and a CTO-20AC column oven. Chromatographic separation was performed on a Kinetex C18 column (2.6 μm particle size, 50 mm length × 3 mm inner diameter). Instrument parameters were set to maintain a column temperature of 30°C with a flow rate of 0.6 mL/min. A gradient elution method was employed using methanol/formic acid and ammonium formate/formic acid mixtures as the mobile phases. System control and data acquisition were performed using LabSolutions software, and quantification was conducted in multiple reaction monitoring (MRM) mode. Endogenous EETs were accounted for by normalizing analyte peak areas to zero via linear regression. Calibration curve slopes and linearity were determined from analyte-to-internal standard peak ratios at each spiked concentration. The results were evaluated against the standard calibration curve. 2.4. Statistical Analysis All statistical analyses were performed using IBM SPSS Statistics version 18. The Kolmogorov–Smirnov and Shapiro–Wilk tests were applied to assess the normality of data distribution. Depending on data distribution, comparisons between groups were conducted using the Kruskal–Wallis and Mann–Whitney U tests for nonparametric variables, and one-way ANOVA for demographic parameters such as age and sex. A p-value of ≤ 0.05 was considered statistically significant. Methods: In this cross-sectional case-control study, 30 patients with AS-LOAD were compared with 30 cognitively healthy (control) individuals. Plasma EET levels were analyzed by liquid chromatography coupled with Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS). results: The statistical analysis of the demographic characteristics of the AS-LOAD and healthy control groups is presented in Table 1. No statistically significant differences were observed between the control and AS-LOAD groups in terms of mean age or sex distribution (p > 0.05). In our study examining plasma EET levels in patients with AS-LOAD, we found that plasma concentrations of EET isomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) were significantly decreased in AS-LOAD patients compared with age- and sex-matched healthy controls (p < 0.05, Figure 1). Specifically, plasma levels of 14,15-EET (29.37 ± 25.65 vs. 90.80 ± 91.02 ng/dL), 11,12-EET (65.79 ± 38.65 vs. 240.1 ± 237.73 ng/dL), 8,9-EET (57.52 ± 6.46 vs. 144.58 ± 133.77 ng/dL), and 5,6-EET (7.31 ± 8.62 vs. 11.76 ± 11.32 ng/dL) were significantly lower in the patient group compared to the controls (Figure 1). Results: Plasma concentrations of all measured EET regioisomers were significantly lower in patients with AS-LOAD compared with controls. Significant reductions were observed for 14,15-EET (p = 0.007), 11,12-EET (p = 0.001), 8,9-EET (p = 0.007), and 5,6-EET (p = 0.011). Discussion: EETs are reportedly implicated in AD development, with most previous investigations using animal models and targeted enzymes involved in EET metabolism, particularly soluble epoxide hydrolase (sEH). Furthermore, no studies have specifically examined EET metabolism in patients with advanced AD. This study revealed defective EET signaling with consequent increased sEH activity in AS-LOAD, suggesting that decreased EET might contribute to tau-mediated neurodegeneration, oxidative stress, and neuroinflammation in these patients. Conclusion: This study emphasizes the crucial role of EETs in AD pathology. Targeting EET metabolism could offer a promising therapeutic strategy for preventing AD. Studies that track disease progression are therefore a prerequisite for delaying its disease onset; thus, larger-scale longitudinal studies are needed to confirm these findings.

Frontotemporal Dementia is an umbrella term for several neurodegenerative disorders that have a similar presentation pattern, which is accompanied by neural damage and brain tissue loss in the frontal and temporal regions. Recent studies have observed that the heterogeneity of Frontotemporal Dementia (FTD) is reflected in clinical features, genetics, and molecular perspectives. Specifically, the major forms of pathology in FTD are linked to abnormal protein accumulation, which includes tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Moreover, genetic research on FTD has identified vital mutations in MAPT (Microtubule-associated protein Tau), GRN (Progranulin Gene), and C9ORF72 genes (Chromosome 9 open reading frame genes). Recent developments in neuroimaging, biomarker levels in body fluids, and molecular profiling have increased diagnostic precision, enabling earlier detection of disease subtypes. Neurofilament light chain (NfL), progranulin, and several other biomarkers, together with novel neuroimaging approaches, are currently being applied for disease classification, prognosis, and disease treatment monitoring. These developments have accelerated the application of precision medicine for FTD, including antisense oligonucleotides, progranulin-restorative drugs, tau-specific therapies, and gene therapy. Despite advances in elucidating the biology of FTD, no disease-modifying therapies have yet been developed, and treatments remain symptomatic until now. Undoubtedly, there are many challenges when taking into account variable presentation, overlapping pathologies, and the lack of robust biomarkers. The aim of this paper is to provide an in-depth analysis of the epidemiology, clinical features, molecular pathologies, biomarkers, and potential therapeutic approaches concerning FTD, with a particular emphasis on the growing role of precision medicine. Omics technologies, biomarker- based patient stratification, and hypothesis-driven clinical trials are undoubtedly essential steps towards personalized therapy for FTD.