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The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease‐modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1–2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18‐month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified. [ABSTRACT FROM AUTHOR]

Background: Clinical trials are essential for testing safety and efficacy of potential treatments for Alzheimer's disease (AD), but recruitment is often difficult due to a variety of factors. Recruitment tactics in AD clinical trials may include media advertising, physician referrals, patient registries, and referral campaigns. Newer strategies such as social media and community outreach have also been successful in increasing recruitment. However, not all recruitment tactics are successful for every study site and a multi‐faceted approach tailored to each site may be more successful. Method: INTERCEPT‐AD is a phase 1 randomized, double‐blind study of ACU193 in mild cognitive impairment or mild dementia due to AD. Seventeen study sites in the U.S. screened potential participants identified through multiple recruitment tactics which were grouped post hoc into seven categories: site database, external referral, physician referral, site campaign, and three sponsor‐initiated campaigns. Recruitment efforts were tailored to each site's patient population, community, and staff availability. Result: INTERCEPT‐AD screened 260 participants and 70 were eligible for study participation. Recruitment was completed in January 2023. The sponsor worked directly with individual sites to develop a tailored recruitment plan that considered each site's target population, historically successful recruitment tactics, and current ability to screen patients from outside sources. Comparisons of the seven types of recruitment sources showed site databases were used most frequently (12/17 sites, 71%) and accounted for the most screenings and eligible participants (107 [41%] and 32 [46%], respectively). Additional data from all recruitment sources and success rates will be presented. Conclusion: Study sites found success using a combination of tactics specifically tailored to their enrollment goals. Sites with robust internal patient databases had higher rates of screening and enrollment. A combination of site‐led and sponsor‐driven recruitment initiatives likely maximized enrollment rates. These findings suggest a strategy using diverse recruitment tactics customized to a study site's capabilities and patient population may be more successful than a one‐size‐fits‐all approach. [ABSTRACT FROM AUTHOR]

Abstract Background Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development. Methods A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death. Results The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90). Conclusions This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.

Background: PET tracers enable the in‐vivo measurement of amyloid in the brain and have been incorporated in eligibility criteria for clinical trials. Automated quantitative image analysis enables the calculation of a standardised uptake value ratio (SUVr) which can enable a rapid amyloid classification without requiring a visual read. However, quantitative analysis may have an equivocal range where amyloid classification does require a visual read. The range of SUVrs that is equivocal is not well understood. Method: Participants in the INTERCEPT‐AD trial of ACU193 (Siemers et al., J Prev Alzheimers Dis. 2023;10(1):19‐24) underwent an amyloid [18F] Florbetapir PET scan and T1‐weighted MRI scans. MRIs were segmented using the LEAP algorithm (Wolz et al., NeuroImage. 2010;49(2):1316‐1325), registered to the PET image, and the global cortical average (GCA) SUVr based on brain regions typically with high amyloid load in Alzheimer's disease (Klunk et al., Alzheimers Dement. 2015;11(1):1‐15) was calculated, using the whole cerebellum as the reference region. SUVrs greater than 1.2 were classified as amyloid positive, SUVrs less than 1.0 were classified as amyloid negative, and SUVrs in the equivocal range were assessed by visual read by trained central radiologists. Results: Of 194 participants who underwent screening, 188 had an SUVr available from automated analysis. Of these, 64 were within the equivocal range (SUVr 1.0 – 1.2) and had a visual read performed. For PET scans in the equivocal range, 53 (83%) were classified as amyloid negative and 11 (17%) were classified as amyloid positive by visual read. Within the equivocal range, there was no difference in SUVrs between the images classified by visual read as amyloid negative or positive. Conclusion: SUVrs may be used as an objective quantitative amyloid classification method at values > 1.2 for trial inclusion; however, in the equivocal range, the GCA SUVr did not correspond with amyloid classification based on a visual read. Further study is required to investigate the equivocal range and the use of combined quantitative measures and visual reads. [ABSTRACT FROM AUTHOR]

Background: ACU193 is a humanized IgG2 subclass monoclonal antibody targeting soluble amyloid‐beta oligomers (sAβOs). Growing evidence supports the view that sAβOs may be the most toxic and pathogenic form of Aβ relative to Aβ monomers and amyloid plaques and are one of the primary drivers of Alzheimer's disease (AD) neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 is a promising approach for treating AD. Method: INTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐ ascending dose (SAD/MAD) study of the safety, tolerability, and pharmacokinetics (PK) of intravenous ACU193 in participants with early AD, i.e., mild cognitive impairment or mild dementia due to AD. Key inclusion criteria are 55‐90 years of age, confirmation of amyloid pathology with a PET scan, MMSE score of 18‐30, and CDR‐Global score (CDR‐GS) of 0.5 or 1.0. The MAD portion of the study includes three administrations of ACU193 at doses of 10, 25, or 60 mg/kg. In addition to standard safety measures, MRI is assessed periodically. Cerebrospinal fluid is collected to assess PK and evidence of target engagement. The study also includes exploratory measures such as standard cognitive and functional assessments, a computerized cognitive test battery, measures of cerebral blood flow via arterial spin labeling on MRI, and various plasma biomarkers. Result: Sixty‐five participants from 17 U.S. study sites were randomized to INTERCEPT‐AD, with 53% female and baseline age of 72.1 ± 7.8 years (mean ± SD). The baseline MMSE was 24.2 ± 3.6, CDR‐GS was 0.64 ± 0.27, and CDR‐Sum of Boxes was 3.5 ± 1.8. In addition to baseline characteristics, the presentation will provide topline safety results, frequency of amyloid‐related imaging abnormalities (ARIA), PK assessments, and evidence of target engagement. Some exploratory measures including cognitive and functional assessments, computerized cognitive testing, and endpoint florbetapir PET results will also be presented. Conclusion: We will present topline results, along with key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. The data generated from this trial will guide further development of ACU193 in a subsequent trial to test the novel mechanism of action of ACU193 in the treatment of early AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disorder affecting approximately 40 million people worldwide. There are few treatments available that affect the underlying degenerative process, making AD one of the largest unmet medical needs. ACU193 is a humanized, IgG2 subclass monoclonal antibody that targets soluble amyloid beta oligomers (sAβOs). Evidence supports the view that sAβOs are one of the primary instigators of AD neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 may be a promising approach for the treatment of AD. Method: INTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐dose study investigating the safety, tolerability, and pharmacokinetics of intravenous ACU193 in mild cognitive impairment or mild dementia due to AD. The SAD portion includes four cohorts with 2 mg/kg, 10 mg/kg, 25 mg/kg, and 60 mg/kg ACU193 or placebo. The MAD portion includes three cohorts receiving three doses of ACU193 or placebo: 10 mg/kg once every four weeks (Q4W), 60 mg/kg Q4W and 25 mg/kg once every 2 weeks (Q2W). Key inclusion criteria are 55‐90 years of age, PET scan positive for brain amyloid, MMSE 18‐30 and CDR‐Global score 0.5 or 1.0. The INTERCEPT‐AD trial is fully enrolled. Result: At 17 sites in the U.S., 260 participants were screened, 65 were randomized, and 62 received at least one dose of ACU193 or placebo, including 33 females (53%) and 29 males (47%). Negative PET (61%) was the most common reason for screen failure. Baseline age was 72.1 ± 7.8 years (mean ± SD), CDR Sum of Boxes score was 3.5 ± 1.8, ADAS‐Cog‐13 was 24.2 ± 9.0 and screening MMSE was 24.2 ± 3.6. ApoE e4 homozygotes accounted for 13% of the study population and ApoE e4 heterozygotes for 46.7%. Traditionally underrepresented ethnoracial populations comprised 23% of the study (5% Black/African American, 16% Hispanic/Latino, 2% Other). Additional baseline measures including demographics, clinical characteristics, AD medication, and imaging data will be presented. Conclusion: We describe key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. Data generated from this trial will guide further development of ACU193 for the treatment of early AD. [ABSTRACT FROM AUTHOR]

Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population. [ABSTRACT FROM AUTHOR]

Introduction: Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time. Methods: Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time. Results: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors' studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection. Conclusions: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs. [ABSTRACT FROM AUTHOR]

Background: Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin B1 and plexin B2 receptors. SEMA4D is upregulated in neurons and oligodendrocytes in response to stress and triggers inflammatory activation of plexin B1/B2 positive astrocytes with concomitant loss of some normal astrocyte functions. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington's disease (HD) and Alzheimer's disease (AD). SIGNAL‐HD is a double‐blind, placebo‐controlled study of pepinemab in HD. Given previous studies of fluorodeoxyglucose (FDG) positron emission tomography (PET) loss in HD and the mechanism of action of pepinemab, FDG‐PET imaging was included in the SIGNAL‐HD study. Method: Transgenic mouse models for HD (Q175) and AD (CVN) as well as human pathological tissue was used for immunohistochemistry. The SIGNAL‐HD study includes participants with late prodromal and early manifest HD. Results from 36 subjects in Cohort A informed group size and treatment duration in Cohort B. A subset of participants in Cohort A underwent PET scanning using FDG at baseline, at the end of the 6‐month placebo‐controlled period and at 12 months at the end of the open‐label treatment period. Result: SEMA4D was upregulated and astrocyte activation was present for HD and AD based on samples from transgenic models and staged patient autopsy samples. SIGNAL‐HD Cohort A (n=36) has been completed and Cohort B (n=265) is fully enrolled. For participants in Cohort A undergoing FDG‐PET imaging (n=19), those in the pepinemab group showed increases in FDG uptake compared to baseline (median 8.6%, range: 0.5‐20.4%) while participants taking placebo showed the expected decrease after 6 months. Nominal statistical significance (p<0.05) pepinemab compared to placebo was achieved for 11/14 frontal and parietal brain regions. Conclusion: Transgenic mouse models and human neuropathological analyses are consistent with an upregulation of SEMA4D in HD and AD. The increase in FDG‐PET signal in SIGNAL‐HD Cohort A suggests central target engagement and improvement in brain metabolic activity. SIGNAL‐AD, a randomized, placebo‐controlled, phase 1b/2 study of pepinemab in early AD, will also incorporate FDG‐PET and is planned to begin mid‐2020. [ABSTRACT FROM AUTHOR]

Abstract: Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer’s disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer’s disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107–8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer’s Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III. [Copyright &y& Elsevier]

The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer's Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial. [ABSTRACT FROM AUTHOR]

Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer's disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST® hTAU Ag and the INNOTEST® PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools. Specimens from Phase 2 studies of the γ-secretase inhibitor semagacestat and the therapeutic antibody solanezumab at baseline and following 12-14 weeks of treatment were also tested. Estimated intra-assay CV for repeated testing of 3 CSF pools were ≤11.5% and RE varied between -14.1% and +6.4%. Inter-assay CV for t-tau was <5% and RE was within ±8%. For p-tau181, inter-assay CV was <9% and RE was within ±2.5%. Total CV (intra-assay plus inter-assay) were below 10% for both analytes. Up to 20-fold dilutional linearity was demonstrated for both analytes. Stability of t-tau and p-tau181 was demonstrated in CSF during five freeze-thaw cycles at ≤-20°C and ≤-70°C and at 18-22°C for up to 24 h. Neither semagacestat nor solanezumab interfered with either assay. Inter-individual t-tau and p-tau181 concentrations were highly variable but intra-individual variations were small. These assays are suitable for analysis of CSF t-tau and p-tau181 in a single laboratory supporting multi-center AD clinical trials. No effect of treatment with semagacestat or solanezumab was observed in response to three months of drug administration. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development. Methods: A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age =55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death. Results: The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90). Conclusions: This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials. [ABSTRACT FROM AUTHOR]

Objective Accumulation of amyloid-β (Aβ) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Aβ production or clearance in the human CNS. The objective of this study was to determine the effects of a γ-secretase inhibitor on the production of Aβ in the human CNS. Methods We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Aβ production during treatment of a γ-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Aβ production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group). Results LY450139 significantly decreased the production of CNS Aβ in a dose-dependent fashion, with inhibition of Aβ generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Aβ clearance. Interpretation Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009 [ABSTRACT FROM AUTHOR]

Objective: Accumulation of amyloid-beta (Abeta) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Abeta production or clearance in the human CNS. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Abeta in the human CNS.Methods: We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Abeta production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Abeta production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group).Results: LY450139 significantly decreased the production of CNS Abeta in a dose-dependent fashion, with inhibition of Abeta generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Abeta clearance.Interpretation: Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009. [ABSTRACT FROM AUTHOR]

Abstract: Drug discovery has traditionally been almost exclusively the purview of pharmaceutical and biotechnology companies, whereas universities have focused on basic research. However, given the challenges involved in discovering and developing truly effective, symptomatic treatments and disease-modifying drugs for Alzheimer’s disease, there is a need to reassess this simple division of labor. Whereas each sector is likely to retain a core interest and expertise at either end of the drug discovery spectrum, there is room for closer cooperation at the intersection of the for-profit and not-for-profit sectors. The Alzheimer’s Association Research Roundtable convened a meeting of senior industry researchers and academic investigators to discuss this intersection and to assess the opportunity for closer partnership on Alzheimer’s disease drug discovery and development. [Copyright &y& Elsevier]

Immunoprecipitation (IP) combined with matrix-assisted laser desorption ionization (MALDI) time of flight (Tof) mass spectrometry has been used to develop quantitative assays for amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF). Inclusion of ISN labelled standard peptides allows for absolute quantification of multiple Aβ isoforms in individual samples. Characterization of variability associated with all steps of the assay indicated that the IP step is the single largest contributor to overall variability. Optimization of the assay resulted in overall coefficient of variation ≤8% with high agreement to an Aβ1-40 and Aβ1-42 ELISA assay. Application of the MALDI-Tof assay to CSF obtained from healthy volunteers and Alzheimer's disease patients indicated statistically significant 43% lower levels of Aβ1-42 in the AD group (P = 0.0025). [ABSTRACT FROM AUTHOR]

Participants in early Phase I clinical trials for drugs designed to enhance cognition are typically healthy volunteers. If improvement can be detected with a battery of cognitive tests in healthy volunteers, such a battery could be a pharmacodynamic marker in the future development of the compound for treatment of cognitive disorders. In the present exploratory study, a battery of neuropsychological (NP) tests was used to determine if changes in cognition from a pharmacological intervention could be detected in healthy volunteers. A drug with known cognitive-enhancing effects in Alzheimer's disease, donepezil, was compared with placebo and no treatment arms. Carry-over effects of repeated test administration were also assessed. In this double-blind study, 27 healthy adults were randomized into one of three arms (eight donepezil, nine placebo and 10 no treatment) and completed 14 days of donepezil (5 mg q.h.s.) or placebo (q.h.s.). A battery of NP tests was administered on days 0, 7, 14 (randomization), 21, 28 (end of treatment) and 42 (washout). There were no differences in performance between the placebo and the no treatment arms. However, on day 21, subjects in the donepezil group performed slightly but significantly worse on some tests of speed, attention and memory (p < 0.05) compared to the pooled control group (placebo and no treatment arms). No improvement in performance was present while on donepezil at days 21 or 28. While the results are counter to expectations, some tests in the battery did detect a cognitive change (transient mild worsening during drug administration) in healthy volunteers. [ABSTRACT FROM AUTHOR]

Current theories of the basal ganglia suggest a functional role in filtering stimuli that are competing for response selection. We hypothesised that damage to the basal ganglia, as occurs in Huntington's disease (HD) and Parkinson's disease (PD), may alter the effects of distractors on this filtering process. Fourteen HD subjects, 16 PD subjects, and age-matched healthy controls performed an ignored repetition test of negative priming. Negative priming was defined as a significant time cost in responding to a target that shared features with the distractor from the previous trial. Results indicated that whereas healthy controls and PD subjects showed normal negative priming, HD subjects failed to show negative priming. The results indicate that disruption to cells in the neostriatum, but not necessarily to cells in the substantia nigra, may affect selective attention by altering the influence of distractor stimuli competing for action. [ABSTRACT FROM AUTHOR]