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Alzheimers disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aβ and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aβ and hIAPP. We found that EGCG molecules substantially diminish the β-sheet structures within the amyloid core regions of Aβ and hIAPP in their co-aggregates. Through hydrogen-bond, π-π and cation-π interactions targeting polar and aromatic residues of Aβ and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aβ and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders.

Background: It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes. Objective: In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL--F). Methods: At 2–4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Results: Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. Conclusions: These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes. [ABSTRACT FROM AUTHOR]

Background: Physical exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. Methods: Six-month-old Amyloid precursor protein/Presenilin 1 (APP/PS1) transgenic (Tg) mice and wild-type (Wt) mice were randomly assigned to either a sedentary group (Tg-Sed, Wt-Sed) or an exercise group (Tg-Ex, Wt-Ex) undertaking a 12-week, moderate-intensity treadmill running program. Consequently, all mice were tested for memory function and amyloid β (Aβ) levels and phosphorylation of tau and protein kinase B (Akt)/glycogen synthase kinase-3 (GSK3) were examined in tissues of both the cortex and hippocampus. Results: Tg-Sed mice had severely impaired memory, higher levels of Aβ, and increased phosphorylation of tau, GSK3α tyrosine279, and GSK3β tyrosine216, but less phosphorylation of GSK3α serine21, GSK3β serine9, and Akt serine473 in both tissues than Wt-Sed mice in respective tissues. Tg-Ex mice showed significant improvement in memory function along with lower levels of Aβ and less phosphorylation of tau (both tissues), GSK3α tyrosine279 (both tissues), and GSK3β tyrosine216 (hippocampus only), but increased phosphorylation of GSK3α serine21 (both tissues), GSK3β serine9 (hippocampus only), and Akt serine473 (both tissues) compared with Tg-Sed mice in respective tissues. Conclusions: Moderate-intensity aerobic exercise is highly effective in improving memory function in 9-month-old APP/PS1 mice, most likely through differential modulation of GSK3α/β phosphorylation in the cortex and hippocampus. [ABSTRACT FROM AUTHOR]

Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid‐β uptake estimates. Harmonization of tracer‐specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data‐driven harmonization model, for reducing tracer‐specific biases in regional amyloid PET measurements from [18F]‐florbetapir (FBP) and [11C]‐Pittsburgh compound‐B (PiB). One hundred thirteen head‐to‐head FBP‐PiB scan pairs, scanned from the same subject within 90 days, were selected from the Open Access Series of Imaging Studies 3 (OASIS‐3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM‐ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Variants of ComBat, including longitudinal ComBat and PEACE, were also tested. Intraclass correlation coefficient (ICC) and mean absolute error (MAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti‐amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates‐of‐change between simulated treatment and placebo groups were tested, and change in statistical power/Type‐I error after harmonization was quantified. In the head‐to‐head tracer comparison, ComBat with no covariates was the best at increasing ICC and decreasing MAE of both global summary and regional amyloid PET SUVRs between scan pairs of the same group of subjects. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate‐of‐change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FBP‐to‐PiB proportions. ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate‐of‐change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses. [ABSTRACT FROM AUTHOR]

The accumulation of amyloid‐β (Aβ) and overactivation of microglia contribute to the pathogenesis of Alzheimer's disease (AD), but the interaction between microglial activation and Aβ deposition in AD remains elusive. Here we revealed that Aβ activates microglia and promotes the release of Galectin‐9 (Gal‐9), a member of the β‐galactoside–binding family of lectins. The levels of Gal‐9 in the cerebrospinal fluid and brain tissues of AD patients are higher than those in control subjects. Gal‐9 interacts with Aβ and promotes its aggregation, generating Gal‐9‐Aβ fibrils with enhanced seeding activity and neurotoxicity. The expression of Gal‐9 increases with age in the brains of APP/PS1 transgenic mice. Knockout of Gal‐9 in APP/PS1 mice substantially reduced Aβ sedimentation, neuroinflammation, and cognitive impairment. Moreover, depletion of Gal‐9 inhibited the seeding activity of brain homogenates from APP/PS1 mice. These findings reveal a mechanism by which microglia‐derived Gal‐9 accelerates Aβ aggregation and seeding in AD. Thus, strategies aimed at inhibiting Gal‐9 may hold promise as a disease‐modifying therapy to alleviate AD pathology. [ABSTRACT FROM AUTHOR]

Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid. The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological cascade that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical trials of monoclonal antibodies targeting amyloid-β have shown mixed results, highlighting the need for further research into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes, including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Background: Early detection of amyloid-β (Aβ) positivity is essential for an accurate diagnosis and treatment of Alzheimer's disease (AD), but it is currently costly and/or invasive. Objective: We aimed to classify Aβ positivity (Aβ+) using morphometric features from magnetic resonance imaging (MRI), a more accessible and non-invasive technique, in two clinical population scenarios: one containing AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects, and another only cognitively impaired subjects (AD and MCI). Methods: Demographic, cognitive (Mini-Mental State Examination [MMSE] scores), regional morphometry MRI (volumes, areas, and thicknesses), and derived morphometric graph theory (GT) features from all subjects (302 Aβ+, age: 73.3±7.2, 150 male; 246 Aβ–, age: 71.1±7.1, 131 male) were combined in different feature sets. We implemented a machine learning workflow to find the best Aβ+ classification model. Results: In an AD+MCI+CN population scenario, the best-performing model selected 120 features (107 GT features, 12 regional morphometric features and the MMSE total score) and achieved a negative predictive value (NPVadj) of 68.4%, and a balanced accuracy (BAC) of 66.9%. In a AD+MCI scenario, the best model obtained NPVadj of 71.6%, and BAC of 70.7%, using 180 regional morphometric features (98 volumes, 52 areas and 29 thicknesses from temporal, parietal, and frontal brain regions). Conclusions: Although with currently limited clinical applicability, regional MRI morphometric features have clinical usefulness potential for detecting Aβ status, which may be augmented by a combination with cognitive data when cognitively normal subjects make up a substantial part of the population presenting for diagnosis. [ABSTRACT FROM AUTHOR]

Background: Semantic intrusion errors (SIEs) are both sensitive and specific to PET amyloid-β (Aβ) burden in older adults with amnestic mild cognitive impairment (aMCI). Objective: Plasma Aβ biomarkers including the Aβ42/40 ratio using mass spectrometry are expected to become increasingly valuable in clinical settings. Plasma biomarkers are more clinically informative if linked to cognitive deficits that are salient to Alzheimer's disease (AD). Methods: This study included 119 older adults enrolled in the 1Florida Alzheimer's Disease Research Center (ADRC), 45 aMCI participants scored below the established Aβ42/40 ratio cut-off of 0.160 using the Quest AD-Detect™ assay indicating Aβ positivity (Aβ+), while 50 aMCI participants scored above this cut-off indicating Aβ negative status (Aβ–). Additionally, 24 cognitively unimpaired (CU) persons scored above the cut-off of 0.160 (Aβ–). Results: The aMCI plasma Aβ+ group evidenced the greatest percentage of SIEs, followed by the aMCI Aβ–. The CU Aβ– group exhibited the lowest percentage of SIEs. After adjustment for global cognitive impairment, aMCI plasma Aβ+ continued to demonstrate greater SIEs on tests tapping the failure to recover from proactive semantic interference (frPSI) as compared to the aMCI Aβ–group. Using pre-established cut-offs for frPSI impairment, 8.3% of CU Aβ– participants evidenced deficits, compared to 37.8% of aMCI Aβ–, and 74.0% of aMCI Aβ+. Conclusions: SIEs reflecting frPSI were associated with aMCI Aβ+ status based on the Aβ42/40 ratio. Results suggest the importance of SIEs as salient cognitive markers that map onto underlying AD pathology in the blood. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) is hypothesized to be a component of the glymphatic system, a pathway for removing brain interstitial solutes like amyloid-β (Aβ). Evidence exists that genetic variation of AQP4 impacts Aβ clearance, clinical outcome in Alzheimer's disease as well as sleep measures. We examined whether a risk score calculated from several AQP4 single-nucleotide polymorphisms (SNPs) is related to Aβ neuropathology in older cognitively unimpaired white individuals. We used a machine learning approach and explainable artificial intelligence to extract information on synergistic effects of AQP4 SNPs on brain amyloid burden from the ADNI cohort. From this information, we formulated a sex-specific AQP4 SNP-based risk score and evaluated it using data from the screening process of the A4 study. We found in both cohorts significant associations of the risk score with brain amyloid burden. The results support the hypothesis of an involvement of the glymphatic system, and particularly AQP4, in brain amyloid aggregation pathology. They suggest also that different AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden. • AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden. • AQP4 SNP based risk score is related to Aβ burden in healthy white individuals. • Explainable AI could extract information on synergistic effects of SNPs. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a debilitating progressively neurodegenerative disease. The best-characterized hallmark of AD, which is marked by behavioral alterations and cognitive deficits, is the aggregation of deposition of amyloid-beta (Aβ) and hyper-phosphorylated microtubule-associated protein Tau. Despite decades of experimental progress, the control rate of AD remains poor, and more precise deciphering is needed for potential therapeutic targets and signaling pathways involved. In recent years, phosphoinositide 3-kinase (PI3K) and Akt have been recognized for their role in the neuroprotective effect of various agents, and glycogen synthase kinase 3 (GSK3), a downstream enzyme, is also crucial in the tau phosphorylation and Aβ deposition. An overview of the function of PI3K/Akt pathway in the pathophysiology of AD is provided in this review, along with a discussion of recent developments in the pharmaceuticals and herbal remedies that target the PI3K/Akt signaling pathway. In conclusion, despite the challenges and hurdles, cumulative findings of novel targets and agents in the PI3K/Akt signaling axis are expected to hold promise for advancing AD prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: Clausena harmandiana (CH), commonly known as song fa dong, was a medicinal plant traditionally used to treat illnesses and as a health tonic. CH root extract (CHRE) exhibited various bioactivities, including neuroprotective, antioxidant, antimicrobial, antifungal, anti-inflammatory, and anti-cancer effects. However, CHRE data on neuroprotective in AD-like animal models were still scarce. Objectives: This study aimed to investigate the effects of CHRE on Aβ1-42-induced cognitive deficits, free radical damage, and neuronal death in rats. Methods: Forty-eight adult male Sprague-Dawley rats (250–300 g) were classified as sham control (SC), V+Aβ, Vit C+Aβ, CHRE125+Aβ, CHRE250+Aβ, and CHRE500+Aβ (n = 8 in each group). Animals were orally administered with 0.5% sodium carboxymethylcellulose, vitamin C (200 mg/kg BW), or CHRE (125, 250, and 500 mg/kg BW) and were untreated for 35 days. On day 21, all treated rats were injected with 1 µl of aggregated Aβ1-42 (1 µg/µl) into the lateral ventricles, bilaterally, whereas untreated rats were injected with sterilized normal saline (NS). The Morris water maze test estimated the rat's learning and memory one week later. At the end of the treatment, all rats were sacrificed, and their brains were removed and divided into two hemispheres. On the left, morphological changes and neuronal density were observed in hippocampal CA1 and CA3 regions. While, on the right, changes in free radical damage markers (SOD, CAT, GPx, MDA, and Nrf2) and protein expression of active caspase-3 were evaluated in the hippocampus. Results: Pretreatment with CHRE at all doses could alleviate spatial learning and memory defects. CHRE also improved morphological changes and a decrease in neuronal density in CA1 and CA3 regions. Additionally, CHRE significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx) and Nrf2 expression. This was coupled with significantly decreased MDA levels and active caspase-3 expression in the hippocampus of Aβ1-42-induced rats, which was similar to vitamin C exposure. Conclusions: Our findings suggested that CHRE ameliorated cognitive deficits and exhibited neuroprotective effects by reducing free radical damage and mitigating neuronal abnormality and neuronal death. [ABSTRACT FROM AUTHOR]

Circadian rhythm disruptions have been implicated in numerous health issues, including cognitive decline and the exacerbation of neurodegenerative diseases, like Alzheimer disease (AD). Brain-derived neurotrophic factor (BDNF), vital for neuronal plasticity and cognitive function, is regulated by the circadian clock and exerts protective effects against AD. Thus, we investigated the impact of circadian rhythm disorders (CRDs) on cognitive impairment and explored the underlying neurobiological mechanisms by assessing BDNF and amyloid-β (Aβ) levels. We divided male C57BL/6 mice into three groups (n = 30): a control group (normal 12/12 hour light-dark cycle) and two CRD model groups (3/3 and 22/22 hour cycles, respectively). After 12 weeks, we assessed cognitive functions using the Morris water maze. Following behavioral tests, hippocampal levels of BDNF and Aβ were quantified using enzyme-linked immunosorbent assays. CRDs significantly impaired learning and memory, as evidenced by longer times to reach and find the platform in the CRD groups (p < 0.01). Furthermore, BDNF levels were notably decreased and Aβ levels increased in the CRD groups compared with the control group (p < 0.01). Thus, CRDs elicit cognitive impairment by reducing BDNF levels and increasing Aβ deposition in the hippocampus. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a prevalent cognitive disorder among the elderly, is frequently linked to the abnormal accumulation of myloid-β (Aβ), which is mainly as a result of neuronal death and inflammation. Diosmin, a flavonoid, is considered a potential drug for the treatment of AD. Our study aimed to uncover the molecular mechanism of diosmin in AD therapy. Here, rats were randomly divided into three groups: control, Aβ25−35, and Aβ25−35 + diosmin groups. AD model rats were induced by Aβ25−35 intraventricular injection, meanwhile 50 mg/kg diosmin was orally administered for 6-week intervention. Morris water maze test assessed learning and memory abilities. Hippocampal neuronal damage was determined by HE, Nissl, and TUNEL staining. These assays indicate that diosmin improves cognitive dysfunction and reduces hippocampal neuronal loss and apoptosis. Western blot showed that diosmin reduced Bax (1.21 ± 0.12) and cleaved caspase-3 (1.27 ± 0.12) expression, and increased Bcl-2 (0.70 ± 0.06), p-PI3K (0.71 ± 0.08), and p-AKT (0.96 ± 0.10) in the hippocampus. ELISA indicated diosmin reduces IL-1β, IL-6, and TNF-α levels, suggesting anti-inflammation effect. These results suggest that diosmin inhibits neuronal apoptosis and neuroinflammatory responses to improve cognitive dysfunction in AD rats, possibly related to upregulation of the PI3K/AKT pathway, providing a scientific basis for its use in AD treatment. [ABSTRACT FROM AUTHOR]

Objective: This meta‐analysis aimed to evaluate the comparative diagnostic performance of amyloid‐β positron emission tomography (Aβ PET) and magnetic resonance imaging (MRI) in diagnosing Alzheimer's disease (AD). Methods: An extensive search was conducted in the PubMed and Embase databases to identify available publications up to December 2023. Head‐to‐head comparative studies were included if they evaluated the diagnostic performance of Aβ PET and MRI in diagnosing Alzheimer's disease. Sensitivity and specificity were assessed using the DerSimonian and Laird method, followed by transformation via the Freeman–Tukey double inverse sine transformation. Results: Six articles involving 560 patients were included in the meta‐analysis. When distinguishing AD from mild cognitive impairment (MCI), both methods showed comparable sensitivity (Aβ PET: 0.71, MRI: 0.62) and specificity (Aβ PET: 0.68, MRI: 0.69), with no statistically significant differences observed (p = 0.34 and 0.99). When identifying AD from normal cognitive control (NC), both Aβ PET and MRI showed similar results, with comparable sensitivity (Aβ PET: 0.93, MRI: 0.85) and specificity (Aβ PET: 0.95, MRI: 0.82), without significant differences (p = 0.38 and 0.19). Similarly, in detecting MCI from NC, both Aβ PET and MRI demonstrated similar sensitivity (Aβ PET: 0.69, MRI: 0.64) and specificity (Aβ PET: 0.75, MRI: 0.76) without significant differences (p = 0.40 and 0.94). However, 18F‐FMM seems to have a higher specificity compared to MRI when distinguishing AD from MCI (P = 0.03) and AD from NC (p = 0.04). Conclusions: Our meta‐analysis indicates that Aβ PET demonstrates similar sensitivity and specificity to MRI in diagnosing Alzheimer's disease. However, the limited number of studies may impact the evidence of the current study; further larger sample prospective research is required to confirm these findings. [ABSTRACT FROM AUTHOR]

Treatment with melatonin is routinely prescribed for its potent antioxidant and cognitive‐promoting effects, nevertheless, it has yet to find neuromodulatory effects in normal and disease conditions. Therefore, to investigate its neuromodulatory mechanisms, melatonin was systemically administered over 10 consecutive days to both intracortical normal saline‐ and amyloid‐β 1‐42 (Aβ) peptide‐injected rats. At the behavioral level, treatment with melatonin was associated with reduced efficacy in restoring Aβ‐induced deficit in passive‐avoidance memory. Whole‐cell patch‐clamp recordings from CA1 pyramidal neurons revealed that melatonin treatment reduced spontaneous and evoked intrinsic excitability in control rats while exerting a reduction of spontaneous, but not evoked activity, in the Aβ‐injected group. Interestingly, treatment with melatonin enhances after‐hyperpolarization in control, but not Aβ‐injected rats. In contrast, our voltage‐clamp study showed that Ih current is significantly enhanced by Aβ injection, and this effect is further strengthened by treatment with melatonin in Aβ‐injected rats. Finally, we discovered that the transcription of melatonin receptors 1 (MT1) and 2 (MT2) is significantly upregulated in the hippocampi of Aβ‐injected rats. Collectively, our study demonstrates that systemic treatment with melatonin has differential neuromodulation on CA1 neuronal excitability, at least in part, via differential effects on after‐hyperpolarization and Ih currents due to Aβ‐induced neurotoxicity. Summary: The molecular and cellular underpinnings of AD pathology are accompanied by developing aberrant neuronal excitability. These neuronal properties are also a part of melatonin effectors by which melatonin exerts its cognitive‐promoting and anti‐seizure effects. In this paper, we answer the question of how melatonin may influence neuronal excitability in healthy and AD‐like conditions. Answering this query is important considering the fact that melatonin effectiveness is altered with the development of AD. This may be due to, as we demonstrate, the deregulation of melatonin receptors in the hippocampus of AD rats. These findings are significant because shed further light on the cellular mechanisms of melatonin and help us to understand AD pathophysiology. [ABSTRACT FROM AUTHOR]

The study of metal ion's role in the biological processes of Alzheimer's disease has spurred investigations into the coordination chemistry of amyloid beta peptide and its fragments. Nano‐electrospray ionization mass spectrometry (nESI‐MS) has been utilized to examine the stabilization of bound anions on multiprotein complexes without bulk solvent. However, the effects of anions on metal ion binding interactions with amyloid beta peptide have not been explored. This study directly examined metal‐peptide complexes using nESI‐MS and investigated the effects of various anions on the binding ratio and stability of these complexes from ammonium salt solutions. The results indicate that different anions have distinct effects on the binding ratio and stability of various metal‐peptide complexes. Of these, the bicarbonate ion exhibits the highest binding ratios for metal‐peptide complexes, while binding ratios for these complexes in phosphate are comparatively low. Our results suggest that acetate, formate, bicarbonate, and phosphate have weak affinities and act as weak stabilizers of the metal‐peptide complex structure in the gas phase. Intriguingly, chloride and sulfate act as stabilizers of the metal‐peptide complex in the gas phase. The rank order determined from these data is substantially different from the Hofmeister salt series in solution. Although this outcome was anticipated due to the reduced influence of anions and water solvation, our findings correlate well with expected anion binding in solution and emphasize the importance of both hydration layer and anion‐metal‐peptide binding effects for Hofmeister‐type stabilization in solution. This approach proved useful in examining the interactions between metal ions and amyloid beta peptide, which are relevant to Alzheimer's disease, using direct ESI‐MS. [ABSTRACT FROM AUTHOR]

Background: Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer's disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4's association with AD was unknown. Objective: To assess GLOD4's role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh–/–5xFAD mouse AD model of AD. Methods: GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4, Aβ precursor protein (Aβpp), Atg5, p62, and Lc3 proteins and mRNAs were quantified. Results: GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh–/–5xFAD mice compared to Blmh+/+5xFAD sibling controls, but not in Blmh–/– mice without the 5xFAD transgene compared to Blmh+/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh–/– mice of both sexes and in Blmh+/+ males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh–/–5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5, p62, and Lc3 genes. Conclusions: These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits. [ABSTRACT FROM AUTHOR]

The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD. [ABSTRACT FROM AUTHOR]

Background: Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer's disease (AD). Aggregates are also recognized by microglia, which in early phases may be protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic. Objective: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide. Methods: The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed. Results: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40- and Aβ42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys. Conclusions: Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously. [ABSTRACT FROM AUTHOR]

Background and purpose: The co‐occurrence of amyloid‐β pathology in Parkinson's disease (PD) is common; however, the role of amyloid‐β deposition in motor prognosis remains elusive. This study aimed to investigate the association between striatal amyloid deposition, motor complications and motor prognosis in patients with PD. Methods: Ninety‐six patients with PD who underwent 18F florbetaben (FBB) positron emission tomography were retrospectively assessed. The ratio of the striatum to global (STG) FBB uptake was obtained for each individual, and patients were allotted into low and high STG groups according to the median value. The effect of STG group on regional amyloid deposition, the occurrence of motor complications and longitudinal change in levodopa equivalent dose (LED) requirement were investigated after controlling for age, sex, LED and disease duration at FBB scan. Results: The high STG group was associated with lower cortical FBB uptake in the parietal, occipital and posterior cingulate cortices and higher striatal FBB uptake compared to the low STG group. Patients in the high STG group had a higher risk of developing wearing off and levodopa‐induced dyskinesia than those in the low STG group, whereas the risk for freezing of gait was comparable between the two groups. The high STG group showed a more rapid increase in LED requirements over time than the low STG group. Conclusions: These findings suggest that relatively high striatal amyloid deposition is associated with poor motor outcomes in patients with PD. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? Are there specific anxiety symptoms associated with Alzheimer's disease pathologies, amyloid-β and tau, in cognitively unimpaired older adults? • What is the main finding of this study? Greater amyloid-β deposition was associated with higher levels of self-reported worry but not global anxiety, independent of subjective and objective cognition and depression. No associations were found between regional tau deposition and either worry or global anxiety. • What is the meaning of the finding? These findings implicate worry as an early, specific behavioral marker and possible therapeutic target in preclinical AD. Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory–6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD. [ABSTRACT FROM AUTHOR]

Monitoring the progression of Alzheimer's disease (AD) is crucial for mitigating dementia symptoms, alleviating pain, and improving mobility. Traditionally, AD biomarkers like amyloid plaques are predominantly identified in cerebrospinal fluid (CSF) due to their concentrated presence. However, detecting these markers in blood is hindered by the blood–brain barrier (BBB), resulting in lower concentrations. To address this challenge and identify pertinent AD biomarkers—specifically amyloid plaques and apolipoprotein E4 (ApoE4)—in blood plasma, we propose an innovative approach. This involves enhancing a screen-printed carbon electrode (SPCE) with an immobilization matrix comprising gold nanostars (AuNSs) coated with chitosan. Morphological and electrical analyses confirmed superior dispersion and conductivity with 0.5% chitosan, supported by UV–Vis spectroscopy, cyclic voltammetry, and Nyquist plots. Subsequent clinical assays measured electrical responses to quantify amyloid-β 42 (Aβ42) (15.63–1000 pg/mL) and APoE4 levels (0.41 to 40 ng/mL) in human blood plasma samples. Differential pulse voltammetry (DPV) responses exhibited peak currents proportional to biomarker concentrations, demonstrating high linear correlations (0.985 for Aβ42 and 0.919 for APoE4) with minimal error bars. Cross-reactivity tests with mixed solutions of amyloid-β 40 (Aβ40), Aβ42, and ApoE4 indicated minimal interference between biomarkers (<3% variation), further confirming the high specificity of the developed sensor. Validation studies demonstrated a strong concurrence with the gold-standard enzyme-linked immunosorbent assay (ELISA), while interference tests indicated a minimal variation in peak currents. This improved device presents promising potential as a point-of-care system, offering a less invasive, cost-effective, and simplified approach to detecting and tracking the progression of AD. The substantial surface binding area further supports the efficacy of our method, offering a promising avenue for advancing AD diagnostics. [ABSTRACT FROM AUTHOR]

Background: Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease. Methods: 92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1–38, Aβ1–40 and Aβ1–42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models. Results: Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1–38 compared to controls (p < 0.05). There was no difference in Aβ1–42/1–40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1–42/1–40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC. Conclusion: These data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts. [ABSTRACT FROM AUTHOR]

Background: Blood–brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer's disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods: For this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (Ktrans) were calculated within regions of interest. Spearman's correlation and multivariate linear regression were applied to analyze associations between Ktrans and specific clinical characteristics. Results: In members of the DLB (vs HC) group, Ktrans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and Ktrans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased Ktrans values of parietal (β = 0.391; p = 0.001) and occipital (β = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased Ktrans values of cerebral cortex (β = 0.285; p = 0.015), frontal lobe (β = 0.237; p = 0.043), and parietal lobe (β = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments. Conclusion: BBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity. [ABSTRACT FROM AUTHOR]

Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca2+ influx through postsynaptic NMDA-type glutamate receptors (NMDARs) initiates signaling pathways that coordinate changes in dendritic spine structure and synaptic function. During long-term potentiation (LTP), high levels of NMDAR Ca2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca2+-dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca2+-dependent protein phosphatase calcineurin (CaN), which is anchored at synapses via the scaffold protein A-kinase anchoring protein (AKAP)150. In Alzheimer's disease (AD), the pathological agent amyloid-β (Aβ) may impair learning and memory through biasing NMDAR Ca2+ signaling pathways toward LTD and spine elimination. By employing AKAP150 knock-in mice of both sexes with a mutation that disrupts CaN anchoring to AKAP150, we revealed that local, postsynaptic AKAP–CaN–LTD signaling was required for Aβ-mediated impairment of NMDAR synaptic Ca2+ influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aβ acutely engages AKAP–CaN signaling through activation of G-protein-coupled metabotropic glutamate receptor 1 (mGluR1) leading to dephosphorylation of NMDAR GluN2B subunits, which decreases Ca2+ influx to favor LTD over LTP, and cofilin, which promotes F-actin severing to destabilize dendritic spines. These findings reveal a novel interplay between NMDAR and mGluR1 signaling that converges on AKAP-anchored CaN to coordinate dephosphorylation of postsynaptic substrates linked to multiple aspects of Aβ-mediated synaptic dysfunction. [ABSTRACT FROM AUTHOR]

The introduction of lecanemab has dramatically changed the field of dementia medicine. Lecanemab, defined as an anti‐amyloid‐β (Aβ) drug, comprises an antibody against Aβ, a protein structure believed to cause Alzheimer's disease. This drug represents a new direction in dementia treatment. In a phase III study, lecanemab was found to significantly slow cognitive decline, while showing manageable levels of amyloid‐related imaging abnormalities, which are side‐effects of lecanemab. Furthermore, lecanemab has been shown to effectively reduce Aβ accumulation in patients with early Alzheimer's disease, which might contribute not only to delaying the progression of cognitive decline, but also to improving the quality of life of patients and their families. However, there are conditions for the use of lecanemab, for which the Ministry of Health, Labor and Welfare has issued the Guidelines for Promotion of Optimal Use. These guidelines specify requirements for appropriate patient selection, prescribing physicians and administering medical institutions to ensure safe and effective use. Particular emphasis is placed on the confirmation of amyloid‐β accumulation, amyloid‐related imaging abnormalities risk management and appropriate handling of side‐effects. The clinical use of lecanemab represents an important advancement in the treatment of dementia; however, the understanding and cooperation of healthcare professionals, patients and families are essential to maximize its efficacy and safety. Future issues to be addressed include the sustainability and long‐term efficacy of treatment, improvement of clinical symptoms after removal of Aβ and motivation to administer the drug. Although lecanemab offers hope for the treatment of dementia, its use requires careful management. Geriatr Gerontol Int 2024; 24: 841–844. [ABSTRACT FROM AUTHOR]

Gantenerumab, a human monoclonal antibody (mAb), has been thought of as a potential agent to treat Alzheimer's disease (AD) by specifically targeting regions of the amyloid-β (Aβ) peptide sequence. Aβ protein accumulation in the brain leads to amyloid plaques, causing neuroinflammation, oxidative stress, neuronal damage, and neurotransmitter dysfunction, thereby causing cognitive decline in AD. Gantenerumab involves disrupting Aβ aggregation and promoting the breakdown of larger Aβ aggregates into smaller fragments, which facilitates the action of Aβ-degrading enzymes in the brain, thus slowing down the progression of AD. Moreover, Gantenerumab acts as an opsonin, coating Aβ plaques and enhancing their recognition by immune cells, which, combined with its ability to improve the activity of microglia, makes it an intriguing candidate for promoting Aβ plaque clearance. Indeed, the multifaceted effects of Gantenerumab, including Aβ disaggregation, enhanced immune recognition, and improved microglia activity, may position it as a promising therapeutic approach for AD. Of note, reports suggest that Gantenerumab, albeit its capacity to reduce or eliminate Aβ, has not demonstrated effectiveness in reducing cognitive decline. This review, after providing an overview of immunotherapy approaches that target Aβ in AD, explores the efficacy of Gantenerumab in reducing Aβ levels and cognitive decline. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) deposition throughout the neuroaxis is a classical hallmark of several neurodegenerative diseases, most notably Alzheimer's disease (AD). Aβ peptides of varied length and diverse structural conformations are deposited within the parenchyma and vasculature in the brains of individuals with AD. Neuropathologically, Aβ pathology can be assessed using antibodies to label and characterize their features, which in turn leads to a more extensive understanding of the pathological process. In the present study, we generated a novel monoclonal antibody, which we found to be specific for the N-terminal region of Aβ. This antibody reacted to amyloid precursor protein expressed in cultured cells and labels Aβ plaques and cerebral amyloid angiopathy in brain tissue from a mouse model of amyloidosis as well as post-mortem brain tissue from patients diagnosed with AD. This highly specific novel antibody will serve as a unique tool for future studies investigating Aβ deposition in novel mouse models and cross-sectional studies using post-mortem human tissue. [ABSTRACT FROM AUTHOR]

Disputes about the scientific validity of the amyloid‐β hypothesis of Alzheimer's disease have been held since the early 1990s, with little constructive progress made between opposing sides despite recent therapeutic progress. Here, I argue that philosophy of science can improve the chance of constructive debate by giving researchers technical language to describe and assess scientific progress. To do so, I interpret the amyloid hypothesis using a modified version of the research programme concept from philosopher of science Imre Lakatos. I first outline the amyloid‐β hypothesis and study critiques of its central place in Alzheimer's research. Then, I draw on the complexity of amyloid‐β and Alzheimer's research to discuss the limits of using concepts from popular philosophers of science Karl Popper or Thomas Kuhn, before finally arguing that an adaptation of the research programme concept can foster constructive debates about the science of Alzheimer's and within it. I will argue that the amyloid‐β hypothesis has contributed to significant progress in the Alzheimer's field based on what Lakatos called the "positive heuristic" (motivating the programme to test its predictions) and the "negative heuristic" (protecting the programme from refutation). I consider the amyloid research agenda to be progressive despite the fact that its claims about disease aetiology could be wrong. [ABSTRACT FROM AUTHOR]

Background: The concept of amnestic mild cognitive impairment (aMCI) was developed to identify patients at an initial stage of Alzheimer's disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology or neuronal injury. Objective: To know the natural history of amyloid-negative and neurodegeneration-negative patients with aMCI, namely to ascertain: 1) whether these patients remain cognitively stable or they present a slow decline in neuropsychological tests; 2) whether the memory complaints subside with the apparently benign clinical course of the disorder or if they persist along the time. Methods: Patients who fulfilled criteria for aMCI with no biomarkers of amyloid pathology or neuronal injury were selected from a large cohort of non-demented patients with cognitive complaints, and were followed with clinical and neuropsychological assessments. Results: Twenty-one amyloid-negative and neurodegeneration-negative aMCI patients were followed for 7.1±3.7 years. At the baseline they had more pronounced deficits in verbal learning (California Verbal Learning Test) and were also impaired in Word Recall and Logical Memory. However, they did not decline in any cognitive test during follow-up. The patients maintained a high level of subjective memory complaints from baseline (9.7±4.1) to the follow-up visit (9.2±4.1, a non-significant difference), in spite of a statistically significant decrease in the depressive symptoms, with Geriatric Depression Scale (15 items) score 4.9±2.8 at baseline and 3.2±1.8 at the follow-up visit. Conclusions: Amyloid-negative, neurodegeneration-negative aMCI is a chronic clinical condition characterized by the long-term persistence of cognitive deficits and distressing memory complaints. Adequate strategies to treat this condition are needed. [ABSTRACT FROM AUTHOR]

Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients. [ABSTRACT FROM AUTHOR]

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer's disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI. [ABSTRACT FROM AUTHOR]

Abstract Background Clausena harmandiana (CH), commonly known as song fa dong, was a medicinal plant traditionally used to treat illnesses and as a health tonic. CH root extract (CHRE) exhibited various bioactivities, including neuroprotective, antioxidant, antimicrobial, antifungal, anti-inflammatory, and anti-cancer effects. However, CHRE data on neuroprotective in AD-like animal models were still scarce. Objectives This study aimed to investigate the effects of CHRE on Aβ1-42-induced cognitive deficits, free radical damage, and neuronal death in rats. Methods Forty-eight adult male Sprague-Dawley rats (250–300 g) were classified as sham control (SC), V+Aβ, Vit C+Aβ, CHRE125+Aβ, CHRE250+Aβ, and CHRE500+Aβ (n = 8 in each group). Animals were orally administered with 0.5% sodium carboxymethylcellulose, vitamin C (200 mg/kg BW), or CHRE (125, 250, and 500 mg/kg BW) and were untreated for 35 days. On day 21, all treated rats were injected with 1 µl of aggregated Aβ1-42 (1 µg/µl) into the lateral ventricles, bilaterally, whereas untreated rats were injected with sterilized normal saline (NS). The Morris water maze test estimated the rat’s learning and memory one week later. At the end of the treatment, all rats were sacrificed, and their brains were removed and divided into two hemispheres. On the left, morphological changes and neuronal density were observed in hippocampal CA1 and CA3 regions. While, on the right, changes in free radical damage markers (SOD, CAT, GPx, MDA, and Nrf2) and protein expression of active caspase-3 were evaluated in the hippocampus. Results Pretreatment with CHRE at all doses could alleviate spatial learning and memory defects. CHRE also improved morphological changes and a decrease in neuronal density in CA1 and CA3 regions. Additionally, CHRE significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx) and Nrf2 expression. This was coupled with significantly decreased MDA levels and active caspase-3 expression in the hippocampus of Aβ1-42-induced rats, which was similar to vitamin C exposure. Conclusions Our findings suggested that CHRE ameliorated cognitive deficits and exhibited neuroprotective effects by reducing free radical damage and mitigating neuronal abnormality and neuronal death.

Abstract Background Blood–brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer’s disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods For this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (K trans) were calculated within regions of interest. Spearman’s correlation and multivariate linear regression were applied to analyze associations between K trans and specific clinical characteristics. Results In members of the DLB (vs HC) group, K trans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and K trans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased K trans values of parietal ( $$\upbeta$$ β = 0.391; p = 0.001) and occipital ( $$\upbeta$$ β = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased K trans values of cerebral cortex ( $$\upbeta$$ β = 0.285; p = 0.015), frontal lobe ( $$\upbeta$$ β = 0.237; p = 0.043), and parietal lobe ( $$\upbeta$$ β = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments. Conclusion BBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity.

Abstract Background Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease. Methods 92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1–38, Aβ1–40 and Aβ1–42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models. Results Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p

In patients with Alzheimer’s disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer’s disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease (Aβ1–42–treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-β in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of β-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

Alzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and β-amyloid (Aβ) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aβ on AD development. Longitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of β-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence. Individuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001). These findings emphasized that the MDS-Aβ interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage. • MDS worsened amyloid-related neurodegeneration and cognitive decline, increasing AD risk in pre-dementia. • The co-existence of MDS and amyloid pathology predicted a specifically higher risk of incident AD. • Early MDS management may lower AD risk in preclinical/prodromal stages. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer’s disease (AD) is a progressive neurological disorder that primarily impacts cognitive function. Currently there are no disease-modifying treatments to stop or slow its progression. Recent studies have found that several peripheral and systemic abnormalities are associated with AD, and our understanding of how these alterations contribute to AD is becoming more apparent. In this review, we focuse on amyloid‑beta (Aβ), a major hallmark of AD, summarizing recent findings on the source of brain-derived Aβ and discussing where and how the brain-derived Aβ is cleared in vivo. Based on these findings, we propose future strategies for AD prevention and treatment, from a novel perspective on Aβ metabolism.

Abstract Background Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA. Methods Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings. Results rhApoJ-treated APP23 presented fewer cortical CMBs (50–300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036). Conclusions Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

Abstract Background Idiopathic Normal Pressure Hydrocephalus (iNPH) is a chronic condition affecting the elderly. It is characterized by a triad of symptoms and radiological findings. Glaucoma is the leading cause of irreversible blindness worldwide. Earlier studies have proposed that the rate of glaucoma is higher in iNPH patients, and of a possible link between ventriculoperitoneal shunt (VP) treatment and the development of glaucoma. Objectives This study aimed to determine the prevalence of glaucoma among iNPH patients and assess the impact of VPs on glaucoma prevalence. Methods A cohort study was conducted at Kuopio University Hospital (KUH), including 262 patients with a ventriculoperitoneal shunt. Clinical data were obtained from the Kuopio NPH Registry and medical records. Patients were grouped by iNPH status: iNPH (+) – probable/possible iNPH (n = 192), and iNPH (-) – other causes of hydrocephalus (congenital, secondary, obstructive) (n = 70). We conducted statistical analysis using the Independent Samples T-test, Fisher’s exact test, and Pearson Chi-Square. We compared demographics, glaucoma prevalence, brain biopsies positive for Amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) as well as comorbidities for hypertension and diabetes medication. Age stratification assessed glaucoma prevalence in the full cohort. Results Both iNPH (+) and iNPH (-) groups had comparable demographic and comorbidity profiles. The prevalence of glaucoma in the iNPH (+) group was 11.5% (n = 22) and 11.4% (n = 8) in the iNPH (-) group without a statistically significant difference (p = 1.000). Brain biopsies positive for Amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) were similar. Conclusions Neither shunted iNPH patients nor those with a comorbid condition other than iNPH showed a markedly higher prevalence of glaucoma. Instead, both groups exhibited age-related increases in glaucoma prevalence, similar to the trends observed in population-based studies. Our data does not suggest a correlation between VP shunts and an elevated rate of glaucoma.

Abstract Background Alzheimer's disease (AD) is a common type of dementia characterized by amyloid-β (Aβ) accumulation, lysosomal dysfunction, and tau hyperphosphorylation, leading to neurite dystrophy and memory loss. This study aimed to investigate whether Rhei Undulati Rhizoma (RUR), which has been reported to have anti-neuroinflammatory effect, attenuates Aβ-induced memory impairment, neuritic dystrophy, and tau hyperphosphorylation, and to reveal its mode of action. Methods Five-month-old 5xFAD mice received RUR (50 mg/kg) orally for 2 months. The Y-maze test was used to assess working memory. After behavioral testing, brain tissue was analyzed using thioflavin S staining, western blotting, and immunofluorescence staining to investigate the mode of action of RUR. To confirm whether RUR directly reduces Aβ aggregation, a thioflavin T assay and dot blot were performed after incubating Aβ with RUR. Results RUR administration attenuated the Aβ-induced memory impairment in 5xFAD mice. Furthermore, decreased accumulation of Aβ was observed in the hippocampus of the RUR-treated 5xFAD group compare to the vehicle-treated 5xFAD group. Moreover, RUR reduced the dystrophic neurites (DNs) that accumulate impaired endolysosomal organelles around Aβ. In particular, RUR treatment downregulated the expression of β-site amyloid precursor protein cleaving enzyme 1 and the hyperphosphorylation of tau within DNs. Additionally, RUR directly suppressed the aggregation of Aβ, and eliminated Aβ oligomers in vitro. Conclusions This study showed that RUR could attenuate Aβ-induced pathology and directly regulate the aggregation of Aβ. These results suggest that RUR could be an efficient material for AD treatment through Aβ regulation. Graphical Abstract

Introduction: Anticipating the diagnosis of Alzheimer's disease (AD) at an early asymptomatic at-risk stage, where therapeutics can more effectively delay conscious cognitive decline, is currently among the biggest challenges in the field. Herein, we aimed to compare the capacity of the Memory Binding Test (MBT) with the official diagnostic tool, the Free and Cued Selective Reminding Test (FCSRT), to anticipate AD diagnosis at an early preclinical stage based on the associative memory component of MBT (binding), suggested as more sensitive to the emergence of subtle episodic memory (EM) deficits (AD hallmark). Methods: We assessed the tests performance longitudinally (over 5 years) in 263 cognitively-normal elderly individuals at risk of AD (>6 months of subjective memory complaints) using linear mixed-effect models controlled for age, sex, and education. We stratified participants in 2 models: amyloid-β (Aβ)/neurodegeneration (N) model, assessing Aβ burden and neurodegeneration effect [3 groups: controls (Aβ-/N-); stable/N- (Aβ+); stable/N+ (Aβ+)]; and the stable/progressors model, assessing progression to prodromal-AD effect [2 groups: stable (Aβ+); progressors (Aβ+)], based on 15 subjects who progressed to AD during follow-up (excluded once diagnosed). Results: Aβ burden was associated with significantly less MBT-intrusions, while Aβ burden and neurodegeneration together, with the most. Progression status had a strong negative effect on both tests performance. When compared with the FCSRT, the MBT seems to anticipate diagnosis based on a worst performance in a higher number of scores (including binding) in at least a year. Discussion: Anticipation of diagnosis to an asymptomatic at-risk stage, while participants remain cognitively-normal according to FCSRT cut-offs and unaware of objective EM deficits, has the potential to delay the onset of AD-linked cognitive decline by applying promising therapeutics before decline becomes too advanced. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurological disorder that primarily impacts cognitive function. Currently there are no disease-modifying treatments to stop or slow its progression. Recent studies have found that several peripheral and systemic abnormalities are associated with AD, and our understanding of how these alterations contribute to AD is becoming more apparent. In this review, we focuse on amyloid‑beta (Aβ), a major hallmark of AD, summarizing recent findings on the source of brain-derived Aβ and discussing where and how the brain-derived Aβ is cleared in vivo. Based on these findings, we propose future strategies for AD prevention and treatment, from a novel perspective on Aβ metabolism. [ABSTRACT FROM AUTHOR]

Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered—meningeal lymphatic vessels (mLVs)—which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF's actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer's disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging. [ABSTRACT FROM AUTHOR]

Background: The causal relationships of late-life body mass index (BMI) with Alzheimer's disease (AD) remains debated. Objective: We aimed to assess the associations of dynamic BMI features (ΔBMIs) with cognitive trajectories, AD biomarkers, and incident AD risk. Methods: We analyzed an 8-year cohort of 542 non-demented individuals who were aged ≥65 years at baseline and had BMI measurements over the first 4 years. ΔBMIs were defined as changing extent (change ≤ or >5%), variability (standard deviation), and trajectories over the first 4 years measured using latent class trajectory modeling. Linear mixed-effect models were utilized to examine the influence of ΔBMIs on changing rates of AD pathology biomarkers, hippocampus volume, and cognitive functions. Cox proportional hazards models were used to test the associations with AD risk. Stratified analyzes were conducted by the baseline BMI group and age. Results: Over the 4-year period, compared to those with stable BMI, individuals who experienced BMI decreases demonstrated accelerated declined memory function (p = 0.006) and amyloid-β deposition (p = 0.034) while BMI increases were associated with accelerated hippocampal atrophy (p = 0.036). Three BMI dynamic features, including stable BMI, low BMI variability, and persistently high BMI, were associated with lower risk of incident AD (p < 0.005). The associations were validated over the 8-year period after excluding incident AD over the first 4 years. No stratified effects were revealed by the BMI group and age. Conclusions: High and stable BMI in late life could predict better cognitive trajectory and lower risk of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various factors, including liver function, which may impact the clearance of amyloid-β (Aβ) in the brain. This study aimed to explore how the apolipoprotein E (APOE) ε4 allele affects the relationship of liver function markers with AD pathology and cognition. Methods: We analyzed data from two independent cohorts, including 732 participants from the Hallym University Medical Center and 483 from the Alzheimer’s Disease Neuroimaging Initiative, each group consisting of individuals with and without the APOE ε4 allele. Cross-sectional analyses evaluated the associations of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, total bilirubin, and albumin) with AD diagnosis, amyloid positron emission tomography (PET) burden, and cerebrospinal fluid biomarkers for AD (Aβ42, total tau, and phosphorylated tau181) at baseline. Longitudinally, we investigated the associations between these liver enzymes and changes in cognitive performance over the course of a year. Logistic and linear regression models were used to analyze these associations and mediation analyses were conducted to assess whether age and amyloid PET burden mediated these associations. Results: Only in the APOE ε4 carrier group, a high AST to ALT ratio and low ALT levels were significantly associated with AD diagnosis, increased amyloid PET burden, and faster longitudinal decline in cognitive function in both cohorts. In particular, the AST to ALT ratio was associated with cerebrospinal fluid Aβ42 levels exclusively in the APOE ε4 carrier group in the Alzheimer’s Disease Neuroimaging Initiative cohort but not with phosphorylated tau181 or total tau levels. Moreover, mediation analyses from both cohorts revealed that in the APOE ε4 carriers group, age did not mediate the associations between liver enzymes and AD diagnosis or amyloid PET burden. However, amyloid PET burden partially mediated the association between liver enzymes and AD diagnosis exclusively in the APOE ε4 carriers group. Conclusion: This study provides valuable insights into the significant association of the APOE ε4 allele with liver enzymes and their potential role in Aβ-related pathogenesis and cognition in AD. Further research is required to elucidate the underlying mechanisms and potential therapeutic implications of these findings. [ABSTRACT FROM AUTHOR]