Prevention Of Alzheimer's Disease Research Articles

Nervonic acid reduces the cognitive and neurological disturbances induced by combined doses of D-galactose/AlCl3 in mice.

Nervonic acid (NA) is a kind of ultra-long-chain monounsaturated fatty acid, which can repair nerve cell damage caused by oxidative stress. Alzheimer's disease (AD) is a nervous system disease and often accompanied by the decline of learning and memory capacity. In this study, the combined dose of D-galactose/AlCl3 was used to establish a mouse model of AD. Meanwhile, the mice were treated with different doses of NA (10.95 and 43.93 mg/kg). The results showed that NA delayed the decline of locomotion and learning ability caused by D-galactose/AlCl3, increased the activity of total superoxide dismutase, catalase, glutathione peroxidase, and reduced the content of malondialdehyde in vivo. Besides, NA reduced the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), aspartate aminotransferase, alanine aminotransferase, increased the levels of 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, alleviated the cell morphology damage induced by D-galactose/AlCl3 in hippocampus and liver tissue. Furthermore, the intervention of NA upregulated the expression levels of PI3K, AKT, and mTOR genes and downregulated the expression levels of TNF-α, IL-6, and IL-1β genes. Therefore, we speculate the intervention of NA could be an effective way in improving cognitive impairment through the activation of PI3K signaling pathway. These results suggest that NA has the potential to be developed as antioxidant drug for the prevention and early therapy of AD.

The Potential of Herbal Plants and Bioactive β Sitosterol in Circumventing Alzheimer’s Disease – A Review

Alzheimer’s Disease (AD), a neurological ailment, mostly affects the older population all around the world. Rational therapies show limited efficacy, adverse effects, and poor patient compliance therefore herbal drugs are considered as a suitable supplementation to the drug therapy for the treatment of AD. According to research, herbal drugs reduce symptoms of AD and also improve brain functioning by the inhibition of β amyloid, γ-secretase, and acetylcholine along with the regulation of antioxidants and the activation of α-secretase. Various herbal plants like Salvia officinalis, Bertholletia excelsa, Withania somnifera and Urtica dioica help in slowing down the progression of AD by scavenging the free radicals, inhibiting of lipid peroxidation, β amyloid, and tau phosphorylation. β sitosterol, a phytosterol found abundantly in plants has the ability to cross the Blood Brain Barrier and thus acts as a bioactive constituent in circumventing various neurological disorders. Numerous in vitro and in vivo investigations indicate that β sitosterol shows immunomodulatory, lipid-lowering as well as antioxidant properties. The plant sterol, β sitosterol has the capacity to decrease β amyloid platelet synthesis, indicating that it might be helpful in the treatment of prevention of AD. Treatment with β sitosterol can lessen plaque burden and also enhance spatial learning and recognition ability in patients suffering from AD.

Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-β (Aβ) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aβ metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aβ is essential for preventing Aβ deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepaticsEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology,and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.

Identification of tau-tubulin kinase 1 inhibitors by microfluidics-based mobility shift assay from a kinase inhibitor library

Tau tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that phosphorylates multiple residues in tau protein. Hyperphosphorylated tau is the main cause of tauopathy, such as Alzheimer's disease (AD). Therefore, preventing tau phosphorylation by inhibiting TTBK1 has been proposed as a therapeutic strategy for AD. However, few substrates of TTBK1 are reported for a biochemical assay and few inhibitors targeting TTBK1 have been reported so far. In this study, we identified a fluorescein amidite (FAM)-labeled peptide 15 from a small peptide library as the optimal peptide substrate for human TTBK1 (hTTBK1). We then developed and validated a microfluidics-based mobility shift assay (MMSA) with peptide 15. We further confirmed that peptide 15 could also be used in the ADP-Glo kinase assay. The established MMSA was applied for screening of a 427-compound kinase inhibitor library, yielding five compounds with IC50s of several micro molars against hTTBK1. Among them, three compounds, AZD5363, A-674,563 and GSK690693 inhibited hTTBK1 in an ATP competitive manner and molecular docking simulations revealed that they enter the ATP pocket and form one or two hydrogen bonds to the hinge region with hTTBK1. Another hit compound, piceatannol, showed non-ATP competitive inhibitory effect on hTTBK1 and may serve as a starting point to develop highly selective hTTBK1 inhibitors. Altogether, this study provided a new in vitro platform for the development of novel hTTBK1 inhibitors that might have potential applications in AD prevention.

Meta-Analysis of Animal Fluency Performance in Amnestic Mild Cognitive Impairment and Cognitively Unimpaired Older Adults.

Animal fluency is a commonly used neuropsychological measure that is used in the diagnosis of amnestic mild cognitive impairment (aMCI) and Alzheimer disease. Although most individuals with aMCI have clinically normal scores on this test, several studies have shown that aMCI individuals' performance is significantly lower than that of cognitively unimpaired (CU) individuals. The aim of this meta-analysis was to characterize the effect size of animal fluency performance differences between aMCI and CU individuals. Literature search with search terms used were: "animal fluency and mild cognitive impairment," "semantic fluency and mild cognitive impairment," "category fluency and mild cognitive impairment." Both the standardized mean difference and the raw mean difference were derived from random effects analyses. Demographically adjusted z-scores for animal fluency performance for the aMCI groups were obtained to determine normative performance. Nineteen studies were included in the analysis. The standardized mean difference for animal fluency performance between CU and aMCI was 0.89 (95% confidence interval: [0.73; 1.04], P <0.001), I2 =70.3% [52.7%; 81.4%], which reflects a large effect size with moderate heterogeneity. The raw mean difference was -4.08 [-4.75; -3.38], P <0.001. The mean animal fluency z-score for aMCI groups was in the Low Average range (z=-0.77). This study found a substantial difference in animal fluency performance between aMCI and CU individuals. The aMCI groups' normative performance did not fall into the impaired range, indicating that there are important subclinical differences in animal fluency performance that may inform the design of cognitive end points for Alzheimer's disease prevention trials.

Therapeutic Implications of Probiotics in the Gut Microbe-Modulated Neuroinflammation and Progression of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the accumulation of specific proteins in the brain. A recent study revealed that manipulating gut microbiota (GM) significantly reduced tau pathology and neurodegeneration in an apolipoprotein E isoform-dependent manner. The resilience of a healthy microbiota protects it from a variety of dysbiosis-related pathologies. Convincing evidence has demonstrated the roles of GM in the pathogenesis of AD, which are partly mediated by modified microglial activity in the brain. Therefore, modulation of GM may be a promising therapeutic option for AD prevention. In addition to providing the cells with energy and affecting microglial maturation, these microbial metabolites appear to influence neuronal function. One of the potential therapeutic approaches targeting GM may involve using probiotics. Additionally, human GM and its metabolites have also become potential therapeutic targets for developing interventions for the prevention of disorders. Synbiotics and postbiotics can also be used to treat AD by modulating GM. In addition, physical activity, exercise, and physical fitness are being considered as potential nonpharmacological therapies to reduce signaling pathways related to neuroinflammation. Therefore, interventions targeting GM might be promising strategies for health promotion.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

The Impact of Dance Movement Interventions on Psychological Health in Older Adults without Dementia: A Systematic Review and Meta-Analysis.

Lifestyle-based multimodal interventions that integrate physical, sensory, cognitive and social enrichment are suggested to promote healthy mental aging and resilience against aging and Alzheimer's disease (AD). This meta-analysis examined the efficacy of dance movement interventions (DMI) as an integrated mind-body activity on outcomes of psychological health in older adults. Pre-registration was carried out with PROSPERO (CRD42021265112). PubMed, Web of Science and PsycINFO were searched for randomized controlled trials (RCT) evaluating the effects of DMI (>4 weeks' duration) compared to comparators on measures of psychological health (primary outcome) and cognitive function (additional outcome) among older adults without dementia (aged ≥55). Data of 14 primary RCT (n = 983, n-DMI = 494, n-control = 489) were synthesized using a random effects meta-analysis with robust variance estimation. DMI had a small positive effect on overall psychological health (g = 0.30; 95% confidence interval [CI]: 0.06, 0.53; p = 0.02, I2= 65.04) compared to control conditions. Small effects of DMI on positive and negative psychological domains as well as quality of life were not statistically significant. DMI had a medium positive effect on general cognitive function (g = 0.50; 95% CI: 0.12, 0.89, p = 0.02, I2= 79.61) over comparators. None of the primary intervention studies evaluated measures of neuroplasticity. We found that DMI was effective in promoting mental health amongst older adults without dementia, suggesting that the multimodal enrichment tool is a potential strategy for health promotion and prevention of AD. High-quality intervention studies are needed to expand evidence on DMI-induced changes in specific psychological domains and identify underlying neurophysiological correlates.

Metabolic Pathway Pairwise-Based Signature as a Potential Non-Invasive Diagnostic Marker in Alzheimer's Disease Patients.

Alzheimer's disease (AD) is an incurable neurodegenerative disorder. Early screening, particularly in blood plasma, has been demonstrated as a promising approach to the diagnosis and prevention of AD. In addition, metabolic dysfunction has been demonstrated to be closely related to AD, which might be reflected in the whole blood transcriptome. Hence, we hypothesized that the establishment of a diagnostic model based on the metabolic signatures of blood is a workable strategy. To that end, we initially constructed metabolic pathway pairwise (MPP) signatures to characterize the interplay among metabolic pathways. Then, a series of bioinformatic methodologies, e.g., differential expression analysis, functional enrichment analysis, network analysis, etc., were used to investigate the molecular mechanism behind AD. Moreover, an unsupervised clustering analysis based on the MPP signature profile via the Non-Negative Matrix Factorization (NMF) algorithm was utilized to stratify AD patients. Finally, aimed at distinguishing AD patients from non-AD groups, a metabolic pathway-pairwise scoring system (MPPSS) was established using multi-machine learning methods. As a result, many metabolic pathways correlated to AD were disclosed, including oxidative phosphorylation, fatty acid biosynthesis, etc. NMF clustering analysis divided AD patients into two subgroups (S1 and S2), which exhibit distinct activities of metabolism and immunity. Typically, oxidative phosphorylation in S2 exhibits a lower activity than that in S1 and non-AD group, suggesting the patients in S2 might possess a more compromised brain metabolism. Additionally, immune infiltration analysis showed that the patients in S2 might have phenomena of immune suppression compared with S1 and the non-AD group. These findings indicated that S2 probably has a more severe progression of AD. Finally, MPPSS could achieve an AUC of 0.73 (95%CI: 0.70, 0.77) in the training dataset, 0.71 (95%CI: 0.65, 0.77) in the testing dataset, and an AUC of 0.99 (95%CI: 0.96, 1.00) in one external validation dataset. Overall, our study successfully established a novel metabolism-based scoring system for AD diagnosis using the blood transcriptome and provided new insight into the molecular mechanism of metabolic dysfunction implicated in AD.

Precious but convenient means of prevention and treatment: physiological molecular mechanisms of interaction between exercise and motor factors and Alzheimer's disease.

Disproportionate to the severity of Alzheimer's disease (AD) and the huge number of patients, the exact treatment and prevention of AD is still being explored. With increasing ageing, the search for means to prevent and treat AD has become a high priority. In the search for AD, it has been suggested that exercise may be one of the more effective and less costly means of preventing and treating AD, and therefore a large part of current research is aimed at exploring the effectiveness of exercise in the prevention and treatment of AD. However, due to the complexity of the specific pathogenesis of AD, there are multiple hypotheses and potential mechanisms for exercise interventions in AD that need to be explored. This review therefore specifically summarises the hypotheses of the interaction between exercise and AD from a molecular perspective, based on the available evidence from animal models or human experiments, and explores them categorised according to the pathologies associated with AD: exercise can activate a number of signalling pathways inhibited by AD (e.g., Wnt and PI3K/Akt signalling pathways) and reactivate the effects of downstream factors regulated by these signalling pathways, thus acting to alleviate autophagic dysfunction, relieve neuroinflammation and mitigate Aβ deposition. In addition, this paper introduces a new approach to regulate the blood-brain barrier, i.e., to restore the stability of the blood-brain barrier, reduce abnormal phosphorylation of tau proteins and reduce neuronal apoptosis. In addition, this paper introduces a new concept." Motor factors" or "Exerkines", which act on AD through autocrine, paracrine or endocrine stimulation in response to movement. In this process, we believe there may be great potential for research in three areas: (1) the alleviation of AD through movement in the brain-gut axis (2) the prevention and treatment of AD by movement combined with polyphenols (3) the continued exploration of movement-mediated activation of the Wnt signalling pathway and AD.

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer's Disease (AD) cases, pE3Aβ represents a major constituent of the amyloid plaque. The data show that pE3Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aβ3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105-106 against pE3Aβ and 103-104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.

Examining factors that influence African‐Americans and Blacks’ participation in Alzheimer’s biomarker research

AbstractBackgroundAfrican Americans and Blacks in the US are less likely to engage in Alzheimer’s disease (AD) research studies, despite having two to three times higher risks of developing AD compared to Whites. Understanding the various factors influencing African Americans and Blacks’ participation in AD research, especially studies that involve biomarkers, is important for increasing equity in AD research, and advancing AD diagnosis and treatment for diverse populations.MethodStudy participants included 164 community‐dwelling African Americans and Blacks in the Indianapolis metropolitan area, aged 55 and older, and who had no prior participation in AD research. Participants were administered a 24‐item survey to examine their knowledge of AD, willingness to participate in biomarker research procedures (genetic testing, brain MRI, and PET Scan), and views of incentives for participation.ResultMost participants were female (68%) and had less than 16 years of education (71%). About half were 65 years old or older. Most participants (84%) reported that they did not know what caused AD or how to manage it, and only 43% were aware that “Black people are at higher risk of developing dementia, including Alzheimer’s disease, compared to Whites.” Most participants were willing to do or consider participating in biomarker procedures common in AD research studies (90% genetic testing, 86% MRI, and 82% PET scan).The majority (85%) were agreeable to future contact for research participation. Most participants viewed return of test results, particularly from cognitive testing (81%) and brain scans (82%), and information about brain health (72%) as incentives to participate in research.ConclusionOur findings revealed that older African‐American and Black participants are willing to engage in Alzheimer’s disease biomarker research study procedures. They also viewed knowledge (in the form of return of results and information about brain health) as a major incentive for participation. Our findings suggest that future outreach and recruitment strategies tailored towards African Americans and Blacks may benefit from focusing on the value of knowledge these studies can provide to participants. We also identified opportunities to educate African Americans and Blacks about their increased risk for AD and the causes and prevention of AD.

What Can Economics Say about Alzheimer’s Disease?

Alzheimer’s disease (AD) affects one in ten people aged 65 or older and is the most expensive disease in the United States. We describe the central economic questions raised by AD. Although there is overlap with the economics of aging and health, the defining feature of the “economics of Alzheimer’s disease” is an emphasis on choice by cognitively impaired patients that affects health and financial well-being, and situations in which dynamic contracts between patients and caregivers are useful but difficult to enforce. A focus on innovation in AD prevention, treatment, and care is also critical given the enormous social cost of AD and present lack of understanding of its causes, which raises questions of optimal resource allocation and alignment of private and social incentives. The enormous scope for economists to contribute to our understanding of AD-related issues including drug development, efficient care delivery, dynamic contracting, long-term care risk, financial decision-making, and the design of public programs for AD suggests a rich research program for many areas of economics. (JEL G22, G50, I10, I38, J14, L65, O31)

Predicting Conversion to Alzheimer Disease using Module‐Based Polygenic Risk Scores Informed by Brain Proteome Profiles

AbstractBackgroundNeuropathologically confirmed Alzheimer disease (AD) patients are heterogeneous in their cognitive functions, brain atrophy patterns, and neuropathological traits. Genetic risk profiles informed by brain proteome signatures may predict the conversion of clinically normal individuals to AD.MethodWe discovered co‐expressed proteome networks using 201 AD brains from the prefrontal cortex area in the Religious Orders Study and Memory and Aging Project (ROSMAP) and validated the findings using 328 AD brains in the Emory study. Of the preserved modules, we selected modules with significant association (P&lt;0.01) between neuropathologically and clinically confirmed AD (symptomatic) and neuropathologically confirmed AD but clinically unimpaired brains. We generated polygenic risk scores of the symptom‐associated modules (mbPRSs) using existing genome‐wide summary statistics for AD (Kunkle, 2019) in 309 AD, 483 mild cognitive impairment (MCI), and 301 cognitively normal (CN) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated relationships between the derived mbPRSs and previously clustered brain atrophy patterns in the ADNI (Yang, 2021). We defined at‐risk CN and MCI subjects in the ADNI for each module if mbPRSs of the subject &gt; the third quantile. Age‐adjusted Cox proportional hazard models were applied for conversion status to AD with at‐risk subjects of the symptom‐associated modules comparing with all CN and MCI subjects as a reference group.ResultWe detected 12 preserved modules that showed significant associations for symptomatic AD (P‐value&lt;0.05). The mbPRSs of the yellow and the lightcyan modules were significantly associated with brain atrophy cluster 3 (P‐value: yellow‐mbPRS = 5.5e‐03; lightcyan‐mbPRS = 7.1e‐05). At the same time, Of the mbPRSs for the 12 symptom‐associated modules, the at‐risk subjects defined by the lightcyan‐mbPRS were also predicted to be earlier conversion from CN or MCI to AD (Hazard ratio = 1.63, P‐value = 3.8e‐02). Lightcyan‐mbPRS shows a good prediction of conversion to AD and also the association with MRI endophenotypes.ConclusionThis study demonstrates for the first time that PRSs informed by symptom‐associated protein networks may identify at‐risk CN and MCI subjects who will develop clinical symptoms and enable targeted prevention and treatment trials for AD for these at‐risk subjects in preclinical stages of AD.

The impact of increasing levels of blood C‐reactive protein on the loci for inflammatory, SPI1 and CD33, for Alzheimer’s disease

AbstractBackgroundPreviously, we found that elevated blood C‐reactive protein (CRP) increased the impact of the apolipoprotein ε4 allele (APOE ε4) on the risk of Alzheimer’s disease (AD).1 In this study, we hypothesized that interactions between CRP and other AD‐associated genes also increase AD risk.MethodSNPs in 10 AD risk loci, which also encode proteins related to inflammation, were used to test interaction with CRP on AD risk using additive model or dominant model with Cox proportional hazards regression and survival analysis.ResultThere were 279,176 UKBB white participants with average age (mean±SD) 60.1 ± 5.5 years including 53.9% females and 803 (0.3%) incident AD cases among 8.3 ± 0.9 years follow‐up on average. We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD associated genes (SPI1, CD33 and CLU). Using Cox proportional hazards model in stratified genotype analysis, the hazard ratios (HR) for the association between higher CRP level (≥ 10 vs &lt; 10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33‐2.84, p&lt;0.001) among SPI1 rs1057233‐AA genotype, 1.75 (95% CI: 1.20‐2.55, p = 0.004) for CD33 rs3865444‐CC genotype, and 1.76 (95% CI: 1.25‐2.48, p = 0.001) for CLU rs9331896‐CC+CT genotype, respectively. All models adjusted for age at baseline, sex, years of education, APOE ε4 and population principal components. In contrast, these associations were not observed in the other genotypes of these genes. Similar results for SPI1 and CD33 genotypes impacted by elevated CRP levels were observed for MCI to AD conversion and CSF AD biomarkers including t‐Tau and p‐Tau in the ADNI cohort (p&lt;0.01).ConclusionElevated blood CRP released in peripheral inflammation may be an important mediator in the association of genetic variants in SPI1, CD33 and CLU in addition to APOE ε4 for AD risk. Monitoring of CRP levels may be useful for more precise intervention and prevention of AD for these genotype carriers.1. Tao Q, Ang TFA, DeCarli C, et al. Association of Chronic Low‐grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers. JAMA Netw Open. Oct 5 2018;1(6):e183597. https://doi.org/10.1001/jamanetworkopen.2018.3597

Longitudinal lumbar puncture adherence in the Alzheimer’s Prevention Initiative Autosomal‐Dominant Alzheimer’s Disease Colombia Trial

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers have potentially important roles in Alzheimer’s disease (AD) treatment and prevention trials. The Alzheimer’s Prevention Initiative Autosomal‐Dominant AD (API ADAD) trial protocol (NCT01998841) includes optional CSF biomarker measurements at baseline, 24 months, and 60 months. We determined the adherence to lumbar puncture (LP) procedures and predictors of dropout rates in trial participants who had a baseline LP.MethodAvailable data from cognitively unimpaired 30–60‐year‐old members of the Presenilin 1 E280A kindred were used to characterize LP participation rates at baseline, LP‐related complications and potential factors associated with adherence to 24‐month follow‐up LPs (age, sex, education, place of residence, puncture site, needle gauge, number of attempts, and traumatic puncture). Logistic regression was used to investigate associations.Result130 (51.6%) of 252 trial individuals consented to participate in the CSF biomarkers substudy. Consent was not associated with age, sex, education or location of residence. 43 (33.1%) participants had 49 LP‐related complications at baseline. The most frequent complications were headache in 25 (19.2%) participants and low back pain in 14 (10,8%) participants. Other baseline LP‐related events were dizziness, photopsia, and tremor. Complications at baseline were not associated with puncture site (L3‐L4 or L4‐L5), needle gauge (22 or 24 G), number of attempts or traumatic puncture. Ninety‐eight (75.4%) of the eligible participants consented to have the 24‐month follow‐up LP. Absence of any baseline LP‐related complications was associated with less attrition in this subsequent LP consent (0R = 0.25; 95%CI 0.10‐0.61), after controlling for age, sex, years of schooling, rural home and city of residence.ConclusionAdherence to 24‐month follow‐up LP in API ADAD trial was 75.4%. This clinical trial is conducted in young people, active at work. Although some participants live far from the city where LP’s are performed or in remote areas, this did not affect their willingness to consent to a second LP. However, the presence of any complication did increase the risk of withdrawal for the subsequent procedure since it impacted ability to work. This information could help to inform the design and statistical power of future AD prevention trials using CSF biomarker endpoints.

How to Prevent and/or Revert Alzheimer's Disease Continuum During Preclinical Phases.

The development of Alzheimer's disease (AD) follows three consecutive phases: namely preclinical, prodromal or mild cognitive impairment (MCI), and dementia. In addition, the preclinical phase can be divided into subphases related to the presence of biomarkers that appear at different points before the onset of MCI. Indeed, an early risk factor could promote the appearance of additional ones through a continuum. The presence of various risk factors may trigger specific biomarkers. In this review, we comment on how modifiable risk factors for AD may be reverted, thus correlating with a possible decrease in the specific biomarkers for the disease. Finally, we discuss the development of a suitable AD prevention strategy by targeting modifiable risk factors, thereby increasing the level of "precision medicine" in healthcare systems worldwide.

Molecular mechanisms and therapeutic potential of icariin in the treatment of Alzheimer's disease

BackgroundIcariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. MethodsThe PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. ResultsThe study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aβ via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca2+, and PI3K/Akt signaling. ICA exhibits neuroprotective properties by inhibiting neuronal apoptosis through the suppression of ER stress in AD mice, potentially linked to NF-κB, MAPK, ERK, and PERK/Eif2α signaling pathways. Moreover, ICA may safeguard neurons by attenuating mitochondrial oxidative stress injury. ICA can also enhance learning, memory, and cognition by improving synaptic structure via regulation of the PSD-95 protein. Furthermore, ICA can mitigate neuroinflammation by inactivating microglial activity through the upregulation of PPARγ, TAK1/IKK/NF-κB, and JNK/p38 MAPK signaling pathways. ConclusionThis study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD.

Aβ Oligomer Toxicity-Reducing Therapy for the Prevention of Alzheimer’s Disease: Importance of the Nrf2 and PPARγ Pathways

Recent studies have revealed that soluble amyloid-β oligomers (AβOs) play a pathogenetic role in Alzheimer’s disease (AD). Indeed, AβOs induce neurotoxic and synaptotoxic effects and are also critically involved in neuroinflammation. Oxidative stress appears to be a crucial event underlying these pathological effects of AβOs. From a therapeutic standpoint, new drugs for AD designed to remove AβOs or inhibit the formation of AβOs are currently being developed. However, it is also worth considering strategies for preventing AβO toxicity itself. In particular, small molecules with AβO toxicity-reducing activity have potential as drug candidates. Among such small molecules, those that can enhance Nrf2 and/or PPARγ activity can effectively inhibit AβO toxicity. In this review, I summarize studies on the small molecules that counteract AβO toxicity and are capable of activating Nrf2 and/or PPARγ. I also discuss how these interrelated pathways are involved in the mechanisms by which these small molecules prevent AβO-induced neurotoxicity and neuroinflammation. I propose that AβO toxicity-reducing therapy, designated ATR-T, could be a beneficial, complementary strategy for the prevention and treatment of AD.

Pathophysiological Role of Microglial Activation Induced by Blood-Borne Proteins in Alzheimer's Disease.

The blood-brain barrier (BBB) restricts entry of neurotoxic plasma components, blood cells, and pathogens into the brain, leading to proper neuronal functioning. BBB impairment leads to blood-borne protein infiltration such as prothrombin, thrombin, prothrombin kringle-2, fibrinogen, fibrin, and other harmful substances. Thus, microglial activation and release of pro-inflammatory mediators commence, resulting in neuronal damage and leading to impaired cognition via neuroinflammatory responses, which are important features observed in the brain of Alzheimer's disease (AD) patients. Moreover, these blood-borne proteins cluster with the amyloid beta plaque in the brain, exacerbating microglial activation, neuroinflammation, tau phosphorylation, and oxidative stress. These mechanisms work in concert and reinforce each other, contributing to the typical pathological changes in AD in the brain. Therefore, the identification of blood-borne proteins and the mechanisms involved in microglial activation and neuroinflammatory damage can be a promising therapeutic strategy for AD prevention. In this article, we review the current knowledge regarding the mechanisms of microglial activation-mediated neuroinflammation caused by the influx of blood-borne proteins into the brain via BBB disruption. Subsequently, the mechanisms of drugs that inhibit blood-borne proteins, as a potential therapeutic approach for AD, along with the limitations and potential challenges of these approaches, are also summarized.