Alzheimer's disease (AD) is a devastating form of dementia, with the number of affected individuals rising sharply. The main hallmarks of the disease include amyloid-beta plaque deposits and neurofibrillary tangles consisting of hyperphosphorylated tau protein, besides other pathological features that contribute to the disease's complexity. The causes of sporadic AD are multifactorial and mostly age-related and involve risk factors such as diabetes and cardiovascular or cerebrovascular disorders. Frontotemporal dementia (FTD) is another type of dementia characterized by a spectrum of behaviors, memory, and motor abnormalities and associated with abnormal depositions of protein aggregation, including tau protein. Currently approved medications are symptomatic, and no disease-modifying therapy is available to halt the disease progression. Therefore, the development of multi-targeted therapeutic approaches could hold promise for the treatment of AD and other neurodegenerative disorders, including tauopathies. In this article, we will discuss the pathophysiology of AD and FTD, the proposed hypotheses, and current therapeutic approaches, highlighting the development of novel drug candidates and the progress of clinical trials in this field of research.

Microtubule affinity regulating kinase 4 (MARK4) is a vital protein kinase that serves as a dual target in cancer and neurodegenerative diseases. It is implicated in the development of tauopathies and also linked to the pathogenesis of several cancer types, implying its importance. Syringic acid is a naturally occurring phenolic molecule that has shown significant efficacies in cancer and neurodegenerative diseases by modulating several key pathways. Thus, the present study aims to investigate the inhibitory potential of syringic acid against the protein kinase MARK4, employing a combination of experimental and computational approaches. Molecular docking revealed the binding of syringic acid in the MARK4's binding pocket, interacting with key functional residues of the protein kinase. Molecular dynamic simulation (MD) studies demonstrated the conformational dynamics and structural stability of MARK4 upon the binding of syringic acid. In silico findings were further complemented by experimental assays. Enzyme inhibition assay showed that syringic acid effectively inhibits MARK4 with an IC50 value of 4.32 μM. Fluorescence binding assays revealed a strong binding affinity (K = 2.8 × 106 M-1). The findings of our study establish syringic acid as a potent MARK4 inhibitor, providing a perfect platform for its use in tackling MARK4-associated diseases.

Slow-onset neurodegenerative disease in a low-expresser 2N4R P301L transgenic (Tg) mouse model is marked by neuroinflammation and by differing patterns of CNS deposition and accumulation of tau conformers, with such heterogeneities present even within inbred backgrounds. Gut microbial genotypes were notably divergent within C57BL6/Tac or 129SvEv/Tac congenic (Cg) sublines of TgTauP301L mice, and these sublines differed when challenged with antibiotic treatment and fecal microbial transplantation. Whereas aged, transplanted Cg 129SvEv/Tac TgTauP301L mice had neuroanatomical deposition of tau resembling controls, transplanted Cg C57BL6/Tac TgTauP301L mice had different proportions of rostral versus caudal tau accumulation (p = 0.0001). These data indicate the potential for environmental influences on tau neuropathology in this model. Furthermore, Cg C57BL6/Tac TgTauP301L cohorts differed from 129SvEv/Tac counterparts by showing 28% versus 9% net intercurrent loss (p = 0.0027). While the origin of this phenomenon is not established, it offers a parallel to differing patterns of frailty observed in C57BL6 versus 129 SvEv Tg mice expressing the 695 amino acid isoform of human amyloid precursor protein. We infer that generalized responses to protein aggregation might account for similar reductions in viability even when expressing different human proteins in the same inbred strain background.

Microbial infection, the strong trigger to directly induce inflammation in brain, is long considered a risk factor of Alzheimer's disease (AD), but how these infections contribute to neurodegeneration remains underexplored. To examine the effect of herpes simplex virus type 1 (HSV-1) infection on tauopathy in local hippocampus of P301S mice, we utilized a modified HSV-1 strain (mHSV-1) potentially relevant to AD, we found that its infection promotes tau-related pathology in part via activating neuroimmune cGAS-STING pathway in the tau mouse model. Specifically, Sting ablation causes the detectable improvement of neuronal dysfunction and loss in P301S mice, which is causally linked to lowered proinflammatory status in the brain. Administration of STING inhibitor H-151 alleviates neuroinflammation and tau-related pathology in P301S mice. These results jointly suggest that herpesviral infection, as the vital environmental risk factor, could induce tau-related pathology in AD pathogenesis partially via neuroinflammatory cGAS-STING pathway.

Alzheimer's disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classification of amyloid plaques (diffuse, non-cored, dense core, compact). Tau pathology and its involvement with Aβ plaques and cell death are discussed. Amyloid cascade hypotheses, aggregation mechanisms, and molecular species formed in vitro and in vivo (on- and off-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ-derived diffusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofibrils, fibrils, and plaques are characterized (structure, size, morphology, solubility, toxicity, mechanistic steps). An update on AD-approved drugs by regulatory agencies, along with new Aβ-based therapies, is presented. Beyond prescribing Aβ plaque disruptors, cholinergic agonists, or NMDA receptor antagonists, other therapeutic strategies (RNAi, glutaminyl cyclase inhibitors, monoclonal antibodies, secretase modulators, Aβ aggregation inhibitors, and anti-amyloid vaccines) are already under clinical trials. New drug discovery approaches based on "designed multiple ligands", "hybrid molecules", or "multitarget-directed ligands" are also being put forward and may contribute to tackling this highly debilitating and fatal form of human dementia.

Alzheimer's disease (AD) is not a single-cause disease; rather, it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors. Aggregation and accumulation of amyloid beta (Aβ) and tau are the most prominent features in the brains of AD patients. Aggregated Aβ and tau exert neurotoxic effects in the central nervous system, contributing to the pathogenesis and progression of AD. They also act synergistically to cause neurodegeneration, resulting in memory loss. In this context, dual inhibition of Aβ and tau aggregation, or dissociation of these two aggregates, is considered promising for AD treatment. Recently, dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβ and tau have been investigated. Specific amino acid domains of Aβ and tau associated with their aggregation/dissociation have been identified. Subsequently, therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed. In this review, we summarize the major domains and properties involved in Aβ and tau aggregation, as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation. This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβ and tau, potentially leading to the development of more effective therapeutic strategies for AD.

The role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Alzheimer's disease (AD) is critical for linking amyloid-beta (Aβ) and Tau pathology. The activity of GSK-3β is dysregulated in the regulation of Tau hyperphosphorylation, formation of neurofibrillary tangles (NFTs), and production of Aβ by modulating amyloid precursor protein (APP) processing. This review discusses the mechanisms controlling GSK-3β dysregulation in aging and its influence on AD progression, focusing on the role of neuroinflammation, oxidative stress, and defective signaling pathways, including PI3K/Akt and Wnt. Critical analysis is presented for therapeutic strategies targeting GSK-3β using natural compounds (e.g., curcumin, geniposide) and emerging approaches such as TREM2 modulation and miRNA therapies. In preclinical models, these interventions promise to reduce Tau hyperphosphorylation and Aβ burden, along with associated neurodegeneration. Nevertheless, achieving selective GSK-3β inhibition and optimizing drug delivery are still critical barriers to clinical translation. This review underscores the central role of GSK-3β in AD pathogenesis to highlight its potential as a multifaceted therapeutic target of an innovative strategy for treating this complex neurodegenerative disease.

The insula is a critical node of the salience network responsible for initiating network switching, and its dysfunctional connections are linked to the mechanisms of mild cognitive impairment (MCI). This study aimed to explore the changes in functional connectivity (FC) of insular subregions in MCI patients with varying levels of cerebrospinal fluid (CSF) pathological proteins, and to investigate the impact of these proteins on the brain network alterations in MCI.

Based on CSF Amyloid-beta (Aβ, A) and phosphorylated tau protein (p-tau, T), MCI patients were classified into 54 A-T-, 28 A+T-, and 52 A+T+ groups. Seed-based FC analysis was employed to compare the FC differences of insular subregions across the three groups. Correlation analysis was further conducted to explore the relationship between altered FC and cognitive function. Finally, ROC curve analysis was used to assess the diagnostic value of altered FC of insular subregion in distinguishing between the groups.

In the left ventral anterior insula, left dorsal anterior insula, and bilateral posterior insular subnetworks, both the A+T- and A+T+ groups showed increased FC compared to the A-T- group, with the A+T+ group showing further increased FC compared to the A+T- group. Additionally, FC of the left cerebellar posterior lobe was negatively correlated with RAVLT-learning, and FC of the left middle frontal gyrus was negatively correlated with p-tau levels. Finally, logistic regression analysis demonstrated that multivariable analysis had high sensitivity and specificity in distinguishing between the groups.

This study showed that MCI patients with abnormal CSF pathological protein levels exhibit compensatory increases in FC of insular subregions, which in turn affect cognitive function. Our findings contributed to a better understanding of the pathophysiology and underlying neural mechanisms of MCI.

Biofilm-associated amyloid proteins have emerged as significant contributors to the progression of neurodegenerative diseases, representing a complex intersection of microorganisms and human health. The cross-beta sheet structure characteristic of amyloids produced by gut-colonizing bacteria remains intact, crucial for the resilience of biofilms. These amyloids exacerbate neurodegenerative disorders such as Alzheimer's and Parkinson's by cross-seeding human amyloidogenic proteins like amyloid-beta and α-synuclein, accelerating their misfolding and aggregation. Despite molecular chaperones and heat shock proteins maintaining protein homeostasis, bacterial amyloids can overwhelm them, worsening neuronal damage. Genetic variations in chaperone genes further influence amyloidogenesis and neurodegeneration. Persistent bacterial infections and inflammation compromise the blood-brain barrier, allowing inflammatory molecules and amyloids to enter the brain, perpetuating the cycle of neurodegeneration. The gut-brain axis underscores the impact of dysbiosis and gut microbiota on brain function, potentially contributing to neurodegeneration. The enhancement of biofilm resilience and antibiotic resistance by functional amyloid fibrils complicates the treatment landscape. The interplay among chaperone systems, microbial amyloids, and neurodegenerative diseases underscores the urgent need for advanced treatment strategies targeting these pathways to attenuate disease progression. Understanding the processes that relate biofilm-associated amyloids to the onset of neurological disorders is critical for diagnosing and developing novel treatment strategies.

Biomolecular condensates (BMCs) are membrane-less protein compartments with physiological and pathological relevance. The formation of BMCs is driven by a process known as liquid-liquid phase separation (LLPS), a field that has largely focused on the study of micron-sized condensates. However, there have been recent studies showing that proteins that undergo LLPS also form nanometer-sized condensates. These nanometer-sized condensates, or nanocondensates, are distinct from microcondensates and potentially exhibit more relevance in cell biology. The field of nanocondensate research is in its infancy, with limited biophysical studies of these structures. Here, we studied condensate formation and dissolution of wild-type and disease-linked (hyperphosphorylated and missense mutated) Tau. We investigated the effects of solution condition modulation on nanocondensate formation and dissolution, and observed that Tau condensation is strongly regulated by electrostatic forces and less affected by hydrophobic disruption. We observed that all three Tau variants studied shared condensate formation properties when in solution conditions with the same ionic strength. However, hyperphosphorylated and missense-mutated Tau exhibited higher resistance to dissolution compared to wild-type Tau. This study uncovers additional distinctions between different types of condensates, which provides further insight into the distinctions between physiological and pathological condensates.

Cardiovascular health (CVH), defined by the American Heart Association as Life's Simple 7 to promote a healthy lifestyle and manage vascular risk factors, has been associated with a low risk of Alzheimer disease and less vascular dementia. However, the association between CVH and biomarkers of neurodegeneration remains less understood.

To investigate the association of CVH with serum biomarkers of neurodegeneration, including neurofilament light chain (NfL) and total tau (t-tau).

This cohort study was conducted within the biracial, population-based Chicago Health and Aging Project (CHAP) of adults aged 65 years or older between 1993 and 2012. Participants who had measured serum NfL and t-tau levels and data on all components of the CVH score were included. The statistical analysis was conducted from April 10 to September 26, 2024.

The CVH score includes 7 components: a healthy diet; regular exercise; normal body mass index; nonsmoking status; and the absence of dyslipidemia, diabetes, and hypertension. The scores were divided into 3 groups from lowest to highest CVH (0-6 points, 7-9 points, and 10-14 points).

The main outcome was the association of CVH score with serum biomarkers of NfL and t-tau as measured using linear regression and mixed-effects models.

A total of 1018 CHAP participants were included in the analysis (mean [SD] age, 73.1 [6.1] years; 625 female [61.4%]; 610 Black or African American [59.9%] and 408 White [40.1%]). Participants with a high CVH score (ie, 10-14 points) were predominantly White (151 [64.3%]) and had a higher education (mean [SD], 13.6 [3.7] years). Compared with participants with low CVH scores (ie, 0-6 points), those with CVH scores of 10 to 14 points had significantly lower serum levels of NfL (relative difference, -18.9%; β = -0.091; SE, 0.025). A higher CVH score was associated with a slower annual increase in NfL levels as participants aged (relative difference in rate, -1.7%; β = -0.008; SE, 0.004). Cardiovascular health was not associated with serum levels of t-tau.

These findings suggest that promoting CVH in older adults may help alleviate the burden of neurodegenerative diseases, particularly among Black adults, who are known to experience a higher prevalence of cardiovascular disease.

Alzheimer's disease (AD) is the leading cause of dementia, and the early detection of the disease-associated changes allows early interventions. The locus coeruleus (LC) has been reported to be the first brain region to develop tau pathology in AD. However, the functional brain network of the LC in both healthy aging and AD pathology is largely unknown due to technical difficulties associated with the small size of the LC. In this study, we used the measurement of spontaneous pupil constriction/dilation as a surrogate for LC activity to study LC brain network changes during healthy aging.

Thirty-seven healthy younger and thirty-nine healthy older adults were included from the Emory Healthy Brain Study and underwent resting-state functional MRI while simultaneously tracking pupil diameter. The measurements of pupil diameter dynamics were used as reference signals in brain connectivity analysis. The connectivity of the identified networks was then compared between younger and older participants. Correlations of the identified regions with neuropsychological assessments and cerebrospinal fluid (CSF) biomarkers were also evaluated.

A brain network of 20 clusters associated with pupil diameter dynamics was identified, including the LC as well as brain regions functionally connected to the LC. The pupil diameter network was found to positively correlate with the salience network and negatively correlate with the central executive network. Functional connectivity decreased within the pupil diameter network with healthy aging. The pupil diameter connectivity was associated with memory, executive, and visuospatial functioning. CSF total tau closely correlated with pupil diameter network.

Pupil diameter dynamics provide valuable insights into LC-related processes. While they are not solely influenced by LC activity, spontaneous pupil constrictor/dilatory activity shows promise as a non-invasive approach to probe the LC network and warrants further studies to evaluate its value as an early biomarker of AD.

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.

Metabolic disorders such as diabetes and obesity are linked to neurodegenerative diseases, with evidence of lower brain glucose metabolism and insulin resistance in dementia patients. Dietary methionine restriction (MR) is a nutritional intervention that enhances insulin sensitivity and delays ageing-associated metabolic alterations, however, its impact on neurodegenerative diseases is not fully understood. Here, we examined the behavioural and metabolic phenotypes of a murine tauopathy model (rTg4510), which overexpresses human P301L mutated tau, at 6 and 12 months of age, assessing the impact of an 8-week dietary MR in the older group. While rTg4510 mice displayed progressive behavioural and motor impairments at both ages, MR led to significant benefits in the 12-month-old cohort, improving motor coordination, short-term memory, and social recognition. These effects were accompanied by increased glycolysis markers and FGF21R1 levels in the hippocampus, alongside unaltered glucose metabolism/adiposity. Overall, our results reveal the impact of MR on an FTD-mouse model, suggesting this as a potential therapeutic intervention to delay and/or improve the progression of tau-related disease.

Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA) has been considered as a strategy to decrease tau and amyloid-beta phosphorylation, aggregation, and pathology in Alzheimer's disease (AD). There is still more to be learned about the impact of enhancing global protein O-GlcNAcylation, which is important for understanding the potential of using OGA inhibition to treat neurodegenerative diseases. In this study, we investigated the acute effect of pharmacologically increasing O-GlcNAc levels, using the OGA inhibitor Thiamet G (TG), in normal mouse brains. We hypothesized that the transcriptome signature in response to a 3 h TG treatment (50 mg/kg) provides a comprehensive view of the effect of OGA inhibition. We then performed mRNA sequencing of the brain using NovaSeq PE 150 (n = 5 each group). We identified 1234 significant differentially expressed genes with TG versus saline treatment. Functional enrichment analysis of the upregulated genes identified several upregulated pathways, including genes normally down in AD. Among the downregulated pathways were the cell adhesion pathway as well as genes normally up in AD and aging. When comparing acute to chronic TG treatment, protein autophosphorylation and kinase activity pathways were upregulated, whereas cell adhesion and astrocyte markers were downregulated in both datasets. AMPK subunit Prkab2 was one gene in the kinase activity pathway, and the increase after acute and chronic treatment was confirmed using qPCR. Interestingly, mitochondrial genes and genes normally down in AD were up in acute treatment and down in chronic treatment. Data from this analysis will enable the evaluation of the mechanisms underlying the impact of OGA inhibition in the treatment of AD. In particular, OGA inhibitors appear to have downstream effects related to bioenergetics which may limit their therapeutic benefits.

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.

The efficacy of 40 synthesized variants of 3,5-diaryl-1H-pyrazole and spiropyrazoline' derivatives as acetylcholinesterase inhibitors is verified using a quantitative three-dimensional structure-activity relationship (3D-QSAR) by comparative molecular field analysis (CoMFA) and molecular similarity index analysis (CoMSIA) models. In this research, different field models proved that CoMSIA/SE model is the best model with high predictive power compared to several models (Qved2 = O.65; R2 = 0.980; R2test = 0.727). Also, contour maps produced by CoMSIA/SE model have been employed to prove the key structural needs of the activity. Consequently, six new compounds have been generated. Among these compounds, M4 and M5 were the most active but remained toxic and had poor absorption capacities. While the M1, M2, M3 and M6 remained highly active while respecting ADMET's characteristics. Molecular docking results showed compound M2 better with acetylcholinesterase than compound 22. The interactions are classical hydrogen bonding with residues TYR:124, TYR:72, and SER:293, which play a critical role in the biological activity as AChE inhibitors. MD results confirmed the docking results and showed that compound M2 had satisfactory stability with (ΔGbinding = -151.225 KJ/mol) in the active site of AChE receptor compared with compound 22 (ΔGbinding = -133.375 KJ/mol). In addition, both compounds had good stability regarding RMSD, Rg, and RMSF. The previous results show that the newly designed compound M2 is more active in the active site of AChE receptor than compound 22.Communicated by Ramaswamy H. Sarma.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease, with tau pathology caused by abnormally activated dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) being one of the culprits. Coumestrol, a phytoestrogen and natural antioxidant found in various plants, has been reported to alleviate AD, but the underlying mechanism remains unclear. We confirmed coumestrol as a novel DYRK1A inhibitor through enzyme-based assays, X-ray crystallography, and cell line experiments. Coumestrol exhibited minimal cytotoxicity at concentrations up to 100 μM in cell types such as N2A and SH-SY5Y and reduced DYRK1A-induced phosphorylated tau protein levels by >50 % at 60 μM. In the tau protein phosphorylation and microtubule assembly assay, coumestrol at 30 μM reduced phosphorylated tau by >50 % and restored the microtubule assembly process. Coumestrol also significantly reduced amyloid-β (Aβ)-induced oxidative stress in microglia at 1 μM. In zebrafish larvae co-overexpressing DYRK1A and tau, coumestrol mitigated neuronal damage and protected motor function at 48 h-postfertilization. Our results suggest that coumestrol has potential therapeutic effects in AD by inhibiting DYRK1A, lowering p-Tau levels, restoring microtubule assembly, and protecting microglia cells from Aβ-induced cell death, providing new insights into the development of coumestrol as a potential AD treatment.

Intracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer's disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

Seven treatments are approved for Alzheimer's disease, but five of them only relieve symptoms and do not alter the course of the disease. Aducanumab (Adu) and lecanemab are novel disease-modifying antiamyloid-β (Aβ) human monoclonal antibodies that specifically target the pathophysiology of Alzheimer's disease (AD) and were recently approved for its treatment. However, their administration is associated with serious side effects, and their use is limited to early stages of the disease. Therefore, drug discovery remains of great importance in AD research. To gain new insights into the development of novel drugs for Alzheimer's disease, a combination of techniques was employed, including mutation screening, molecular dynamics, and quantum biochemistry. These were used to outline the interfacial interactions of the Aducanumab::Aβ2-7 complex. Our analysis identified critical stabilizing contacts, revealing up to 40% variation in the affinity of the Adu chains for Aβ2-7 depending on the conformation outlined. Remarkably, two complementarity determining regions (CDRs) of the Adu heavy chain (HCDR3 and HCDR2) and one CDR of the Adu light chain (LCDR3) accounted for approximately 77% of the affinity of Adu for Aβ2-7, confirming their critical role in epitope recognition. A single mutation, originally reported to have the potential to increase the affinity of Adu for Aβ2-7, was shown to decrease its structural stability without increasing the overall binding affinity. Mimetic peptides that have the potential to inhibit Aβ aggregation were designed by using computational outcomes. Our results support the use of these peptides as promising drugs with great potential as inhibitors of Aβ aggregation.

Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA) is explored as a strategy to decrease tau and amyloid-beta phosphorylation, aggregation, and pathology in Alzheimer's disease (AD). There is still more to be learned about the impact of enhancing global protein O-GlcNAcylation, which is important for understanding the mechanistic path of using OGA inhibition to treat AD. In this study, we investigated the acute effect of pharmacologically increasing O-GlcNAc levels, using OGA inhibitor Thiamet G (TG), on normal mouse brains. We hypothesized that the transcritome signature in respones to TG treatment provides a comprehensive view of the effect of OGA inhibition. We sacrificed the mice and dissected their brains after 3 hours of saline or 50 mg/kg TG treatment, and then performed mRNA sequencing using NovaSeq PE 150 (n=5 each group). We identified 1,234 significant differentially expressed genes with TG versus saline treatment. Functional enrichment analysis of the upregulated genes identified several upregulated pathways, including genes normally down in AD. Among the downregulated pathways were the cell adhesion pathway as well as genes normally up in AD and aging. When comparing acute to chronic TG treatment, protein autophosphorylation and kinase activity pathways were upregulated, whereas cell adhesion and astrocyte markers were downregulated in both datasets. Interestingly, mitochondrial genes and genes normally down in AD were up in acute treatment and down in chronic treatment. Data from this analysis will enable the evaluation of the mechanisms underlying the potential benefits of OGA inhibition in the treatment of AD. In particular, although OGA inhibitors are promising to treat AD, their downstream chronic effects related to bioenergetics may be a limiting factor.

The aggregation of the proteins tau and amyloid-β is a salient feature of Alzheimer's disease, the most common form of neurodegenerative disorders. Upon aggregation, proteins transition from their soluble, monomeric, and functional state into insoluble, fibrillar deposits through a complex process involving a variety of intermediate species of different morphologies, including monomers, toxic oligomers, and insoluble fibrils. To control and direct peptide aggregation, a complete characterization of all species present and an understanding of the molecular processes along the aggregation pathway are essential. However, this is extremely challenging due to the transient nature of oligomers and the complexity of the reaction networks. Therefore, we have employed a combined approach that allows us to probe the structure and kinetics of oligomeric species, following them over time as they form fibrillar structures. Targeting the tau protein peptide segment Ac-PHF6-NH2, which is crucial for the aggregation of the full protein, soft nano-electrospray ionization combined with ion mobility mass spectrometry has been employed to study the kinetics of heparin-induced intact oligomer formation. The oligomers are identified and characterized using high-resolution ion mobility mass spectrometry, demonstrating that the addition of heparin does not alter the structure of the oligomeric species. The kinetics of fibril formation is monitored through a Thioflavin T fluorescence assay. Global fitting of the kinetic data indicates that secondary nucleation plays a key role in the aggregation of the Ac-PHF6-NH2 tau segment, while the primary nucleation rate is greatly accelerated by heparin.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder constituting the most common form of dementia (60%-70% of cases). Although AD presents majorly a neurodegenerative pathology, recent clinical evidence highlights myelin impairment as a key factor in disease pathogenesis. The lack of preventive or restorative treatment is emphasizing the need to develop novel therapeutic approaches targeting to the causes of the disease. Recent studies in animals and patients have highlighted the loss of myelination of the neuronal axons as an extremely aggravating factor in AD, in addition to the formation of amyloid plaques and neurofibrillary tangles that are to date the main pathological hallmarks of the disease. Myelin breakdown represents an early stage event in AD. However, it is still unclear whether myelin loss is attributed only to exogenous factors like inflammatory processes of the tissue or to impaired oligodendrogenesis as well. Neurotrophic factors are well established protective molecules under many pathological conditions of the neural tissue, contributing also to proper myelination. Due to their inability to be used as drugs, many research efforts are focused on substituting neurotrophic activity with small molecules. Our research team has recently developed novel micromolecular synthetic neurotrophin mimetics (MNTs), selectively acting on neurotrophin receptors, and thus offering a unique opportunity for innovative therapies against neurodegenerative diseases. These small sized, lipophilic molecules address the underlying biological effect of these diseases (neuroprotective action), but also they exert significant neurogenic actions inducing neuronal replacement of the disease areas. One of the significant neurotrophin molecules in the Central Nervous System is Brain-Derived-Neurotrophin-Factor (BDNF). BDNF is a neurotrophin that not only supports neuroprotection and adult neurogenesis, but also mediates pro-myelinating effects in the CNS. BDNF binds with high-affinity on the TrkB neurotrophin receptor and enhances myelination by increasing the density of oligodendrocyte progenitor cells (OPCs) and playing an important role in CNS myelination. Conclusively, in the present review, we discuss the myelin pathophysiology in Alzheimer's Diseases, as well as the role of neurotrophins, and specifically BDNF, in myelin maintenance and restoration, revealing its valuable therapeutic potential against AD.

Coxsackievirus A6 (CV-A6) has emerged as the predominant epidemic strain responsible for hand, foot and mouth disease (HFMD). CV-A6 infection can result in severe clinical manifestations, including encephalitis, meningitis, and potentially life-threatening central nervous system disorders. Our previous research findings demonstrated that neonatal mice infected with CV-A6 exhibited limb weakness, paralysis, and ultimately succumbed to death. However, the underlying mechanism of CV-A6-induced nervous system injury remains elusive. Numerous reports have highlighted the pivotal role of miRNAs in various viral infections.

Separately established infection and control groups of mice were used to create miRNA profiles of the brain tissues before and after CV-A6 transfection, followed by experimental verification, prediction, and analysis of the results.

At 2 days post-infection (dpi), 4 dpi, and 2dpi vs 4dpi, we identified 175, 198 and 78 significantly differentially expressed miRNAs respectively using qRT-PCR for validation purposes. Subsequently, we predicted target genes of these differentially expressed miRNAs and determined their potential targets through GO (Gene Ontology) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Finally, we verified the miRNA-mRNA pairing via double luciferase experiments while confirming functional enrichment of target genes through Western Blotting analyses.

The results from this study suggest that transcriptional regulation, neuronal necrosis, pro-inflammatory cytokine release, and antiviral immunity are all implicated in the pathogenesis of central nervous system injury in mice infected with CV-A6. Brain injury resulting from CV-A6 infection may involve multiple pathways, including glial cell activation, neuronal necrosis, synaptic destruction, degenerative diseases of the nervous system. It can even encompass destruction of the blood-brain barrier, leading to central nervous system injury. The dysregulated miRNAs and signaling pathways discovered in this study provide valuable insights for further investigations into the pathogenesis of CV-A6.

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A knockout (CgA-KO) mice. This study investigates the role of CgA in Alzheimer's disease (AD) and corticobasal degeneration (CBD). CgA ablation in tauopathy mice (hTau) (CgA-KO/hTau) exhibited reduced tau aggregation, spreading, extended lifespan, and improved cognitive function. Transcriptomic and metabolite analysis of mouse cortices revealed altered alpha1-adrenergic receptors (Adra1) and high epinephrine (EPI) levels in hTau mice compared to WT mice, mirroring observations in AD and CBD patients. CgA-KO/hTau mice exhibited a reversal of EPI levels in the cortex and the expression of Adra1, nearly returning them to WT levels. Treatment of hippocampal slices with EPI or Adra1 agonist intensified, while an Adra1 antagonist inhibited tau hyperphosphorylation and aggregation. These findings highlight the interplay between the EPI-Adra signaling system and CgA in tauopathy.

Neurodegenerative diseases are challenging to cure. To date, no cure has been found for Alzheimer's disease or Parkinson's disease, and current treatments are able only to slow the progression of the diseases and manage their symptoms. After an introduction to the complex biology of these diseases, we discuss the beneficial effect of selenium-containing agents, which show neuroprotective effects in vitro or in vivo. Indeed, selenium is an essential trace element that is being incorporated into innovative organoselenium compounds, which can improve outcomes in rodent or even primate models with neurological deficits. Herein, we critically discuss recent findings in the field of selenium-based applications in neurological disorders.

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral β-amyloid protein (Aβ) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of β-amyloid converting enzyme 1 (BACE1) and Aβ. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 β (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.

Tau, a microtubule-associated protein predominantly localized in neuronal axons, plays a crucial role in promoting microtubule assembly, stabilizing their structure, and participating in axonal transport. Perturbations in tau's structure and function are implicated in the pathogenesis of neurodegenerative diseases collectively known as tauopathies, the most common disorder of which is Alzheimer's disease (AD). In tauopathies, it has been found that tau has a variety of post-translational modification (PTM) abnormalities and/or tau is cleaved into a variety of fragments by some specific proteolytic enzymes; however, the precise contributions of these abnormal modifications and fragments to disease onset and progression remain incompletely understood. Herein, we provide an overview about the involvement of distinctive abnormal tau PTMs and different tau fragments in the pathogenesis of AD and other tauopathies and discuss the involvement of proteolytic enzymes such as caspases, calpains, and asparagine endopeptidase in mediating tau cleavage while also addressing the intercellular transmission role played by tau. We anticipate that further exploration into PTMs and fragmented forms of tau will yield valuable insights for diagnostic approaches and therapeutic interventions targeting AD and other related disorders.

In small clinical studies, the application of transcranial photobiomodulation (PBM), which typically delivers low-intensity near-infrared (NIR) to treat the brain, has led to some remarkable results in the treatment of dementia and several neurodegenerative diseases. However, despite the extensive literature detailing the mechanisms of action underlying PBM outcomes, the specific mechanisms affecting neurodegenerative diseases are not entirely clear. While large clinical trials are warranted to validate these findings, evidence of the mechanisms can explain and thus provide credible support for PBM as a potential treatment for these diseases. Tubulin and its polymerized state of microtubules have been known to play important roles in the pathology of Alzheimer's and other neurodegenerative diseases. Thus, we investigated the effects of PBM on these cellular structures in the quest for insights into the underlying therapeutic mechanisms. In this study, we employed a Raman spectroscopic analysis of the amide I band of polymerized samples of tubulin exposed to pulsed low-intensity NIR radiation (810 nm, 10 Hz, 22.5 J/cm2 dose). Peaks in the Raman fingerprint region (300-1900 cm-1)-in particular, in the amide I band (1600-1700 cm-1)-were used to quantify the percentage of protein secondary structures. Under this band, hidden signals of C=O stretching, belonging to different structures, are superimposed, producing a complex signal as a result. An accurate decomposition of the amide I band is therefore required for the reliable analysis of the conformation of proteins, which we achieved through a straightforward method employing a Voigt profile. This approach was validated through secondary structure analyses of unexposed control samples, for which comparisons with other values available in the literature could be conducted. Subsequently, using this validated method, we present novel findings of statistically significant alterations in the secondary structures of polymerized NIR-exposed tubulin, characterized by a notable decrease in α-helix content and a concurrent increase in β-sheets compared to the control samples. This PBM-induced α-helix to β-sheet transition connects to reduced microtubule stability and the introduction of dynamism to allow for the remodeling and, consequently, refreshing of microtubule structures. This newly discovered mechanism could have implications for reducing the risks associated with brain aging, including neurodegenerative diseases like Alzheimer's disease, through the introduction of an intervention following this transition.

Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimer's disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.

The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aβ biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting a growing number of elderly people. In order to improve the early and differential diagnosis of AD, better biomarkers are needed. Glycosylation is a protein post-translational modification that is modulated in the course of many diseases, including neurodegeneration. Aiming to improve AD diagnosis and differential diagnosis through glycan analytics methods, we report the glycoprotein glycome of cerebrospinal fluid (CSF) isolated from a total study cohort of 262 subjects. The study cohort consisted of patients with AD, healthy controls and patients suffering from other types of dementia. CSF free-glycans were also isolated and analyzed in this study, and the results reported for the first time the presence of 19 free glycans in this body fluid. The free-glycans consisted of complete or truncated N-/O-glycans as well as free monosaccharides. The free-glycans Hex1 and HexNAc1Hex1Neu5Ac1 were able to discriminate AD from controls and from patients suffering from other types of dementia. Regarding CSF N-glycosylation, high proportions of high-mannose, biantennary bisecting core-fucosylated N-glycans were found, whereby only about 20% of the N-glycans were sialylated. O-Glycans and free-glycan fragments were less sialylated in AD patients than in controls. To conclude, this comprehensive study revealed for the first time the biomarker potential of free glycans for the differential diagnosis of AD.

Alzheimer's disease (AD) is a age-related neurodegenerative disease and is a major public health concern both in Texas, US and Worldwide. This neurodegenerative disease is mainly characterized by amyloid-beta (Aβ) and phosphorylated Tau (p-Tau) accumulation in the brains of patients with AD and increasing evidence suggests that these are key biomarkers in AD. Both Aβ and p-tau can be detected through various imaging techniques (such as positron emission tomography, PET) and cerebrospinal fluid (CSF) analysis. The presence of these biomarkers in individuals, who are asymptomatic or have mild cognitive impairment can indicate an increased risk of developing AD in the future. Furthermore, the combination of Aβ and p-tau biomarkers is often used for more accurate diagnosis and prediction of AD progression. Along with AD being a neurodegenerative disease, it is associated with other chronic conditions such as cardiovascular disease, obesity, depression, and diabetes because studies have shown that these comorbid conditions make people more vulnerable to AD. In the first part of this review, we discuss that biofluid-based biomarkers such as Aβ, p-Tau in cerebrospinal fluid (CSF) and Aβ & p-Tau in plasma could be used as an alternative sensitive technique to diagnose AD. In the second part, we discuss the underlying molecular mechanisms of chronic conditions linked with AD and how they affect the patients in clinical care.

Tau is a microtubule-associated protein that plays a critical role in the stabilization and modulation of neuronal axons. Tau pathology is stronger associated with cognitive decline in patients with Alzheimer's disease (AD) than amyloid beta (Aβ) pathology. Hence, tau targeting is a promising approach for the treatment of AD. Previous studies have demonstrated that the non-saponin fraction with rich polysaccharide (NFP) from Korean red ginseng (KRG) can modulate tau aggregation and exert a therapeutic effect on AD. Therefore, we investigated the efficacy of NFP isolated from KRG on tau pathology in experimental models of AD. Our results showed that NFP from KRG ameliorated deposition and hyperphosphorylation of tau in the brain of 3xTg mice. Moreover, NFP from KRG modulated the aggregation and dissociation of tau K18 in vitro. We demonstrated the alleviatory effects of NFP from KRG on hyperphosphorylated tau and tau kinase in okadaic acid-treated HT22 cells. Furthermore, NFP from KRG mitigated Aβ deposition, neurodegeneration, and neuroinflammation in 3xTg mice. We revealed the neuroprotective effects of NFP from KRG on tau-induced neuronal loss in HT22 cells. Our results indicate that NFP extracted from KRG is a novel therapeutic agent for the treatment of AD associated with tau pathology.

Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.

Alzheimer's Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe cute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD such as the lytic replication and axonal transport of HSV-1, the various mechanisms of ZIKV neurotropism through the human protein Musashi-1 (MSI1), and the spread of SARS-CoV-2 through the transfer of the virus through the BBB endothelial cells to glial cells and then to neurons via transsynaptic transfer. We will also explore beyond these mere associations by carefully analyzing the potential mechanisms by which these viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, the dysregulation of immune responses, and the impact on protein processing (Aβ42 and hyperphosphorylated tau). Controversies and challenges of the virus-AD relationship emerge as we tease out these potential mechanisms. Looking forward, we emphasize future directions, such as distinct questions and proposed experimentations to explore, that the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development while encouraging further discussion.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.