Prevention Of Alzheimer's Disease Research Articles

Metabolic-associated steatotic liver disease and risk of Alzheimer's disease: a real-world retrospective cohort study.

Alzheimer's Disease (AD) is increasingly recognized as being associated with metabolic disorders, including Metabolic Associated Steatotic Liver Disease (MASLD). This study aimed to assess the relative risk of AD in individuals with MASLD. In this retrospective cohort study, we analyzed data from individuals aged over 65 who underwent health check-ups between January 2018 and June 2023. MASLD was diagnosed based on ultrasound findings and cardiometabolic criteria. AD incidence was identified using ICD-10 codes and self-reports. Poisson regression models estimated the relative risk of AD in relation to MASLD, adjusting for age, BMI, sex, SBP, HbA1c, HDL-c, triglycerides, hs-CRP, GGT, and estimated GFR. The study included 4,582 MASLD patients and 6,318 controls. MASLD patients showed a higher incidence of AD (127 cases) compared to controls (61 cases). The fully adjusted Poisson regression model indicated an increased AD risk in MASLD patients [RR: 2.80 (95% CI: 1.79-4.38)]. Our findings suggested MASLD as an independent risk factor for AD, underlining the role of metabolic dysfunctions in AD pathogenesis. The study emphasized the need for comprehensive metabolic health management in AD prevention strategies, particularly among high-risk groups.

Mechanisms and Functions of the Cerebral-Cognitive Reserve in Patients with Alzheimer's Disease: A Narrative Review

BACKGROUND: The need for scientific knowledge about aging is predicated on the demand of modern society to extend the active life of a person. To maintain intellectual longevity, it is necessary to take into account not only the pathological, but also compensatory mechanisms that arise during aging. The cerebral-cognitive reserve (CCR) influences the rate of transition from pre-phenomenological stages to the clinical stage of the disease, thereby changing the prognosis of Alzheimer’s disease (AD). AIM: The aim of this work was to review meta-analyses from studies that have examined the principles and functions of the CCR in people with AD. METHODS: The work included 83 scientific publications devoted to the issues of the CCR in neurodegenerative diseases such as AD. The Results and Discussion sections of this article provide reviews of the results of 12 meta-analyses published from 2012 to 2024 and selected from the PubMed and eLibrary databases using the following keywords in English and Russian: “cerebral reserve”, “cognitive “reserve”, and “Alzheimer’s disease”. The scope of the definition was not limited, since the goal here was to determine the terminological boundaries of the concepts of “cognitive reserve” and “single brain reserve”. RESULTS: The modern understanding of AD as a biological continuum covering the preclinical, prodromal, and clinical phases of the disease makes it possible to infer that insufficiency of protective factors underlies the progression of AD. The cognitive reserve is involved in the sanogenetic protective mechanism during neurodegeneration. The cognitive reserve is a theoretical concept that reflects modern research’s understanding of how the integrative functioning of the brain (cerebral) and cognitive reserves extend the period of active intellectual longevity through energy-saving mechanisms. It considers these mechanisms as central to healthy mental activity and in slowing the progression of neurodegenerative diseases. At some point, an increase in excess interneuronal activity that reflects the hypercompensatory function of the reserve would accelerate the depletion of brain structures and contribute to clinical and psychopathological manifestations of AD. CONCLUSION: The concept of the CCR puts the spotlight on the need to determine the compensatory indicators of cognitive deficit in AD, assess the architecture and volume of the reserve, and develop and follow protocols for its maintenance. It appears just as crucial to adopt measures to prevent the Reserve’s depletion as early as at the preclinical stages of the disease. Elaborating protective and compensatory mechanisms that help to maintain the functional activity of the brain in conditions of neurodegeneration, that is, CCR, require further research and can form a conceptual basis for the prevention of AD, starting from the preclinical stages of the disease.

Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-β Toxicity in C.elegans via Distinct Mechanisms.

Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. We sought to identify probiotics that can delay Aβ-induced paralysis. Using C. elegans expressing human amyloid-β (Aβ)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.

Establishing network pharmacology between natural polyphenols and Alzheimer’s disease using bioinformatic tools – An advancement in Alzheimer’s research

Alzheimer’s disease (AD) is a major cause of disability and one of the top causes of mortality globally. AD remains a major public health challenge due to its prevalence, impact on patients and caregivers, and the current lack of a cure. In recent years, polyphenols have garnered attention for their potential therapeutic effects on AD. The objective of the study was to establish network pharmacology between selected polyphenols of plant origin and AD. Insilico tools such as SwissADME, ProTox3.0, pkCSM, Swiss Target Prediction, DisGeNET, InterActiVenn, DAVID database, STRING database, Cytoscape/CytoHubba were employed to establish the multi-target potential of the polyphenolic compounds. The present study revealed that out of 17 polyphenols, 10 ligands were found to possess a drug-likeness nature along with desirable pharmacokinetic parameters and a lesser toxicity profile. Also, the results highlighted the possible interactions between the polyphenols and the disease targets involved in AD. Further, this study has shed light on the mTOR pathway and its impact on AD through the autophagic mechanism. Overall, this study indicated that polyphenols could be a better therapeutic option for treating AD. Hence, the consumption of polyphenolic cocktails as a part of the diet could produce more effective outcomes against the disease. Additional studies are warranted in the future to explore additional pathways and genes to provide a comprehensive understanding regarding the usage of the shortlisted polyphenols and their derivatives for the prevention and treatment of AD.

Pros and Cons of APOE4 Homozygosity and Effects on Neuroplasticity, Malnutrition, and Infections in Early Life Adversity, Alzheimer's Disease, and Alzheimer's Prevention.

Fortea et al.'s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer's disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.

Autoimmune hypothesis of Alzheimer's disease: unanswered question.

Alzheimer's disease (AD) was described more than a century ago. However, there are still no effective approaches to its treatment, which may suggest that the search for the cure is not being conducted in the most productive direction. AD begins as selective impairments of declarative memory with no deficits in other cognitive functions. Therefore, understanding of the AD pathogenesis has to include the understanding of this selectivity. Currently, the main efforts aimed at prevention and treatment of AD are based on the dominating hypothesis for the AD pathogenesis: the amyloid hypothesis. But this hypothesis does not explain selective memory impairments since β-amyloid accumulates extracellularly and should be toxic to all types of cerebral neurons, not only to "memory engram neurons." To explain selective memory impairment, I propose the autoimmune hypothesis of AD, based on the analysis of risk factors for AD and molecular mechanisms of memory formation. Memory formation is associated with epigenetic modifications of chromatin in memory engram neurons and, therefore, might be accompanied by the expression of memory-specific proteins recognized by the adaptive immune system as "non-self" antigens. Normally, the brain is protected by the blood-brain barrier (BBB). All risk factors for AD provoke BBB disruptions, possibly leading to an autoimmune reaction against memory engram neurons. This reaction would make them selectively sensitive to tauopathy. If this hypothesis is confirmed, the strategies for AD prevention and treatment would be radically changed.

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial.

Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s. An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia. A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

Advances in Developing Small Molecule Drugs for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia among middle-aged and elderly individuals. Accelerating the prevention and treatment of AD has become an urgent problem. New technology including Computer-aided drug design (CADD) can effectively reduce the medication cost for patients with AD, reduce the cost of living, and improve the quality of life of patients, providing new ideas for treating AD. This paper reviews the pathogenesis of AD, the latest developments in CADD and other small-molecule docking technologies for drug discovery and development; the current research status of small-molecule compounds for AD at home and abroad from the perspective of drug action targets; and the development trend of new drug development for AD in the future.

Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer’s disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ. Ultimately, our findings are relevant for AD prevention and therapeutic strategies.

Lifestyle Empowerment for Alzheimer's Prevention Prescribed by Physicians: Methods and Adaptations to COVID-19.

The health care system is insufficiently capitalizing on the benefits of physical exercise in America's aging population. Few tools exist to help clinicians incorporate physical activity into their clinical care, while barriers limit older adults from initiating and maintaining exercise programs. The Lifestyle Empowerment for Alzheimer's Prevention (LEAP! Rx) Program has been designed to support providers and participants in lifestyle change. LEAP! Rx uses two forms of participant enrollment: physician referrals through electronic health records and self-referrals to test the efficacy of delivering a community-based exercise and healthy lifestyle program to older adults. After referral into the program, participants are randomized to receive the LEAP! Rx Program or are placed in a standard-of-care group to receive the program later. The LEAP! Rx program consists of a personalized and structured exercise program, lifestyle education, and mobile health monitoring. This includes a 12-week Empowerment phase with coaching and supervised exercise training, followed by a 40-week Lifestyle phase with intermittent supervised exercise and coaching. Lifestyle education includes monthly, evidence-based classes on optimal aging. The evaluation of LEAP! Rx focuses on 1) the assessment of implementation and scalability of the LEAP!Rx Program for clinicians and patients 2) the effect of the LEAP! Rx Program on cardiorespiratory fitness, 3) the impact of the LEAP! Rx Program on secondary intervention outcome measures of chronic disease risk factors, including insulin resistance, body composition, and lipids. If successful, this study's findings could advance future healthcare practices, providing a new and practical approach to aging and chronic disease prevention.

Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline. Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+. EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL. These findings indicate EXT may be more sensitive to Aβ's role in preclinical AD than level and improve targeting of individuals for AD prevention trials. Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aβ EXT improved detection of Aβ below traditional PET thresholds. Early regional Aβ deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aβ EXT than Aβ level. Neocortical tau onset aligned with reaching widespread neocortical Aβ.

Story recall performance and AT classification via positron emission tomography: A comparison of logical memory and Craft Story 21

BackgroundEarly detection of Alzheimer's disease (AD) is one of the critical components of the global response to the growing dementia crisis. Analysis of serial position performance in story recall tests has yielded sensitive metrics for the prediction of AD at low cost. In this study, we examined whether serial position markers in two story recall tests (the logical memory test, LMT, and the Craft Story 21 test, CST) were sensitive to cross-sectional biomarker-based assessment of in vivo neuropathology. MethodsParticipants were selected from the Wisconsin Registry of Alzheimer's Prevention (n = 288; WRAP) and the Alzheimer's Disease Research Center (n = 156; ADRC), both from the University of Wisconsin–Madison. Average age at PET was 68.9 (6.7) and 67.0 (8.0), respectively. Data included tau and PiB PET, and LMT for WRAP participants and CST for ADRC participants. Two sets of Bayesian analyses (logistic regressions and ANCOVAs) were conducted within each cohort, separately. ResultsResults indicated that the A+T+ classification was best predicted, cross-sectionally, by the recency ratio (Rr), indexing how much of the end of the story was forgotten between initial learning and delayed assessment. Rr outperformed traditional scores and discriminated between A+T+ and A+T−/A-T-, in both cohorts. ConclusionsOverall, this study confirms that serial position analysis of LMT and CST data, and particularly Rr as an index of recency loss, is a valuable tool for the identification of in vivo tau pathology in individuals free of dementia. Diagnostic considerations are discussed.

Evaluating Life Simple Seven's influence on brain health outcomes: The intersection of lifestyle and dementia.

Lifestyle factors have been studied for dementia risk, but few have comprehensively assessed both Alzheimer's disease (AD) and cerebrovascular disease (CBVD) pathologies. Our research aims to determine the relationships between lifestyle and various dementia pathologies, challenging conventional research paradigms. Analyzing 1231 Wisconsin Registry for Alzheimer's Prevention (WRAP) study participants, we focused on Life Simple Seven (LS7) score calculations from questionnaire data and clinical vitals. We assessed brain health indicators including CBVD, AD, and cognition. Higher LS7 scores were associated with better CBVD outcomes, including lower percent white matter hyperintensities and higher cerebral blood flow, and higher Preclinical Alzheimer's Composite 3 and Delayed Recall scores. No significant associations were observed between LS7 scores and AD markers of amyloid and tau accumulation. This study provides evidence that the beneficial effects of LS7 on cognition are primarily mediated through cerebrovascular pathways rather than direct influences on AD pathology.

Blue paper on Alzheimer's disease in China(simplified version)

With the population aging in China, the prevalence and mortality rate of Alzheimer's disease (AD) have been rising in China. AD has become one of the major threats to people's health and social sustainable development. In order to support the Healthy China Initiative and promote health in China, "Chinese Alzheimer's Disease Blue Book (Simplified Edition)"(refer to as the Blue Book) was compiled by experts and scholars from the National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University; the National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention; the National Health Commission Capacity Building and Continuing Education Center; and the China Population and Development Research Center. The epidemiological characteristics, diagnosis and treatment status, prevention and treatment management of AD and related cognitive disorders in China were systematically reviewed in the Blue Paper, aiming to provide references for the prevention of AD, provide support for the standardized diagnosis and treatment of the disease, and provide a reference for the government to formulate relevant health policies. Specifically, the Blue Book covers the following topics of AD and related cognitive disorders: (1)epidemiology characteristics; (2)economic burden; (3)influencing factors; (4)China Brain Cognitive Health Index; (5) diagnosis status; (6)treatment status; (7)construction of national center for cognitive disorders;(8)community-based prevention and control; (9) AD patients care; (10)public health resources for prevention and control.

Naringenin ameliorates amyloid-β pathology and neuroinflammation in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and neuroinflammation. Naringenin (NRG), a natural flavonoid widely present in citrus fruits, has been reported can penetrate the blood-brain barrier and exert anti-inflammatory effects in the central nervous system. Here, we investigate the protective effects of long-term NRG treatment on AD. The novel object recognition test and Morris water maze test reveal that NRG treatment can improve the learning and memory ability of APP/PS1 mice. Besides, we find that NRG can significantly reduce Aβ deposition, microglial and astrocytic activation, and pro-inflammatory cytokine levels in APP/PS1 mice. Results further show that NRG effectively decreases pro-inflammatory cytokines in LPS/Aβ-stimulated BV2 cells. Lastly, the molecular mechanistic study reveals that NRG attenuates neuroinflammatory responses via inhibition of the MAPK signaling pathway in vivo and in vitro. Overall, NRG may emerge as a promising compound for the prevention and treatment of AD.

Protective signature of xanthohumol on cognitive function of APP/PS1 mice: a urine metabolomics approach by age.

Alzheimer's disease (AD) has an increasing prevalence, complicated pathogenesis and no effective cure. Emerging evidences show that flavonoid compounds such as xanthohumol (Xn) could play an important role as a dietary supplement or traditional Chinese herbal medicine in the management of diseases such as AD. This study aims to analyze the target molecules of Xn in the prevention and treatment of AD, and its potential mechanism from the perspective of metabolites. APP/PS1 mice 2- and 6-months old were treated with Xn for 3months, respectively, the younger animals to test for AD-like brain disease prevention and the older animals to address therapeutic effects on the disease. Memantine (Mem) was selected as positive control. Behavioral tests were performed to assess the course of cognitive function. Urine samples were collected and analyzed by high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) coupled with online Compound Discoverer software. Morris Water Maze (MWM) tests showed that Xn, like Mem, had a therapeutic but not a preventive effect on cognitive impairment. The expression levels of urinary metabolites appeared to show an opposite trend at different stages of Xn treatment, downregulated in the prevention phase while upregulated in the therapy phase. In addition, the metabolic mechanisms of Xn during preventive treatment were also different from that during therapeutic treatment. The signaling pathways metabolites nordiazepam and genistein were specifically regulated by Xn but not by Mem in the disease prevention stage. The signaling pathway metabolite ascorbic acid was specifically regulated by Xn in the therapeutic stage. In conclusion, dietary treatment with Xn altered the urinary metabolite profile at different stages of administration in APP/PS1 mice. The identified potential endogenous metabolic biomarkers and signal pathways open new avenues to investigate the pathogenesis and treatment of AD.

Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study

BackgroundClinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.ObjectivesWe sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) secondary prevention study.DesignAll participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment/problem solving) and function (community affairs and home/hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.SettingThe A4 study took place at 67 sites in Australia, Canada, Japan and the United States.Participants1,147 individuals, ages 65–85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.MeasurementsGeneralized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.ResultsThere were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.ConclusionsThe findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.

CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease.

We examined whether baseline glial markers soluble triggering receptor expressed on myeloid cell 2 (sTREM2), chitinase 3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF), and plasma GFAP are associated with cognitive change in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD). A total of 353 CU (mean age 60.9 years) participants were included (mean follow-up time 3.28 years). Linear regression models with cognition as outcome were used. We also tested whether amyloid beta (Aβ) status modified these associations. Higher baseline CSF sTREM2 was associated with a positive global cognition (Preclinical Alzheimer's Cognitive Composite) rate of change, and better memory and executive outcomes, independently of AD pathology. Higher baseline plasma GFAP was associated with a decline on attention rate of change. Stratified analyses by Aβ status showed that CSF sTREM2 and YKL-40 were positively associated with executive functioning in amyloid negative (Aβ-) individuals. Our results suggest that a TREM2-mediated microglial response may be associated with better longitudinal cognitive performance. Higher cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cell 2 (sTREM2) relates to better longitudinal cognitive performance. The association between CSF sTREM2 and cognition is independent of Alzheimer's disease (AD) pathology. Targeting microglial reactivity may be a therapeutic strategyfor AD prevention.

Zinc(II) Induced Alzheimer’s Disease Prevention and Progression With Early, Middle and Lately Stages

Zinc(Ⅱ) induced Alzheimer’s Disease (AD) prevention and suppressive progression with early, middle, and lately stages are elucidated, and subsequently zinc binding molecular mechanism on each Aβ peptide and Tau protein in progressing stages is clarified. Zinc homeostasis regulates MCI and AD prevention, in which ZnCl2 could prevent AD pathology by that zinc can reduce β-Amyloid (Aβ) and Tau proteins. Zinc transporters may allow the novel therapies that ZnT-6 functions to a likely site of Aβ generation. At AD progression with early stage, zinc-induced aggregation of Aβ peptides and tau hyperphosphorylation on amyloid and tau aggregation consider the involvement of environmental zinc in Aβ and tau pathology. Zinc can suppress spreading of the Aβ peptide and the Tau protein that elemental zinc 150 mg daily is showed to be evident for an improvement of memory, understanding, communication, and social contact in AD. Zinc induced middle stage AD progression is pathologically characterized by the deposition of Aβ plaques and hyperphosphorylated Tau Proteins (p-tau). Zinc Finger Proteins (ZNFs) regulate the accumulation of tau proteins to affect the Neurofibrillary Tangles (NFTs), resulting in the formation of NFTs, and can inhibit protein phosphatase, promoted abnormal phosphorylation of tau protein. Zinc(Ⅱ) can prevent heavy stage AD with pathological deposits of Senile Plaques (SPs) and NFTs that the tau-zinc interaction will help understanding the zinc-related tau regulation or aggregation processes in both physiological and pathological conditions. Zinc accelerates the fibrillization of human Tau and thereby increases Tau toxicity in neuronal cells with zinc exacerbated tauopathic deficits. Zinc induced toxic Reactive Oxygen Species (ROS) generation and hyperphosphorylated tau cause oxidative stress and neurotoxicity, leading to hyperphosphorylated tau damages. Zinc(Ⅱ) binding AD molecular mechanism on Aβ and Tau proteins is that Zn2+ ions which having Zn2+ ions-centered tetrahedral geometric coordination pattern and Zn-CysHis Ligands complexes with tetrahedral geometry formed, bind with Aβ and Tau proteins in each three AD progressing stages, causing Zn2+ ions-each stages protein complex formations and oxidative stress to Aβ and Tau protein cells, leading the Zn-CysHis Ligands complexes to molecular and apoptosis activities of synaptic cells.

Herbal medicines in Alzheimer's disease and the involvement of gut microbiota.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. It severely affects the quality of life of victims. The prevalence of AD has been increasing in recent years. Therefore, it is of great importance to elucidate the pathogenic mechanism of AD and search for effective therapeutic approaches. Gut microbiota dysbiosis, an altered state of gut microbiota, has been well known for its involvement in the pathogenesis of AD. Much effort has been made in searching for approaches capable of modulating the composition of gut microbiota in recent years. Herbal medicines have attracted extensive attention in recent decades for the prevention and treatment of AD. Here, we gave an overview of the recent research progress on the modulatory effects of herbal medicines and herbal formulae on gut microbiota as well as the possible beneficial effects on AD, which may provide new insights into the discovery of anti-AD agents and their therapeutic potential for AD through modulating the composition of gut microbiota.