Alzheimer's Disease Symptoms Research Articles

Enhanced detection of mild cognitive impairment in Alzheimer’s disease: a hybrid model integrating dual biomarkers and advanced machine learning

Alzheimer's disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder marked by cognitive decline and memory loss. Early diagnosis is the most effective strategy to slow the disease's progression. Mild Cognitive Impairment (MCI) is frequently viewed as a crucial stage before the onset of AD, making it the ideal period for therapeutic intervention. AD is marked by the buildup of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs), which are believed to cause neuronal loss and cognitive decline. Both Aβ plaques and NFTs accumulate for many years before the clinical symptoms become apparent in AD. As a result, in this study, CerebroSpinal Fluid (CSF) biomarker information is combined with hippocampal volumes to differentiate between MCI and AD. For this, a novel two-stage hybrid learning model that leverages 3D CNN and the notion of a Fuzzy and Machine learning model is proposed. A 3D-CNN architecture is employed to segment the hippocampus from the structural brain 3D-MR images and quantify the hippocampus volume. In stage 1, the hippocampus volume is passed through thirteen machine learning models and fuzzy clustering for classifying symptomatic AD and healthy brain (Normal Control - NC). The CSF data is fuzzified to capture the inherent uncertainty and overlap in clinical data. The identified symptomatic AD data in the stage1 are further classified into MCI and AD with the aid of a fuzzified CSF biomarker in stage 2. The experimental work presented in this study utilized the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The proposed hybrid model achieved an average accuracy of 93.6% for distinguishing between NC and symptomatic AD and 93.7% for discriminating between MCI and AD. This approach enhances diagnostic accuracy and provides a more comprehensive assessment, allowing for earlier and more targeted therapeutic interventions.

Plasma N-terminal tau fragment is an amyloid-dependent biomarker in Alzheimer's disease.

Novel fluid biomarkers for tracking neurodegeneration specific to Alzheimer's disease (AD) are greatly needed. Using two independent well-characterized cohorts (n=881 in total), we investigated the group differences in plasma N-terminal tau (NT1-tau) fragments across different AD stages and their association with cross-sectional and longitudinal amyloid beta (Aβ) plaques, tau tangles, brain atrophy, and cognitive decline. Plasma NT1-tau significantly increased in symptomatic AD and displayed positive associations with Aβ PET (positron emission tomography) and tau PET. Higher baseline NT1-tau levels predicted greater tau PET, with 2- to 10-year intervals and faster longitudinal Aβ PET increases, AD-typical neurodegeneration, and cognitive decline. Plasma NT1-tau showed negative correlations with baseline regional brain volume and thickness, superior to plasma brain-derived tau (BD-tau) and neurofilament light (NfL) in Aβ-positive participants. This study suggests that plasma NT1-tau is an Aβ-dependent biomarker and outperforms BD-tau and NfL in detecting cross-sectional neurodegeneration in the AD continuum. Plasma N-terminal tau (NT1-tau) was specifically increased in the A+/T+ stage. Plasma NT1-tau was positively associated with greater amyloid beta (Aβ) and tau PET (positron emission tomography) accumulations. Higher plasma NT1-tau predicted greater tau burden and faster Aβ increases. Plasma NT1-tau was more related to neurodegeneration than plasma brain-derived tau (BD-tau) and neurofilament light (NfL).

Rapid screening of acetylcholinesterase inhibitors in Qi-Fu-Yin using magnetic metal-organic frameworks immobilized with acetylcholinesterase.

Current immobilization approaches for ligand fishing often experience challenges such as limited protein loading capacity and difficulties in the recycling process. To overcome these challenges, we synthesized a magnetic metal-organic frameworks (MMOFs) composite, which can be rapidly separated and has a large specific surface area, and employed it to immobilize acetylcholinesterase (AChE). The synthesized MMOFs@AChE composite exhibited a high immobilization yield (129.7mg/g) and excellent relative activity recovery (88.1%). Furthermore, immobilized AChE can improve its resistance to alkaline environments and high temperatures. After being stored at 4°C for a month, the immobilized enzyme maintained 91.4% of its original activity, significantly higher than the free enzyme (77.6%). Furthermore, it preserved more than 80% of its initial activity after five cycles and 68.7% after eight cycles. The composite MMOFs@AChE was then incubated with Qi-Fu-Yin extract to fish for ligands binding to AChE. Notably, Qi-Fu-Yin can alleviate Alzheimer's disease (AD) symptoms by modulating the AChE pathway, while active compounds remain unclear. Sixteen potential AChE inhibitors were identified through UHPLC-Q-Exactive-Orbitrap-MS/MS. The results of ligand fishing were validated through molecular docking studies, molecular dynamics simulation, surface plasmon resonance and AChE inhibitory activity assays. The screened compounds may exert inhibitory effects on AChE by altering the spatial configuration of the catalytic site or by influencing the binding of the substrate to the catalytic site, catalytic anionic site and peripheral anionic site regions. The MMOFs@AChE-based ligand fishing platform offers an efficient, effective, and convenient approach for enzymatic inhibitors discovery from natural products.

Anti-amyloid therapy and cerebral blood flow changes on Magnetic Resonance Imaging: a potential longitudinal biomarker of treatment response?

Amyloid-targeting therapy has recently become widely available in the U.S. for the treatment of patients with symptomatic mild Alzheimer's disease (AD). At present, there are no biomarkers that have been clinical validated to assess treatment response in routine clinical practice; longitudinal amyloid PET could play a role but is not cost effective. This report presents a case series of six patients with AD, whose amyloid positivity was confirmed by PET or CSF biomarkers, who underwent baseline and longitudinal arterial spin-labeling magnetic resonance imaging (ASL-MR) as part of FDA-mandated, clinical standard-of-care, non-contrast MR monitoring to assess for amyloid-related imaging abnormalities (ARIA). We and others have previously reported that ASL-MR can screen for neurodegenerative disease, as a proxy for FDG-PET, and can be easily added on as a cost-effective, repeatable method to monitor post-therapy changes. This series highlights varied cerebral blood flow (CBF) changes in response to lecanemab therapy. For instance, Cases 1, 3, and 5 showed increased CBF after multiple infusions, with subjective cognitive improvement in Case 1 and improved MoCA scores in Case 3. Case 2 showed improved CBF initially before the 5th infusion, but this returned to baseline on the subsequent study, with no cognitive improvement over the course of therapy. Cases 4 and 6 have demonstrated no significant changes in regional CBF thus far on therapy, with cognitive decline in Case 4. This case series underscores the potential utility of ASL-MR as an adjunct sequence to current imaging protocols to monitor treatment response to anti-amyloid therapy.ABBREVIATIONS: ASL-MR= arterial spin-labeling magnetic resonance imaging; MRI= magnetic resonance imaging; CBF= cerebral blood flow; AD= Alzheimer's disease; PET= positron emission tomography; CSF= cerebrospinal fluid; FDG= fluorodeoxyglucose.

Design, Synthesis, Biological Evaluation and Docking Studies of 2-hydroxy-4-benzyloxy Chalcone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, but no drugs can cure this disease. Chalcones possess good antioxidant activity, anti-neuroinflammatory activity, neuroprotective effects, inhibitory effects on Aβ aggregation, and Aβ disaggregation ability. Therefore, chalcones are ideal lead compounds, and the discovery of novel anti-AD agent-based chalcones is necessary. Hydroxy groups and aryl benzyl ether groups were introduced into chalcone scaffolds to obtain a series of 2-hydroxyl-4-benzyloxy chalcone derivatives. These derivatives were further synthesized, biologically evaluated, and docked. Most target derivatives exhibited good anti-AD activities. In particular, compound 11d had excellent inhibitory effects on self-induced Aβ1-42 aggregation (90.8% inhibition rate at 25 μM) and Cu2+ induced Aβ1-42 aggregation (93.4% inhibition rate at 25 μM). In addition, it also exhibited good Aβ1-42 fibril disaggregation ability (64.7% at 25 μM), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 μM), selective metal chelation, appropriate BBB permeation, and dramatic anti-neuroinflammatory ability. In addition, compound 11d relieved AD symptoms and protected hippocampal neurons in vivo. Compound 11d is a promising multifunctional anti-Aβ agent.

OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.

Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/ PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.

INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.

Soluble species of multimeric amyloid-beta including globular amyloid-beta oligomers (AβOs) and linear amyloid-beta protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against globular species of soluble AβO, that has over 650-fold greater binding affinity for AβOs over monomers and appears to have relatively little binding to amyloid plaque. To assess safety, pharmacokinetics, and exploratory measures including target engagement, biomarker effects, and clinical efficacy of sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment and mild dementia due to AD). Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study. Fifteen study centers in the United States. Sixty-five participants with early symptomatic AD. Participants received one infusion of sabirnetug 2 mg/kg, 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part A) or three infusions of sabirnetug 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part B). Safety, tolerability, serum pharmacokinetics, and central target engagement of single and multiple doses of sabirnetug, cerebrospinal fluid (CSF) concentrations of sabirnetug, and amyloid plaque load, as determined by positron emission tomography. Sabirnetug was generally well tolerated. A larger percentage of participants receiving sabirnetug (56.3%) versus placebo (42.9%) had at least one treatment emergent adverse event, with approximately 29% in each group considered related to study drug. Most events were mild-to-moderate in severity. Of 48 participants given sabirnetug, five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg. Notably, none of the six apolipoprotein E Ɛ4 homozygotes who received sabirnetug developed amyloid related imaging abnormalities - edema/effusion or - hemorrhage/hemosiderin deposition. Infusion reactions, such as rash, pain, or erythema, were not frequent (6.3% for sabirnetug versus 0.0% for placebo). Sabirnetug exposure was dose proportional in both serum and CSF. Target engagement, defined as drug bound to AβOs in CSF, was shown to be dose and exposure dependent. Over three months, approximately 25% and 20% reduction in amyloid plaques, respectively, were observed in participants receiving three infusions of sabirnetug 60 mg/kg every four weeks and 25 mg/kg every two weeks. The Phase 1 INTERCEPT-AD study provided safety, tolerability, dosing, and target engagement data that supported the design of the ongoing ALTITUDE-AD study (NCT06335173).

Disease-modifying therapies for Alzheimer's disease: Clinical trial progress and opportunity.

The U.S. Food and Drug Administration (FDA) recently approved lecanemab and donanemab for the treatment of early symptomatic Alzheimer's disease (AD) after their phase III trials reached endpoints. These two anti-amyloid β monoclonal antibodies represent the latest promise of disease-modifying therapy (DMT) for AD, which undoubtedly reignites new hope for DMTs to combat the staggering financial and human costs of AD. However, in addition to these two successful antibodies, there have been enormous efforts to develop DMTs in various aspects to meet the therapeutic requirement of AD. In this review, we delineate the core principles and methodologies of diverse DMTs, covering the advances in clinical trials of drug candidates that either have been discontinued, completed, or are ongoing, as well as brain stimulation and lifestyle interventions. In addition, by overseeing the fate of various candidate molecules, we hope to provide references and ideas for prospective approaches and promising applications of DTMs for AD, particularly in terms of universality and clinical application economics, to optimize efficacy and maximize AD patient benefits in the future.

3 + 2] Cycloaddition Synthesis of New (Chromene‐1,3,4‐Oxadiazole) Hybrids Linked to Pyrazole Units as Potential Acetylcholinesterase Inhibitors

AbstractA lot of interest has been gained recently in developing novel acetylcholinesterase (AChE) inhibitors that can alleviate Alzheimer's symptoms. In the current study, we aimed to explore AChE inhibitory activity of new chromenes attached to 1,3,4‐oxadiazole and/or pyrazole units. The new hybrids were obtained via [3 + 2] cycloaddition reaction between the appropriate chromene‐based enaminones and hydrazonyl chlorides. The inhibition percentages of the new products against AChE were recorded at tested concentrations of 15 and 25 µM compared to donepezil. 3‐(3‐Acetyl‐1‐(4‐methoxyphenyl)‐1H‐pyrazole‐4‐carbonyl)‐6‐(((5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)thio)methyl)‐2H‐chromen‐2‐one displayed promising activity with inhibition percentages of 73.2 and 87.3, respectively, at the aforementioned concentrations. Moreover, the previous hybrid gave promising 2,2‐diphenylpicrylhydrazyl (DPPH) inhibitory activity using the reference ascorbic acid. It had an inhibition percentage of 86.6 at a tested concentration of 25 µM.

ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease.

PSEN1 E280A carrier for the APOE3 Christchurch variant (R136S) is protected against Alzheimer's disease (AD) symptoms with a distinct anatomical pattern of Tau pathology. However, the molecular mechanism accounting for this protective effect remains incompletely understood. Here, we show that the ApoE3 R136S mutant strongly binds to Tau and reduces its uptake into neurons and microglia compared with ApoE3 wild type (WT), diminishing Tau fragmentation by asparagine endopeptidase (AEP), proinflammatory cytokines by Tau pre-formed fibrils (PFFs) or β-amyloid (Aβ), and neurotoxicity. Further, ApoE3 R136S demonstrates more robust effects in attenuating AEP activation and Tau PFF spreading in the brains of both 5xFAD and Tau P301S mice than in ApoE3 WT, leading to improved cognitive functions. Thus, our findings support the idea that ApoE3 R136S strongly binds Tau and decreases its cellular uptake, abrogating Tau pathology propagation in AD brains.

Sleep-wake modulation and pathogenesis of Alzheimer disease: Suggestions for postponement and treatment.

Sleep-wake disorders are recognized as one of the earliest symptoms of Alzheimer disease (AD). Accumulating evidence has highlighted a significant association between sleep-wake disorders and AD pathogenesis, suggesting that sleep-wake modulation could be a promising approach for postponing AD onset. The suprachiasmatic nucleus (SCN) and the pineal hormone melatonin are major central modulating components of the circadian rhythm system. Cerebrospinal fluid (CSF) melatonin levels are dramatically decreased in AD. Interestingly, the number of neurofibrillary tangles in the hippocampus, which is one of the two major neuropathologic AD biomarkers, increases in parallel with the decrease in CSF melatonin levels. Furthermore, a decrease in salivary melatonin levels in middle-aged persons is a significant risk factor for the onset of the early stages of AD. Moreover, the disappearance of rhythmic fluctuations in melatonin may be one of the best biomarkers for AD diagnosis. Light therapy combined with melatonin supplementation is the recommended first-line treatment for sleep-wake disorders in AD patients and may be beneficial for ameliorating cognitive impairment. Sleep-wake cycle modulation based on AD risk gene presence is a promising early intervention for AD onset postponement.

Artificial intelligence-enabled safety monitoring in Alzheimer's disease clinical trials.

Investigators conducting clinical trials have an ethical, scientific, and regulatory obligation to protect the safety of trial participants. Traditionally, safety monitoring includes manual review and coding of adverse event data by expert clinicians. Our study explores the use of natural language processing (NLP) and artificial intelligence (AI) methods to streamline and standardize clinician coding of adverse event data in Alzheimer's disease (AD) clinical trials. Our quantitative retrospective study aimed to develop a gold standard AD adverse event data set, evaluate the predictive performance of NLP-based models to classify adverse events, and determine whether automated coding is more efficient, accurate, reliable, and consistent than clinician coding. Our study was conducted at the University of Southern California's Alzheimer's Therapeutic Research Institute (ATRI). ATRI serves as the clinical and data coordinating center for the Alzheimer's Clinical Trial Consortium (ACTC). We collected demographic and adverse event data from eight completed clinical trials in participants (n=1920) with symptomatic AD conducted between 2005 and 2020. Original expert clinician-confirmed codes were used for all model performance comparisons. F1 score was used as the primary model selection metric. Final classifier performance was evaluated using predictive accuracy. Clinician effort was measured in time to code, review, and confirm coded adverse events. In a sample of 1000 adverse events, AI-based AE coding achieved higher accuracy (∼20% increase in accuracy) and was more cost-effective (∼80% cost reduction) than traditional clinician coding. Our study results demonstrate how approaches that effectively combine AI and human expertise can improve the efficiency and quality of adverse event coding and clinical trial safety monitoring.

Beta-Site APP-Cleaving Enzyme-1 Inhibitory Role of Natural Flavonoids in the Treatment of Alzheimer's Disease.

Alzheimer's Disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive function, including memory loss, reasoning difficulties, and disorientation. Its hallmark features include the formation of neurofibrillary tangles and neuritic plaques in the brain, disrupting normal neuronal function. Neurofibrillary tangles, composed of phosphorylated tau protein and neuritic plaques, containing amyloid-β protein (Aβ) aggregates, contribute to the degenerative process. The discovery of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in 1999 revolutionized our understanding of AD pathogenesis. BACE1 plays a crucial role in the production of Aβ, the toxic protein implicated in AD progression. Elevated levels of BACE1 have been observed in AD brains and bodily fluids, underscoring its significance in disease onset and progression. Despite setbacks in clinical trials of BACE1 inhibitors due to efficacy and safety concerns, targeting BACE1 remains a promising therapeutic strategy for early-stage AD. Natural flavonoids have emerged as potential BACE1 inhibitors, demonstrating the ability to reduce Aβ production in neuronal cells and inhibit BACE1 activity. In our review, we delve into the pathophysiology of AD, highlighting the central role of BACE1 in Aβ production and disease progression. We explore the therapeutic potential of BACE1 inhibitors, including natural flavonoids, in controlling AD symptoms. Additionally, we provide insights into ongoing clinical trials and available patents in this field, shedding light on future directions for AD treatment research.

Domain-specific cognitive impairment is differentially affected by Alzheimer disease tau pathologic burden and spread

Abstract Tau pathology in Alzheimer disease (AD) is often evaluated in regions associated with episodic memory impairment. However, heterogeneous spreading patterns of tau are observed and correspond to impairment in different cognitive domains. We have previously developed a metric to quantify tau spread extent that is robustly sensitive to atypical spreading patterns. Here, we evaluate tau spread relative to domain-specific and general cognitive impairments during early stages of AD. In total, 529 participants with baseline tau positron emission tomography (PET) and neuropsychological testing were separated into disease-stage groups based on amyloid PET positivity and clinical status via Clinical Dementia Rating® (CDR®). General cognition was assessed using the Knight Preclinical Alzheimer Cognitive Composite (Knight PACC). Domain-specific composites were calculated for episodic memory, semantic memory, working memory, and attention/processing speed. Baseline tau burden, the average tau intensity across previously defined AD signature regions, and baseline tau spread extent, the proportion of the brain with elevated tau pathology, were quantified for each participant as Tau Index and Tau Spatial Spread, respectively. Tau burden and tau spread were evaluated relative to baseline and longitudinal cognitive performance, as well as longitudinal clinical progression. Tau burden and tau spread extent both significantly correlate with cognitive impairment in symptomatic AD. Tau burden is most strongly correlated with episodic (r = -0.37, p = 0.02) and semantic (r = -0.36, p = 0.02) memory. In contrast, tau spread extent is most strongly correlated with the Knight PACC (r = -0.37, p = 0.01) and attention/processing speed (r = -0.44, p < 0.01), especially in preclinical AD (r = -0.27, p < 0.01). Tau burden captures more variance than tau spread extent in longitudinal change in the Knight PACC, episodic memory, semantic memory, attention/processing speed, and clinical progression. Tau burden strongly relates to baseline episodic and semantic memory, which may reflect that it is heavily weighted by entorhinal tau, a region previously linked to memory processing. In contrast, stronger associations between tau spread extent and baseline attention/processing speed could reflect the inclusion of additional brain regions, particularly the frontal lobe, which support a wider range of cognitive processing. Additionally, tau spread extent is generally more sensitive to baseline preclinical deficits; however, tau burden better estimates future decline across all cognitive domains and clinical symptom onset. Together, these findings suggest complementary utility of evaluating both tau burden and tau spread extent in early AD progression.

Alzheimer’s Disease: A Comprehensive Overview

The primary factor contributing to dementia, which is defined by a decrease in one's capacity for independent thought and action and everyday actions, is Alzheimer's disease (AD), a syndrome that sources the degradation of mind lockups. The two primary theories proposed as the etiology of AD, a complex sickness, remain the cholinergic and amyloid hypotheses. The disease is influenced by many risk factors, such as aging, inheritances, head trauma, vascular matters, impurities, and ecological variables. Cholinesterase enzyme inhibitors and N-methyl d-aspartate (NMDA) opponents are the only dual forms of approved treatments available to indulge AD at this time. Only AD symptoms can be effectively treated with these drugs. They neither stop nor cure the condition. Over 20 danger features aimed at the Alzheimer's virus were identified in the primary assessments. These included stage, disturbing mind damage, exposure near aluminum, familial inheritance, and related comorbidities such as infection and then vascular illness. This review reexamines these risk variables in light of new data, highlights those that are currently thought to be significant, and explores a number of theories to explain how they might contribute to AD. Both presenilin (PSEN1/2) and amyloid precursor protein (APP) gene mutations are the causative genetic factor changes that stay closely related to rare forms of familial AD with an early onset (EO-FAD). Sporadic AD with late onset (LO-SAD), on the other hand, is a complex condition where age-linked alterations, risk factors related to genetics, including allelomorphic differences in the immune system, infection, metal exposure, vascular disease, traumatic brain damage, apolipoprotein E (Apo E), then various extra DNA segments, and dietary danger features are all concerned.

The Effect of Zeolite Zinc on Memory Performance and Hippocampal Cell Death in a Rat Model of Alzheimer's-like Disease Induced by Aβ1-42.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the slow and progressive loss of brain structure and function, primarily affecting older individuals. Evidence has shown that disruption of zinc homeostasis in the brain contributes to synaptic dysfunction, as well as impairments in learning and memory. In this study, we evaluated the effect of zeolite zinc on memory performance and hippocampal cell death in a rat model of Alzheimer's disease (AD) induced by intracerebroventricular administration of Aβ1-42. We employed the Morris water maze, shuttle box, and open field tests to assess spatial memory, passive avoidance memory, and anxiety-like behavior, respectively. P-Tau and the amyloid precursor protein (APP) expression, along with hippocampal cell death, were also evaluated. Both Aβ1-42 and zeolite zinc were injected intracerebroventricularly. The results showed that zeolite zinc partially reversed Aβ1-42-induced impairments in memory performance and mitigated the effects of Aβ1-42 on locomotor activity, although it did not fully restore baseline levels. In addition, Aβ1-42 increased the expression of APP and P-Tau, as well as the number of dead cells, whereas zeolite zinc reduced these effects. In conclusion, our findings suggest that while zeolite zinc plays a role in modulating the pathophysiology of AD, its therapeutic effects only partially reverse the progression or symptoms of AD, indicating the need for further investigation into optimal dosing or combination therapies.

Health System Readiness for Disease-Modifying Therapies for Alzheimer Disease

What Is the Issue? Alzheimer disease (AD) is a chronic neurological degenerative disease and one of the most common causes of dementia. It affected an estimated 368,200 people in Canada in 2020. Mild cognitive impairment (MCI) is a clinical condition involving memory loss that can progress to dementia and is often due to underlying AD. It was estimated to affect around 917,000 people in Canada aged 60 and older in 2020. Disease-modifying therapies (DMTs) are being developed that target underlying pathologic processes of AD to slow disease progression, unlike contemporary treatments that focus on managing symptoms. A prominent target of these therapies is amyloid-beta, a protein known to contribute to amyloid plaques. Many of the anti–amyloid-beta DMTs are intended for people with early-stage AD, which includes MCI and mild dementia due to AD. At least 7 countries have approved a therapy from this treatment class, and, at the time of writing, 2 therapies are undergoing regulatory review by Health Canada and reimbursement review by Canada's Drug Agency (CDA-AMC). DMTs demand more frequent health care visits and higher use of medical imaging for safe treatment and monitoring. This would greatly impact current care pathways for early-stage AD, necessitating an examination of health system readiness in Canada. What Did CDA-AMC Do? CDA-AMC sought to examine health system readiness in Canada and care pathways for early-stage patients with AD in preparation for the potential use of these anti–amyloid-beta DMTs in Canada. CDA-AMC reviewed publicly available data and literature about health systems and AD treatment pathways for improving dementia care to prepare for the possible introduction of DMTs in health systems in Canada. What Did CDA-AMC Find? CDA-AMC found that, if DMTs were approved by Health Canada and provincial and territorial drug plans, a new model of care for AD in Canada would be necessary. The new care pathway would require: earlier screening and diagnosis, at the MCI or mild dementia stages of AD guidance for optimal use of diagnostic imaging and biomarker-based tests, as well as an increase in equitable access to PET-CT units for amyloid PET exams or cerebrospinal fluid (CSF) testing to assess treatment eligibility increased capacity to administer IV infusions guidance for optimal use of MRI to avoid overuse and increase equitable access to MRI to monitor individuals through treatment a combination of reliable and validated methods and tools for evaluating cognitive decline in diverse populations, including Indigenous Peoples and racialized groups, presenting with cognitive symptoms or undergoing treatment clear criteria for discontinuing treatment. CDA-AMC found that assessment and diagnosis of early-stage AD and timely access to DMTs could be delayed due to: a lack of education and awareness of symptoms of early-stage AD among the general public and care providers, as well as cultural barriers, including a fear of stigma or cultural perceptions of the condition staffing shortages in care providers capable of assessing and treating dementia and other supporting staff, including primary care providers (PCPs), dementia specialists, nurses, imaging staff, and social care providers limited capacity of medical imaging (e.g., PET-CT and MRI) and laboratory services (i.e., CSF analysis) to confirm early-stage AD and treatment eligibility and to monitor drug response and disease progression. A variety of new technologies are in development, including new AD biomarker testing methods, that may alleviate some capacity concerns in dementia detection, treatment eligibility screening, treatment administration, and patient monitoring. Alternative DMTs that target other AD pathologic processes are also in development. What Does This Mean? There may be challenges in providing equitable and timely access to DMTs for AD, given the geographic distribution of the population (especially in rural and remote locations), cultural barriers, and lack of awareness of the condition in the population in Canada. Not all individuals with mild dementia due to early-stage AD or MCI who are eligible for treatment may have timely access to screening and diagnosis, which could prevent them from receiving DMTs. Additionally, an increased number of individuals — some of whom may not be eligible for DMTs — may be motivated to seek screening, leading to higher demand and potential delays in the screening process. Health system decision-makers may want to consider system-wide adaptations to enhance screening and care for individuals with suspected early-stage AD, given the projected rise in AD prevalence, which is expected to exceed 1.1 million people by 2050. This may include: adding more health and social care staff providing enhanced training to effectively assess and diagnose early-stage AD improving access to diagnostic imaging to screen and monitor patients using anti–amyloid-beta DMTs.

Timeline to symptomatic Alzheimer's disease in people with Down syndrome as assessed by amyloid-PET and tau-PET: a longitudinal cohort study

Adults with Down syndrome are at risk for Alzheimer's disease. Natural history cohort studies have characterised the progression of Alzheimer's disease biomarkers in people with Down syndrome, with a focus on amyloid β-PET and tau-PET. In this study, we aimed to leverage these well characterised imaging biomarkers in a large cohort of individuals with Down syndrome, to examine the timeline to symptomatic Alzheimer's disease based on estimated years since the detection on PET of amyloid β-positivity, referred to here as amyloid age, and in relation to tau burden as assessed by PET. In this prospective, longitudinal, observational cohort study, data were collected at four university research sites in the UK and USA as part of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. Eligible participants were aged 25 years or older with Down syndrome, had a mental age of at least 3 years (based on a standardised intelligence quotient test), and had trisomy 21 (full, mosaic, or translocation) confirmed through karyotyping. Participants were assessed twice between 2017 and 2022, with approximately 32 months between visits. Participants had amyloid-PET and tau-PET scans, and underwent cognitive assessment with the modified Cued Recall Test (mCRT) and the Down Syndrome Mental Status Examination (DSMSE) to assess cognitive functioning. Study partners completed the National Task Group-Early Detection Screen for Dementia (NTG-EDSD). Generalised linear models were used to assess the association between amyloid age (whereby 0 years equated to 18 centiloids) and mCRT, DSMSE, NTG-EDSD, and tau PET at baseline and the 32-month follow-up. Broken stick regression was used to identify the amyloid age that corresponded to decreases in cognitive performance and increases in tau PET after the onset of amyloid β positivity. 167 adults with Down syndrome, of whom 92 had longitudinal data, were included in our analyses. Generalised linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and at the 32-month follow-up. Using broken stick regression models, differences in mCRT total scores were detected beginning 2·7 years (95% credible interval [CrI] 0·2 to 5·4; equating to 29·8 centiloids) after the onset of amyloid β positivity in cross-sectional models. Based on cross-sectional data, increases in tau deposition started a mean of 2·7-6·1 years (equating to 29·8-47·9 centiloids) after the onset of amyloid β positivity. Mild cognitive impairment was observed at a mean amyloid age of 7·4 years (SD 6·6; equating to 56·8 centiloids) and dementia was observed at a mean amyloid age of 12·7 years (5·6; equating to 97·4 centiloids). There is a short timeline to initial cognitive decline and dementia from onset of amyloid β positivity and tau deposition in people with Down syndrome. This newly established timeline based on amyloid age (or equivalent centiloid values) is important for clinical practice and informing the design of Alzheimer's disease clinical trials, and it avoids the limitations of timelines based on chronological age. National Institute on Aging and the National Institute for Child Health and Human Development.

Diagnosing Alzheimer Disease.

This article reviews the current understanding of Alzheimer disease (AD), including the natural history, common risk factors, and expected progression of AD neuropathologic change so that neurologists can apply this knowledge to identify patients with symptoms, signs, and findings on common diagnostic tests consistent with AD. The advent of potential disease-modifying therapies emphasizes the need to develop and deploy a practical and efficient approach to diagnose patients with cognitive impairment due to AD. The accumulation and spread of cerebral amyloid plaques and tau tangles in patients with AD leads to synaptic dysfunction, neuronal loss, and the eventual emergence and progression of cognitive impairment. A pragmatic and organized approach is needed to recognize patients with symptomatic AD in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making.

A Review on Tau Targeting Biomimetics Nano Formulations: Novel Approach for Targeting Alzheimer's Diseases.

Central nervous system disorders are prevalent, profoundly debilitating, and poorly managed. Developing innovative treatments for these conditions, including Alzheimer's disease, could significantly improve patients' quality of life and reduce the future economic burden on healthcare systems. However, groundbreaking drugs for central nervous system disorders have been scarce in recent years, highlighting the pressing need for advancements in this field. One significant challenge in the realm of nanotherapeutics is ensuring the precise delivery of drugs to their intended targets due to the complex nature of Alzheimer's disease. Although numerous therapeutic approaches for Alzheimer's have been explored, most drug candidates targeting amyloid-β have failed in clinical trials. Recent research has revealed that tau pathology can occur independently of amyloid-β and is closely correlated with the clinical progression of Alzheimer's symptoms. This discovery suggests that tau could be a promising therapeutic target. One viable approach to managing central nervous system disorders is the administration of nanoparticles to neurons, intending to inhibit tau aggregation by directly targeting p-tau. In Alzheimer's disease, beta-amyloid plaques and neurofibrillary tau tangles hinder neuron transmission and function. The disease also triggers persistent inflammation, compromises the blood-brain barrier, leads to brain shrinkage, and causes neuronal loss. While current medications primarily manage symptoms and slow cognitive decline, there is no cure for Alzheimer's.