Aβ Deposition In Brain Research Articles

Intestinal homeostasis disrupted by Periodontitis exacerbates Alzheimer’s Disease in APP/PS1 mice

Periodontitis exacerbates Alzheimer’s disease (AD) through multiple pathways. Both periodontitis and AD are intricately correlated to intestinal homeostasis, yet there is still a lack of direct evidence regarding whether periodontitis can regulate the progression of AD by modulating intestinal homeostasis. The current study induced experimental periodontitis in AD mice by bilaterally ligating the maxillary second molars with silk and administering Pg-LPS injections in APPswe/PS1ΔE9 (APP/PS1) mice. Behavioral tests and histological analyses of brain tissue were conducted after 8 weeks. Gut microbiota was analyzed and colon tissue were also evaluated. Then, fecal microbiota from mice with periodontitis was transplanted into antibiotic-treated mice to confirm the effects of periodontitis on AD and the potential mechanism was explored. The results indicated periodontitis exacerbated cognitive impairment and anxious behaviour in APP/PS1 mice, with increased Aβ deposition, microglial overactivation and neuroinflammation in brain. Moreover, the intestinal homeostasis of AD mice was altered by periodontitis, including affecting gut microbiota composition, causing colon inflammation and destroyed intestinal epithelial barrier. Furthermore, AD mice that underwent fecal transplantation from mice with periodontitis exhibited worsened AD progression and disrupted intestinal homeostasis. It also impaired intestinal barrier function, elevated peripheral inflammation, damaged blood-brain barrier (BBB) and caused neuroinflammation and synapses impairment. Taken together, the current study demonstrated that periodontitis could disrupt intestinal homeostasis to exacerbate AD progression potential via causing gut microbial dysbiosis, intestinal inflammation and intestinal barrier impairment to induce peripheral inflammation and damage BBB, ultimately leading to neuroinflammation and synapse impairment. It underscores the importance of maintaining both periodontal health and intestinal homeostasis to reduce the risk of AD.

Amyloid-Directed Antibodies: Past, Present, and Future.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as "probable AD", and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD. This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD. Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval. This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies. We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies

BackgroundSHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects.MethodsTwo randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg).ResultsSixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed.ConclusionsA single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development.Trial registrationNCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Physical function is associated with cognitive status, brain amyloid-beta deposition, and blood biomarkers in Chinese Han population.

The physical function of elderly individuals reflects whether they have had a history of regular physical activity over the long term. Such indicators have been found to have a certain connection with cognitive function these years. However, there is limited research that associates it with mechanisms such as cerebral Aβ deposition. We aim to investigate this relationship and unveil the underlying mechanisms. Physical function and cognition data of 4189 participants were obtained from the Chinese preclinical Alzheimer's disease study. Participants were divided into six groups according to disease severity. Among them, 1048 participants underwent the positron emission tomography-computed tomography (PET-CT) and plasma biomarker test. Grip strength and gait were combined into a score indicating physical function. Multiple linear regression models and logistic regression models were mainly used to conduct the analysis. There was a significant positive correlation between physical function and cognitive function (R = 0.48, p < 0.001), independent of sex, age, apolipoprotein E-ε4 genotype, and disease stages (p < 0.001). Physical function was effective in distinguishing individuals with cognitive impairment from those without (AUC = 0.835). Physical function was negatively associated with brain Aβ deposition (p = 0.008) and brain Aβ had an intermediary effect (p < 0.01) on the association between physical function and cognition in women. This association was mainly evident in the lateral parietal, lateral temporal, posterior cingulate, frontal, occipital, and precuneus regions. Physical function was negatively associated with plasma neurofilament light-chain (Nfl) level (p < 0.001). Physical function is strongly associated with cognitive function in the Chinese elderly, and brain Aβ deposition partly mediates the linkage in women. Plasma Nfl can be used as a potential target for exercise intervention in cognitive function. Improving physical function will contribute to the alleviation of cognition decline.

Suppressing UBE2N ameliorates Alzheimer's disease pathology through the clearance of amyloid beta.

Aging is one of the risk factors for the early onset of Alzheimer's disease (AD). We previously discovered that the age-dependent increase in Ubiquitin Conjugating Enzyme E2 N (UBE2N) plays a role in the accumulation of misfolded proteins through K63 ubiquitination, which has been linked to AD pathogenesis. However, the impact of UBE2N on amyloid pathology and clearance has remained unknown. We observed the elevated UBE2N during the amyloid beta (Aβ) generation in the brains of 5×FAD, APP/PS1 mice, and patients with AD, in comparison to healthy individuals. UBE2N overexpression exacerbated amyloid deposition in 5×FAD mice and senescent monkeys, whereas knocking down UBE2N via CRISPR/Cas9 reduced Aβ generation and cognitive deficiency. Moreover, pharmacological inhibition of UBE2N ameliorated Aβ pathology and subsequent transcript defects in 5×FAD mice. We have discovered that age-dependent expression of UBE2N is a critical regulator of AD pathology. Our findings suggest that UBE2N could serve as a potential pharmacological target for the advancement of AD therapeutics. Ubiquitin Conjugating Enzyme E2 N (UBE2N) levelwas elevated during amyloid beta (Aβ) deposition in AD mouse and patients' brains. UBE2N exacerbated Aβ generation in the AD mouse and senescent monkey. Drug inhibition of UBE2N ameliorated Aβ pathology and cognitive deficiency.

Correlations between plasma markers and brain Aβ deposition across the AD continuum: Evidence from SILCODE.

Previous studies have found that Alzheimer's disease (AD)-related plasma markers are associated with amyloid beta (Aβ) deposition, but the change of this association in different Aβ pathological stages remains unclear. Data were obtained from the SILCODE. According to the standardized uptake value ratio (SUVR) and Aβ stage classification, correlation analysis was performed among plasma biomarkers, and voxel/SUVR values in the regions of interest (ROI) and clinical scale information, respectively. Mediation analysis was used to study the possible pathways. The proportion of cognitively normal (CN) and subjective cognitive decline (SCD) was the highest in stages A0 to 1, while in stages A2 to 4, the proportion of mild cognitive impairment (MCI) and AD increased. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) levels were significantly lower in stage A0 compared to the later phases. Two pathways demonstrated fully mediated effects: positron emission tomography (PET) SUVR-plasma p-tau181-Mini-Mental State Examination (MMSE) and PET SUVR-plasma GFAP-MMSE. This study demonstrated the role of plasma biomarkers in the early stage of AD, especially in SCD, from both the clinical diagnosis and Aβ stage dimensions. Plasma ptau181 and GFAP level serve as indicators of early Alzheimer's disease and the pathologic Aβ staging classification. A possible ceiling effect of GFAP was observed in the mid-to-late stages of the AD course. This study confirms the role of AD plasma markers in promoting Aβ deposition at an early stage, particularly in females with subjective cognitive decline(SCD). The overlapping brain regions of plasma p-tau181, GFAP, and neurofilament light for Aβ deposition in the brain in early AD were distributed across various regions, including the posterior cingulate gyrus, rectus gyrus, and inferior temporal gyrus.

Association Between Clonal Hematopoiesis of Indeterminate Potential and Brain β-Amyloid Deposition in Korean Patients With Cognitive Impairment.

Few studies have focused on the association between clonal hematopoiesis of indeterminate potential (CHIP) and β-amyloid (Aβ) deposition in the brain, which causes Alzheimer's disease. We aimed to investigate the potential role of CHIP in brain Aβ deposition in Korean patients. We enrolled 58 Korean patients over 50 yrs of age with cognitive impairment who underwent brain Aβ positron emission tomography. We explored CHIP in their peripheral blood using deep-targeted next-generation sequencing. Irrespective of the presence or absence of brain Aβ deposition, mutations in DNMT3A and the C:G>T:A single-nucleotide variants were identified as the primary characteristics, which reflect aged hematopoiesis in the study population. Multivariate logistic regression revealed that the presence of CHIP was not associated with brain Aβ deposition. As both CHIP and brain Aβ deposition are associated with aging, further research is required to elucidate their possible interplay.

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults

Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aβ) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aβ deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aβ deposition were included. Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Baseline levels and longitudinal changes of global Aβ and AD-signature region tau deposition measured by PET scans. Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aβ deposition (β = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (β = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (β = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aβ deposition (β = 0.006; 95% CI, 0.00-0.02; P = .27). The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aβ and tau deposition.

Expression of regional brain amyloid-β deposition with [18F]Flutemetamol in Centiloid scale -a multi-site study.

The Centiloid project helps calibrate the quantitative amyloid-β (Aβ) load into a unified Centiloid (CL) scale that allows data comparison across multi-site. How the smaller regional amyloid converted into CL has not been attempted. We first aimed to express regional Aβ deposition in CL using [18F]Flutemetamol and evaluate regional Aβ deposition in CL with that in standardized uptake value ratio (SUVr). Second, we aimed to determine the presence or absence of focal Aβ deposition by measuring regional CL in equivocal cases showing negative global CL. Following the Centiloid project pipeline, Level-1 replication, Level-2 calibration, and quality control were completed to generate corresponding Centiloid conversion equations to convert SUVr into Centiloid at regional levels. In equivocal cases, the regional CL was compared with visual inspection to evaluate regional Aβ positivity. 14 out of 16 regional conversions from [18F]Flutemetamol SUVr to Centiloid successfully passed the quality control, showing good reliability and relative variance, especially precuneus/posterior cingulate and prefrontal regions with good stability for Centiloid scaling. The absence of focal Aβ deposition could be detected by measuring regional CL, showing a high agreement rate with visual inspection. The regional Aβ positivity in the bilateral anterior cingulate cortex was most prevalent in equivocal cases. The expression of regional brain Aβ deposition in CL with [18F]Flutemetamol has been attempted in this study. Equivocal cases had focal Aβ deposition that can be detected by measuring regional CL.

Inhibition of Alzheimer's disease by 4-octyl itaconate revealed by RNA-seq transcriptome analysis

AimsThis study aimed to examine the therapeutic effects and response mechanisms of 4-OI in Alzheimer's disease (AD). MethodsIn this study, network pharmacology was employed to analyze potential targets for AD drug therapy. Immunofluorescence and quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques were utilized to detect inflammatory phenotypes in a 4-OI-resistant mouse microglia cell line (BV2). We conducted four classical behavioral experiments, namely the open field test, new object recognition test, Y maze test, and Morris water maze, to assess the emotional state and cognitive level of APPswe/PS1dE9 (referred to as APP/PS1) mice after 4-OI treatment. Hematoxylin and eosin (HE) staining, along with immunofluorescence staining, were performed to detect amyloid (Aβ) deposition in mouse brain tissue. To explore the potential molecular mechanisms regulating the effects of 4-OI treatment, we performed RNA-SEQ and transcription factor prediction analyses. Additionally, mouse BV2 cells underwent Western blotting analysis to elucidate potential molecular mechanisms underlying the observed effects. ResultsWe discovered that 4-OI exerts an inhibitory effect on neuroinflammation by promoting autophagy. This effect is attributed to the activation of the AMPK/mTOR/ULK1 pathway, achieved through enhanced phosphorylation of AMPK and ULK1, coupled with a reduction in mTOR phosphorylation. Furthermore, 4-OI significantly enhances neuronal recovery in the hippocampus and diminishes Aβ plaque deposition in APP/PS1 mice, improved anxiety in mice, and ultimately led to improved cognitive function. ConclusionsOverall, the results of this study demonstrated that 4-OI improved cognitive deficits in AD mice, confirming the therapeutic effect of 4-OI on AD.

Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer’s disease

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the predominant type of dementia worldwide. It is characterized by the progressive and irreversible decline of cognitive functions. In addition to the pathological beta-amyloid (Aβ) deposition, glial activation, and neuronal injury in the postmortem brains of AD patients, increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology. Vascular endothelial growth factor (VEGF) plays a critical role in regulating physiological functions and pathological changes in blood vessels, but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear.MethodsWe used an antiangiogenic agent for clinical cancer treatment, the humanized monoclonal anti-VEGF antibody bevacizumab, to block VEGF binding to its receptors in the 5×FAD mouse model at an early age. After treatment, memory performance was evaluated by a novel object recognition test, and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis. Immunofluorescence staining was used to measure glial activation and Aβ deposits. VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting. RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice.ResultsBevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions, reduced glial activation, and restored long-term memory in both sexes of 5×FAD mice. Notably, a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice. Soluble VEGFR1 was decreased in female mice, while full-length VEGFR2 was increased in male mice. Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice. Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood–brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice.ConclusionsOur study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice. These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.

Huanshaodan regulates microglial glucose metabolism reprogramming to alleviate neuroinflammation in AD mice through mTOR/HIF-1α signaling pathway.

Abnormal glucose metabolism in microglial is closely associated with Alzheimer's disease (AD). Reprogramming of microglial glucose metabolism is centered on regulating the way in which microglial metabolize glucose to alter microglial function. Therefore, reprogramming microglial glucose metabolism is considered as a therapeutic strategy for AD. Huanshaodan (HSD) is a Chinese herbal compound which shows significant efficacy in treating AD, however, the precise mechanism by which HSD treats AD remains unclear. This study is aim to investigate whether HSD exerts anti-AD effects by regulating the metabolic reprogramming of microglial through the mTOR/HIF-1α signaling pathway. SAMP8 mice and BV2 cells were used to explore the alleviative effect of HSD on AD and the molecular mechanism in vivo and in vitro. The pharmacodynamic effects of HSD was evaluated by behavioral tests. The pathological deposition of Aβ in brain of mice was detected by immunohistochemistry. ELISA method was used to measure the activity of HK2 and the expression of PKM2, IL-6 and TNF-α in hippocampus and cortex tissues of mice. Meanwhile, proteins levels of p-mTOR, mTOR, HIF-1α, CD86, Arg1 and IL-1β were detected by Western-blot. LPS-induced BV2 cells were treated with HSD-containing serum. The analysis of the expression profiles of the CD86 and CD206 markers by flow cytometry allows us to distinguish the BV2 polarization. Glucose, lactic acid, ATP, IL-6 and TNF-α levels, as well as lactate dehydrogenase and pyruvate dehydrogenase activities were evaluated in the BV2. Western-blot analysis was employed to detect mTOR, p-mTOR, HIF-1α and IL-1β levels in BV2. And the mTOR agonist MHY1485 (MHY) was chosen to reverse validate. In this study, it is found that HSD improved cognitive impairment in SAMP8 mice and reduced Aβ deposition, suppressed the levels of glycolysis and neuroinflammation in mice. In LPS-induced BV2 cells, HSD also regulated glycolysis and neuroinflammation, and suppressed the mTOR/HIF-1α signaling pathway. More importantly, these effects were reversed by MHY. It is demonstrated that HSD regulated microglial glucose metabolism reprogramming by inhibiting the mTOR/HIF-1α signaling pathway, alleviated neuroinflammation, and exerted anti-AD effects. This study provided scientific evidence for the clinical application of HSD for treating AD.

Associations and Potential Multiple Mechanisms between Subjective Hearing Loss and Cognitive Impairment.

Subjective hearing loss (SHL) refers to an individual's self-assessment of their hearing loss. The association and underlying mechanisms between SHL and cognitive impairment still necessitate elucidation. To validate potential mechanisms between SHL and cognitive impairment. Cross-section. Shanghai, China. A total of 2369 individuals from communities and the cognitive disorder clinic. All participants were subjected to a comprehensive neuropsychological assessment, encompassing the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S). The participants' brain β-amyloid (Aβ) deposition status, plasma biomarkers associated with Alzheimer's disease (AD), and cardiovascular risk factors were also collected. In individuals with a heightened SHL, elevated HHIE-S score was linked to diminished cognitive and daily functioning as well as heightened levels of depressed mood. This correlation was observed in auditory memory performance but not in visual memory. The influence of SHL on cognitive function was mediated by depressed mood. SHL was associated with diabetes and smoking, whereas cognitive function was associated with hyperlipidemia and alcohol consumption. In individuals with positive brain Aβ deposition, SHL demonstrated associations with cognitive function independent of plasma Aβ42/40 ratio, P-tau181, neurofilament light chain, and APOE allele status. SHL has an independent effect on cognitive impairment. The findings do no provide evidence for the common cause mechanism. Instead, the findings support the presence of a cognitive resource mechanism and an impoverished environment mechanism, along with the potential for a pathological interaction mechanism.

Nicotinic acetylcholine receptor activation induces BACE1 transcription via the phosphorylation and stabilization of nuclear SP1

Epidemiological studies have shown that cigarette smoking increases the risk of Alzheimer disease. However, inconsistent results have been reported regarding the effects of smoking or nicotine on brain amyloid β (Aβ) deposition. In this study, we found that stimulation of the nicotinic acetylcholine receptor (nAChR) increased Aβ production in mouse brains and cultured neuronal cells. nAChR activation triggered the MEK/ERK pathway, which then phosphorylated and stabilized nuclear SP1. Upregulated SP1 acted on two recognition motifs in the BACE1 gene to induce its transcription, resulting in enhanced Aβ production. Mouse brain microdialysis revealed that nAChR agonists increased Aβ levels in the interstitial fluid of the cerebral cortex but caused no delay of Aβ clearance. In vitro assays indicated that nicotine inhibited Aβ aggregation. We also found that nicotine modified the immunoreactivity of anti-Aβ antibodies, possibly through competitive inhibition and Aβ conformation changes. Using anti-Aβ antibody that was carefully selected to avoid these effects, we found that chronic nicotine treatment in Aβ precursor protein knockin mice increased the Aβ content but did not visibly change the aggregated Aβ deposition in the brain. Thus, nicotine influences brain Aβ deposition in the opposite direction, thereby increasing Aβ production and inhibiting Aβ aggregation.

A randomized, double‐blind, placebo‐controlled phase 1b study to evaluate the safety, tolerability, and pharmacodynamics of an anti‐amyloid‐β antibody SHR‐1707 in patients with mild cognitive impairment and mild Alzheimer’s disease

AbstractBackgroundSHR‐1707 is a humanized monoclonal antibody against amyloid‐β (Aβ). Pharmacodynamic studies in vitro showed that SHR‐1707 is more potent than lecanemab. SHR‐1707 had similar affinity to Aβ fibrils and protofibrils and relatively higher affinity to Aβ monomers than lecanemab. In 5xFAD transgenic mouse model of Alzheimer’s disease (AD), SHR‐1707 safely reduced brain Aβ deposition and ameliorated memory deficits. Phase 1 studies in China (NCT04973189) and Australia (NCT04745104) had demonstrated the safety and tolerability of SHR‐1707 in healthy young adults and elderly subjects at up to 60 mg/kg. The preclinical and clinical evidence support further development of SHR‐1707. Hence, we designed a phase 1b trial of SHR‐1707 to evaluate the safety, effective dosage, and effects on brain Aβ deposition in patients with mild cognitive impairment (MCI) due to AD or mild AD.MethodThis is a randomized, double‐blind, dose‐escalation, placebo‐controlled phase 1b study (NCT05681819; Figure 1). Patients with MCI due to AD or mild AD aged 55‐85 years will be randomized to placebo or intravenous SHR‐1707 at escalated doses of 5, 10, 20, and 40 mg/kg every 2 weeks for 26 weeks. Randomization will be based on the treatment to placebo ratio of 3:2 for 5 mg/kg dose group (N = 5, ≥3 ApoE ε4 carriers) and 10:2 for the remaining dose groups (for each group: N = 12, ≥5 ApoE ε4 carriers). In the following open‐label extension study, all patients will be assigned to SHR‐1707 for 52 weeks. The primary objective is to assess the safety and tolerability of 26‐week treatment of SHR‐1707. Secondary objectives are to assess effects on brain Aβ deposition by positron‐emission tomography, pharmacokinetic and pharmacodynamic profiles in blood and cerebrospinal fluid, immunogenicity, and clinical efficacy with 26‐week treatment of SHR‐1707; and long‐term safety, tolerability, and effects on brain Aβ deposition with 78‐week treatment. Figure 2 lists all study endpoints.ResultThe study is ongoing in China. Topline results are expected in Q1 2024.ConclusionThis trial will obtain safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical efficacy data of SHR‐1707 to support advancement to confirmatory phase 2 or 3 studies in patients with MCI due to AD and mild AD.

Effect of calcineurin/NFAT inhibitors on biomarkers and cognition in a canine model of Alzheimer disease

AbstractBackgroundCalcineurin/NFAT signaling increases in Alzheimer disease (AD) and is associated with neurodegeneration, neuroinflammation, amyloid‐β (Aβ) production, and cognitive decline. Hence, calcineurin/NFAT inhibitors (e.g., tacrolimus and Q134R) are attractive potential therapeutics to improve/prevent AD‐associated cognitive impairments. In AD mouse models, both tacrolimus and Q134R improved cognition and ameliorated neuroinflammation and synapse dysfunction.We hypothesized that 1) chronic low‐dose administration of tacrolimus and Q134R will delay cognitive decline over time in middle‐aged beagles, a model of human brain aging and AD; and 2) canine plasma and CSF biomarkers will be improved with treatment.MethodsCognitive outcomes were evaluated in 37 middle‐aged beagles at baseline and during follow‐up (years 1‐3) by assessing spatial learning [landmark‐discrimination (1, 2 and 4cm)], visual discrimination learning, reversal learning (executive function), and spatial working memory (20‐, 70‐, and 110‐second delays). Dogs were ranked for cognition at baseline and randomized into treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day), and tacrolimus (n = 13; 0.075mg/kg/day). Concentrations of Aβ40, Aβ42, and NfL in plasma and CSF were measured using the Quanterix SIMOA.ResultsAccuracy at all landmark‐discrimination distances declined significantly among controls 20% faster than tacrolimus, and 15% faster than Q134R dogs, at the most difficult distance of 4cm. Accuracy on spatial working memory task declined 21% faster/year among controls than tacrolimus (years 2&amp;3); and 18% faster than Q134R dogs (year 1). Performance on visual discrimination and reversal tasks declined with age but there was no treatment effect.Biomarkers in plasma tended to increase over time with no significant differences between treatment groups. In CSF, relative decreases in Aβ40 and Aβ42 in tacrolimus (2.9 and 2, respectively) and Q134R (5.4 and 3.7, respectively) were less than in control dogs. Finally, relative increases of NfL in tacrolimus and Q134R were less than in control dogs (2.3 and 3.7, respectively).ConclusionBoth tacrolimus and Q134R showed beneficial preventative effects on age‐related decline in spatial functions and memory but not on associative learning nor executive function in a canine model of AD. Finally, only CSF biomarkers tended to improve relative to treatment and are suggestive of less Aβ deposition in brain and higher clearance.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR‐1707 in healthy adult subjects: two randomized, double‐blind, phase 1 studies

AbstractBackgroundSHR‐1707 is a novel humanized anti‐Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques and to promote the microglial phagocytosis of Aβ. Preclinical studies in 5xFAD transgenic mice showed that SHR‐1707 reduced brain Aβ deposition and ameliorated memory deficits. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR‐1707 in healthy adult subjects.MethodTwo randomized, double‐blind, single‐ascending‐dose, phase 1 studies were conducted in China (Study CHN; NCT04973189) and Australia (Study AUS; NCT04745104). Study CHN consisted of 2 parts. In part 1, eligible healthy young adults (18‐45 years) were sequentially randomized 8:2 to receive SHR‐1707 (5 cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in part 2, elderly subjects (55‐80 years) were randomized 8:4 to receive SHR‐1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across 3 dosing cohorts (2, 20, and 60 mg/kg).Result62 (part 1/2, n = 50/12; mean age, 27.0/57.2 years) and 30 subjects (mean age, 26.1 years) were treated in Study CHN and Study AUS respectively. In Study CHN, across all dose levels, all TRAEs were mild in severity, with the most common being laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR‐1707/placebo); the most common TRAEs with SHR‐1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR‐1707 increased in a slightly greater than dose‐proportional manner over the dose range of 2‐60 mg/kg in young adults; there was a dose‐dependent increase in plasma Aβ42 concentration following SHR‐1707 administration compared with the placebo group. The safety and PK/PD profiles of SHR‐1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety and PK/PD of SHR‐1707 was observed.ConclusionA single intravenous dose of SHR‐1707 at 2‐60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK/PD profiles are supportive of further clinical development.

Association between known Alzheimer’s disease risk loci and in vivo brain amyloid pathology in a Korean Cohort

AbstractBackgroundMost genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have been conducted in populations of European ancestry. It is important to determine if known AD‐related variants from these studies are associated with AD biomarkers. Therefore, we investigated the association between known AD risk loci and in vivo brain Aβ deposition in older Korean adults.MethodParticipants (n = 503) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) were analyzed. Older adults who were cognitively normal (CN), had mild cognitive impairment (MCI) or AD dementia (264 CN, 148 MCI, 91 AD) underwent comprehensive assessments including 11C‐PiB‐PET/MRI and blood sampling. Among 76 AD‐related target single nucleotide polymorphisms (SNPs) with genetic evidence compiled by the AD Sequencing Project (ADSP), 38 SNPs with minor allele frequency (MAF)&gt;1% were extracted from TOPMed‐based imputed GWAS genotyping data in KBASE. We employed exploratory univariable logistic regression analysis with Aβ positivity as the dependent variable for each SNP. Then, SNPs with a significance level of p&lt;0.05 were subjected to confirmatory multivariable logistic regression analysis, adjusting for age and sex, with Bonferroni correction.ResultIn the first step of exploratory analyses, we discovered significant differences in Aβ positivity rates between carriers and noncarriers of minor allele of several loci, including rs16824536 in MME, rs11218343 in SORL1, rs4985556 in IL34, rs4277405 in ACE and rs3851179, located in the intergenic region between EED and PICALM. The subsequent confirmatory analysis found an association between these variants and Aβ positivity after adjusting age and sex (Table 1). Notably, the negative association of rs3851179 with Aβ positivity remained significant after correcting for multiple comparisons and after controlling for APOE4 carrier status, age, and sex (OR 0.529, 95% CI 0.345–0.813).ConclusionWe identified associations between several known AD risk loci and Aβ positivity on PET. rs3851179, demonstrated a robust association with in vivo brain Aβ positivity that was independent of APOE4 status. Our findings suggest that rs3851179 may be protective for in vivo Aβ accumulation. Additionally, the findings are needed to be replicated in other populations with different ancestries.

Individualized assessment of brain Aβ deposition with fMRI using deep learning.

PET-based Alzheimer's disease (AD) assessment has many limitations in large-scale screening. Non-invasive techniques such as resting-state functional magnetic resonance imaging (rs-fMRI) have been proven valuable in early AD diagnosis. This study investigated feasibility of using rs-fMRI, especially functional connectivity (FC), for individualized assessment of brain amyloid-β deposition derived from PET. We designed a Graph Convolutional Networks (GCNs) and random forest (RF) based integrated framework for using rs-fMRI-derived multi-level FC networks to predict amyloid-β PET patterns with the OASIS-3 (N = 258) and ADNI-2 (N = 291) datasets. Our method achieved satisfactory accuracy not only in Aβ-PET grade classification (for negative, intermediate, and positive grades, with accuracy in the three-class classification as 62.8% and 64.3% on two datasets, respectively), but also in prediction of whole-brain region-level Aβ-PET standard uptake value ratios (SUVRs) (with the mean square errors as 0.039 and 0.074 for two datasets, respectively). Model interpretability examination also revealed the contributive role of the limbic network. This study demonstrated high feasibility and reproducibility of using low-cost, more accessible magnetic resonance imaging (MRI) to approximate PET-based diagnosis.

Multimodal assessment of brain fluid clearance is associated with amyloid-beta deposition in humans

PurposeThe present study investigates a multimodal imaging assessment of glymphatic function and its association with brain amyloid-beta deposition. MethodsTwo brain CSF clearance measures (vCSF and DTI-ALPS) were derived from dynamic PET and MR diffusion tensor imaging (DTI) for 50 subjects, 24/50 were Aβ positive (Aβ+). T1W, T2W, DTI, T2FLAIR, and 11C-PiB and 18F-MK-6240 PET were acquired. Multivariate linear regression models were assessed with both vCSF and DTI-ALPS as independent variables and brain Aβ as the dependent variable. Three types of models were evaluated, including the vCSF-only model, the ALPS-only model and the vCSF+ALPS combined model. Models were applied to the whole group, and Aβ subgroups. All analyses were controlled for age, gender, and intracranial volume. ResultsSample demographics (N=50) include 20 males and 30 females with a mean age of 69.30 (sd=8.55). Our results show that the combination of vCSF and ALPS associates with Aβ deposition (p < 0.05, R2 = 0.575) better than either vCSF (p < 0.05, R2 = 0.431) or ALPS (p < 0.05, R2 = 0.372) alone in the Aβ+ group. We observed similar results in whole-group analyses (combined model: p < 0.05, R2 = 0.287; vCSF model: p <0.05, R2 = 0.175; ALPS model: p < 0.05, R2 = 0.196) with less significance. Our data also showed that vCSF has higher correlation (r = -0.548) in subjects with mild Aβ deposition and DTI-ALPS has higher correlation (r=-0.451) with severe Aβ deposition subjects. ConclusionThe regression model with both vCSF and DTI-ALPS is better associated with brain Aβ deposition. These two independent brain clearance measures may better explain the variation in Aβ deposition than either term individually. Our results suggest that vCSF and DTI-ALPS reflect complementary aspects of brain clearance functions.