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Introduction: A quantitative model of Alzheimer's disease (AD) based on the amyloid/tau/neurodegeneration biomarker framework (Q‐ATN model) was developed to sequentially link amyloid positron emission tomography (PET), tau PET, medial temporal cortical thickness, and clinical outcome (Clinical Dementia Rating – Sum of Boxes; CDR‐SB). Methods: Published data and biologically plausible mechanisms were used to construct, calibrate, and validate the model. Clinical trial simulations were performed for different anti‐amyloid antibodies, including a 5‐year simulation of subcutaneous gantenerumab treatment. Results: The simulated time‐course of biomarkers and CDR‐SB was consistent with natural history studies and described the effects of several anti‐amyloid antibodies observed in trials with positive and negative (or non‐significant) outcomes. The 5‐year simulation predicts that the beneficial effects of continued anti‐amyloid treatment should increase markedly over time. Discussion: The Q‐ATN model offers a novel approach for linking amyloid PET to CDR‐SB, and provides theoretical support for the potential clinical benefit of anti‐amyloid therapy. Highlights: A semi‐mechanistic model was developed to link amyloid/tau/neurodegeneration biomarkers to clinical outcome (Q‐ATN model).The Q‐ATN model describes the disease progression seen in natural history studies.Model simulations agree well with mean data from the aducanumab EMERGE study.A 5‐year simulation of gantenerumab predicts greater benefit with longer treatment. [ABSTRACT FROM AUTHOR]

Background: GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two Phase III trials that investigated the efficacy and safety of gantenerumab, a subcutaneous fully human monoclonal antibody that binds aggregated forms of amyloid‐beta, in participants with early Alzheimer's disease (AD). Although the studies did not meet their primary endpoints, participant characteristics that might influence response to gantenerumab were evaluated. Method: Eligible participants with early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) were randomized 1:1 to receive gantenerumab or placebo. Gantenerumab‐treated participants were up‐titrated to 510 mg subcutaneous gantenerumab every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Secondary endpoints of cognition (ADAS‐Cog13) and function (ADCS‐ADL, FAQ) were assessed. Pre‐specified and exploratory post‐hoc subgroup analyses on these endpoints were performed. Result: Across endpoints, there were consistent trends towards larger point estimates of gantenerumab treatment effect compared with placebo at Week 116 in males (using CDR‐SB as representative example: GRADUATE I: 16% relative reduction (RR); GRADUATE II: 17% RR) vs females (GRADUATE I: 3% RR; GRADUATE II: –2% RR) and participants with MCI (GRADUATE I:15% RR; GRADUATE II:10% RR) vs mild AD (GRADUATE I: 4% RR; GRADUATE II: 2% RR). This pattern was not consistently seen when using CDR‐Global Score (0.5 vs >0.5) to define disease stage. Compliers, defined as participants who received ≥90% of the intended cumulative dose, had an increased point estimate of treatment effect (CDR‐SB: GRADUATE I: 17% RR; GRADUATE II: 18% RR) vs non‐compliers (CDR‐SB: GRADUATE I: –1% RR; GRADUATE II: –3% RR). In a pooled analysis, a larger point estimate of treatment effect vs placebo was observed in East‐Asian vs Non‐East‐Asian countries (CDR‐SB: RR 38% vs 5%). The East‐Asian population had lower baseline weight, greater treatment compliance, and accordingly higher plasma exposure, than the Non‐East‐Asian population, suggesting this observation is not driven by racial differences in treatment response. Conclusion: Subgroup analyses in the GRADUATE studies provide insights into participant characteristics that may influence the degree of clinical response to gantenerumab treatment. Higher gantenerumab exposure may result in greater clinical efficacy. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab is a subcutaneous fully human monoclonal antibody targeting aggregated forms of amyloid‐beta. Phase III GRADUATE I (NCT03444870) and II (NCT03443973) trials were designed based on previous key learnings to provide evidence on the benefit:risk profile of subcutaneous gantenerumab in early symptomatic AD. Although primary endpoints were not met, gantenerumab showed treatment effects on amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) and plasma biomarkers. Correlations of biomarkers with clinical outcomes in the GRADUATE studies were assessed to further evaluate their utility. Method: Participants aged 50‐90 years with mild cognitive impairment due to AD or mild AD dementia were randomised 1:1 to subcutaneous gantenerumab or placebo. Gantenerumab was up‐titrated over 36 weeks to target dose of 510 mg every 2 weeks. Changes in amyloid centiloid levels were obtained from [18F]Florbetaben or [18F]Flutemetamol PET. Regional changes in tau standardised uptake value ratio were obtained with [18F]GTP1 PET. Whole brain and regional atrophy were assessed via volumetric MRI. Fluid pharmacodynamics biomarkers were measured using Elecsys® immunoassays from Roche Diagnostics. Result: Significant (but not corrected for multiple testing) treatment effects of gantenerumab on change from baseline to Week 116 were observed for CSF biomarkers (pooled GRADUATE I and II population) including Aβ40 (–10.42%, p = 0.0188), Aβ42 (26.06%, p<0.0001), tTau (–16.49%, p<0.0001), pTau181 (–23.35%; p < 0.0001), NfL (10.76%; p = 0.0159), GFAP (–5.49%; p = 0.0003), and plasma biomarkers including Aβ42 (GRADUATE I: 65.1%, p<0.0001; GRADUATE II: 54.9%, p<0.0001) and pTau181 (GRADUATE I: –17.2%, p<0.0001; GRADUATE II: –15.3%, p<0.0001). Preliminary biomarker analyses showed changes in amyloid PET in gantenerumab‐treated participants had a numerically higher correlation with changes in plasma Aβ42 (R = –0.43), versus pTau181 (R = 0.34) and GFAP (R = 0.16). Biomarker changes in subgroups will also be presented. Conclusion: Phase III GRADUATE I and II study results provide evidence of the effect of subcutaneous gantenerumab on biomarkers of AD pathology and neurodegeneration in subgroups. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia). Method: Eligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed. Result: GRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL). Conclusion: The GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined. [ABSTRACT FROM AUTHOR]

Background: A number of extended families in Colombia with early‐onset ADAD have a PSEN1 mutation at codon 280 (E280A), comprise the largest ADAD kindred in the world. Trial participants have been treated with crenezumab (an experimental anti‐amyloid monoclonal antibody) or placebo. Topline results were presented in August, 2022 at AAIC. Although the trial did not demonstrate a statistically significant clinical benefit in either of its co‐primary endpoints, multiple statistical innovations were incorporated into this trial. Method: The API ADAD Colombia trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 2b study evaluating the efficacy, safety, and tolerability of crenezumab in cognitively unimpaired ADAD PSEN1 E280A mutation carriers in Colombia (NCT01998841). Due to under enrollment and concerns with the sensitivity of the primary endpoint, the protocol was amended mid‐trial to change from 260 weeks of treatment to a common‐close design whereby treatment continued in the double‐blind portion until the last enrolled participant received 260 weeks of treatment. Because of the change in trial design and power considerations, the primary analysis was adapted from a traditional mixed model with repeated measures (MMRM) based analysis to a random coefficient regression model (RCRM) based analysis. To quantitatively examine the adequacy of the RCRM assumptions, a robust variance estimator (Huber 1967; White 1982) was prespecified as a sensitivity analysis to calculate the standard errors and p‐values of the co‐primary endpoints. This study used a type‐I‐error‐controlled statistical procedure to identify and elevate the Free and Cued Selective Reminding Test (FCSRT) cueing index to a co‐primary endpoint. To comprehensively assess the crenezumab effect across primary and secondary endpoints, the prespecified relative reduction point estimates along with the bootstrapped 95% confidence intervals were generated. Result: Innovative statistical methods in this trial will be presented. Conclusion: Although the API Colombia study did not meet its co‐primary endpoints, statistical learnings from this trial can benefit development of future AD trials. To further maximize the value of this unique trial dataset, participant‐level data will be made publicly available, including clinical, imaging, and biomarker data. Funding: NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer's Foundation. FlorbetapirPET was partly supported by Avid and Lilly. [ABSTRACT FROM AUTHOR]

Background: The Q‐ATN model (Mazer et al., Alzheimer's & Dementia. 2022; https://doi.org/10.1002/alz/12877) is a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework for simulating the natural history of Alzheimer's disease and the effects of anti‐amyloid treatment. The recently reported phase 3 trials of gantenerumab (GRADUATE 1&2) and lecanemab (CLARITY) provide additional data to update model parameters and assess the assumptions of the model. Method: The drug‐specific amyloid removal parameters (αrem) for gantenerumab and lecanemab were re‐estimated from the mean amyloid PET data in GRADUATE 1&2 and CLARITY. Using the new αrem values, Q‐ATN simulations of the Clinical Dementia Rating – Sum of Boxes (CDR‐SB) and tau PET trajectories were made for each study. The rate constant for pathogenic tau turnover (ktau), which was uncertain due to limited data, was re‐estimated using a sensitivity analysis of the CDR‐SB treatment effects. Results from the aducanumab EMERGE and ENGAGE studies were also included in the analysis. Result: The simulated increase in amyloid PET agreed well with the mean data from the placebo groups. For GRADUATE 1&2, αrem was 34% and 41% lower, respectively, than the prior value (0.0137 Yr−1/(ug/mL)) estimated from the gantenerumab open‐label extension studies. For CLARITY, αrem was 26% lower than the prior value (0.0109 Yr−1/(ug/mL)) estimated from the lecanemab phase 2 study. For GRADUATE 1&2, the simulated CDR‐SB trajectories for the placebo groups were in good agreement with the observed increases from baseline. For CLARITY, the simulation overestimated the observed increase. The re‐estimated value of ktau (0.2 Yr−1), which corresponds to a 3.5 Yr half‐life, yielded treatment effect sizes on CDR‐SB within the 95% confidence intervals for all treatment arms (N = 7). The prior value (0.5 Yr−1) yielded treatment effect sizes that were too large in three cases (see Figure). Tau PET simulations (with ktau = 0.2 Yr−1) were consistent with medial temporal ROI data from lecanemab and aducanumab; tau PET data from gantenerumab are pending. Conclusion: The updated αrem and ktau parameters bring the Q‐ATN model into better alignment with recent phase 3 data. Forthcoming data from the Donanemab TRAILBLAZER‐ALZ 2 study could further help assess the model assumptions. [ABSTRACT FROM AUTHOR]

Background: The Q‐ATN model (Mazer et al., Alzheimer's & Dementia. 2022; https://doi.org/10.1002/alz/12877) is a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework for simulating the natural history of Alzheimer's disease and the effects of anti‐amyloid treatment. The recently reported phase 3 trials of gantenerumab (GRADUATE 1&2) and lecanemab (CLARITY) provide additional data to update model parameters and assess the assumptions of the model. Method: The drug‐specific amyloid removal parameters (αrem) for gantenerumab and lecanemab were re‐estimated from the mean amyloid PET data in GRADUATE 1&2 and CLARITY. Using the new αrem values, Q‐ATN simulations of the Clinical Dementia Rating – Sum of Boxes (CDR‐SB) and tau PET trajectories were made for each study. The rate constant for pathogenic tau turnover (ktau), which was uncertain due to limited data, was re‐estimated using a sensitivity analysis of the CDR‐SB treatment effects. Results from the aducanumab EMERGE and ENGAGE studies were also included in the analysis. Result: The simulated increase in amyloid PET agreed well with the mean data from the placebo groups. For GRADUATE 1&2, αrem was 34% and 41% lower, respectively, than the prior value (0.0137 Yr−1/(ug/mL)) estimated from the gantenerumab open‐label extension studies. For CLARITY, αrem was 26% lower than the prior value (0.0109 Yr−1/(ug/mL)) estimated from the lecanemab phase 2 study. For GRADUATE 1&2, the simulated CDR‐SB trajectories for the placebo groups were in good agreement with the observed increases from baseline. For CLARITY, the simulation overestimated the observed increase. The re‐estimated value of ktau (0.2 Yr−1), which corresponds to a 3.5 Yr half‐life, yielded treatment effect sizes on CDR‐SB within the 95% confidence intervals for all treatment arms (N = 7). The prior value (0.5 Yr−1) yielded treatment effect sizes that were too large in three cases (see Figure). Tau PET simulations (with ktau = 0.2 Yr−1) were consistent with medial temporal ROI data from lecanemab and aducanumab; tau PET data from gantenerumab are pending. Conclusion: The updated αrem and ktau parameters bring the Q‐ATN model into better alignment with recent phase 3 data. Forthcoming data from the Donanemab TRAILBLAZER‐ALZ 2 study could further help assess the model assumptions. [ABSTRACT FROM AUTHOR]

It is well recognized that sharing rich and rigorously collected clinical trial data with researchers who were not conducting the study has the potential to accelerate progress in Alzheimer's disease.. Such data sharing can contribute to an understanding of pathophysiology, natural history, performance of outcome measures, and the profile of response to treatments, and can help researchers to design better studies and health authorities and payors to evaluate the benefits of therapies. The complexities involved in such data sharing include the need to keep up with evolving patient privacy laws, protecting participant anonymity, ensuring trial integrity, and balancing regulatory and publication requirements. In 2012 Roche/Genentech made a commitment to Banner Alzheimer's Institute and the NIH to share baseline and longitudinal trial data from the Alzheimer's Prevention Initiative Autosomal Dominant AD trial, a public‐private partnership. We will describe the mechanisms developed to share data from the API ADAD Trial (baseline data now available; longitudinal clinical, imaging, and biomarker data to follow) including methods employed to protect confidentiality and anonymity of participants, and the process for requesting and accessing baseline data. We will also offer learnings from our experiences in sharing data from other neurodegeneration trials. The API ADAD trial was funded by NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer's Foundation. Florbetapir PET was partly supported by Avid and Lilly. [ABSTRACT FROM AUTHOR]

Background: One of the profound innovations in Alzheimer's disease research has been the ability to image beta‐amyloid plaques in living patients with the use of amyloid PET imaging. This technology, coupled with advances in basic research that supported mechanisms of action targeting beta amyloid, and innovations in the clinical profiling of AD patients and in clinical trial designs have enabled the disease‐modification era for AD therapeutics. Method: While identifying amyloid plaques in living patients has greatly helped to stratify populations for study and treatment, measured changes in plaque burden during treatment with anti‐beta amyloid drugs has not proven to be a simple outcome measure that directly quantifies clinical benefit. Dissociations between amyloid reduction and downstream markers of AD pathology, such as those seen in the crenezumab and gantenerumab Autosomal Dominant AD studies (NCT01998841 and NCT05552157) suggest that the brain processes associated with AD can improve without causing concurrent measurable benefits in people at risk for or affected by genetic forms of AD, with or without lowering plaque burden. Result: Biomarker results in the phase III GRADUATE I and II (NCT03444870 and NCT03443973) trials with gantenerumab in early AD (sporadic) also suggest that even moderate reduction of beta‐amyloid plaques may not result in clinically meaningful benefits over a therapeutic time course that makes sense for patients, while the phase III CLARITY‐AD trial (NCT01767311) with lecanemab and phase III TRAILBLAZER‐ALZ 2 trial (NCT04437511) with donanemab suggest that enough reduction can cross the threshold for clinical efficacy. Taken together, these study data suggest that plaque depletion to a level near or below the amyloid PET positivity threshold may be necessary to see clinical benefit with this type of monotherapy. Conclusion: This observation, if confirmed, would not rule out the use of beta amyloid lowering therapies that do not completely clear beta amyloid when used in combination approaches. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer's disease (AD). SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) were two Phase III trials which assessed the efficacy and safety of subcutaneous (SC), low‐dose gantenerumab in participants with prodromal and mild AD, respectively, for up to 2 years. Following a gap period gantenerumab treatment was continued with uptitration to a dose of 1,200 mg monthly in open‐label extensions (OLE), which demonstrated substantial Abeta removal by positron emission tomography without new or unexpected safety findings. Here, we describe the study design, present baseline characteristics, and safety data from an additional open‐label, multicenter, rollover study, Open RoAD (OR) (NCT04339413), collecting long‐term safety and tolerability data for gantenerumab in participants who completed the SR OLE or MR OLE. Method: Participants who completed either OLE study and were treated with doses up to 1,200 mg of gantenerumab for up to 5 years continue to receive the same dose of SC gantenerumab (every 4 weeks [q4w]) for 2 additional years in OR. The primary objective is to evaluate long‐term safety and tolerability by assessing adverse events, including amyloid‐related imaging abnormalities, and injection‐site reactions. Exploratory efficacy objectives include Mini‐Mental State Examination (MMSE) total score. The long‐term effect of gantenerumab on pharmacodynamic measures and biomarkers will also be explored. Result: Baseline characteristics Fifty‐nine participants from SR OLE and 56 participants from MR OLE received at least one dose of gantenerumab in OR. The median participant age at baseline was 78 years, and the majority of the participants were female (61%). Sixty‐seven percent of participants were apolipoprotein‐E‐e4 (APOE e4) carriers. The median total MMSE score at baseline was 16. Safety data will be presented. Conclusion: The RoAD studies are among the longest‐duration OLEs of an anti‐amyloid monoclonal antibody. Data from the OR study demonstrate that gantenerumab at doses of 1,200 mg administered SC q4w is well tolerated, with no new or unexpected safety findings in patients with early AD. [ABSTRACT FROM AUTHOR]

Background: Vasogenic edema and sulcal effusions detected with magnetic resonance imaging (MRI) are known and manageable possible side effects of many anti‐amyloid immunotherapies. Periodic MRI scans and severity assessment of these imaging findings, known as amyloid‐related imaging abnormalities – edema (ARIA‐E) are currently mandated in clinical trials evaluating these therapies. Previous studies of gantenerumab have used a 60‐point severity scale (the Barkhof Grand Total Scale [BGTS]),1 which is effective for research purposes with good inter‐rater reliability (ICC = 0.78, 95%CI[0.36‐0.94]) between trained neuroradiologists. Other anti‐amyloid studies have used a simpler 3‐point severity scale, which has excellent inter‐rater reliability (ICC = 0.93, 95%CI[0.89‐0.96])2 and is likely to be of more practical use in clinical practice. This work compares the BGTS with the 3‐point scale, and with a more refined, 5‐point scale.2 Method: T2‐FLAIR and T2*‐GRE MRI scans (5 mm slices, no gap, 256 × 256 matrix) from 100 participants (87 with previously detected ARIA‐E, 13 without ARIA from original BGTS assessment) in the Marguerite RoAD gantenerumab study (NCT02051608) were selected. After excluding 3 scans due to missing data or unacceptable quality, all valid scans were re‐read using all three severity scales by one neuroradiologist with extensive experience (>500 reads) on all three scales. The reader was presented with pairs of baseline/follow‐up scans, blinded to prior read results. Assessment of ARIA‐H was also completed. Tables 1 and 2 summarize the scale definitions. Result: Median(inter‐quartile range) BGTS scores for the 3‐point scale were 0 = 0(0‐0), 1 = 1(1‐3), 2 = 8(5‐14), and 3 = 20(20‐20), and for the 5‐point scale were 0 = 0(0‐0), 1 = 1(1‐3), 2 = 6(4‐9), 3 = NA, 4 = 15(10‐20), and 5 = 20(20‐20) (Figure 1). Spearman's rank correlation between BGTS and the 3‐point scale was 0.85 and 0.91 for the 5‐point scale. Regression analysis of ARIA‐E severity scale to ARIA‐H count showed moderate positive association with Pearson's r of 0.37, 0.40, 0.50 for the 3‐point, 5‐point, and BGTS scales, respectively. Conclusion: The simplified 3‐ and 5‐point scales are well correlated to the 60‐point BGTS ARIA‐E severity scale; the 5‐point scale had better correlation than the 3‐point scale. Further study is warranted to assess reliability for reads performed by non‐specialist radiologists in real‐world applications. References: (1) AJNR 2013. (2) Alz&Dementia 2017. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer's disease (AD). SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) were two Phase III trials with open‐label extensions (OLEs), during which participants were treated with up to 1,200 mg/month of subcutaneous gantenerumab for up to 5 years. Substantial Abeta removal was confirmed without new or unexpected safety findings. This work aims to evaluate the gantenerumab treatment effect during the SR and MR uncontrolled OLE studies by using an external control group based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Method: Participants from the ADNI studies were weighted using the inverse probability of treatment weighting method1 to make their demographics and baseline characteristics more comparable to the patients in the OLE stages of the pooled SR and MR studies. In the weighted sample, the treatment effects of gantenerumab, per change from the OLE Baseline in Clinical Dementia Rating – Sum of Boxes (CDR‐SB), Alzheimer's Disease Assessment Scale – Cognitive subscale 13 (ADAS‐Cog13), and Mini‐Mental State Exam (MMSE) at Weeks 104 and 156 were investigated by a mixed‐effect model of repeated measure. Results: Applying inclusion and exclusion criteria from the ongoing GRADUATE gantenerumab trials (NCT03444870, NCT03443973) to the SR and MR OLE cohorts, 164 participants from the SR and MR OLE studies and 1,218 participants from ADNI were selected. After weighting, the demographics and baseline characteristics were comparable between the two populations. A comparison of relative reductions between the pooled participants in SR and MR OLE studies and weighted ADNI participants can be found in Table 1. Conclusions: When comparing participants in the SR and MR OLE studies to a matched ADNI control group, a slower progression was observed with gantenerumab treatment. Specifically, gantenerumab showed effects on slowing cognitive decline in the SR and MR OLE studies compared with weighted ADNI participants on the CDR‐SB and ADAS‐Cog13 scales, although with a smaller effect on MMSE. The efficacy and safety of gantenerumab in early AD participants will be assessed in the two ongoing Phase III GRADUATE trials. 1. Austin PC & Stuart EA, 2015; Stat Med. 34:28 [ABSTRACT FROM AUTHOR]

Background: Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer's disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to doses of up to 1,200 mg every 4 weeks (q4w) confirmed substantial Abeta removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of subcutaneous gantenerumab in early AD, using a target dose of 510 mg q2w (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (q1w) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous q1w administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience. Methods: In this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg q4w, followed by 255 mg q4w and q2w for 12 weeks each, and a target dose of 255 mg q1w. This target dose is equivalent to the 1,020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a q1w dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography. Secondary objectives include assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, and cognitive and functional assessments. Results: Recruitment for GRADUATION is complete. Participants were enrolled from Belgium, France, Germany, Italy, Poland, Spain, UK, and US. Detailed baseline characteristics will be presented. Conclusion: The GRADUATION study will determine the effect of q1w administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home. 1. Ostrowitzki S, et al. Alzheimers Res Ther 2017;9:95 2. Klein G, et al. Alzheimers Res Ther 2019;11:101 [ABSTRACT FROM AUTHOR]

Background: Vasogenic edema and sulcal effusions detected with Magnetic Resonance Imaging (MRI), known as Amyloid‐Related Imaging Abnormalities‐Edema (ARIA‐E), are manageable side effects of anti‐amyloid immunotherapies. Periodic MRI scans with severity assessment of ARIA‐E are used in clinical trials or to guide practice with these therapies. Several scales with varying complexity measure radiological ARIA‐E severity to guide dosing. The ongoing GRADUATE studies use the 60‐point Barkhof Grand Total Scale (BGTS)1, continuing treatment for asymptomatic ARIA‐E ≤ 3, and temporarily suspending dosing for BGTS > 3. Other studies have used Simple ARIA‐E Severity Scales2 (SAESS‐3, SAESS‐5), continuing treatment for asymptomatic SAESS‐3 ≤ 1, but temporarily suspending dose for SAESS‐3 > 13. We previously reported good correlation between BGTS, SAESS‐3, and SAESS‐5 by a single reader. Here we report correlations among these scales scored by multiple readers and assess the impact of these various scores on ARIA management. Methods: T2‐FLAIR MRI scans were selected from a representative set of incident ARIA‐E cases (70 with previously detected ARIA‐E, 5 without ARIA‐E from original BGTS assessment) in the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) Phase III studies. Three experienced neuroradiologists scored ARIA‐E severity using the 3 scales from pairs of baseline/follow‐up scans, blinded to prior read results. Median results of the 3 readers were computed for further analysis. Result: Inter‐reader agreement for all 3 scales was high (ICC=0.866 [0.811, 0.908], 0.888 [0.841, 0.924], and 0.858 [0.776, 0.910] for the SAESS‐3, SAESS‐5, and BGTS scales respectively). Spearman's rank correlation with BGTS scale was 0.88 for the SAESS‐3 scale and 0.90 for SAESS‐5. Median interquartile range (IQR) BGTS scores for the two simplified scales are shown in Figure 1. Best agreement for the SAESS‐3 > 1 treatment management threshold was achieved with BGTS > 3, with an accuracy of 93.3% (Figure 2). Conclusions: SAESS‐3 and SAESS‐5, which may be more suitable for routine clinical practice, are well correlated to the BGTS scale. Treatment management based on the SAESS‐3 > 1 threshold shows high agreement with the BGTS > 3 threshold. 1. Barkhof et al., 2013; AJNR 34:8. 2. Bracoud et al., 2017; AAIC. P1‐047. 3. ADUHELM (aducanumab‐avwa) FDA PI. [ABSTRACT FROM AUTHOR]

Background: According to FDA's literature review of clinical trial data from a number of anti‐amyloid antibodies, a "clear relationship" was demonstrated between the extent of amyloid plaque removal measured by amyloid PET and the magnitude of clinical benefit measured by the placebo‐corrected difference in the CDR sum of boxes (CDR‐SB). To understand this relationship from a theoretical perspective we developed a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework (the Q‐ATN model) in order to simulate the natural history of disease progression and the effects of anti‐amyloid therapy. Method: Published data and biologically plausible mechanisms were used to construct, calibrate and validate the components of the Q‐ATN model (anti‐amyloid effect, amyloid PET, tau PET, cortical thickness [CT] and clinical outcome [CDR‐SB]). A parabolic input function was used to describe the annual rate of increase of the amyloid PET level in placebo patients (in Centiloids/Yr) as a function of the baseline level. Clinical trial simulations corresponding to mean treatment responses were made for different anti‐amyloid antibodies using individualized pharmacokinetic (PK) and pharmacodynamic (PD) models of the anti‐amyloid effect. A 5‐Yr simulation of gantenerumab treatment, based on the dosing regimen employed in the ongoing phase 3 GRADUATE trials (NCT03444870; NCT03443973), was performed to illustrate the predicted long‐term effects of gantenerumab maintained at the target dose. Result: The simulated time‐course of biomarkers and clinical outcomes were consistent with natural history studies and described the effects of several anti‐amyloid antibodies observed in trials with positive and negative outcomes. Figure 1A‐D shows the simulated 5‐Yr time‐course of gantenerumab and placebo treatment on A. amyloid PET; B. tau PET; C. medial temporal cortical thickness and D. CDR‐SB. The model predicts that the difference in CDR‐SB between active and placebo groups increases markedly with the time of treatment, reaching ‐5.2 units at the 5‐Yr endpoint of the simulation. Conclusion: The Q‐ATN model provides a novel theoretical approach for linking amyloid to clinical outcome based on the A/T/N framework. It illustrates the predicted disease‐modifying potential of gantenerumab – with increasing treatment benefits over time. The predictions of the Q‐ATN model will be compared with forthcoming clinical trial data. [ABSTRACT FROM AUTHOR]

The Alzheimer's Prevention Initiative (API) ADAD Colombia trial enrolled 252 cognitively unimpaired 30‐ 60‐year‐old Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers; carriers were randomized 1:1 to crenezumab or placebo, non‐carriers received placebo only. Crenezumab is an anti‐amyloid monoclonal antibody that binds beta‐amyloid (Aβ) oligomers that is hypothesized to prevent the buildup of pathogenic Aβ plaques and modify Alzheimer's disease (AD) progression with a low risk of amyloid related imaging abnormalities. The presentation will begin with a summary of the partnership between the Neurosciences Group of Antioquia and ADAD kindreds, including those who volunteered for the trial. Next will be a brief summary of the trial design and baseline participant characteristics, including the distribution of Aβ‐positive and ‐negative individuals, followed by the results for the co‐primary endpoints, change in cognitive function (using the API ADAD Cognitive Composite Test Battery) or episodic memory function (using the Free and Cued Selective Reminding Test); secondary efficacy results including time to clinical progression to MCI or dementia due to AD, time to Clinical Dementia Rating (CDR) score >0, and increase in CDR Sum of Boxes; other outcomes including FAST, NPI, MMSE, CERAD word recall and RBANS results; and safety and tolerability. Last will be a presentation of results for changes in Aβ, FDG and tau PET; volumetric brain MRI; CSF biomarkers; a preview of pending plasma biomarker data; and a brief summary of the historical context and strategic aims of API and the trial. There will be an interactive question and answer session. [ABSTRACT FROM AUTHOR]

Background: Aduhelm's recent approval, and the potential approval of additional effective therapies in early (prodromal‐to‐mild) Alzheimer's disease (AD), will impact the conduct of clinical trials, including trials designed to delay or prevent cognitively unimpaired participants from progressing to mild cognitive impairment (MCI) or AD dementia. Allowing "rescue therapy" with these approved therapies during preclinical AD trials ("treatment policy design") is expected to increase participation and improve adherence in these very large and long clinical trials. Our goal was to evaluate the impact of allowing "rescue therapy" on the study power using simulation. Method: In the simulated study, cognitively unimpaired elderly adults with elevated levels of beta‐amyloid were randomized 1:1 to the control arm (starting on placebo and initiating "rescue therapy" upon progression to Clinical Dementia Rating [CDR] scale score > 0) or to the experimental arm (same experimental treatment throughout the study). Key simulation parameters (placebo decline and variance) were based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) and other cohort data. The continuous endpoint was Preclinical Alzheimer's Cognitive Composite (PACC) scores. The triggering event to allow the start of "rescue therapy" was progression to CDR > 0. A range of different study design parameters (study duration, magnitude and timing of treatment effect, and continuous outcome vs time to event) were explored. Result: Preliminary simulation results indicated that allowing "rescue therapy" had limited impact on the study power/sample size. They also suggested that continuous endpoints provided more power compared with a time‐to‐event endpoint in this setting. Conclusion: This initial simulation study suggests that clinical trials of subjects in preclinical or at‐risk stages of AD that allow rescue medications during the trial may retain adequate power, with a limited impact on sample size, when analyzed with a primary treatment policy estimand. The potential benefit of the "treatment policy" approach in terms of recruitment and adherence/engagement cannot yet be quantified but could be substantial. [ABSTRACT FROM AUTHOR]

Background: SKYLINE is a secondary prevention study in Alzheimer's disease (AD) enrolling amyloid‐positive, cognitively normal (CN) individuals at risk for clinical AD between 60–80 years and treating them with gantenerumab or placebo for 4 years. There is no gold standard for determining amyloid positivity for this purpose. Thresholds for amyloid positivity used in trials in symptomatic AD may be suboptimal in a secondary prevention setting, where amyloid positivity prevalence is lower. We compared various amyloid‐positive definitions in a CN elderly population based on how well they enrich for clinical progression over 4 years and operational feasibility. Method: Four cohorts (ADNI, BioFINDER‐1, AIBL, and HABS) were used to explore the relationship between amyloid PET visual read, centiloid values and CSF pTau/Abeta42 values in a CN population. For amyloid PET, we compared visual read with centiloid thresholds by evaluating the amyloid positivity prevalence, magnitude and variability of endpoint progression, and positive and negative predictive value (PPV and NPV). Operational advantages of CSF motivated a comparison of elevated CSF pTau/Abeta42 thresholds with amyloid PET. We interrogated which CSF thresholds were robust to preanalytical differences, had a high PPV and NPV compared with amyloid PET, and resulted in an acceptable degree of cognitive decline and variability. Result: Higher centiloid thresholds (≥40 CL) showed good agreement with visual read, but visual read resulted in a lower coefficient of variation (CV) for change from baseline in PACC5, the primary endpoint in SKYLINE (CV=118–210 vs. CV=150–336). An elevated CSF pTau/Abeta42 threshold resulted in a similar amyloid positivity prevalence to amyloid PET (14–17% vs. 10–20%), had acceptable NPV (95–97%), PPV (69–87%), sensitivity (71–82%), and specificity (95–98%) for visual read, and resulted in a similar CV for change from baseline in PACC5. Conclusion: There is no gold standard for determining the optimal amyloid positivity threshold in a secondary prevention trial. Determining patients to be amyloid‐positive if they are amyloid PET visual read‐positive or have elevated CSF pTau/Abeta42 offers not only operational advantages but also likely results in a trial population that has an acceptable level of endpoint progression and variability over the trial duration. [ABSTRACT FROM AUTHOR]

Background: There is precedent in the AD field for confusion and dissonance due to the naming of clinical phenomena. Early on, Alzheimer's disease (AD) or Alzheimer's dementia could mean anyone with progressive dementia, and did not require the application of standardised criteria. As standardisation improved at the stage of dementia, the terms Mild Cognitive Impairment or Minimal Cognitive Impairment came into usage and the clinical conditions encompassed by these terms were variably named and defined in different nomenclature systems (eg., AAN, DSM, ICD) and required different criteria depending upon the definitions used by different academic working groups. A similar controversy now exists regarding the naming of individuals who have biological markers consistent with AD, but do not have any clinical symptoms or functional decline from baseline. Method: Other speakers in this symposium will review the history and advocate for particular approaches to describing individuals who have AD biological markers bur are cognitively unimpaired. This presentation will respond to those arguments and bring in additional external perspectives from experience as a clinician treating patients, as a researcher performing non‐interventional trials, and a drug developer. Result: The implications of naming the condition preclinical AD versus individuals at risk for AD will be explicated for clinical practice, general research, and clinical trials. Conclusion: TBD. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer's disease (AD). SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) were two Phase III trials which assessed the efficacy and safety of subcutaneous, low‐dose gantenerumab in participants with prodromal and mild AD, respectively, for up to 2 years. Following a gap period gantenerumab treatment was continued with uptitration to a dose of 1,200 mg monthly in open‐label extensions (OLE), which demonstrated substantial Abeta removal by positron emission tomography without new or unexpected safety findings. The aim of this work is to investigate the pharmacodynamic effects of gantenerumab on plasma markers for amyloid and tau during both double‐blind and OLE periods. Method: We evaluated the pharmacodynamic effects of subcutaneous gantenerumab on blood‐based biomarkers for amyloid and tau proteins in plasma samples collected once every year from participants who completed the double‐blind periods of SCarlet RoAD and Marguerite RoAD and participated in the OLE for up to 3 years. We measured Abeta(1–42) and phosphorylated Tau (pTau) in plasma samples using prototype Elecsys® immunoassays from Roche Diagnostics. Result: Plasma Abeta(1–42) increases by 106% (95% confidence interval [CI]: 48% to 163%) in SCarlet RoAD and 63% (95% CI: 49% to 77%) in Marguerite RoAD after 3 years of OLE treatment. Plasma pTau decreases by 24% (95% CI: –44% to –4%) in SCarlet RoAD and 11% (95% CI: –23% to +2%) in Marguerite RoAD after 3 years of OLE treatment. Conclusion: Chronic treatment with 1,200 mg subcutaneous injections of gantenerumab every 4 weeks increases levels of plasma Abeta(1–42) and decreases levels of plasma pTau consistently across both studies. [ABSTRACT FROM AUTHOR]

Background: SKYLINE is a new secondary prevention study in Alzheimer's disease (AD) enrolling amyloid‐positive, cognitively normal individuals at risk for clinical AD between 60 and 80 years and treating them with gantenerumab or placebo for 4 years. Based on available data from other studies, we expect only 15% of individuals to be amyloid‐positive in this screening population. We developed a blood‐based biomarker (BBBM) prescreening test to screen out participants who have a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing before entering the main screening of SKYLINE. Method: We explored multiple individual key AD BBBMs (measured with Elecsys® prototype assays) and combinations in three large cohorts (BioFINDER‐1, AIBL, A4) of cognitively unimpaired and subjective cognitive decline/mild cognitive impairment participants. We used predefined thresholds for amyloid PET and/or CSF pTau/Abeta42 as the reference standard for amyloid positivity. The performance of the BBBM was assessed by evaluating the positive and negative predictive value (PPV and NPV) for amyloid positivity, and screen‐out proportions based on a range of potential thresholds. Those metrics were translated into the total number of participants that need to be screened and the reduction of the number of participants that need to be screened with PET or CSF testing to reach the target sample size. Result: We identified a combination of two key AD biomarkers expected to enable a high NPV at moderate PPV, screening out 40–50% of participants, amongst whom are only 3–5% true amyloid positives (falsely ruled out). This BBBM prescreening would reduce the need for PET or CSF testing by 40% while requiring screening of 8% more participants to compensate for the wrongly excluded amyloid positives. Conclusion: The implementation of Elecsys® blood‐based prescreening in SKYLINE will significantly reduce site and participant burden, accelerate the study enrollment, and save screening costs by reducing unnecessary downstream screening assessments such as cognitive batteries, magnetic resonance imaging, and PET or CSF testing. [ABSTRACT FROM AUTHOR]

Introduction As drug development research efforts move toward studying patients earlier in the course of Alzheimer's disease (AD), it is important to incorporate the patient's perspective into measurement of outcomes. Methods This article summarizes the qualitative work of the Patient-Reported Outcome Consortium's Cognition Working Group in the development of a new self-reported outcome measure in persons with mild cognitive impairment (MCI) due to suspected AD, herein referred to as MCI. Results The draft measure captures the patient's voice for two functional domains, complex activities of daily living and interpersonal functioning. Discussion This work represents a series of initial steps in the development of this rating scale. The next steps are to conduct psychometric analysis and evaluate the role of insight. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Aβ), is a potential disease‐modifying treatment for early Alzheimer's disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post‐hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to a target dose of up to 1200 mg confirmed significant Aβ removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of gantenerumab in early AD, using a 1020 mg/month regimen at target dose (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). These studies maximise exposure with a single titration scheme and target dose regardless of APOE genotype over more than two years of treatment. The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (Q1W) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous Q1W administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience. Methods: In this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg every 4 weeks (Q4W), followed by 255 mg Q4W and Q2W for 12 weeks each, and a target dose of 255 mg Q1W. This target dose is equivalent to the 1020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a Q1W dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography (PET). Secondary objectives include the assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, cognitive and functional assessments. Result: Results to come. Conclusion: The GRADUATION study will determine the effect of once‐weekly administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home. References: (1) Ostrowitzki et al., 2017; Alzheimers Res Ther. 9:95. (2) Klein et al., 2019; Alzheimers Res Ther. 11:101. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity in the pattern of cognitive deficits seen in probable AD patients is well recognized. Two reliably reproducible profiles are ones that have an extreme deficit in either visuo‐spatial (Vis‐D) or language (Lang‐D) domains compared to all other domains, independent of memory performance. Information on variability in progression rates and overall survival associated with these profiles is lacking. Method: Right handed probable AD patients followed longitudinally in a memory clinic, 50‐90 years old with baseline MMSE score ≥10, were classified as Vis‐D or Lang‐D if their scores on tests of visual and language function varied by ≥ 2 standard deviations. Proportional hazards analysis was used to compare time to reach an MMSE < 10, CDR global score=3, and survival time from diagnosis to death in Vis‐D, Lang‐D and balanced deficits (Bal‐D) groups, adjusting for age, sex, education, ethnicity, baseline co‐morbidity, and APOE genotype. Result: Of 540 patients meeting inclusion criteria, 86 (15.9%) were Vis‐D and 61 (11.3%) were Lang‐D. Median follow‐up time after baseline was 3.30 years (range 0.9, 13.3) and median time to death was 5.50 years (range=1.0, 16.8). The Vis‐D group was younger at diagnosis and had a higher prevalence of APOE e4 homozygosity than the Lang‐D and Bal‐D groups (69.8±8.5 vs 76.3±7.1 and 75.0±7.5 years and 25.9% vs 10.2% and 14.1% APOE e4 homozygosity respectively). Lang‐D patients reached a severe stage on the MMSE more rapidly than Vis‐D and Bal‐D (HRLang‐d vs Bal‐D=1.68, 95% CI=0.99‐2.73, p=.054; HRLang‐D vs Vis‐D=2.04, 95% CI=1.06‐3.78, p=.032). Results for the CDR endpoint were similar (HRLang‐D vs Bal‐D=1.64, 95% CI=1.04‐2.56, p=.032; HRLang‐D vs Vis‐D=2.32, 95%CI=1.40‐4.57, p=.002). Cognitive profile did not affect time to death. Conclusion: Probable AD patients with a Lang‐D cognitive profile decline faster on the MMSE and CDR than those with other cognitive profiles. Cognitive profile at diagnosis does not affect overall survival. Understanding the neuropathology underlying these cognitive profile differences could have implications for development or selection of disease modifying treatments. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity in the pattern of cognitive deficits seen in probable AD patients is well recognized. Two reliably reproducible profiles are ones that have an extreme deficit in either visuo‐spatial (Vis‐D) or language (Lang‐D) domains compared to all other domains, independent of memory performance. Information on variability in progression rates and overall survival associated with these profiles is lacking. Method: Right handed probable AD patients followed longitudinally in a memory clinic, 50‐90 years old with baseline MMSE score ≥10, were classified as Vis‐D or Lang‐D if their scores on tests of visual and language function varied by ≥ 2 standard deviations. Proportional hazards analysis was used to compare time to reach an MMSE < 10, CDR global score=3, and survival time from diagnosis to death in Vis‐D, Lang‐D and balanced deficits (Bal‐D) groups, adjusting for age, sex, education, ethnicity, baseline co‐morbidity, and APOE genotype. Result: Of 540 patients meeting inclusion criteria, 86 (15.9%) were Vis‐D and 61 (11.3%) were Lang‐D. Median follow‐up time after baseline was 3.30 years (range 0.9, 13.3) and median time to death was 5.50 years (range=1.0, 16.8). The Vis‐D group was younger at diagnosis and had a higher prevalence of APOE e4 homozygosity than the Lang‐D and Bal‐D groups (69.8±8.5 vs 76.3±7.1 and 75.0±7.5 years and 25.9% vs 10.2% and 14.1% APOE e4 homozygosity respectively). Lang‐D patients reached a severe stage on the MMSE more rapidly than Vis‐D and Bal‐D (HRLang‐d vs Bal‐D=1.68, 95% CI=0.99‐2.73, p=.054; HRLang‐D vs Vis‐D=2.04, 95% CI=1.06‐3.78, p=.032). Results for the CDR endpoint were similar (HRLang‐D vs Bal‐D=1.64, 95% CI=1.04‐2.56, p=.032; HRLang‐D vs Vis‐D=2.32, 95%CI=1.40‐4.57, p=.002). Cognitive profile did not affect time to death. Conclusion: Probable AD patients with a Lang‐D cognitive profile decline faster on the MMSE and CDR than those with other cognitive profiles. Cognitive profile at diagnosis does not affect overall survival. Understanding the neuropathology underlying these cognitive profile differences could have implications for development or selection of disease modifying treatments. [ABSTRACT FROM AUTHOR]

Abstract: An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer’s disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit. [Copyright &y& Elsevier]

Abstract: Background: Randomized controlled trials (RCTs) provide safety and efficacy data for regulatory approval of antidementia drugs, but offer limited data regarding real-world effectiveness. Long-term observational controlled studies (LTOCs) extend our understanding by providing longitudinal data across multiple stages of Alzheimer’s disease (AD). Methods: Comparisons of strengths, limitations, evidence level, and results for monotherapy (cholinesterase inhibitors) and combination therapy (cholinesterase inhibitors + memantine) in RCTs versus LTOCs were made. Results: Similar to RCTs, LTOCs have shown that both monotherapy and combination therapy are associated with slower cognitive and functional decline. Combination therapy is associated with better cognitive outcomes and greater delays in time to nursing home admission versus monotherapy or no treatment. Persistent antidementia drug treatment is associated with slower decline in cognition, daily function, and global severity, even in patients with advanced disease. Conclusions: LTOCs provide complementary evidence regarding effectiveness of antidementia therapy over many years, a time course relevant to AD management. These findings also provide compelling arguments in favor of using LTOCs to estimate effectiveness, risk–benefit, and costs of AD treatments. [Copyright &y& Elsevier]

Abstract: Background: The Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) is a commonly used measure for assessing cognitive dysfunction in patients with Alzheimer’s disease (AD). The measure has 11 subscales, each of which captures an important aspect of cognitive dysfunction in AD. Traditional scoring of the ADAS-cog involves adding up the scores from the subscales without regarding their varying difficulty or their strength of relationship to AD-associated cognitive dysfunction. The present article analyzes problems associated with this approach and offers solutions for gaining measurement precision by modeling how the subscales function. Methods: We analyzed data collected at the Baylor College of Medicine Alzheimer’s Disease and Memory Disorders Clinic from 1240 patients diagnosed with varying degrees of dementia. Item response theory was used to determine the relationship between total scores on the ADAS-cog and the underlying level of cognitive dysfunction reflected by the scores. Results: Results revealed that each total score corresponded to a spectrum of cognitive dysfunction, indicating that total scores were relatively imprecise indicators of underlying cognitive dysfunction. Furthermore, it was common for two individuals with the same total score to have significantly different degrees of cognitive dysfunction. Conclusions: These findings suggest that item response theory scoring of the ADAS-cog may measure cognitive dysfunction more precisely than a total score method. [Copyright &y& Elsevier]

Abstract: The number of clinical trials for Alzheimer’s disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer’s Association Research Roundtable. Regulatory issues, including regional differences in study registration procedures, rules for collecting and reporting serious adverse events, requirements for national identity of study populations, and regulatory audits were also discussed by individuals who are knowledgeable about global clinical trials for Alzheimer’s disease. [Copyright &y& Elsevier]

The article presents information on a study which determined factors predicting development of aggression in patients with dementia. The study, conducted from September 3, 2003 to June 10, 2005, enrolled community-dwelling patients ages 60 years old and beyond from a Veterans Affairs Medical Center who had a documented ICD-9-CM code for dementia within 12 months of screening and no other dementia codes recorded for two preceding years but no aggressive behavior. A discussion on the research findings is offered.

Introduction: The Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) was modified for use in mild cognitive impairment (MCI) trials and tested in the ADCS MCI randomized clinical trial of donepezil, vitamin E, and placebo. We assessed feasibility for its use by determining whether or not: (I) it distinguished a medication effect at 6 months and 12 months, (2) baseline demographic or clinical characteristics predicted change, (3) there was an association between MCI-CGIC and change in other clinical measures in order to evaluate external or concurrent validity. Methods: We used a generalized estimating equations approach for ordinal outcome data to test the effects of treatment, baseline characteristics, and change in clinical measures on the MCI-CGIC over 12 months, and ordinal logistic regression to assess the association between MCI-CGIC and change in clinical measures at 6 months and 12 months. Results: On the MCI-CGIC overall, 12.9% and 10.6% were rated as having improved, and 3 1.6% and 39.8% as having worsened over 6 months and 12 months, respectively. The MCI-CGIC did not distinguish the donepezil or vitamin E groups from placebo at 6 and 12 months treatment. Variables at screening or baseline that were associated with worse CGIC scores over 6 and 12 months included white race, greater years of education, worse depression, dementia severity rating, cognitive, and daily activities scores, and lower memory domain scores on a neuropsychological battery. Rate of worsening on the MCI-CGIC over 12 months was associated with change on the Alzheimer Disease Assessment Scale-cognitive and on executive function. Worsening at 6 months and 12 months, separately, were associated with the corresponding change in Alzheimer Disease Assessment Scale-cognitive, Activities of Daily Living, Beck Depression Inventory, Mini-Mental State Examination, Clinical Dementia Rating sum of boxes, memory, and executive function. Conclusions: Change detected by the MCI-CGIC was associated with baseline clinical severity and with change in clinical ratings over 6 and 12 months, supporting the validity of a COIC approach in MCI. The effect size of the donepezil-placebo difference was similar to that of other outcomes at 12 months. About 40% of MCI patients were judged worse and about 11% improved, consistent with clinical experience and other ratings. [ABSTRACT FROM AUTHOR]

Abstract: Despite enormous worldwide public and private interest in improving the prevention and treatment of Alzheimer''s disease (AD), we have not made as much of an impact as we would like, and the number of affected individuals continues to grow. Even more alarmingly, whereas global efforts to identify AD cases and to develop new treatments are increasing, patient-care options are disappearing, so that even if a highly efficacious therapy or prevention approach arose, it would not be used effectively. As a first step toward organizing a better way forward, we should establish AD centers of excellence that mandate both patient care and research in the same setting. These centers would benefit from changes in public health policies related to chronic-disease surveillance, Center for Medicare and Medicaid Services funding for the care of chronic diseases, institutional review boards, good clinical practice guidelines, National Institutes of Health regulations for the use of research funds, Food and Drug Administration guidelines for the approval of AD drugs, and Department of Commerce regulations related to patent protection of AD diagnostic aids and treatments. This new form of AD centers of excellence would also provide direct care to many patients and their families, model care for communities and medical trainees, enhance the voluntary recruitment of AD patients to clinical trials, and improve our understanding of AD and its management. [Copyright &y& Elsevier]

Abstract: Background: Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer’s disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily). Methods: This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy. Results: Enrollment of 641 subjects is complete. The baseline mean data are age 74 ± 8 years, 53% women, MMSE 22 ± 3, ADAS-cog 23 ± 10, AD Functional Assessment and Change Scale (ADFACS) 13 ± 9, Neuropsychiatric Inventory (NPI) 10 ± 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 ± 3. Mean prior donepezil treatment was 409 ± 407 days. Mean baseline lipid levels are total cholesterol 5.8 ± 0.8 mmol/L (224 ± 33 mg/dL), LDL-C 3.7 ± 0.7 mmol/L (143 ± 26 mg/dL), triglycerides 1.5 ± 0.7 mmol/L (132 ± 64 mg/dL), and high-density lipoprotein cholesterol 1.6 ± 0.5 mmol/L (64 ± 18 mg/dL). Conclusions: LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD. [Copyright &y& Elsevier]

Abstract: Background: Clinical trials have suggested benefits of memantine for all stages of Alzheimer’s disease (AD). A meta-analysis of memantine trials in outpatients with probable AD was conducted. Methods: Six randomized, placebo-controlled trials fulfilled inclusion criteria. Cognitive, global, functional, behavioral, and safety measures were evaluated by using fixed or random effects models. Sensitivity analysis was performed to determine potential effects of disease severity and concomitant cholinesterase inhibitor use. Results: Overall, memantine showed statistically significant, homogenous benefits on global and functional outcomes and statistically significant but heterogeneous benefit on cognition. In pooled moderate to severe AD studies, effects were significant and homogeneous on global, functional, and behavioral measures; in pooled mild to moderate studies, significant and homogeneous effects were found on global rating and cognition. Safety profiles suggested excellent safety and tolerability, with no differences between the severity groups. Conclusions: Memantine consistently benefited patients in all stages of AD and was well-tolerated. [Copyright &y& Elsevier]