HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.

Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.

FASTKD2 is associated with memory and hippocampal structure in older adults.

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.

Deposition of amyloid-ß (Aß) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aß load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aß levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aß load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aß levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aß deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aß burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

A Pragmatic, Investigator-Driven Process for Disclosure of Amyloid PET Scan Results to ADNI-4 Research Participants.

BACKGROUND: Prior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples. METHODS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included. RESULTS: Data collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators. CONCLUSION: The pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.

Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Lecanemab: Appropriate Use Recommendations.

Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.

Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force.

In randomized clinical trials (RCTs) for Alzheimer's Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.

Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab.

OBJECTIVES: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. DESIGN: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. SETTING: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. PARTICIPANTS: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. INTERVENTION: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. MEASUREMENTS: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. RESULTS: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. CONCLUSIONS: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.

Aducanumab: Appropriate Use Recommendations Update.

Aducanumab (Aduhelm) is approved in the United States for the treatment of patients with mild cognitive impairment due to Alzheimer's disease or mild AD dementia. Aducanumab Appropriate Use Recommendations (AURs) have been published and have helped guide best practices for use of aducanumab. As real-world use has occurred and more information has accrued, the AURs require refinement. We update the AURs to better inform appropriate patient selection and improve shared decision-making, safety monitoring, and risk mitigation in treated patients. Based on evolving experience we emphasize the importance of detecting past medical conditions that may predispose to amyloid related imaging abnormalities (ARIA) or may increase the likelihood of ARIA complications including autoimmune or inflammatory conditions, seizures, or disorders associated with extensive white matter pathology. The apolipoprotein E ε4 (APOE4) genotype is strongly associated with ARIA and exhibits a gene dose effect. We recommend that clinicians perform APOE genotyping to better inform patient care decisions, discussions regarding risk, and clinician vigilance concerning ARIA. As most ARIA occurs during the titration period of aducanumab, we suggest performing MRI before the 5th, 7th, 9th, and 12th infusions to improve detection. Uncommonly, ARIA may be recurrent or serious; we suggest additional parameters for treatment discontinuation taking these observations into account. It is important to continue to learn from the real-world use of aducanumab and the AURs will continue to evolve as new information becomes available. This AUR update does not address efficacy, price, or insurance coverage and is provided to assist clinicians to establish best practices for use of aducanumab in the treatment of patients with mild cognitive impairment and mild Alzheimer's dementia.

Therapeutic Targets for Alzheimer's Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report.

There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer's disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies.

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. OBJECTIVE: To evaluate the association between amyloid (Aß) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. SETTING: The EARLY study was conducted at 143 centers across 14 countries. PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aß status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aß levels (Aß-, n=2,824) and those with pathological Aß levels (Aß+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aß1-42. MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aß groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aß status. RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aß+ participants performed worse versus Aß- participants on all cognitive composites though the magnitude of the Aß effect was generally small. The Aß+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aß+/- effect sizes. CONCLUSIONS: Cross-sectional relationships between Aß and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aß+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aß status cross-sectionally cannot be generalized to sensitivity to change over time.

Tackling a Major Deficiency of Diversity in Alzheimer's Disease Therapeutic Trials: An CTAD Task Force Report.

As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer's Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials. New and innovative recruitment initiatives and enhanced infrastructure facilitate increased participant diversity in AD clinical studies.

Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid.

BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aß+; n = 1250, A4) and without elevated cerebral amyloid (Aß-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aß+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aß+ or Aß- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aß+ cohort compared with 8% in Aß- (P < 0.001). In the Aß+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aß-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aß+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aß+ cohort compared with Aß- (P < 0.001). Females showed reduced odds of MCH in the Aß+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aß+ and Aß- populations prior to anti-amyloid drug intervention. ARIA-H in Aß+ was greater than in Aß- populations.

Alzheimer's Disease Clinical Trial Research Adaptation Following COVID-19 Pandemic Onset: National Sample of Alzheimer's Clinical Trial Consortium Sites.

BACKGROUND: The COVID-19 pandemic created challenges in clinical research operations that required immediate and lasting changes. OJBECTIVES: The purpose of this study was to explore adaptations to clinical trial research due to COVID-19 and develop a theoretical framework of emergent strategies related to pandemic mitigation in a national network of Alzheimer's disease clinical trial sites. DESIGN: This qualitative study used a grounded theory approach including semi-structured interviews, constant comparative methods, and multi-level, iterative coding. PARTICIPANTS: Twenty-six member sites of the Alzheimer's Clinical Trial Consortium participated with a total of 49 participants. RESULTS: Findings demonstrate processes of adaptation following COVID-19 onset including establishing safety as priority, focus on scientific preservation, accommodations (creating policies, leadership mindset, maintaining operations, and determining research procedures), and evaluation of changes throughout the course of the pandemic. Communication and maintaining integrity were vital throughout these processes. CONCLUSION: Processes of accommodation among clinical research sites during the pandemic provide critical insights and direction for future clinical trials development and emergent methods in Alzheimer's disease and other therapeutic areas.

Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Aducanumab: Appropriate Use Recommendations.

Aducanumab has been approved by the US Food and Drug Administration for treatment of Alzheimer's disease (AD). Clinicians require guidance on the appropriate use of this new therapy. An Expert Panel was assembled to construct Appropriate Use Recommendations based on the participant populations, conduct of the pivotal trials of aducanumab, updated Prescribing Information, and expert consensus. Aducanumab is an amyloid-targeting monoclonal antibody delivered by monthly intravenous infusions. The pivotal trials included patients with early AD (mild cognitive impairment due to AD and mild AD dementia) who had confirmed brain amyloid using amyloid positron tomography. The Expert Panel recommends that use of aducanumab be restricted to this population in which efficacy and safety have been studied. Aducanumab is titrated to a dose of 10 mg/kg over a 6-month period. The Expert Panel recommends that the aducanumab be titrated to the highest dose to maximize the opportunity for efficacy. Aducanumab can substantially increase the incidence of amyloid-related imaging abnormalities (ARIA) with brain effusion or hemorrhage. Dose interruption or treatment discontinuation is recommended for symptomatic ARIA and for moderate-severe ARIA. The Expert Panel recommends MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA. Recommendations are made for measures less cumbersome than those used in trials for the assessment of effectiveness in the practice setting. The Expert Panel emphasized the critical importance of engaging in a process of patient-centered informed decision-making that includes comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits.

Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: Intranasally administered insulin has shown promise in both rodent and human studies in Alzheimer's disease; however, both effects and mechanisms require elucidation. OBJECTIVE: We assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer's disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909). DESIGN: A randomized (1:1) double-blind clinical trial. SETTING: Twelve sites across the United States. PARTICIPANTS: Adults with mild cognitive impairment or Alzheimer's disease. INTERVENTION: Participants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled. MEASUREMENTS: Changes from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer's Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite. RESULTS: The insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer's disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group. CONCLUSION: Intranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin's potential as a therapeutic option for Alzheimer's disease.

Platform Trials to Expedite Drug Development in Alzheimer's Disease: A Report from the EU/US CTAD Task Force.

A diverse range of platforms has been established to increase the efficiency and speed of clinical trials for Alzheimer's disease (AD). These platforms enable parallel assessment of multiple therapeutics, treatment regimens, or participant groups; use uniform protocols and outcome measures; and may allow treatment arms to be added or dropped based on interim analyses of outcomes. The EU/US CTAD Task Force discussed the lessons learned from the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) platform trial and the challenges addressed by other platform trials that have launched or are in the planning stages. The landscape of clinical trial platforms in the AD space includes those testing experimental therapies such as DIAN-TU, platforms designed to test multidomain interventions, and those designed to streamline trial recruitment by building trial-ready cohorts. The heterogeneity of the AD patient population, AD drugs, treatment regimens, and analytical methods complicates the design and execution of platform trials, yet Task Force members concluded that platform trials are essential to advance the search for effective AD treatments, including combination therapies.