Onset Alzheimer's Disease Research Articles

Externalizing Behaviors and Alzheimer's Disease and Any Dementia: A Multigeneration Cohort Study in Sweden.

We examined the extent to which externalizing behaviors such as violent and nonviolent criminal behavior, and substance use disorders (SUD) are associate with the onset of Alzheimer's disease (AD) and any dementia in prior generations. A nationwide cohort of 2,463,033 individuals born between 1973 and 1997 (index persons) were linked to their biological relatives (parents, grandparents, and uncles/aunts) using Swedish national registers. Cox regression models were used to examine the association between each measure of externalizing behaviors with AD and any dementia in each of the relative cohorts. Parents of index persons with externalizing behaviors had an increased risk for AD compared with parents of index persons without externalizing behaviors-nonviolent criminal behavior: Hazard Ratio (HR) = 1.16, 95% Confidence Intervals (CI) 1.10-1.22; violent criminal behavior: HR = 1.32 (95% CI: 1.19-1.45); SUD: HR = 1.28 (95% CI: 1.17, 1.40). The associations attenuated with decreasing familial relatedness. Relatives of individuals with externalizing behaviors compared with relatives of individuals without, showed an increased risk of having both early-onset and late-onset AD but the strength of the associations was higher for early-onset AD than for late-onset AD. A similar pattern of results was observed for the association with any dementia. Externalizing behaviors are associated with AD and any dementia in prior generations. The associations were stronger for parents in comparison with grandparents and uncles/aunts, suggesting shared familial risks between conditions. This warrants further studies examining common genetic and family-wide environmental factors that may contribute to identifying common underlying mechanisms to the development of externalizing behaviors, AD, and any dementia.

Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. The study identifies the APOE ε4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease.Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

Toxic Advanced Glycation End-Products-Dependent Alzheimer's Disease- Like Alternation in the Microtubule System.

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's Disease (AD). However, the detailed mechanism underlying T2DM-related AD remains unknown. In DM, many types of advanced glycation end-products (AGEs) are formed and accumulated. In our previous study, we demonstrated that Glyceraldehyde (GA)-derived Toxic Advanced Glycation End-products (Toxic AGEs, TAGE) strongly showed cytotoxicity against neurons and induced similar alterations to those observed in AD. Further, GA induced dysfunctional neurite outgrowth via TAGE-β-- tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation. Herein, we provide a perspective on the possibility that T2DM increases the probability of AD onset and accelerates its progression.

Environmental factors in the development of Alzheimer’s disease

This article delves into the profound significance of the early diagnosis of Alzheimer’s disease (AD), the leading cause of dementia worldwide. With no current cure for AD, early detection stands as a cornerstone in managing the disease. Early diagnosis not only enables symptomatic treatment to enhance the quality of life but also facilitates proactive planning, addressing health care and living arrangements for the future. Additionally, early diagnosis can promote participation in clinical trials, granting patients access to emerging treatments. An essential component to this early detection is a robust understanding of the disease's causes. The paper examines the pathological indicators, such as beta-amyloid plaques and neurofibrillary tangles, while highlighting the multifaceted origins of AD encompassing genetics, environmental factors, inflammation, and potential links with other diseases. An in-depth discussion on the influence of the environment further illustrates the complex interplay between genetics and external factors. Toxic chemicals, lifestyle choices in western societies, and other environmental determinants are scrutinized for their potential role in AD onset. In summary, the piece underscores the importance of a holistic understanding of Alzheimer's etiology, emphasizing that only through comprehensive knowledge can we aspire to identify, manage, and ultimately find a cure for this debilitating condition.

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer's disease.

Introduction: Hyperphosphorylation of tau is an important event in Alzheimer's disease (AD) pathogenesis, leading to the generation of "neurofibrillary tangles," a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics. Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4-GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT. Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250ns demonstrated the stability and conformational dynamics of the MARK4-GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC50 = 5.87µM). Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT's inhibition of MARK4 provides newer insights into the mechanism of GLT's action, which is already used to improve cognition in AD patients.

Preliminary PET Imaging of Microtubule-Based PET Radioligand [11C]MPC-6827 in a Nonhuman Primate Model of Alzheimer's Disease.

The microtubule (MT) instability observed in Alzheimer's disease (AD) is commonly attributed to hyperphosphorylation of the MT-associated protein, tau. In vivo PET imaging offers an opportunity to gain critical information about MT changes with the onset and development of AD and related dementia. We developed the first brain-penetrant MT PET ligand, [11C]MPC-6827, and evaluated its in vivo imaging utility in vervet monkeys. Consistent with our previous in vitro cell uptake and in vivo rodent imaging experiments, [11C]MPC-6827 uptake increased with MT destabilization. Radioactive uptake was inversely related to (cerebrospinal fluid) CSF Aβ42 levels and directly related to age in a nonhuman primate (NHP) model of AD. Additionally, in vitro autoradiography studies also corroborated PET imaging results. Here, we report the preliminary results of PET imaging with [11C]MPC-6827 in four female vervet monkeys with high or low CSF Aβ42 levels, which have been shown to correlate with the Aβ plaque burden, similar to humans.

Multimodal magnetic resonance imaging on brain structure and function changes in subjective cognitive decline: a mini-review.

Subjective cognitive decline (SCD) is the initial stage of Alzheimer's disease (AD). Early identification of SCD and its risk factors is of great importance for targeted interventions and for delaying the onset of AD. We reviewed the relevant literature on structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), and other techniques regarding SCD research in recent years. This study applied sMRI and fMRI techniques to explore abnormal brain structures and functions, which may help provide a basis for SCD diagnosis.

Systematic characterization of a non-transgenic Aβ1–42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

BackgroundThe amyloid-β (Aβ) cascade is one of the most studied theories linked to AD. In multiple models, Aβ accumulation and dyshomeostasis have shown a key role in AD onset, leading to excitatory/inhibitory imbalance, the impairments of synaptic plasticity and oscillatory activity, and memory deficits. Despite the higher prevalence of Alzheimer’s disease (AD) in women compared to men, the possible sex difference is scarcely explored and the information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data regarding the early stages of amyloidosis in female mice, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of Aβ1–42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1–CA3 synapse, in both male and female mice.MethodsTo do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings as well as encoding and retrieval of spatial (working, short- and long-term) and exploratory habituation memories using Barnes maze and object location, or open field habituation tasks, respectively.ResultsAβ1–42 administration impaired all forms of memory evaluated in this work, regardless of sex. This effect was displayed in a long-lasting manner (up to 17 days post-injection). LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underlie memory deficits.ConclusionsIn conclusion, our results provide further evidence on the shifting of LTP/LTD threshold due to a single icv. Aβ1–42 injection, which underly cognitive deficits in the early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.

Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice.

Extracellular proteolytic activity plays an important role in memory formation and the preservation of cognitive function. Previous studies have shown increased levels of plasminogen activator inhibitor-1 (PAI-1) in the brain of mouse models of Alzheimer's disease (AD) and plasma of AD patients, associated with memory and cognitive decline; however, the exact function of PAI-1 in AD onset and progression is largely unclear. In this study, we evaluated a novel PAI-1 inhibitor, TM5A15, on its ability to prevent or reverse memory deficits and decrease Aβ levels and plaque deposition in APP/PS1 mice. We administered TM5A15 mixed in a chow diet to 3-month and 9-month-old APP/PS1 mice before and after neuropathological changes were distinguishable. We then evaluated the effects of TM5A15 on memory function and neuropathology at 9 months and 18 months of age. In the younger mice, 6 months of TM5A15 treatment protected against recognition and short-term working memory impairment. TM5A15 also decreased oligomer levels and amyloid plaques, and increased mBDNF expression in APP/PS1 mice at 9 months of age. In aged mice, 9 months of TM5A15 treatment did not significantly improve memory function nor decrease amyloid plaques. However, TM5A15 treatment showed a trend in decreasing oligomer levels in APP/PS1 mice at 18 months of age. Our results suggest that PAI-1 inhibition could improve memory function and reduce the accumulation of amyloid levels in APP/PS1 mice. Such effects are more prominent when TM5A15 is administered before advanced AD pathology and memory deficits occur.

A Novel Presenilin-1 Mutation (Leu226Val) In Early Onset Alzheimer's Disease With Parkinsonism.

A Novel Presenilin-1 Mutation (Leu226Val) In Early Onset Alzheimer's Disease With Parkinsonism.

Brain Hydrophobic Peptides Antagonists of Neurotoxic Amyloid β Peptide Monomers/Oligomers-Protein Interactions.

Amyloid β (Aβ) oligomers have been linked to Alzheimer's disease (AD) pathogenesis and are the main neurotoxic forms of Aβ. This review focuses on the following: (i) the Aβ(1-42):calmodulin interface as a model for the design of antagonist Aβ peptides and its limitations; (ii) proteolytic degradation as the major source of highly hydrophobic peptides in brain cells; and (iii) brain peptides that have been experimentally demonstrated to bind to Aβ monomers or oligomers, Aβ fibrils, or Aβ plaques. It is highlighted that the hydrophobic amino acid residues of the COOH-terminal segment of Aβ(1-42) play a key role in its interaction with intracellular protein partners linked to its neurotoxicity. The major source of highly hydrophobic endogenous peptides of 8-10 amino acids in neurons is the proteasome activity. Many canonical antigen peptides bound to the major histocompatibility complex class 1 are of this type. These highly hydrophobic peptides bind to Aβ and are likely to be efficient antagonists of the binding of Aβ monomers/oligomers concentrations in the nanomolar range with intracellular proteins. Also, their complexation with Aβ will protect them against endopeptidases, suggesting a putative chaperon-like physiological function for Aβ that has been overlooked until now. Remarkably, the hydrophobic amino acid residues of Aβ responsible for the binding of several neuropeptides partially overlap with those playing a key role in its interaction with intracellular protein partners that mediates its neurotoxicity. Therefore, these latter neuropeptides are also potential candidates to antagonize Aβ peptides binding to target proteins. In conclusion, the analysis performed in this review points out that hydrophobic endogenous brain neuropeptides could be valuable biomarkers to evaluate the risk of the onset of sporadic AD, as well as for the prognosis of AD.

From genetic correlations of Alzheimer’s disease to classification with artificial neural network models

Sporadic Alzheimer’s disease (AD) is a complex neurological disorder characterized by many risk loci with potential associations with different traits and diseases. AD, characterized by a progressive loss of neuronal functions, manifests with different symptoms such as decline in memory, movement, coordination, and speech. The mechanisms underlying the onset of AD are not always fully understood, but involve a multiplicity of factors. Early diagnosis of AD plays a central role as it can offer the possibility of early treatment, which can slow disease progression. Currently, the methods of diagnosis are cognitive testing, neuroimaging, or cerebrospinal fluid analysis that can be time-consuming, expensive, invasive, and not always accurate. In the present study, we performed a genetic correlation analysis using genome-wide association statistics from a large study of AD and UK Biobank, to examine the association of AD with other human traits and disorders. In addition, since hippocampus, a part of cerebral cortex could play a central role in several traits that are associated with AD; we analyzed the gene expression profiles of hippocampus of AD patients applying 4 different artificial neural network models. We found 65 traits correlated with AD grouped into 9 clusters: medical conditions, fluid intelligence, education, anthropometric measures, employment status, activity, diet, lifestyle, and sexuality. The comparison of different 4 neural network models along with feature selection methods on 5 Alzheimer’s gene expression datasets showed that the simple basic neural network model obtains a better performance (66% of accuracy) than other more complex methods with dropout and weight regularization of the network.

Association Between Common Urologic Medications and Onset of Alzheimer’s Disease and Related Dementias in Men With Prostate Cancer Managed by Different Primary Treatment Modalities

To understand the relationship between common urologic medications phosphodiesterase-5 inhibitors (PDE5i) and anticholinergics (AC) and risk of dementia onset in men who underwent different primary treatments for prostate cancer. Patients (>50years) with prostate cancer (1998-2022) without Alzheimer's disease or related dementias were selected from Cancer of the Prostatic Strategic Urologic Research Endeavor Registry. Minimum medication use was 3months. Fine-Gray regression was performed to determine the association between medication exposure and dementia onset ≥12months after primary treatment in men matched on age, race, comorbid conditions, smoking, and type of clinical site, with competing risk of death. Among 5937 men (53% PDE5i; 14% AC), PDE5i users were younger (63 vs 70, P<.01) with less CAD, CVA, DM (all P<.01); AC users were older (68 vs 66, P<.01) with higher incidence of comorbidities (P<.01). Median months of use was 24.3 (IQR 12.1, 48.7) for PDE5i and 12.2 (IQR 6.1, 24.3) for AC users. Cumulative incidence of Alzheimer's disease or related dementias was 6.5% at 15years. PDE5i (P=.07) and AC (P=.06) were not associated with dementia regardless of primary treatment modality. In this retrospective cohort study, PDE5i and AC use do not appear independently associated with risk of dementia. Notably, our cohort was generally healthy and younger which may limit our ability to detect significance. We recommend prospective investigation into association between PDE5i and dementia and advise continued judicious stewardship of AC in older patient populations.

Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer's disease.

Alzheimer's Disease (AD) is an aging-associated neurodegenerative disorder, threatening millions of people worldwide. The onset and progression of AD can be accelerated by environmental risk factors, such as bacterial and viral infections. Human herpesviruses are ubiquitous infectious agents that underpin numerous inflammatory disorders including neurodegenerative diseases. Published studies concerning human herpesviruses in AD imply an active role HSV-1 in the pathogenesis of AD. This review will summarize the current understanding of HSV-1 infection in AD and highlight some barriers to advance this emerging field.

Amyloid-β exposed astrocytes induce iron transport from endothelial cells at the blood-brain barrier by altering the ratio of apo- and holo-transferrin.

Excessive brain iron accumulation is observed early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-β disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-β stimulates iron transport from endothelial cells and induces changes in iron transport pathway proteins. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes, which in turn increases levels of apo-transferrin in the amyloid-β conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease that can lead to iron accumulation. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation.

Abstract 106: Vascular Dysfunction In The Mesenteric Resistance Arteries Occurs Prior To The Occurrence Of Early-onset Alzheimer’S Disease In A Sex-dependent Manner

Alzheimer’s Disease (AD) and cardiovascular diseases (CVDs) are a major cause ofdisability and death among the older population. Familial Alzheimer’s Disease (FAD) islinked with an early onset AD (EOAD) pathology (&lt;65years) that manifests throughpathogenic mutations in the presenilin (PSEN)1 and PSEN2 genes, leading to theincreased production of central amyloid β (Aβ) peptides. There is increasing evidencethat elevated blood pressure and peripheral arterial stiffness contribute to thedevelopment and increase the risk of β-amyloid deposition in the brain leading to cognitivedecline later in life. We hypothesized that peripheral vascular remodeling and vasculardysfunction in the aorta and mesenteric resistance arteries (MRA) would be observedprior to the development of EOAD. The MRA of male and female C57Bl/6J (control) andAD mice (B6. CApptm1DboTg(APPswe,PSEN1dE9)85Dbo) at 9-weeks-old were isolatedprior to the onset of AD. Acetylcholine-induced relaxation (1pM-30μM) andphenylephrine-induced contraction (0.1nM-30μM) were evaluated using wire myography.Pulse wave velocity (PWV) and H&amp;E staining were used to measure vascular stiffnessand morphology, respectively. Data were analyzed as non-linear curve regression andmaximum response (Rmax) using the Student t test ( p &lt;0.05*). MRA from AD miceshowed impaired relaxation in both males (Rmax: control 90±0.9 vs. AD 59±6.4* %, n=3-4) and females (Rmax: control 90±2.8 vs. AD 70±8.3*%, n=4-6). Interestingly,phenylephrine-induced contraction was reduced in arteries from males (Rmax: control11.7±0.9 vs . AD 7.7±0.8* mN, n=3-4), but not in arteries from females (Rmax: control9.3±1.3 vs. AD 8.1±0.6 mN, n=6-7). However, no differences were observed in the aortawall thickness in the male (control 51.8±2.9 vs. AD 72±9.2 μm, n=3-4), or female (control63.7±9.8 vs. AD 54±4.8μm, n=2-3) AD mice, as well as the PWV analysis from male ADmice (control 2.41±0.44 vs. AD 4.05±1.4 mm/ms, n=6). These data suggest that thechanges observed in the peripheral microvasculature prior to the onset of AD could laterhave direct effects on cerebral blood flow leading to areas of altered blood perfusion andmicrovascular damage, thus contributing to the genesis and maintenance of AD.

Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer's disease.

Dysregulation of physiological processes may contribute to Alzheimer's disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.g., amyloid, tau, neurodegeneration) in the literature. Here, we tested the hypothesis that genes involved in PD and axon guidance/synapse function may jointly influence onset of AD. We assessed the impact of interactions between SNPs in such genes on AD onset in the Long Life Family Study and sought to replicate the findings in the Health and Retirement Study. We found significant interactions between SNPs in the UNC5C and CNTN6, and PLXNA4 and EPHB2 genes that influenced AD onset in both datasets. Associations with individual SNPs were not statistically significant. Our findings, thus, support a major role of genetic interactions in the heterogeneity of AD and suggest the joint contribution of genes involved in PD and axon guidance/synapse function (essential for the maintenance of complex neural networks) to AD development.

Hydroxytyrosol-Donepezil Hybrids Play a Protective Role in an In Vitro Induced Alzheimer's Disease Model and in Neuronal Differentiated Human SH-SY5Y Neuroblastoma Cells.

Alzheimer's disease (AD) is the most common neurodegenerative pathology among progressive dementias, and it is characterized by the accumulation in the brain of extracellular aggregates of beta-amyloid proteins and neurofibrillary intracellular tangles consisting of τ-hyperphosphorylated proteins. Under normal conditions, beta-amyloid peptides exert important trophic and antioxidant roles, while their massive presence leads to a cascade of events culminating in the onset of AD. The fibrils of beta-amyloid proteins are formed by the process of fibrillogenesis that, starting from individual monomers of beta-amyloid, can generate polymers of this protein, constituting the hypothesis of the "amyloid cascade". To date, due to the lack of pharmacological treatment for AD without toxic side effects, chemical research is directed towards the realization of hybrid compounds that can act as an adjuvant in the treatment of this neurodegenerative pathology. The hybrid compounds used in this work include moieties of a hydroxytyrosol, a nitrohydroxytyrosol, a tyrosol, and a homovanillyl alcohol bound to the N-benzylpiperidine moiety of donepezil, the main drug used in AD. Previous experiments have shown different properties of these hybrids, including low toxicity and antioxidant and chelating activities. The purpose of this work was to test the effects of hybrid compounds mixed with Aβ1-40 to induce fibrillogenesis and mimic AD pathogenesis. This condition has been studied both in test tubes and by an in vitro model of neuronal differentiated human SH-SY5Y neuroblastoma cells. The results obtained from test tube experiments showed that some hybrids inhibit the activity of the enzymes AChE, BuChE, and BACE-1. Cell experiments suggested that hybrids could inhibit fibrillogenesis, negatively modulating caspase-3. They were also shown to exert antioxidant effects, and the acetylated hybrids were found to be more functional and efficient than nonacetylated forms.

Clinical and biochemical markers of neurodegenerative process in Alzheimer's disease

Recently, numerous studies have been devoted to describing the heterogeneity of Alzheimer's disease (AD). The aim of our work was to study the clinical, biochemical, and neuropsychological signs of AD depending on the form of the disease. The study involved 173 patients with AD, of whom 65 patients with early onset and 108 with late onset at the stage of moderate cognitive impairment. All study participants underwent the Montreal Cognitive Assessment Scale (MoCA test), the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR), and a lumbar puncture with the determination of the levels of Aβ42 and Aβ40 biomarkers in the cerebrospinal fluid by enzyme immunoassay. The mean age of the patients with early onset of AD was 65.1±0.3 years, and with late onset - 78.6±0.5 years. According to our data, it was found that the majority of the patients with late-onset AD had a longer education (p=0.000) and had coffee more often (p=0.000) than the study participants with early onset of AD. We did not reveal the effect of alcohol and smoking on the neurodegenerative process. The patients with early-onset AD scored lower on the MoCA test than those with late-onset AD (p=0.000). The results of free recall and cue index on the FCSRT-IR test in the patients with late AD were significantly lower than in the patients with early AD onset (p&lt;0.001). We found that the level of Aβ42 and the ratio of Aβ42/Aβ40 in the cerebrospinal fluid was significantly lower (p=0.000) in the patients with early AD onset. The results of our study prove the need for an integrated approach to diagnosing AD using clinical, neuropsychological,and biochemical research methods.

A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.

Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.