Search Results (67)

Background/Objectives: Solanezumab is a humanized monoclonal antibody designed to bind soluble amyloid-beta (Aβ) and facilitate its clearance from the brain, aiming to slow the progression of Alzheimer’s disease (AD). Methods: A systematic search was applied in four medical databases through October 2024 to identify phase 2 or 3 randomized controlled trials evaluating solanezumab in patients aged ≥50 years with mild AD or in preclinical stages. The primary outcomes were changes in cognitive and functional scales, including ADAS-cog14, MMSE, ADCS-ADL, and CDR-SB. Data were pooled using a random-effects model, and certainty of evidence was assessed using GRADE. Results: Seven trials involving 4181 participants were included. Solanezumab did not significantly reduce cognitive decline based on ADAS-cog14 (MD = −0.75; 95% CI: −2.65 to 1.15; very low certainty) or improve functional scores on ADCS-ADL (MD = 0.85; 95% CI: −1.86 to 3.56; very low certainty) and CDR-SB (MD = −0.15; 95% CI: −0.89 to 0.60; very low certainty). A modest but statistically significant improvement was observed in MMSE scores (MD = 0.59; 95% CI: 0.33 to 0.86; moderate certainty). Conclusions: While solanezumab may offer slight benefits in general cognitive performance, its overall impact on clinically meaningful outcomes remains limited. The results do not support its use as a disease-modifying therapy for Alzheimer’s disease in either preclinical or symptomatic stages. Full article

Background: Physical activity (PA) has been shown to prevent Alzheimer’s disease (AD) by reducing amyloid accumulation, lowering inflammatory factors, and increasing hippocampal grey matter. While high lifetime PA engagement is associated with a reduced risk of AD, the relationship between specific types of PA and early-stage AD remains unclear. As AD primarily affects cognitive function before physical capabilities, PA engagement—an important factor in PA—needs further investigation. Objectives: This study explores the potential association between current participation in open-skill sports (OSSs) versus closed-skill sports (CSSs) and early-stage AD. Methods: The sample (N = 128) included a cognitively healthy (HC, n = 78) group and an Alzheimer’s disease (AD) group, combining amnestic mild cognitive impairment due to AD patients (n = 22) and early-stage Alzheimer’s dementia patients (n = 28), reflecting the continuum of progression from aMCI to dAD (n = 50). PA was assessed with the Physical Activity Scale for the Elderly questionnaire, specifically focusing on PA within the last seven days. The statistical analyses included Mann–Whitney U tests and backwards stepwise logistic regression models. Results: Key predictors of group classification (AD vs. NC) included sex, high frequency of PA, and high duration of PA, each for the last seven days. Participation in OSS was significantly associated with medium PA frequency, high PA duration, both within the last seven days, and age, but not with diagnostic status. No statistically significant differences in PA levels (OSSs or CSSs) executed within the last seven days were observed between the AD and HC groups. Conclusions: Participation in OSSs or CSSs within the last seven days was only a marginally significant predictor of AD vs. HC status, and a diagnosis of AD was not predictive of OSS participation within the last seven days. Given the protective role of PA in AD, future research should aim to identify specific PA types that effectively support cognitive health in older adults with early cognitive decline. Full article

Biomarkers currently used to diagnose dementia, including Alzheimer’s disease (AD), primarily detect molecular and structural brain changes associated with the condition’s pathology. Although these markers are pivotal in detecting disease-specific neuropathological hallmarks, their association with the clinical manifestations of dementia frequently remains poorly defined and exhibits considerable variability. These biomarkers may show abnormalities in cognitively healthy individuals and frequently fail to accurately represent the severity of cognitive and functional impairments in individuals with dementia. Research indicates that synaptic degeneration and functional impairment occur early in the progression of AD and exhibit the strongest correlation with clinical symptoms. This identifies brain functional impairment measurements as promising early indicators for AD detection. Electroencephalography (EEG), a non-invasive and cost-effective method with high temporal resolution, is used as a biomarker for the early detection and diagnosis of AD through frequency-domain analysis of quantitative EEG (qEEG). Many researchers demonstrate that qEEG measures effectively identify disruptions in neuronal activity, including alterations in activity patterns, topographical distribution, and synchronization. Specific findings along the stages of AD include impaired neuronal synchronization, generalized EEG slowing, and an increase in lower-frequency bands accompanied by a decrease in higher-frequency bands of resting state EEG. Moreover, qEEG helps clinicians effectively correlate indicators of AD neuropathology and distinguish between various forms of dementia, positioning it as a promising, low-cost, non-invasive biomarker for dementia. However, additional clinical investigation is required to clarify the diagnostic and prognostic significance of qEEG measurements as early functional markers for AD. This narrative review examines time-frequency domain qEEG analysis as a potential biomarker across various types of dementia. Through a structured search of PubMed and Scopus, we identified studies assessing spectral and connectivity-based qEEG features. Consistent findings include EEG slowing, reduced functional connectivity, and network desynchronization. The review outlines key methodological challenges, such as lack of standardization and limited longitudinal validation, and recommends integrative, multimodal approaches to enhance diagnostic precision and clinical applicability. Full article

Alzheimer’s disease (AD) presents significant challenges in clinical practice due to its heterogeneous manifestation and variable progression rates. This work develops a comprehensive anatomical staging framework to predict progression from mild cognitive impairment (MCI) to AD. Using the ADNI database, the scalable Subtype and Stage Inference (s-SuStaIn) model was applied to 118 neuroanatomical features from cognitively normal (n = 504) and AD (n = 346) participants. The framework was validated on 808 MCI participants through associations with clinical progression, CSF and FDG-PET biomarkers, and neuropsychiatric measures, while adjusting for common confounders (age, gender, education, and APOE ε4 alleles). The framework demonstrated superior prognostic accuracy compared to traditional risk assessment (C-index = 0.73 vs. 0.62). Four distinct disease subtypes showed differential progression rates, biomarker profiles (FDG-PET and CSF Aβ42), and cognitive trajectories: Subtype 1, subcortical-first pattern; Subtype 2, executive–cortical pattern; Subtype 3, disconnection pattern; and Subtype 4, frontal–executive pattern. Stage-dependent changes revealed systematic deterioration across diverse cognitive domains, particularly in learning acquisition, visuospatial processing, and functional abilities. This data-driven approach captures clinically meaningful disease heterogeneity and improves prognostication in MCI, potentially enabling more personalized therapeutic strategies and clinical trial design. Full article

Most approved drugs for Alzheimer’s disease (AD) are indicated for early to moderate stages and primarily target amyloid-beta or neurotransmitter systems. While these treatments may slow cognitive decline, they do not halt disease progression and are often limited by high cost and modest efficacy. Natural compounds are increasingly being explored as alternative interventions. Our previous study showed that oral administration of Avenanthramide-C (Avn-C), a natural polyphenol from oats, for 14 days from early AD stages improved cognition and reduced neuroinflammation in AD mice. To assess its long-term potential, in this study we extended Avn-C treatment to three months starting from early disease stages in 5xFAD and Tg2576 models. Sustained administration preserved recovered long-term potentiation (LTP) by maintaining AMPK activation and inhibiting caspase-3 and GSK3β, thereby reducing amyloid accumulation and tau hyperphosphorylation in the hippocampus. Avn-C also maintained anti-inflammatory effects by suppressing NF-κB-mediated proinflammatory cytokine release and preventing chronic microglial activation. This promoted microglial coverage of plaques in vivo and enhanced phagocytosis in vitro. Our findings suggest that early and sustained Avn-C treatment preserves cognitive function, modulates multiple pathological pathways, and may slow or prevent AD progression by targeting early neurodegenerative processes before irreversible damage occurs. Full article

Background/Objectives: The interplay between the gut microbiome (GMB) and neurovascular function in neurodegeneration is unclear. The goal of this proof-of-concept, cross-sectional study is to identify relationships between the GMB, neurovascular functioning, and cognition in amnestic mild cognitive impairment (aMCI), the prototypical prodromal symptomatic stage of Alzheimer’s disease (AD). Methods: Participants (n = 14 aMCI and 10 controls) provided fecal samples for GMB sequencing (16S and shotgun metagenomics), underwent MRI, and completed cognitive testing. Cerebral vascular reactivity (CVR), cerebral blood flow (CBF), and arterial transit time (ATT) were assessed. Statistical analyses evaluated the relationships between discriminatory taxa, cerebrovascular metrics, and cognition. Results: Sequencing revealed differentially abundant bacterial and viral taxa distinguishing aMCI from controls. Spearman correlations revealed that bacteria known to induce inflammation were negatively associated with CVR, CBF, and cognition, and positively associated with ATT. A reciprocal pattern emerged for the association of taxa with gut health. Conclusions: Our results provide preliminary evidence that pro-inflammatory gut bacterial and viral taxa are associated with neurovascular dysfunction and cognitive impairment in prodromal AD, highlighting their potential as candidate microbial biomarkers and targets for early intervention. Full article

Background: Reactive oxygen species (ROS) are involved in the pathophysiology of neurodegeneration and cognitive decline, indicating the potential use of oxidative stress biomarkers for early diagnosis. Mild cognitive impairment (MCI) is defined as a cognitive decline beyond normal aging, without significant impact on daily functioning, and is considered an important stage of early detection of neurodegeneration. This study aimed to investigate serum and cerebrospinal fluid (CSF) levels of oxidative stress biomarkers, total ROS and malondialdehyde (MDA) in patients with MCI to evaluate their utility in the early diagnosis of Alzheimer’s disease (AD). Levels of oxidative stress biomarkers were also assessed according to age and sex, as well as their correlation with the established CSF biomarkers, including amyloid-beta (Aβ40, Aβ42 and Aβ42/Aβ40 ratio), phosphorylated tau protein (p-tau) and total tau (t-tau). Methods: A total of 114 adults were divided into three groups: MCI (A−) patients with a normal CSF Aβ42/Aβ40 ratio (n = 38), MCI (A+) patients with an abnormal Aβ42/Aβ40 ratio (n = 38) and healthy cognitive function individuals with a normal Aβ42/Aβ40 ratio (n = 38). Established CSF biomarkers were conducted using an automated immunochemical method, while total ROS levels were measured by fluorometry and MDA levels were determined by competitive inhibition enzyme immunoassay. Results: A statistically significant difference was observed in CSF MDA levels (p < 0.05) and serum ROS levels (p < 0.05) between the study groups. Sex analysis revealed significantly higher levels of CSF MDA levels in the MCI (A+) males’ group (p < 0.05). In terms of age categorization, serum MDA levels were markedly higher in the MCI (A+) group of older patients (p < 0.01). Conclusions: These findings highlight the importance of individualized approaches, including investigation of oxidative stress biomarkers profile to prevent and manage individuals in the early stages of MCI, considering demographic factors. Full article

Background/Objectives: Alzheimer’s disease (AD) severely hinders cognitive function in the hippocampus (HP) and subiculum (SUB), impacting the expression of nicotinic acetylcholine receptors (nAChRs) such as the α7-subtype. To investigate α7 nAChRs as a potential PET imaging biomarker, we report the quantitative binding of [¹²⁵I]α-Bungarotoxin ([¹²⁵I]α-Bgtx) for binding to postmortem human AD (n = 29; 13 males, 16 females) HP compared to cognitively normal (CN) (n = 28; 13 male, 15 female) HP. Methods: For comparisons with common AD biomarkers, adjacent slices were anti-Aβ and anti-Tau immunostained for analysis using QuPath. Results: The [¹²⁵I]α-Bgtx average SUB/HP ratio was 0.5 among the CN subjects, suggesting higher [¹²⁵I]α-Bgtx binding in the HP gray matter regions. The AD subjects showed overall less binding than the CN subjects, with no statistical significance. A positive correlation was found in the [¹²⁵I]α-Bgtx binding in the AD subjects as the age increased. The Braak stage comparisons of [¹²⁵I]α-Bgtx were made with [¹⁸F]flotaza binding to Aβ plaques and [¹²⁵I]IPPI binding to Tau. A positive correlation was found between [¹²⁵I]α-Bgtx and [¹⁸F]flotaza and there was a negative correlation between [¹²⁵I]α-Bgtx and [¹²⁵I]IPPI, implicating intricate relationships between the different AD biomarkers. Conclusions: [¹²⁵I]α-Bgtx shows complimentary potential as a α7 nAChR imaging agent but needs more preclinical assessments to confirm effectiveness for translational PET studies using α7 nAChR radioligands. Full article

Background: Apathy is a common neuropsychiatric symptom in all stages of dementia, significantly complicating patient management. This study examines the prevalence of apathy across Alzheimer’s Disease (AD), Lewy Body Dementia (LBD), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) and explores its associations with cognitive functions, neuropsychiatric symptoms, and magnetic resonance imaging (MRI) findings. Methods: This retrospective, cross-sectional study included 200 patients diagnosed with AD, LBD, FTD, and VD along with 100 healthy controls (HCs). Apathy was assessed using the Apathy Evaluation Scale. Depression and anxiety in patients were evaluated using the Geriatric Depression Scale and the Geriatric Anxiety Scale, respectively. Cognitive function was measured with the Mini-Mental State Examination (MMSE) and Addenbrooke’s Cognitive Examination-Revised (ACE-R). MRI findings were evaluated using atrophy scales that are routinely utilized in dementia assessments. Results: Apathy was significantly more prevalent in dementia and MCI patients compared to HC. However, there were no significant differences in apathy prevalence among dementia subtypes. Apathy showed no significant correlation with depression, anxiety, or cognitive performance. Notably, MRI analysis revealed a strong association between apathy and orbitofrontal (OF) sulci atrophy. Conclusions: Apathy is a critical symptom in dementia, linked to OF atrophy and presenting challenges in management. These findings emphasize the importance of integrating apathy assessments in clinical practice. Larger, longitudinal studies are needed to further clarify the pathophysiology and management of apathy in dementia. Full article

Tau is a microtubule-associated protein that undergoes liquid–liquid phase separation (LLPS) to form condensates under physiological conditions, facilitating microtubule stabilization and intracellular transport. LLPS has also been implicated in pathological Tau aggregation, which contributes to tauopathies such as Alzheimer’s disease. While LLPS is known to promote Tau aggregation, the relationship between Tau’s structural states and its phase separation behavior remains poorly defined. Here, we examine how oligomerization modulates Tau LLPS and uncover key distinctions between monomeric, oligomeric, and amyloidogenic Tau species. Using dynamic light scattering and fluorescence microscopy, we monitored oligomer formation over time and assessed oligomeric Tau’s ability to undergo LLPS. We found that Tau monomers readily phase separate and form condensates. As oligomerization progresses, Tau’s propensity to undergo LLPS diminishes, with oligomers still being able to phase separate, albeit with reduced efficiency. Interestingly, oligomeric Tau is recruited into condensates formed with 0-day-aged Tau, with this recruitment depending on the oligomer state of maturation. Early-stage, Thioflavin T (ThT)-negative oligomers co-localize with 0-day-aged Tau condensates, whereas ThT-positive oligomers resist condensate recruitment entirely. This study highlights a dynamic interplay between Tau LLPS and aggregation, providing insight into how Tau’s structural and oligomeric states influence its pathological and functional roles. These findings underscore the need to further explore LLPS as a likely modulator of Tau pathogenesis and distinct pathogenic oligomers as viable therapeutic targets in tauopathies. Full article

Synaptic plasticity impairment and behavioral deficits constitute classical pathological hallmarks in early-stage Alzheimer’s disease (AD). Emerging evidence suggests these synaptic dysfunctions may stem from metabolic dysregulation, particularly impaired aerobic glycolysis. As a key product of astrocyte-mediated aerobic glycolysis, lactate serves dual roles as both an energy substrate and a signaling molecule, playing a critical regulatory role in synaptic plasticity and long-term memory formation. This study investigated whether exogenous L-lactate supplementation could ameliorate synaptic dysfunction and cognitive deficits in early-stage AD models. Our findings reveal significant reductions in hippocampal lactate levels in experimental AD mice. Systemic administration of L-lactate (200 mg/kg) effectively restored physiological lactate concentrations in both hippocampal tissue and cerebrospinal fluid (CSF). Chronic L-lactate treatment significantly improved spatial learning and memory performance in behavioral assessments. Electrophysiological recordings demonstrated that either acute bath application of L-lactate (2 mM) to hippocampal slices or chronic intraperitoneal administration enhanced high-frequency stimulation (HFS)-induced long-term potentiation (LTP) magnitude in 3xTg-AD mice. Ultrastructural analysis revealed that L-lactate treatment enhanced synaptic density and improved morphological features of hippocampal synapses. At the molecular level, L-lactate administration upregulated synaptic marker synaptophysin (SYP) expression while downregulating activity-regulated cytoskeletal-associated protein (ARC) levels in AD mice. These multimodal findings demonstrate that exogenous L-lactate supplementation effectively restores synaptic plasticity and cognitive function in early-stage 3xTg-AD mice through concurrent improvements at behavioral, structural, and molecular levels. Full article

Objective: The purpose of this review is to examine the potential role of donanemab-azbt in the treatment and management of early-stage Alzheimer’s disease (AD), with a focus on its efficacy, safety, and clinical relevance based on data from key clinical trials. Data Sources: A comprehensive literature search of PubMed was conducted using relevant keywords such as “donanemab”, “Alzheimer’s disease”, “Kisunla”, “TRAILBLAZER clinical trials”, and “amyloid-related imaging abnormalities (ARIA)”. Additional data were extracted from clinical trial records (clinicaltrials.gov), conference abstracts, and product monographs. Study Selection and Data Extraction: Only English-language studies conducted in human populations were included. Clinical trials and peer-reviewed studies detailing the efficacy, safety, and mechanistic insights of donanemab-azbt were prioritized. Data Synthesis: Key findings from the TRAILBLAZER series of clinical trials highlighted the potential of donanemab-azbt in slowing cognitive and functional decline in early-stage AD: (1) TRAILBLAZER-ALZ (Phase 2): This trial focused on participants with intermediate levels of tau protein. Results demonstrated a statistically significant slowing of cognitive and functional decline. (2) TRAILBLAZER-ALZ 2 (Phase 3): A large-scale, randomized, double-blind, placebo-controlled study confirmed the efficacy of donanemab-azbt in reducing amyloid plaque accumulation and cognitive decline. Key results included a 35% slowing of decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) and a 36% slowing on the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Additional secondary outcomes showed improvements in activities of daily living and reduced risk of disease progression. (3) TRAILBLAZER-ALZ 3: This ongoing trial is evaluating donanemab’s potential in delaying or preventing Alois Alzheimer in cognitively normal individuals with amyloid plaques, broadening the scope of early intervention strategies. (4) TRAILBLAZER-ALZ 4: A head-to-head comparison with aducanumab revealed superior amyloid plaque clearance with donanemab. (5) TRAILBLAZER-ALZ 5: Currently recruiting, this trial aims to evaluate safety and efficacy across diverse populations with varying tau levels and comorbidities. (6) TRAILBLAZER-ALZ 6 (Phase 3b): This trial investigates modified dosing regimens to reduce ARIA while maintaining efficacy, particularly in populations with genetic risk factors like ApoE ε4 homozygotes. Relevance to Patient Care and Clinical Practice: Donanemab-azbt represents a promising treatment option for patients with early-stage AD. It specifically targets and reduces amyloid beta plaques, a hallmark of the disease, potentially slowing progression and preserving cognitive function. However, its administration requires careful patient selection, including genetic testing for ApoE ε4 status, to mitigate risks of ARIA. Furthermore, the findings emphasize the importance of close monitoring during treatment. Conclusions: Donanemab-azbt offers a new avenue for managing early-stage AD, showing promise in reducing amyloid burden and slowing cognitive decline. While its efficacy and safety have been demonstrated in clinical trials, further research is essential to validate long-term outcomes, assess effectiveness across diverse populations, and refine dosing strategies to minimize side effects. With continued investigation, donanemab-azbt could significantly impact the clinical landscape of AD treatment. Full article

We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer’s disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Aβ production in primary Tg immature neural cell cultures after 11 days in vitro. We now investigate the effect of MT5-MMP on incipient pathogenic pathways that are activated in cortical primary cultures at 21–24 days in vitro (DIV), during which time neurons are organized into a functional mature network. Using wild-type (WT), MT5-MMP^−/− (MT5^−/−), 5xFAD (Tg), and 5xFADxMT5-MMP^−/− (TgMT5^−/−) mice, we generated primary neuronal cultures that were exposed to IL-1β and/or different proteolytic system inhibitors. We assessed neuroinflammation, APP metabolism, synaptic integrity, and electrophysiological properties using biochemical, imaging and whole-cell patch-clamp approaches. The absence of MT5-MMP impaired the IL-1β-mediated induction of inflammatory genes in TgMT5^−/− cells compared to Tg cells. Furthermore, the reduced density of dendritic spines in Tg neurons was also prevented in TgMT5^−/− neurons. IL-1β caused a strong decrease in the dendritic spine density of WT neurons, which was prevented in MT5^−/− neurons. However, the latter exhibited fewer spines than the WT under untreated conditions. The spontaneous rhythmic firing frequency of the network was increased in MT5^−/− neurons, but not in TgMT5^−/− neurons, and IL-1β increased this parameter only in Tg neurons. In terms of induced somatic excitability, Tg and TgMT5^−/− neurons exhibited lower excitability than WT and MT5^−/−, while IL-1β impaired excitability only in non-AD backgrounds. The synaptic strength of miniature global synaptic currents was equivalent in all genotypes but increased dramatically in WT and MT5^−/− neurons after IL-1β. MT5-MMP deficiency decreased endogenous and overexpressed C83 and C99 levels but did not affect Aβ levels. C99 appears to be cleared by several pathways, including γ-secretase, the autophagolysosomal system, and also α-secretase, via its conversion to C83. In summary, this study confirms that MT5-MMP is a pivotal factor affecting not only neuroinflammation and APP metabolism but also synaptogenesis and synaptic activity at early stages of the pathology, and reinforces the relevance of targeting MT5-MMP to fight AD. Full article

Late-onset Alzheimer’s disease (LOAD) is a subtype of dementia that manifests after the age of 65. It is characterized by progressive impairments in cognitive functions, behavioral changes, and learning difficulties. Given the progressive nature of the disease, early diagnosis is crucial. Early-onset Alzheimer’s disease (EOAD) is solely attributable to genetic factors, whereas LOAD has multiple contributing factors. A complex pathway mechanism involving multiple factors contributes to LOAD progression. Employing a systems biology approach, our analysis encompassed the genetic, epigenetic, metabolic, and environmental factors that modulate the molecular networks and pathways. These factors affect the brain’s structural integrity, functional capacity, and connectivity, ultimately leading to the manifestation of the disease. This study has aggregated diverse biomarkers associated with factors capable of altering the molecular networks and pathways that influence brain structure, functionality, and connectivity. These biomarkers serve as potential early indicators for AD diagnosis and are designated as early biomarkers. The other biomarker datasets associated with the brain structure, functionality, connectivity, and related parameters of an individual are broadly categorized as clinical-stage biomarkers. This study has compiled research papers on Alzheimer’s disease (AD) diagnosis utilizing machine learning (ML) methodologies from both categories of biomarker data, including the applications of ML techniques for AD diagnosis. The broad objectives of our study are research gap identification, assessment of biomarker efficacy, and the most effective or prevalent ML technology used in AD diagnosis. This paper examines the predominant use of deep learning (DL) and convolutional neural networks (CNNs) in Alzheimer’s disease (AD) diagnosis utilizing various types of biomarker data. Furthermore, this study has addressed the potential scope of using generative AI and the Synthetic Minority Oversampling Technique (SMOTE) for data augmentation. Full article

Background: Alzheimer’s disease (AD) is a common clinical neurodegenerative disorder, primarily characterized by progressive cognitive decline and behavioral abnormalities. The hallmark pathological changes of AD include widespread neuronal degeneration, plaques formed by the deposition of amyloid β-protein (Aβ), and neurofibrillary tangles (NFTs). With the acceleration of global aging, the incidence of AD is rising year by year, making it a major global public health concern. Due to the complex pathology of AD, finding effective interventions has become a key focus of research. Ouabain (OUA), a cardiac glycoside, is well-known for its efficacy in treating heart disease. Recent studies have also indicated its potential in AD therapy, although its exact mechanism of action remains unclear. Methods: This study integrates bioinformatics, multi-omics technologies, and in vivo and in vitro experiments to investigate the effects of OUA on the pathophysiological changes of AD and its underlying molecular mechanisms. Results: This study analyzed the expression of the triggering receptor expressed on myeloid cells 2 (TREM2) across different stages of AD using bioinformatics. Serum samples from patients were used to validate soluble TREM2 (sTREM2) levels. Using an Aβ_1-42-induced microglial cell model, we confirmed that OUA enhances the PI3K/AKT signaling pathway activation by upregulating TREM2, which reduces neuroinflammation and promotes the transition of microglia from an M1 proinflammatory state to an M2 anti-inflammatory state. To evaluate the in vivo effects of OUA, we assessed the learning and memory capacity of FAD^4T transgenic mice using the Morris water maze and contextual fear conditioning tests. We used real-time quantitative PCR, immunohistochemistry, and Western blotting to measure the expression of inflammation-associated cytokines and to assess microglia polarization. OUA enhances cognitive function in FAD^4T mice and has been confirmed to modulate microglial M1/M2 phenotypes both in vitro and in vivo. Furthermore, through bioinformatics analysis, molecular docking, and experimental validation, TREM2 was identified as a potential target for OUA. It regulates PI3K/Akt signaling pathway activation, playing a crucial role in OUA-mediated M2 microglial polarization and its anti-inflammatory effects in models involving Aβ_1-42-stimulated BV-2 cells and FAD^4T mice. Conclusions: These findings indicate that OUA exerts anti-neuroinflammatory effects by regulating microglial polarization, reducing the production of inflammatory mediators, and activating the PI3K/Akt signaling pathway. Given its natural origin and dual effects on microglial polarization and neuroinflammation, OUA emerges as a promising therapeutic candidate for neuroinflammatory diseases such as AD. Full article