Reduction Of Amyloid Research Articles

Critical assessment of anti-amyloid-β monoclonal antibodies effects in Alzheimer’s disease: a systematic review and meta-analysis highlighting target engagement and clinical meaningfulness

Despite most monoclonal antibodies against Aβ in Alzheimer’s failed to demonstrate efficacy, the newest antibodies showed statistically significant clinical effects. We conducted a systematic review and meta-analysis to assess the efficacy, target engagement, and safety of anti-Aβ antibodies in sporadic AD including phase III RCTs published up to November 28, 2023. Antibodies as a drug class, attenuated worsening on the clinical scales CDR-SB and ADAS-Cog by very small effect sizes and reduced amyloid on PET by a very large effect size. Reduction of amyloid on PET was moderately correlated with CDR-SB and ADAS-Cog reductions. However, antibodies increased risk of ARIA-E and ARIA-H by a very large and moderate effect size, respectively. In subgroup analyses by individual drug, Donanemab and Lecanemab induced the largest benefits. In subgroup analyses by binding affinity, antibodies without binding to monomers were associated with the most favorable effects. Despite statistical significance for improvement on clinical measures, antibody effects were below the threshold of clinically meaningful change during the period they were studied. However, the newest antibodies demonstrably interfere with the underlying ΑD pathophysiology and therefore their benefit could be cumulative over time leading to larger clinical effects in subsequent years. PROSPERO registration no. CRD42022381334.

Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer's disease trials.

Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: -0.55; 95% CI: -0.89, -0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: -0.16; 95% CI: -0.26, -0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ-PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.

The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid β levels in Alzheimer's disease model mice.

Alzheimer's disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., App NL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, we treated AD model mice with CDDO-2P-Im. We found that Aβ42 levels were markedly greater in the brains of AppNLGF mice than in those of APP/TAU mice. CDDO-2P-Im treatment significantly decreased Aβ42 levels, but not Aβ40 levels, in APP/TAU mice. Consequently, CDDO-2P-Im also decreased the ratio of Aβ42/Aβ40, a vital marker of amyloid plaque formation. LC-MS/MS analyses revealed that CDDO-2P-Im was delivered to the brains of the APP/TAU mice. CDDO-2P-Im induced the expression of detoxification and antioxidant gene targets of NRF2 and elevated reduced glutathione (GSH) levels in the mouse brain. These results support the notion that CDDO-2P-Im ameliorates AD-related pathologic changes.

Air pollution amyloidogenesis is attenuated by the gamma-secretase modulator GSM-15606.

Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild-type and AD-transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments. We examined the γ-secretase modulator GSM-15606 for potential AirPoll protection by its attenuating of amyloid beta (Aβ)42 peptide production. Male and female wild-type mice were fed GSM-15606 during an 8-week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP). GSM-15606 decreased Aβ42 during nPM and DEP exposure without changing beta- or gamma-secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%. These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aβ42 peptide. GSM-15606 attenuation of Aβ42 may benefit human exposure to AirPoll. Gamma-secretase modulator (GSM-15606) attenuates the amyloidogenic amyloid beta (Aβ)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aβ homeostasis among the chronic effects of GSM-15606 and other amyloid reduction treatments on secretase enzymes.

Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease

Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. ClinicalTrials.gov Identifier: NCT04623242.

Sulfonamide Derivatives: Recent Compounds with Potent Anti-alzheimer's Disease Activity.

Facile synthetic procedures and broad spectrum of biological activities are special attributes of sulfonamides. Sulfonamide derivatives have demonstrated potential as a class of compounds for the treatment of Alzheimer's disease (AD). Recent sulfonamide derivatives have been reported as prospective anti-AD agents, with a focus on analogues that significantly inhibit the function of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and exhibit remarkable antioxidant and anti-inflammatory properties, all of which are critical for the treatment of AD. Sulfonamide- mediated activation of nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the endogenous antioxidant response, has also been suggested as a potential therapeutic approach in AD. Additionally, it has been discovered that a number of sulfonamide derivatives show selectivity for the β- and γ-secretase enzymes and a significant reduction of amyloid B (Aβ) aggregation, which have been implicated in AD. The comparative molecular docking of benzenesulfonamide and donepezil, an AD reference drug showed comparable anti-AD activities. These suggest that sulfonamide derivatives may represent a new class of drugs for the treatment of AD. Thus, the current review will focus on recent studies on the chemical synthesis and evaluation of the anti-AD properties, molecular docking, pharmacological profile, and structure-activity relationship (SAR) of sulfonamide derivatives, as well as their potential anti-AD mechanisms of action. This paper offers a thorough assessment of the state of the art in this field of study and emphasizes the potential of sulfonamide derivatives synthesized during the 2012-2023 period as a new class of compounds for the treatment of AD.

Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice.

Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible. Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality-edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges. Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aβ42 and the plasma Aβ42/ Aβ40 ratio-fluid biomarkers to detect central amyloid negativity-is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10mg/kg (mpk) lecanemab, 10mpk aducanumab, and 20mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period. This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

What Threshold of Amyloid Reduction Is Necessary to Meaningfully Improve Cognitive Function in Transgenic Alzheimer's Disease Mice?

Amyloid-β plaques (Aβ) are associated with Alzheimer's disease (AD). Pooled assessment of amyloid reduction in transgenic AD mice is critical for expediting anti-amyloid AD therapeutic research. The mean threshold of Aβ reduction necessary to achieve cognitive improvement was measured via pooled assessment (n = 594 mice) of Morris water maze (MWM) escape latency of transgenic AD mice treated with substances intended to reduce Aβ via reduction of beta-secretase cleaving enzyme (BACE). Machine learning and statistical methods identified necessary amyloid reduction levels using mouse data (e.g., APP/PS1, LPS, Tg2576, 3xTg-AD, control, wild type, treated, untreated) curated from 22 published studies. K-means clustering identified 4 clusters that primarily corresponded with level of Aβ: untreated transgenic AD control mice, wild type mice, and two clusters of transgenic AD mice treated with BACE inhibitors that had either an average 25% "medium reduction" of Aβ or 50% "high reduction" of Aβ compared to untreated control. A 25% Aβ reduction achieved a 28% cognitive improvement, and a 50% Aβ reduction resulted in a significant 32% improvement compared to untreated transgenic mice (p < 0.05). Comparatively, wild type mice had a mean 41% MWM latency improvement over untreated transgenic mice (p < 0.05). BACE reduction had a lesser impact on the ratio of Aβ42 to Aβ40. Supervised learning with an 80% -20% train-test split confirmed Aβ reduction was a key feature for predicting MWM escape latency (R2 = 0.8 to 0.95). Results suggest a 25% reduction in Aβ as a meaningful treatment threshold for improving transgenic AD mouse cognition.

Examining amyloid reduction as a surrogate endpoint through latent class analysis using clinical trial data for dominantly inherited Alzheimer's disease.

Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes. LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.

Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies.

With the FDA approval of aducanumab and lecanemab, and with the recent statistically significant phase 3 clinical trial for donanemab, there is growing enthusiasm for anti-amyloid antibodies in the treatment of Alzheimer's disease. Here, we discuss three substantial limitations regarding recent anti-amyloid clinical trials: 1) there is little evidence that amyloid reduction correlates with clinical outcome, 2) the reported efficacy of anti-amyloid therapies may be explained by functional unblinding, and 3) donanemab had no effect on tau burden in its phase 3 trial. Taken together, these observations call into question the efficacy of anti-amyloid therapies.

Evaluation of the cerebral vascular morphostructural in a model for Alzheimer’s disease after the intervention with physical exercise.

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disease in the world. It is characterized by impaired memory, thinking, orientation, and learning, thus affecting the quality of life of people whosuffer from it. The two pathognomonic hallmarks are the neuritic plaques and neurofibrillary tangles, however, the vascular system is also affected, aggravating the symptoms of the disease, being a possible hypothesis of the development of the disease. One of the most widely used animal models to study disease mechanisms is the 3xTg‐AD triple transgenic mouse that contains three mutations associated with familial AD (PS1M146V, APPSWE, and tauP301L). Among the non‐pharmacological treatments is physical exercise, which is a variety of planned, repetitive, and dosed physical activity, proving to be safe as part of the adjuvant treatment of the disease, however, its effect on the vascular system is unknown.MethodA total of 40 ten‐month‐old female mice, 3xTg‐AD (n = 20) and NonTg (n = 20), equally divided into exercise and sedentary groups, were used. An intervention of voluntary physical exercise was carried out for 3 months with a frequency of 5 times a week. Subsequently, memory and learning were evaluated using the Barnes maze test. The vascular morphostructure by anatomical analysis through histological assays using markers for vascular basement membrane (anti‐Collagen IV) and pericytes (anti‐PDGFR‐β), in addition to amyloid deposits. No improvement in cognitive ability was observed, however, exercise promoted the recovery of the vascular system, as well as the reduction of amyloid deposits.ResultNo improvement in cognitive ability was observed, however, exercise promoted the recovery of the vascular system, as well as the reduction of amyloid deposits.ConclusionThe intervention with voluntary physical exercise promotes stability of the vascular system as well as the reduction of amyloid deposits in the symptomatic stages of the disease.

The Therapeutic Landscape of Tauopathies: Evaluating the Tau Pipeline

AbstractBackgroundMany disease modifying therapeutics for neurodegenerative diseases (NDs) have focused on the reduction of amyloid, neuroinflammation and synaptic plasticity. Many NDs include tau pathology either with amyloid deposits or without. These NDs can collectively classified as tauopathies. We have provided an overview of the therapeutic landscape of programs targeting tauopathies covering drug candidates in the clinical development as well as programs still in discovery and the preclinical stages.MethodSearch results from targeted queries and key word searches for MAPT and tau were carried out on GlobalData and SciFinder databases as the principal sources of information. Company websites, PubMed and conference proceedings were also researched for additional information. All data presented here is current to Aug. 31, 2022. All therapeutics in clinical phases I, II and III, as well as in preclinical development and discovery phase were included.ResultThe majority of therapeutic approaches focused on tau by directly targeting Microtubule Associated Protein Tau (MAPT) although indirect mechanisms also afford strategies that may ultimately affect tau. Our search through the end of August 2022 showed that the tau landscape currently contains 160 compounds, of which 38 are in clinical development. Of those, a total of 135 drugs directly target MAPT, with 33 of them combining MAPT with other mechanisms, mostly alpha synuclein (α‐syn) or amyloid protein targets. There is a growing variety of modalities that are being explored in targeting tau, with small molecules remaining dominant accounting for approximately 44% of all molecules in development. There were 18 therapies in both phase I and phase II clinical trials, and only one currently in phase three. There were also two therapies currently with an IND/CTA filing in process.ConclusionThere has been a significant increase in the number of researchers focusing on tau as a main therapeutic approach. The landscape of anti‐tau therapeutic agents is growing but special consideration should be given to primary tauopathies which do not share the amyloid burden of other NDs like Alzheimer’s disease, and do not share in the recent success of approved anti‐amyloid therapeutics.

AL002c‐mediated reduction in amyloid β pathology is reflected by changes in plasma Alzheimer’s disease biomarkers in 5XFAD mice

AbstractBackgroundThe R47H variant of the triggering receptor expressed on myeloid cells‐2 (TREM2) gene increases the risk for late‐onset Alzheimer’s disease (LOAD) and reduces TREM2 ligand binding in vitro, suggesting that enhancing TREM2 signaling has therapeutic potential in AD. AL002 is a novel humanized monoclonal Immunoglobulin G1 (IgG1) antibody that targets TREM2 and is currently being tested in a phase 2 trial in patients with early AD. Previously, AL002c, a variant of AL002, reduced filamentous amyloid β (Aβ) plaques and neurite dystrophy and increased inert plaques in a 5XFAD mouse model, while other Aβ pathology measures did not show treatment effects. Total Aβ42/40 ratio in plasma is inversely associated with amyloid burden independent of AD clinical diagnosis2 and is being used as a biomarker in AD clinical trials.3 To further evaluate the impact of AL002c on Aβ pathology, the present study assessed plasma AD biomarkers, including Aβ42/40 ratio, in residual samples from these 5XFAD mice.MethodFive‐month‐old 5XFAD mice (N = 32, n = 6‐13 per group) expressing either common variant (CV) or R47H variant human TREM2 (hTREM2), but lacking endogenous mouse Trem2, were injected intraperitoneally with 30 mg/kg AL002c or control mouse IgG1 weekly for 12 weeks (Figure 1). Levels of plasma Aβ42, Aβ40, and total tau (t‐tau) were quantified using Simoa® assay (Quanterix).ResultAL002c‐treated CV‐5XFAD and R47‐5XFAD mice had a higher plasma Aβ42/40 ratio (CV‐5XFAD p &lt;0.001; R47‐5XFAD p&lt;0.05; pooled CV and R47‐5XFAD p &lt; 0.01) and lower plasma t‐tau (CV‐5XFAD p &lt;0.05; R47‐5XFAD p&lt;0.001; pooled CV and R47‐5XFAD p &lt; 0.01) compared with their IgG1‐treated genotype counterparts (Figure 2). No differences were observed between R47H and CV genotypes in plasma Aβ42/40 ratio or t‐tau.ConclusionAL002c‐associated changes in plasma Aβ42/40 and tau were consistent with a concomitant reduction in filamentous plaques and neurite dystrophy.1 These results lend further support to the clinical utility of plasma Aβ42/40 as a marker for the reduction of neurotoxic amyloid plaques in clinical trials with AL002.

Lecanemab: Amyloid Reduction and Evidence of Downstream Biomarker Modification

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils) which has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in a Phase 3 Study in early AD (Study 301). The objective of this analysis is to report biomarker results from Study 301.MethodsStudy 301 was a double‐blind, randomized, placebo‐controlled study of 1875 patients with early AD randomized to 10 mg/kg IV lecanemab or placebo for 18 months of treatment. Plasma, CSF, and imaging biomarkers of amyloid, tau, neurodegeneration, and gliosis were assessed.ResultsLecanemab met all primary and key secondary clinical endpoints with a high degree of statistical significance. Lecanemab improved markers of amyloid with reduction of brain amyloid by PET in as early as 3 months and improvement in CSF Aß42 and plasma Aß42/40. Biomarkers of tau showed improvement in CSF and plasma p‐tau181, and slowing of tau accumulation relative to placebo in the medial temporal regions by tau PET. For biomarkers of neurodegeneration and gliosis, there was improvement in CSF t‐tau, CSF neurogranin, and plasma GFAP. There were no significant differences in CSF or plasma Nf‐L between lecanemab and placebo. Volumetric MRI results were inconsistent, with reduced hippocampal atrophy on lecanemab, but greater cortical volume loss relative to placebo, possibly “pseudoatrophy” related to amyloid mobilization.ConclusionsLecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Improvements in biomarkers of amyloid, tau, neurodegeneration, and gliosis provide a biological basis for the treatment effects consistent with disease modification.

Toxoplasma gondii‐induced amyloid reduction and neuroimmune responses in Alzheimer’s disease

AbstractBackgroundToxoplasma gondii is a foodborne parasite that induces monocyte recruitment and microglial activation during infection of the brain. Similarly, in Alzheimer’s disease (AD), activated immune cells are often found in the brain and these localize near amyloid beta plaques. However, after infection with T. gondii in AD mouse models, there are fewer amyloid beta plaques in the brain, increased microglial activation, and decreased severity of AD symptoms. We hypothesize that T. gondii infection activates and enhances the phagocytic ability of microglia to clear amyloid beta.MethodFemale 5xFAD mice were infected with T. gondii or PBS treated, and their brains harvested after 6 weeks of infection. Brain tissue from these animals was analyzed for amyloid (Amyloglo) and immune cell markers for microglia, monocytes, and T cells (IBA1, CD68, CD11c, CD11b, CD45, CD3) by light sheet imaging, confocal microscopy, or flow cytometry. Mice were also fitted with headplates and cranial windows and injected with methoxy‐X04 (10 mg/kg) to enable longitudinal imaging of amyloid over the span of infection.ResultConfocal microscopy of brain sections and light sheet imaging of intact brains from infected and uninfected 5xFAD mice have shown increased microglial activation markers (IBA1 and CD68) and decreased amyloid surface area and volume throughout infected brains in infected animals. Infected mouse brains also have increased co‐localization of amyloid and CD68 compared to uninfected mouse brains. Two‐photon imaging reveals that amyloid plaque area in vivo no longer increases in infected mouse brains as early as three weeks post‐infection and lasts as long as thirteen weeks post‐infection. Additionally, after six weeks of infection, we see an increase in Disease Associate Microglia (DAM) by flow cytometry, as well as an influx of other immune cells in the brain of infected mice as compared to PBS treated control mice.ConclusionOur data show that infection with T. gondii increases microglial markers associated with the DAM profile and these cells likely increase phagocytosis of amyloid beta. Infection with T. gondii appears to modulate the neuroimmune environment, including responding microglial cells, resulting in a neuroprotective phenotype.

Exposure‐response modeling to describe the change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. Lecanemab has been tested as a disease‐modifying treatment for early Alzheimer’s disease in two clinical studies (NCT01767311 and CLARITY‐AD, NCT03887455). As part of these studies, amyloid PET scans were collected in a subset of patients, demonstrating that lecanemab leads to pronounced reduction in brain amyloid.MethodA model describing the relationship between serum lecanemab exposure and brain amyloid reduction from baseline was developed using data pooled from Phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population PK model and correlated with amyloid PET using an indirect response model, with a lecanemab‐dependent increase in the degradation rate of amyloid, introduced as linear function. The model was parametrized in terms of baseline amyloid load, elimination rate constant for amyloid removal (Kout) and exposure effect (DESLP). Inter‐subject variability was estimated for each of the model parameters. Covariates were included in the model using a forward‐inclusion (p&lt;0.01) /backwards‐elimination (p&lt;0.001) approach.ResultA total of 4129 observations from 1088 subjects were included in the dataset. The model estimate of Kout was 0.0496 yr−1 (95% confidence interval: 0.0206, 0.0827), suggesting a re‐accumulation half‐life of brain amyloid of ∼14 years. APOE4 carrier status (homozygous and heterozygous together) was a statistically significant predictor of baseline amyloid (APOE4 noncarriers: 65 CL; APOE4 carriers: 83 CL). Age was a significant covariate on DESLP, with older patients removing amyloid at a faster rate than younger patients. None of the other covariates explored, including presence of antidrug antibodies or baseline MMSE score, had a statistically significant effect on any model parameter.ConclusionAn exposure‐response model has been developed that describes the change in brain amyloid over time during treatment with lecanemab and after stopping lecanemab treatment. This model provides additional insights into factors that may drive differences in the rate of brain amyloid removal between patients.

Developing Topics.

TRAILBLAZER-ALZ 4 demonstrated superiority of donanemab versus aducanumab at the 6-month primary endpoint of the percentage of participants achieving amyloid plaque clearance (<24.1 Centiloids [CL]) in patients with early symptomatic AD (Salloway et al. CTAD 2022). Participants (n = 148) were randomized 1:1 to receive donanemab (titration: 700mg IV Q4W [first 3 doses], then 1400mg IV Q4W [subsequent doses]) or aducanumab (titration per USPI: 1mg/kg IV Q4W [first 2 doses], 3mg/kg IV Q4W [next 2 doses], 6mg/kg IV Q4W [next 2 doses] and 10mg/kg IV Q4W [subsequent doses]). The study is ongoing with a total duration of 18 months. Baseline demographics and characteristics were well-balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty-seven donanemab-treated and 28 aducanumab-treated participants had low/medium (intermediate) tau levels based on screening tau PET scans. In all participants at 12 months, 70.2%±6.3% (least square [LS] mean ± standard error [SE]) donanemab-treated vs. 21.9%±5.9% aducanumab-treated participants achieved amyloid plaque clearance (p<0.001) assessed by florbetapir F18 PET scans. In the low/medium tau subpopulation, 80.0%±9.9% donanemab-treated vs. 9.6%±5.4% aducanumab-treated participants achieved amyloid clearance (p<0.001). The percent change (LS mean ± SE) in brain amyloid levels were -82.8%±3.1% (baseline [LS mean ± standard deviation]: 97.59±28.20 CL) and -57.0%±3.1% (baseline: 102.71±35.30 CL) in donanemab and aducanumab arms, respectively (p<0.001). In the low/medium tau subpopulation, percent change in brain amyloid levels were -82.7%±4.6% (baseline: 104.97±25.68 CL) and -57.0%±4.5% (baseline: 102.99±27.87 CL) in donanemab and aducanumab arms, respectively (p<0.001). Adverse events occurred in 78.9% of donanemab-treated and 82.6% of aducanumab-treated participants, respectively. Amyloid-related imaging abnormalities occurred in 29.6% (1.4% serious [n = 1]) and 40.6% (2.9% serious [n = 2]) of participants in the donanemab and aducanumab arms, respectively, with higher rates in ApoE4 carriers. TRAILBLAZER-ALZ 4 provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD and demonstrates the higher brain amyloid reduction of donanemab vs. aducanumab at 12 months when drug titration has been completed and the treatment regime has stabilized.

Use of Zinc Nanoparticles and/or Prodigiosin to Mitigate Heat Stress in Rabbits

Abstract Heat stress (HS) is an environmental challenge affecting animals’ health, productivity and welfare. This work aimed to inspect the protective effect of zinc oxide nanoparticles (ZnNPs) and/or prodigiosin (PRG) against inflammation, immune dysfunction, oxidative stress and endoplasmic reticulum (ER) stress triggered by HS in growing rabbits. Growing weaned rabbits (one hundred males, 35 days of age) were randomly assigned into four groups. The first group was fed a basal diet without supplementation and the 2nd, 3rd, and 4th groups were fed diets containing zinc oxide nanoparticles (ZnNPs, 50 mg/kg diet), prodigiosin (PRG, 100 mg/kg diet) or their mixture (ZnPRG) under HS conditions for eight successive weeks. The dietary inclusion with ZnNPs and/or PRG significantly boosted FBW (final body weight), CBWG (cumulative body weight gain), and FCR (feed conversion ratio) and had no substantial impacts on the CFI (cumulative feed intake) as compared with those in HS one. All supplemented treatments significantly unveiled an increase in the values of RBCs, hemoglobin, and platelets and significant decreases in WBCs, basophils and monocytes with non-statistical effects on hematocrit, MCV, MCHC, neutrophils and eosinophils. Compared with the HS group, all supplemental groups showed a significant reduction in TNFα, IL4, IFN-γ, TLR-4 and amyloid A levels and DNA damage markers (OHdG) and significant increases in the levels of NO and lysosome activity. Rabbits in the ZnPRG group had significantly higher IgG and IgM levels compared to other groups. The highest value of CAT and GSH levels were found in rabbits that received the mixture of ZnNPs (50 mg) and prg (100 mg) in their diets under elevated temperatures. Additionally, both treatments, PRG and ZnNPS, significantly (P&lt;0.001) reduced the values of MDA and MYO, while all treated groups had significantly reduced PC contents compared with the HS group. Co-supplement with ZnPRG showed a considerable restoration in the higher immune expression of reticulum oxidative stress such as GRP78 and IRE1 in hepatic tissues induced by hs conditions. The mixture of ZnNPS and prg presented more robust effects in mitigating the adverse impacts of hs in rabbits compared with the individual treatments. Collectively, ZnNps and/or PRG alleviated oxidative stress and dna damage. In addition, it enhanced the antioxidant capacity and immune function, and downregulated ER stress such as GRP78 and IRE1 signaling in the hepatic tissues of stressed rabbits.