Alzheimer's Disease Clinical Trials Research Articles

Understanding treatment goals and their application in clinical trial design for patients with Alzheimer disease and caregivers.

As research continues towards improved treatments for Alzheimer disease (AD), there is growing interest in the views and needs from patients and caregivers on AD treatments. In this study, we surveyed patients with AD and caregivers to determine the treatment goals that are most important to them. Patients with AD and caregivers were independently recruited in Europe and North America to complete a web-based survey. Eligible participants were ≥18 years old and diagnosed with mild cognitive impairment or mild-to-moderate AD (patient-reported group) or persons involved in the care of patients with AD (caregiver-reported group). A total of 322 patients and 614 caregivers completed the survey. The demographic characteristics of patients in the patient-reported and the caregiver-reported groups were similar. Disease severity of patients was greater in the caregiver-reported group compared with the patient-reported group (72.1% versus 46.9% moderate AD). The most important goal of AD treatment in both groups was maintenance of quality of life (QoL) (patient-reported group 31.1% and caregiver-reported group 38.8%; p=0.01). This was consistent across disease stages or symptom severity except for patients with mild cognitive impairment in the caregiver-reported group where slowing the progression of memory loss was the most important treatment goal. Patient QoL was consistently the most relevant treatment goal for patients with AD and caregivers. In AD clinical trials, patient-relevant outcomes, for example, QoL, should be given high priority to reflect the needs and demands of patients with AD and their caregivers.A preliminary report of this work was presented at the 14th Clinical Trials on Alzheimer's Disease meeting (November 9-12, 2021).

Biomarkers as Endpoints in Clinical Trials for Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. In this retrospective study, trials were collected by searching clinicaltrials.gov using the term "Alzheimer". Primary and secondary outcomes were analyzed separately for each phase. Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials (p = 0.001) and secondary endpoints in phase 3 trials (p = 0.001). The growing recognition of the importance of biomarkers in AD trial' design and drug development is evident by the significant steady increase in biomarkers' utilization in phases 2 and 3.

The β-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/β-Catenin/Notch Signaling Axis

The beta-amyloid precursor protein cleaving enzyme 1 (BACE1) is well known for its role in the development of Alzheimer’s disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in SSc patient skin. Inhibition of BACE1 with small molecule inhibitors or siRNA blocked SSc and fibrotic stimuli mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on β-catenin and Notch signalling. The Neurotropic factor BDNF negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from SSc patients show higher Aβ and lower BDNF levels compared to healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer’s disease and could be repurposed to ameliorate fibrosis progression.

Alzheimer's disease cerebrospinal fluid biomarkers and kidney function in normal and cognitively impaired older adults.

Recent Alzheimer's disease (AD) clinical trials have used cerebrospinal fluid (CSF) biomarker levels for screening and enrollment. Preliminary evidence suggests that AD risk is related to impaired renal function. The impact of kidney function on commonly used AD biomarkers remains unknown. Participants in studies conducted at the Goizueta Alzheimer's Disease Research Center (N=973) had measurements of serum creatinine and CSF AD biomarkers. General linear models and individual data were used to assess the relationships between biomarkers and eGFR. Lower estimated glomerular filtration rate (eGFR) was associated with lower amyloid beta (Aβ)42/tau ratio (p<0.0001) and Aβ42 (p=0.002) and higher tau (p<0.0001) and p-tau (p=0.0002). The impact of eGFR on AD biomarker levels was more robust in individuals with cognitive impairment (all p-values were<0.005). The association between eGFR and CSF AD biomarkers has a significant impact that varies by cognitive status. Future studies exploring this impact on the pathogenesis of AD and related biomarkers are needed. There is a significant association between Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and both estimated glomerular filtration rate (eGFR) and mild cognitive impairment (MCI).Kidney function influences CSF biomarker levels in individuals with normal cognitive function and those with MCI.The impact of kidney function on AD biomarker levels is more pronounced in individuals with cognitive impairment.The variation in CSF tau levels is independent of cardiovascular factors and is likely directly related to kidney function.Tau may have a possible role in both kidney and cognitive function.

Cryo-EM structures of amyloid-β and tau filaments in Down syndrome.

Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

Study Partner Type and Adverse Event Reporting in Mild-to-Moderate Alzheimer's Disease Clinical Trials.

In randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer's disease (AD) RCTs require participants to enroll with a study partner. We examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type. We estimated AE reporting rates using placebo data from seven independent RCTs conducted by the Alzheimer's Disease Cooperative Study. We assessed the heterogeneity of reporting rates as a function of visits using generalized estimating equations. In the primary analysis, we tested the hypotheses that the rates of reporting differed by study partner type and time they spent with the participant weekly using Poisson regression with robust variance estimation. In all regression models, log-transformed total patient years was included. The estimated reporting rates were 2.83 (95% CI: 2.66, 3.02), 1.18 (95% CI: 1.09, 1.28), 0.23 (95% CI: 0.19, 0.27), and 0.28 (95% CI: 0.24, 0.33) events per participant year for grade 1-3 AEs and SAEs, respectively. We estimated that greater number of visits per year was associated with increased reporting for grade 1-2 AEs and SAEs. We did not find evidence to suggest that AE reporting differed by study partner type or by time the study partner spent with the participant. Study partner type and time the study partner spent with the participant did not appear to impact AE reporting. Estimated reporting rates may be useful to evaluate safety in future studies, particularly those with no control arm and similar visit frequencies.

Barriers to Alzheimer Disease Clinical Trial Participation in a Minority Population.

Alzheimer disease (AD), the most common neurodegenerative disorder in the United States, disproportionately burdens minority populations. To explore barriers to AD clinical trial participation by Asian and Native Hawaiian patients diagnosed with AD or mild cognitive impairment. We surveyed 187 patients with a Mini-Mental State Examination score ≥14 between January 2022 and June 2022. The score cutoff for clinical trial eligibility was set by the institution. Individuals also completed a 15-question telephone survey that assessed demographics, barriers to clinical trial participation, and clinical trial improvement methods. Forty-nine patients responded, with a response rate of 26%. Asian and Native Hawaiian patients were less likely than White patients to participate in AD trials. The main barrier to participation was a lack of information about AD trials. Providing additional information regarding AD trials to patients and family members were listed as the top two reasons patients would consider participating in a clinical trial. Insufficient information about AD clinical trials is the primary barrier to participation among Asian and Native Hawaiian patients, followed by difficulty coordinating transportation and, in the case of Asians, the time required for clinical trials. Increased outreach, education, and assistance with logistics in these populations should be pursued to improve rates of participation in clinical trials.

Comparison of cerebrospinal fluid, plasma and neuroimaging biomarker utility in Alzheimer's disease.

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer's disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aβ40lumi and Aβ42/Aβ40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer's disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aβ40lumi and t-tau/Aβ40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aβ40lumi, p-tau181/Aβ40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer's disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer's disease clinical practice and trials.

The Role of Tau Pathology in Alzheimer's Disease and Down Syndrome.

Background: Individuals with Down syndrome (DS) exhibit an almost complete penetrance of Alzheimer's disease (AD) pathology but are underrepresented in clinical trials for AD. The Tau protein is associated with microtubule function in the neuron and is crucial for normal axonal transport. In several different neurodegenerative disorders, Tau misfolding leads to hyper-phosphorylation of Tau (p-Tau), which may seed pathology to bystander cells and spread. This review is focused on current findings regarding p-Tau and its potential to seed pathology as a "prion-like" spreader. It also considers the consequences of p-Tau pathology leading to AD, particularly in individuals with Down syndrome. Methods: Scopus (SC) and PubMed (PM) were searched in English using keywords "tau AND seeding AND brain AND down syndrome". A total of 558 SC or 529 PM potentially relevant articles were identified, of which only six SC or three PM articles mentioned Down syndrome. This review was built upon the literature and the recent findings of our group and others. Results: Misfolded p-Tau isoforms are seeding competent and may be responsible for spreading AD pathology. Conclusions: This review demonstrates recent work focused on understanding the role of neurofibrillary tangles and monomeric/oligomeric Tau in the prion-like spreading of Tau pathology in the human brain.

A multimodal deep learning approach for the prediction of cognitive decline and its effectiveness in clinical trials for Alzheimer's disease.

Alzheimer's disease is one of the most important health-care challenges in the world. For decades, numerous efforts have been made to develop therapeutics for Alzheimer's disease, but most clinical trials have failed to show significant treatment effects on slowing or halting cognitive decline. Among several challenges in such trials, one recently noticed but unsolved is biased allocation of fast and slow cognitive decliners to treatment and placebo groups during randomization caused by the large individual variation in the speed of cognitive decline. This allocation bias directly results in either over- or underestimation of the treatment effect from the outcome of the trial. In this study, we propose a stratified randomization method using the degree of cognitive decline predicted by an artificial intelligence model as a stratification index to suppress the allocation bias in randomization and evaluate its effectiveness by simulation using ADNI data set.

APOE-ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy

APOE-ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, APOE-ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the APOE-ε4 allele's risk for non-ARIA AEs during AD clinical trials. We used data from the Critical Path for Alzheimer's Disease (CPAD) from the placebo arm of randomized controlled trials (RCT) for AD treatment. We determined whether AEs were reported more frequently in APOE-ε4 carriers, quantifying with reporting odds ratio (ROR) using a mixed effect model. We also evaluated the association between ROR levels and the prior probability that an AE is symptomatic ARIA. We analyzed 6,313 patients with AD or mild cognitive impairment in 28 trials. Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: “delusion” (ROR = 4.133), “confusional state” (ROR = 1.419), “muscle spasms” (ROR = 9.849), “irritability” (ROR = 12.62), “sleep disorder” (ROR = 2.944), or “convulsion” (ROR = 13.00). However, none remained significant after adjusting for Mini-Mental State Examination scores. There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE-ε4 carriers. The influence of APOE-ε4 allele[s] on the clinicians' assessment of the likelihood of ARIA during safety monitoring in anti-amyloid beta monoclonal antibody treatment might be unchanged, thus maintaining the current level of awareness of clinicians of AEs.

Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human iPSC-derived neural models

Introduction17β-Estradiol (E2) is a sex hormone that has been previously demonstrated to have neurotherapeutic effects on animal models of Alzheimer's disease (AD). However, clinical trials on E2 replacement therapy for preventing AD onset yielded inconsistent results. Therefore, it is imperative to clarify the therapeutic effects of E2 on human cells. In this study, we utilized induced pluripotent stem cells (iPSCs) derived from multiple AD donors to explore the therapeutic effects of E2 on the in vitro model of human cells. MethodsWe conducted a systematic review and meta-analysis using a random-effects model of the previously reported AD clinical trials to summarize the effects of E2 replacement therapy on AD prevention. Subsequently, we induced iPSCs from the donors of the healthy control (1210B2 line (female) and 201B7 line (female)), the familial AD (APP V717L line (female) and APP KM670/671NL line (female)), and the sporadic AD (UCSD-SAD3.7 line (APOE ε3/ε3) (male), UCSD-SAD7D line (APOE ε3/ε4) (male), and TMGH-1 line (APOE ε3/ε3) (female)), then differentiated to neurons. In addition to the mono-culture model of the neurons, we also examined the effects of E2 on the co-culture model of neurons and astrocytes. ResultsThe meta-analysis of the clinical trials concluded that E2 replacement therapy reduced the risk of AD onset (OR, 0.69; 95 % confidence interval [CI], 0.53–0.91; I2 = 82 %). Neural models from the iPSCs of AD donors showed an increase in secreted amyloid-beta (Aβ) levels in the mono-culture model and an astrogliosis-like phenotype in the co-culture model. E2 treatment to the neuronal models derived from the iPSCs enhanced neuronal activity and increased neurite complexity. Furthermore, E2 treatment of the co-culture model ameliorated the astrogliosis-like phenotype. However, in contrast to the previous reports using mouse models, E2 treatment did not change AD pathogenesis, including Aβ secretion and phosphorylated tau (pTau) accumulation. ConclusionE2 treatment of the human cellular model did not impact Aβ secretion and pTau accumulation, but promoted neuronal plasticity and alleviated the astrogliosis-like phenotype. The limited effects of E2 may give a clue for the mixed results of E2 clinical trials.

CCOG Web-Based Cognitive Assessment Tool.

Cognitive testing is an essential part of clinical diagnostics and clinical trials in Alzheimer's disease. Digital cognitive tests hold a great opportunity to provide more versatile and cost-efficient patient pathways through flexible testing including at home. In this work, we describe a web-based cognitive test, cCOG, that can be used in screening, differential diagnosis, and monitoring the progression of neurodegenerative diseases.

CATALYZING NOVEL METHODS OF MEASURING COGNITION BY HARNESSING TECHNOLOGY

Abstract Early detection of cognitive impairment is essential for enabling access to clinical assessments and treatments and facilitating participation in clinical trials for Alzheimer’s disease. By employing smartphones and digital technologies to capture cognitive behaviors with high precision we may be able to detect novel, subtle biomarkers of cognitive impairment during clinic-based assessments, in-home self-administered tasks, and daily activities. In this Collaborative Symposium from the Alzheimer’s Disease and Related Dementias and Technology and Aging Interest Groups, we will explore the development of technologies to detect cognitive impairment and discuss the feasibility of obtaining these data in non-traditional settings. The first presentation reports on the use of eye-tracking technology to detect cognitive impairment with high accuracy. The second presentation discusses acoustic features from digital voice recordings of a cognitive screener that are associated with cognitive impairment and increase the screener’s specificity. The next presentation describes linguistic features from voice recordings of a memory test that are associated with depression and distinct from those associated with cognitive impairment. The fourth presentation introduces a smartphone application that measures hand grip strength, a known correlate of dementia risk. The symposium concludes with a summary of older adults’ attitudes toward wearable technologies to detect cognitive decline and the development of a smart reminder system to promote adherence to home-based assessment. Overall, these presentations highlight ways we can harness technology to capture unique features of cognitive function that increase the accuracy of traditional testing or detect cognitive impairment in novel settings. This is a collaborative symposium between the Alzheimer’s Disease and Related Dementias and Technology and Aging Interest Groups.

Coumarin Derivatives: Mechanistic Insights and Promising Applications as Potential Alzheimer's Disease (AD) Therapeutic Agents

AbstractIn this review, the therapeutic potential of coumarin derivatives for Alzheimer's disease (AD) is examined. Coumarin derivatives are intriguing options for treating AD since they have a variety of chemical structures and display a wide range of pharmacological properties. The acetylcholinesterase (AChE) enzyme, which can improve cognitive function by boosting cholinergic neurotransmission, is inhibited by these compounds, which underlies their possible therapeutic effects. As a result of acetylcholinesterase inhibition provided by coumarin derivatives, cholinergic neurotransmission and cognitive performance are boosted. They also have anti‐oxidant and anti‐inflammatory qualities, which can mitigate the oxidative stress and neuroinflammation seen in AD. In addition, amyloid‐beta aggregation and tau hyperphosphorylation are decreased by coumarin derivatives, demonstrating the neuroprotective properties of these compounds. To properly assess their effectiveness, safety, and ideal dosage in AD patients, more studies and clinical trials are nonetheless required. Overall, coumarin derivatives hold promise as potential therapeutic options for Alzheimer's disease (AD), and continued investigation will contribute to the development of effective treatments for this devastating disease.

Recruitment and Retention of Underrepresented Minorities in Interventional Alzheimer’s Disease Clinical Trials

AbstractBackgroundAlzheimer’s disease is a progressive neurodegenerative disorder that affects thinking, and behavior and is the most common cause of dementia. In Alzheimer’s disease (AD) clinical trials, there is a severe lack of underrepresented and marginalized populations. Despite overwhelming evidence that these groups are more likely to develop AD, various recruitment barriers impair them from being accepted into current AD clinical studies, which threatens these findings' overall generalizability and scientific impact. As a result, there is less understanding of overall needs, no mechanism for identifying and comparing disease variations, and a limited range of available interventions. In this study, we aim to analyze the recruitment, reporting, and retention strategies of Hispanic/Latinx and Black individuals in AD Clinical Trials for the last 35 years to create a novel model system to increase the diversity and inclusion of minoritized groups in Alzheimer’s Clinical Trials.MethodWe extracted the data from the clinicaltrials.gov database and applied the inclusion criteria: Year: 1999‐Present, Population: Older Adults (65&gt;), Alzheimer’s Diagnosed, and Healthy. Intervention: Pharmaceutical/drug. Funding: NIH, Industry. Status: Completed. For our outcome variables, we included the following: Reported and non‐reported recruitment demographic, the inclusion of white, Hispanic/Latin, Black/African American, Asian, and Unknown. For our analyses, we performed a Linear regression on cohort demographic makeup in five‐year intervals, reported vs. non‐reported demographic, and the percentage of ethnicity recruited.ResultOur search yielded n = 117 clinical trials. 28% of NIH‐sponsored drug‐based clinical trials have reported cohort demographic makeup. 61% of Industry‐sponsored drug‐based reported cohort demographic make‐up.ConclusionWe found that despite the increasing research focusing on the importance of the inclusion of underrepresented individuals in clinical trials. The number of underrepresented minorities in AD clinical trials continues to be significantly and alarmingly low, hindering the scientific process of developing therapeutic methods for Alzheimer’s Disease. Moreover, several laws and policies have been released to enforce the reporting of ethnicity/race of clinical trials cohort have not been adequately enforced and followed, raising concerns for policy efficacy.

Change on the Repeatable Battery for the Assessment of Neuropsychological Status and its relationship to brain amyloid

AbstractBackgroundThe Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer’s disease (AD), including brain amyloid plaque density. However, less is known about if changes in the RBANS across time are also related to brain amyloid deposition. The current study sought to expand on prior work by examining the relationship between changes over time on the RBANS and amyloid deposition via positron emission tomography (PET).MethodOne‐hundred twenty‐six older adults with intact or impaired cognition and daily functioning underwent repeat assessment with the RBANS across nearly 16 months, as well as had a baseline amyloid PET scan.ResultIn the entire sample, amyloid deposition was significantly related to change on all five Indexes and the Total Scale score of the RBANS (rs = ‐0.28 – ‐0.61), with greater amyloid deposition being associated with worsening cognition. This pattern was also observed in 11 of 12 subtests. In the intact individuals, this pattern was only observed on change in the Immediate Memory Index (r = ‐0.32). In the subjects with MCI, this pattern was only observed on change in the Delayed Memory Index (r = ‐0.35). There was no association between change on the RBANS and brain amyloid deposition in those with AD.ConclusionWhereas prior studies have identified a relationship between baseline RBANS and amyloid status, the current findings support that changes in the RBANS are also indicative of AD brain pathology. Although replication in a more diverse sample is needed, these results continue to support the use of the RBANS in AD clinical trials.

Modernizing AD clinical trials: why are we designing studies for disease modifying treatments using the symptomatic treatment paradigm?

AbstractBackgroundUntil the accelerated approvals of aducanumab and lecanemab, the only approved drugs for Alzheimer’s disease (AD) were symptomatic treatments, which showed relatively large improvements but did not alter disease progression. Multiple decades of designing and analyzing trials for symptomatic treatments have optimized the process for acetyl cholinesterase inhibitors and NMDA receptor antagonists, but this paradigm is not optimal for disease‐modifying therapies. As the AD research community continues to transition towards treatments with the potential to alter disease progression, significant course corrections in the design and analysis of clinical trials are required to ensure that treatments with the largest potential for impact do not fail because they’re being evaluated out of context.MethodSeveral design aspects from AD clinical trials are evaluated in the context of disease‐modifying treatments, including the expected effect size, patient population, outcomes, multiplicity adjustments, trial duration, use of biomarkers, and timing of visits. We use publicly available trial results to demonstrate that both the clinical trial process and public interpretation of data will result in costly losses unless significant improvements are accepted and implementedResultIn the context of donepezil’s expected 3‐point change on ADAS‐cog over 6 months, the results for lecanemab (1.5 points over 18 months) seem small, yet lecanemab improvements can be reasonably expected to match donepezil after three years of treatment and continue to increase. Symptomatic treatments were required to demonstrate significant improvement on multiple outcomes, but disease‐modifying treatments should address the underlying disease process. Trials of aducanumab, donanemab, and lecanemab show consistent disease modification of 5 to 6 months less progression over 18 months when outcomes are converted to units of time and combined. This time‐converted composite (which may include biomarkers) can show consistent results earlier in the disease course, allowing prodromal and early AD patients to be studied with greater success.ConclusionThe current message sent by recent approvals is that only sponsors with resources to field clinical trials with thousands of patients have a chance of gaining regulatory approval. By modernizing clinical trials, more sponsors will have a better chance of success, meaning better treatments available to more patients sooner.

Longitudinal cognitive change in older adults with elevated tau PET signal in the absence of amyloid

AbstractBackgroundMost theoretical frameworks for Alzheimer’s disease (AD) pathogenesis propose amyloid as the primary pathologic process, whereas tau in the absence of amyloid (A‐/T+) is considered a “non‐AD pathologic change” (Jack et al., 2018). Previous research has demonstrated AD‐like characteristics of the A‐/T+ biomarker profile, including poorer memory and language performance and entorhinal thinning (Weigand et al., 2022; Yoon et al., 2022). Assessment of domain‐specific longitudinal cognitive decline in this group, however, has not yet been addressed. Our study sought to evaluate 1‐year memory, language, and attention/executive function trajectories of A‐/T+ older adults.MethodWe included 756 older adults at baseline across the AD clinical continuum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of whom 359 had 1‐year follow‐up cognitive data. Four A/T groups were classified based on cortical amyloid‐beta and medial temporal tau positron emission tomography positivity. Linear mixed effects models examined 1‐year trajectories of each baseline A/T group in domains of memory, language, and attention/executive function. Both statistical significance and effect size estimates were evaluated.ResultThe following proportions of A/T groups were observed at baseline: 47.0% A‐/T‐, 13.2% A‐/T+, 13.4% A+/T‐, and 26.4% A+/T+. Only the A+/T+ group exhibited a statistically significant decline in language and attention/executive function domains relative to the A‐/T‐ group. Examination of effect sizes, however, revealed that the A‐/T+ group had a quantitatively similar degree of decline as the A+/T+ group in memory (A‐/T+ and A+/T+ bs = ‐0.13), and an intermediate degree of decline between the A‐/T‐ and A+/T+ groups for language (A‐/T+ b = ‐0.17) and attention/executive function (A‐/T+ b = ‐0.19). Similar patterns were observed when examining cognitively unimpaired participants only.ConclusionOlder adults with the A‐/T+ biomarker profile demonstrate a degree of cognitive decline across multiple domains consistent with a possible AD trajectory. The systematic exclusion of these individuals from AD clinical trials may hinder early intervention efforts to attenuate the cognitive decline observed in this biomarker group, and an expansion of our conceptualization of the AD continuum to include A‐/T+ individuals may offer improved insight into the pathologic and cognitive changes that occur in the context of preclinical AD.

Utilization and future of biomarkers in biofluid as outcome measures in clinical trials for Alzheimer’s disease: a systematic review

AbstractBackgroundIn recent years, the availability of biofluid markers in Alzheimer’s disease (AD) has increased substantially, but it is unclear to what extend these are applied to support drug development. Therefore, we provide an overview of biofluid biomarker use within trials.MethodTo identify how fluid biomarkers are used in clinical trials, we performed a search (8‐FEB‐2022) on www.clinicaltrials.gov, using the search term ‘Alzheimer’s disease’, and selected trials aimed at disease modification starting from 1‐JAN‐2017 to 1‐JAN‐2022. Biofluid markers and their purpose in each trial were described. Results are summarized by trial phase, target class, and endpoint information.ResultWe identified 186 trials of which 44% used biofluid markers. 15% of phase 1 trials, 15% of phase 2 trials, and 6% of phase 3 and 4 trials employ fluid biomarkers as primary outcome (Figure 1). Blood and CSF biomarkers were used equally frequent. CSF biomarkers for Aβ, Tau, and other biomarkers were employed in 21%, 25%, and 16% of the 186 trials, respectively. Blood biomarkers for Aβ, Tau, and other biomarkers were used in 14%, 13%, and 23% of the trials, respectively. Moving further in the drug development phases, contribution of classic AD biomarkers increased, especially in CSF. Overall, a combination of Aβ, Tau and other biomarkers was used most frequent. 25% of the trials use biofluid target engagement markers. Target engagement marker use is most prominent in amyloid and tau targeting drugs. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis, gut‐brain axis targeting drugs.ConclusionThere exists a need for new fluid biomarkers, to reflect pathology which can be used in certain target classes where there currently is a lack of fluid biomarkers. To support future use biofluid markers as surrogate outcomes, research into the specific pathological processes they reflect and their correlation with cognition is warranted. This can pave the way into implementation of surrogacy biomarkers in AD clinical trials.