Journals
2025 EN
Chapin Benjamin A · Pendleton Kathryn · Kimmet Faith
+4 more
Abstract Background Preexisting cognitive impairment is a significant risk factor for post operative delirium (POD), and POD increases morbidity and mortality. Disturbances of attention and awareness are necessary for delirium diagnosis, suggesting dysfunction in frontoparietal networks, which control visuospatial attention. However, preoperative visual attention has not been systematically investigated as a risk factor for delirium and adverse longitudinal outcomes in at‐risk adults. We provide an update from the study “Visual Attention and Postoperative Delirium” (AACSF‐22‐928731). Methods In this prospective observational study, participants aged 65 years and older undergoing elective orthopedic surgery completed preoperative visuospatial attention measures, including the Posner cueing task. Our primary outcome was maximum POD severity, measured by the Confusion Assessment Method Severity (CAM‐S) short form. Secondary outcomes included falls, hospital readmission, and Zarit caregiver burden rating, measured three‐months post‐surgery. Data were summarized (i.e., frequencies, mean (SD), and median [Q1, Q3]) and analyzed (i.e., Spearman correlational testing). Results The majority of the 45 participants were female (58%) and white (93%), with mean (SD) age 74.2 (5.4) years and 15.6 (2.7) years of education. 69% were not delirious post‐surgery, 18% were classified as subsyndromal (CAM‐S > 1), and 13% had POD. The delirium score's median [Q1, Q3] value was 0 [0, 2.0]. The median [Q1, Q3] value for stimulus reaction time was 510 ms [463,558]. The correlation coefficient ( p ‐value) between delirium and Posner stimulus reaction time was 0.45 ( p < 0.001). Correlation coefficients were in the expected direction but not significant between Posner stimulus reaction time and three‐month outcomes. Delirium severity was correlated with caregiver burden (0.34, p = 0.044). Conclusion Data continues to demonstrate that preoperative measures of visual attention predict POD. Additionally, POD measured in this study predicts caregiver burden at three months, supporting the importance of this finding. Further studies with more participants can help to determine how to apply measures of visual attention to better predict and monitor the effects of delirium on cognition and neurodegeneration. Understanding this relationship provides a basis for future research on strategies to prevent, mitigate, or rehabilitate the effects of delirium, improving hospital outcomes and potentially delaying or preventing dementia. Funding AACSF‐22‐928731; K07AG066813
Journals
2025 EN
Ornish Dean · Madison Catherine · Kivipelto Miia
+18 more
Abstract Background We report the 40‐week follow‐up of a RCT to examine whether comprehensive lifestyle changes affect the progression of MCI or early dementia due to AD. Earlier results after 20 weeks showed significant improvement in cognition and function. [Ref: Alzheimers Res Ther . 2024 Jun 7;16(1):122. doi: 10.1186/s13195‐024‐01482‐z. PMID: 38849944; PMCID: PMC11157928.] Methods A 1:1 multicenter randomized controlled phase 2 trial, ages 45‐90 with MCI or early dementia due to AD and MoCA score of 18 or higher. After the first 20 weeks, the intervention group continued to receive the lifestyle intervention for a total of 40 weeks. The intervention group was compared to the usual‐care randomized control group after 20 weeks since the control group crossed over and received the lifestyle intervention after 20 weeks. Results Fifty‐one participants with MCI/AD enrolled, mean age 73.5. Active intervention and comparison groups did not differ in any baseline measures. After 40 weeks, there was significant improvement in the intervention group compared to the randomized nonintervention control group in the Clinical Global Impression of Change (CGIC) ( p = 0.000, Figs 1 & 2), Clinical Dementia Rating–Sum of Boxes ( p = 0.036), and Clinical Dementia Rating Global ( p = 0.045). Improvement in Alzheimer's Disease Assessment Scale (ADAS‐Cog) after 20 weeks ( p = 0.053) was not statistically significant after 40 weeks ( p = 0.258). When comparing changes in the intervention group from 20 weeks to 40 weeks, there were significant additional improvements in the CGIC ( p = 0.0000) and CDR‐SB ( p = 0.0082) and no significant differences (i.e., changes were maintained) from 20 to 40 weeks in CDR Global ( p = 0.1596) and ADAS‐Cog ( p = 0.3892). After 20 weeks, the nonintervention control group crossed over and received the lifestyle intervention for 40 weeks. CGIC values are shown in Figure 3. The plasma Aβ42/40 ratio increased in the intervention group from baseline to 40 weeks when compared to the randomized control group ( p = 0.0001). No significant between‐group changes in p ‐tau 217 occurred. Conclusions Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in early dementia due to AD. After 40 weeks, these improvements were maintained in two measures and showed further improvement after 40 weeks in two measures.
Journals
2025 EN
Cashman Neil R · Plotkin Steven S · Napper Scott
+5 more
Abstract Background Toxic misfolded proteins underlie the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (AD&PD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Generation of therapeutic antibodies selectively targeting only disease‐misfolded isoforms, while sparing normal or irrelevant isoforms, has not yet been successfully achieved by conventional immunization strategies. Method ProMIS Neurosciences has developed a computational platform to identify conformational epitopes that are uniquely exposed on toxic misfolded proteins, which can then be used to generate misfolding‐specific antibodies or vaccine formulations. Result Application of the ProMIS platform produced PMN310, a clinical‐stage, humanized monoclonal antibody highly selective for Abeta oligomers without significant reactivity with Abeta monomers or fibrils, thereby avoiding target distraction by these more abundant species, and reducing the risk of brain edema and microhemorrhages associated with the targeting of vascular/parenchymal amyloid. Similarly, specific epitopes for alpha‐synuclein toxic oligomers/soluble fibrils that drive synucleinopathies, and for pathogenic TDP‐43 in ALS/FTD have been identified and lead candidate antibodies generated. The small size and precise conformation of these epitopes have been translated into vaccines, enabling the specific targeting of pathogenic molecular species in preclinical models. Conclusion ProMIS has circumvented the specificity limitations of conventional immunizations to enable selective passive and active immunotherapies for neurodegenerative diseases.
Journals
2025 EN
Wu ChaoYi · Chen Liu · Arnold Steven E
+1 more
Abstract Background With U.S. Food and Drug Administration (FDA)‐approved anti‐amyloid, partially disease‐modifying treatments now available, the ethical justification for randomly assigning patients to placebo has become controversial. The idea of twin‐controls (or virtual‐controls) has gained significant attention in recent years, with the aim of creating twin patient cohorts that can be used as a surrogate to evaluate the effects of treatment on a personalized level. While promising, the feasibility of digital twins techniques remains largely untested. Method I‐CONECT is a multi‐site, single‐blind, randomized controlled trial (RCT) examining the effects of conversational interactions on cognition among socially isolated subjects aged ≥ 75 years (normal cognition; mild cognitive impairment). 186 participants were randomized into experimental or control groups. The experimental group engaged in video chats with study staff 4 times/week for 6 months, while the control groups received weekly 10‐minute phone calls. The current analysis focused on the efficacy‐shown Montreal Cognitive Assessment (MoCA; global cognition) and category fluency animals (CFA; language‐based executive function) at 6‐month follow‐up. Data from the National Alzheimer’s Coordinating Center‐Uniform Data Set (NACC‐UDS) were used to create digital twins for treatment participants through two methods. Method 1 involved twin mapping, matching participants with 1 to 20 twins who had similar demographic, biological, and social factors, and comparing change scores between each participant and their twins. Method 2 used direct modeling by building random forest models to predict change scores as if participants were assigned to a “usual care” control group. Effect sizes were compared between original and twin‐controls trials, as well as between the two methods. Result Approximately 10% of NACC‐UDS participants (5,332 out of 50,259) were eligible for I‐CONECT. For parallel‐group designs, treatment effect sizes on MoCA closely aligned between original (β=1.67) and twin‐control (β=1.46‐1.97) trials when the Euclidean distance mapping was applied. Similar findings were found in CFA (original trial β=2.56; twin‐control trial β=2.31‐3.34). For single‐case, n‐of‐1 designs, methods 1 and 2 showed substantial agreement in identifying treatment responders (Cohen’s Kappa=1 for MoCA; 0.68 for CFA). Conclusion Digital twins from publicly available datasets enhance the rigor of RCTs by providing mapped twins as controls for early‐phase dementia trials.
Journals
2025 EN
Clayton Brent · Massey Steven M · Chu Shaoyou
+10 more
Abstract Background The role of microglia in neuroinflammation is widely recognized as a key contributor to the pathogenesis of Alzheimer’s disease (AD). Genome‐wide association studies have identified PLCγ2 as a key contributor, with specific variants conferring either risk or protection. Notably, the protective PLCγ2•P522R variant is associated with increased mRNA expression, protein levels, and innate activity, whereas the risk variant PLCγ2•M28L shows the opposite trend. Based on these findings, we hypothesize that small molecules capable of enhancing PLCγ2 expression or directly activating the protein could mimic the protective effects of the P522R variant. Such an approach may represent a promising therapeutic strategy to mitigate disease progression and cognitive decline in AD patients. Method We performed high‐throughput screening including DNA Encoded Library (DEL) and Affinity Selection Mass Spectrometry (ASMS) using full‐length protein to identify novel small molecules which bind to PLCγ2. Target engagement was confirmed using Differential Scanning Fluorimetry (DSF) and Cellular Thermal Shift Assay (CETSA). Structure activity relationship (SAR) studies were performed to synthesize analogs and optimize for binding and cellular pharmacology in IP‐One and phagocytosis assays. Top compounds have been studied in vivo to assess pharmacokinetic properties as well as impact on neuroinflammation. Result Novel PLCγ2 activators have been discovered and preliminary optimization has been completed. These compounds have shown positive results for target engagement, biochemical activity, and cellular pharmacology. In silico predictions indicated the molecule structures are suitable CNS drug discovery program starting points. Conclusion Activation of PLCγ2 is a novel therapeutic strategy for treatment of AD. We identified structurally distinct molecular scaffolds capable of enzyme activation and cellular activity. Recommendations for use of probe molecules in target validation studies and the development of lead‐like molecules for clinical studies will be made.
Journals
2025 EN
Hersch Steven · Gee Michelle · Doherty Thomas
+6 more
Abstract Background Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously was shown in the Clarity AD trial to slow the progression of Alzheimer’s disease (AD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady‐state concentrations (Cav, ss) are associated with amyloid plaque lowering and efficacy, while maximum steady‐state concentrations (Cmax, ss) are correlated with ARIA‐E. A subcutaneous lecanemab formulation was hypothesized to have similar or better safety profile, with lower rates of systemic administration reactions. Herein, we provide an update on the clinical results from the subcutaneous lecanemab development program. Methods Clarity AD is a phase 3, double‐blind, placebo‐controlled study of 18‐month treatment duration with an ongoing open‐label extension (OLE) in patients with early AD. Eligible patients were randomized to placebo or 10 mg/kg lecanemab biweekly. Subcutaneous dosing is under development based on pharmacokinetic (PK) and pharmacodynamic (PD) modeling, bioavailability data, as well as clinically in a substudy of the OLE. A subset of participants in the subcutaneous substudy were lecanemab naïve. Validated anti‐drug antibodies (ADA) and neutralizing antibody (Nab) assays were performed using a tiered approach. Results In the Clarity AD phase 3 study, lecanemab subcutaneous weekly dosing with a single 360 mg autoinjector has low rate of ADA (2%) with low titers and maintains plasma biomarkers at levels consistent with inhibition of AD pathology and neuroinflammation; PK was not affected by immunogenicity. From modeling data, initiating subcutaneous maintenance dosing of 360 mg weekly at 18‐ or 24‐months results in similar effect on amyloid PET and CDR‐SB compared to biweekly dosing for 4 years. There was no ARIA‐E, ARIA‐H, or deaths reported in participants receiving 360 mg subcutaneous lecanemab. Injection site reactions were infrequent and mostly of mild or moderate severity. Systemic reactions to subcutaneous treatment were uncommon. Among dosing options tested, lecanemab subcutaneous 360 mg autoinjector was selected as the optimal formulation for maintenance therapy. Conclusions Subcutaneous lecanemab has low‐risk for immunogenicity. Lecanemab, administered subcutaneously, has a safety, tolerability, and pharmacodynamic profile that favorably compares to the approved 10mg/kg biweekly intravenous dose, and autoinjector administration provides greater patient convenience.
Journals
2025 EN
Reyderman Larisa · Penner Natasha · Bhagunde Pratik
+5 more
Abstract Background Lecanemab is a humanized IgG1 monoclonal antibody with high affinity to Aβ soluble protofibrils. In two clinical studies (phase 2 and phase 3 Clarity AD) in early AD, lecanemab substantially reduced amyloid PET and slowed clinical decline on multiple measures of cognition and function, including CDR‐SB at 18 months. Herein, we present the rationale for continued lecanemab dosing with a weekly 360 mg subcutaneous formulation beyond the initial 18‐month treatment, utilizing semi‐mechanistic models and simulations correlating lecanemab exposure with amyloid PET, plasma biomarkers, and clinical outcomes. Methods Models describing the relationship between serum lecanemab exposure, amyloid PET, and CDR‐SB have been previously described. Individual post‐hoc model estimates for pharmacokinetics, PET, and CDR parameters were obtained from Clarity AD subjects who received lecanemab and were used to simulate change in amyloid PET, CDR‐SB, and biomarkers (Ab42/40 ratio, ptau181, and GFAP) over 4 years. Simulations were conducted to evaluate the effect of lecanemab after continuous every 2‐week treatment or after transitioning to 360 mg subcutaneous weekly dosing at 18 months. Results Models included data for 110 months from the lecanemab phase 2 study and 54 months of continuous lecanemab biweekly dosing from Clarity AD. Continued lecanemab treatment with 360 mg subcutaneous dosing resulted in a similar additional reduction of amyloid PET over 4 years of treatment as continued intravenous lecanemab. There were no differences in clinical outcomes (e.g. CDR‐SB) between continued biweekly intravenous doses and 360 mg subcutaneous maintenance dose regimens. The 360 mg subcutaneous formulation weekly dosing maintains plasma biomarker (Aβ42/40, GFAP, p‐tau181) at levels consistent with inhibition of AD pathology and neuroinflammation. Similar effects were observed across all assessments. Conclusions Maintenance subcutaneous lecanemab dosing will reduce the burden for subjects and their caregivers associated with lecanemab administration while still maintaining the efficacy observed with lecanemab biweekly treatment. Modeling indicates that maintenance therapy with subcutaneous lecanemab prevents biomarker re‐accumulation and has no significant meaningful impact on amyloid or meaningful impact on disease progression compared to the intravenous regimen. A subcutaneous formulation has the potential to improve the lecanemab safety profile with a more patient friendly and convenient route of administration.
Journals
2025 EN
Penner Natasha · Rawal Sumit · Aluri Jagadeesh
+6 more
Abstract Background A subcutaneous formulation of the anti‐amyloid antibody lecanemab is being developed to improve patient convenience and safety. Herein, we will give an update on the early development history of subcutaneous lecanemab, including establishing the bioavailability and bioequivalence of a lecanemab subcutaneous formulation relative to the intravenous formulation. Methods Two single‐dose phase 1 clinical trials in healthy adult participants were performed. The first study was a randomized, parallel‐group study in 60 participants evaluating the absolute bioavailability and pharmacokinetic profile of lecanemab when administered subcutaneously in a 700 mg fixed dose compared to 10 mg/kg of intravenous lecanemab. The second study was a randomized, parallel‐group study in 160 participants to establish the bioequivalence of 720 mg subcutaneous lecanemab when administered by vial compared to autoinjector. Concentrations of lecanemab in serum were measured for 50 days, and noncompartmental PK parameters were calculated. Exposure‐response modeling was conducted to predict efficacy for subcutaneous formulations. Results In the bioavailability study (subcutaneous:29; intravenous:30 subjects), mild/moderate injection site reactions were experienced by 6 (20.7%) subjects who received subcutaneous lecanemab, whereas grade 1 and 2 infusion‐related reactions were experienced by 10 (33.3%) subjects who receive intravenous lecanemab. The absolute bioavailability of subcutaneous vial was 49.7% (90% CI: 43.5, 56.8). In the bioequivalence study (vial/syringe:80; autoinjector: 80 subjects), the mean Cmax for vial/syringe (53.7 μg/mL) was lower than the mean Cmax for the autoinjector (67.4 μg/mL). The mean AUC(0‐t) and AUC(0‐inf) were lower for vial/syringe (17,100 and 17,500 ug·h/mL, respectively) compared to the autoinjector (20,600 and 20,900 ug·h/mL, respectively). The half‐life of lecanemab was approximately 7 days in both treatment groups. Autoinjector administration resulted in approximately 25% higher Cmax and 20% higher AUC compared to administration with vial/syringe. The upper 90% CI of the difference in geometric means were outside the standard reference of 125%, therefore bioequivalence of the autoinjector and vial/syringe administrations was not demonstrated. However, based on these results, exposure‐response models predicted similar amyloid plaque lowering and efficacy for intravenous, subcutaneous vial and autoinjector. Conclusions Subcutaneous injection of lecanemab using a vial or autoinjector yielded comparable average steady‐state concentrations to intravenous administration of lecanemab in healthy patients.
Journals
2025 EN
Cohen Sharon · Andreozzi Erica · Hersch Steven
+3 more
Abstract Background Lecanemab is a novel, humanized monoclonal antibody, which has demonstrated the ability to substantially reduce markers of amyloid and slow clinical decline on multiple measures of cognition and function in early Alzheimer’s disease (AD). A subcutaneous administration of lecanemab is in development, to improve patient and caregiver convenience relative to the intravenous route of administration as well as eliminate the time and resources needed for preparation and administration of intravenous infusions. Herein, we highlight the potential benefits and place in therapy for a subcutaneous formulation of lecanemab based on currently available data and relevant literature. Methods Utilizing the currently available data, expert consensus treatment guidelines, and available AD literature, we will place the results of the subcutaneous lecanemab clinical program in context of the current treatment paradigm in early AD. Results of recent human factors validation study which evaluated whether the new lecanemab autoinjector can be safely and effectively used under the expected use environments will also be presented. The human factors study assessed task performance of 110 trained and untrained participants (patients with self‐ or caregiver‐reported diagnosis of mild cognitive impairment or mild AD [n=63], caregivers [n=32], and healthcare providers [HCPs; n=15]) using the lecanemab autoinjector under the expected use environments/conditions without patterns of use error which could cause serious harm to a user, where harm is defined to include compromised medical care (e.g., incomplete dosing). Results The continuous nature of AD pathophysiological process requires ongoing therapy. Given the burden of frequent intravenous injections, a subcutaneous lecanemab formulation would be a welcome addition for providing on‐going maintenance therapy. The newly developed lecanemab autoinjector offers an additional administration option with a weekly dosing schedule while enabling easier administration, increased access to the medication, and reduced burden. The human factors study revealed that a majority of HCPs (80%; 12/15), caregivers (84.4%; 27/32), and patients (82.5%; 52/63) were observed to administer a full dose successfully. Conclusions Weekly subcutaneous lecanemab has the potential for a prominent place in therapy by providing comparable efficacy relative to intravenous formulation with a more convenient and accessible administration by patients, caregivers or HCPs.
Journals
2025 EN
Feldman Howard H. · Messer Karen · Zhang Jing
+17 more
Abstract Background Varoglutamstat (PQ912) is an oral small molecule inhibitor of glutaminyl cyclases which reduces the pyroglutamate formation of Aβ and CCL2. Preclinical and Ph1 trials support this Ph2 evaluation in early AD. Our objectives included selecting the highest safe and well‐tolerated dose of varoglutamstat with futility analysis at 24 weeks (Ph2A) followed by seamless evaluation of longer‐term safety and efficacy at 72 weeks at this dose (Ph2B). Method Participants with biomarker confirmed early AD were randomized to varoglutamstat or placebo. A sequential design tested 3 descending doses (600mg, 300mg, 150mg BID) using a continuous Pocock safety boundary. A Stage Gate futility analysis of the first 180 subjects at 24 weeks was designed to guide the decision from Ph2A‐B (Figure 1). The Ph2B primary endpoint was CDR‐sum‐of‐boxes (CDR‐SB), with secondary endpoints CFC2, ABC score, spectral EEG, FAQ, ADAS‐Cog‐13, and NPI. Result Table 1 presents baseline characteristics of the 109 randomized and dosed participants. The first dose cohort of varoglutamstat 600mg or placebo did not cross the safety boundary in Ph2A, supporting this dose selection for all participants thereafter. An abbreviated futility analysis was conducted after the trial was terminated prematurely for administrative reasons, with the provisional result of ‘halt enrollment’(yellow) (Figure 1). There were 74% of participants who completed week 24 and 31% week 72 (Figure 2). There were no significant differences between varoglutamstat and placebo in LS mean squares from baseline to week 72 in CDR‐SB (‐0.05 [95% CI ‐1.03, 0.92]), CFC2 (0.97 [95% CI ‐3.34, 5.28]), ABC score (0.10 [95% CI ‐0.10, 0.30]), FAQ (‐0.60 [95% CI ‐4.22, 3.01]), ADAS‐Cog‐13 (2.03 [95% CI ‐2.29, 6.36]); or NPI (‐3.09 [95% CI ‐7.81, 1.62]). At least one TEAE during treatment was reported in 84.9% varoglutamstat and 76.8% placebo with treatment discontinuations due to AE 11.3% varoglutamstat and 3.4% placebo. Severe TEAEs occurred with similar frequencies across arms. Frequency of SAEs/AESIs was 18.9/1.9% varoglutamstat versus 8.9%/5.4% placebo. Conclusion Varoglutamstat was safe and well‐tolerated in this VIVA‐MIND early AD RCT. Efficacy assessment did not demonstrate any significant treatment benefits however, the available sample was limited. Biomarker results and PK/PD are pending.