Paul S. Aisen's research while affiliated with University of California, Los Angeles and other places
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Publications (521)
Longitudinal multimodal biomarker studies reveal that the continuum of Alzheimer's disease (AD) includes a long latent phase, referred to as preclinical AD, which precedes the onset of symptoms by decades. Treatment during the preclinical AD phase offers an optimal opportunity for slowing the progression of disease. However, trial design in this po...
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,...
Background:
Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials.
Objective:
To determine if a blo...
Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categ...
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 co...
Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer’s disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing...
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 elderl...
Introduction:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the Nat...
Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes measured over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized gro...
Introduction:
The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention w...
Rates of tau accumulation in cognitively unimpaired older adults are subtle with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid β-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively...
Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successfu...
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...
Introduction:
Epidemiological studies report an association between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and clinically diagnosed Alzheimer's disease (AD). We examined the association between TBI/PTSD and biomarker-defined AD.
Methods:
We identified 289 non-demented veterans with TBI and/or PTSD and controls who...
The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease.
We compared brain MRI...
Background
The need for preventive therapies that interrupt the progression of Alzheimer’s disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meani...
Background:
Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials.
Objective:
To evaluate the association between amyloid (Aβ) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and R...
Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention...
Alzheimer's Disease (AD) is a growing global public health challenge. The development of new therapies is urgently needed, and a complex ecosystem of organizations has grown to facilitate AD drug discovery and development. Masterfully collating information on the drug development ecosystem, this book emphasizes the contributions of each aspect in t...
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 i...
Bachground and Objectives
To investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized using Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.
Methods
The FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique se...
Introduction:
Cognitive decline follows pathological changes including neurodegeneration on the Alzheimer's disease continuum. However, it is unclear which cognitive domains first become affected by neurodegeneration in amyloid-positive individuals and if sex or apolipoprotein (APOE) ε4 status differences affect this relationship.
Methods:
Data...
Introduction:
An analysis of the ethnocultural and socioeconomic composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants is needed to assess the generalizability of ADNI data to diverse populations.
Methods:
ADNI data collected between October 2004 and November 2020 were used to determine ethnocultural and educational comp...
Objective
The Alzheimer’s Therapeutic Research Institute (ATRI) developed a novel clinical data management system, the ATRI electronic data capture system (ATRI EDC), to address the complex regulatory, operational, and data requirements that arise in the conduct of multicenter Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRDs)...
[This corrects the article DOI: 10.1093/jamiaopen/ooab119.].
Regular reporting and monitoring of Adverse Events (AE) and Serious Adverse Event (SAE) are a crucial part of all randomized, controlled clinical trials, providing an assessment of the intervention’s safety profile. This process of adverse event surveillance is critical for participant’s safety and data quality. Knowledge and previous experience fr...
The Alzheimer's Clinical Trials Consortium (ACTC) aims to provide an optimal infrastructure, utilizing centralized resources and shared expertise, to accelerate the development of effective interventions for Alzheimer’s disease and related disorders (ADRD). Metrics help clinical research sites understand where they stand relative to other sites and...
An analysis of the ethnoracial and educational composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, and the relationship between ethnoracial/education and screening, enrollment, dropout, and biomarkers is needed to assess the generalizability of ADNI data to diverse populations, and to inform efforts to increase diversity...
The overarching goal of the Longitudinal Early‐onset Alzheimer Disease study (LEADS) is to optimally characterize early‐onset AD (EOAD) and establish an EOAD clinical trials network. Here we report the baseline demographic and imaging biomarker comparisons of the LEADS cohort to late‐onset AD (LOAD) subjects from the Alzheimer’s Disease Neuroimagin...
Amyloid beta (Aβ) accumulation begins 10‐20 years before the onset of cortical tauopathy, neurodegeneration, and clinical symptoms in Alzheimer’s disease. Lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ (ie, oligomers, protofibrils), reduced amyloid on PET and slowed cognitive decline in a...
Study Objectives
To examine in a subsample at the screening phase of a clinical trial of an β-amyloid (Aβ) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer’s disease (AD).
Methods
Overall, 26 Aβ-positive (Aβ+) and 33 Aβ-negative (Aβ-) cognitively unimpaired participants...
Introduction:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020.
Methods:
We identified 1442 publications us...
The accelerated approval of aducanumab (AduhelmTM) by the US FDA is a momentous event. For the first time, a therapeutic agent that targets the neurobiology of Alzheimer’s disease (AD) is available for clinical use (1, 2). In addition to the FDA approval of aducanumab, the FDA has also provided “Breakthrough therapy designation” for Lilly’s Donanem...
Introduction:
The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non-invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed wi...
Background:
There is a need for feasible, scalable assessments to detect cognitive impairment and decline. The Cogstate Brief Battery (CBB) is validated for Alzheimer's disease (AD) and in unsupervised and bring your own device contexts. The CBB has shown usability for self-completion in the home but has not been employed in this way in a multisit...
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...
Background:
Selecting cognitively normal elderly individuals with higher risk of brain amyloid deposition is critical to the success of prevention trials for Alzheimer's disease (AD).
Methods:
Based on the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study data, we built machine-learning models and applied them to our ongoing Japan...
Background
Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aβ) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, poten...
Importance
Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs).
Objective
To report efficacy, safety, and biomarker findings...
Background:
Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.
Objective:
To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).
Design:
Cross-se...
Very recently, the Food and Drug Administration (FDA) in the United States gave an “accelerated approval” to aducanumab, the first new drug to be available to patients with Alzheimer’s disease (AD) in nearly two decades and the first ever that targets the underlying neuropathology. The accelerated approval pathway is based on a biomarker effect, in...
The NIA‐AA Research Framework on Alzheimer’s disease (AD) represents an important advance in the biological characterization of the AD spectrum. While this framework predicts disease progression, definitions of amyloid, tau, and neurodegeneration positivity based on cut‐scores may limit the performance of predictive models. 252 cognitively normal (...
The ideal participants for Alzheimer’s disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e. placebo arm) and would also respond to the therapeutic intervention. However, up to 50% of placebo treated participants enrolled in the AD clinical trials do not show cognitive or functional decline during the timeframe...
White matter (WM) hypointensity volume in T1 MRI correlates strongly with T2 hyperintensities and both are typically associated with advancing age and vascular brain injury (VBI). Recent research has suggested that Alzheimer’s Disease (AD) neuropathologic changes (ADNC) also increases WM hypointensity volume. Sporadic early onset AD (EOAD) patients...
Secondary prevention trials in cognitively‐normal older people with brain amyloid beta (Aβ) accumulation are emerging as the next frontier in dementia therapy. The A4 Study is an international randomised placebo controlled trial of immunotherapy against Aβ, a hallmark contributing factor to Alzheimer’s disease (AD). Here we report the screening cha...
Approximately 5% of the 5.6 million (∼280,000) Americans with Alzheimer’s disease (AD) develop symptoms at age 65 or younger and are classified as having early‐onset AD (EOAD). Although EOAD and late‐onset AD (LOAD) share the same pathologic substrate, there are notable differences in their clinical and biological phenotypes. The Longitudinal Early...
Previous studies have reported that age modifies the distribution and burden of tau (and, to a lesser extent, amyloid) pathology in sporadic Alzheimer’s disease (AD). Here we present preliminary baseline amyloid and tau PET results from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), a multi‐site longitudinal study of sporadic early...
Previous research has suggested that, compared to males, females are at greater risk for and have greater pathology burden in late onset. However, sex differences in early onset AD (EOAD) have not yet been studied. We included 167 participants [28 cognitively normal (CN, 68% females), 98 early onset AD (EOAD, 55% females), and 41 cognitively impair...
Aβ pathologies occur years prior to cortical tauopathy, neurodegeneration, and clinical symptoms. BAN2401 is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregated species (oligomers, protofibrils). BAN2401 reduced amyloid on PET and slowed cognitive decline in a Phase 2 study in early symptomatic AD. The...
The Mixed Model for Repeated Measures (MMRM; Mallinckrodt, et al. 2001) is the most commonly used approach for assessing treatment effects in Alzheimer’s clinical trials. An alternative nonlinear Disease Progression Model (DPM) which assumes the ratio of group means is fixed over time has been proposed for DIAN‐TU (e.g. Wang, et al. 2018). We asses...
Differences between chronological age and biological age can be used to communicate health related information to the general population. For the brain, cognitive performance can be used to define biological age. We utilized data from performance on tests from the Cogstate Brief Battery (CBB) to develop a ‘Brain Age’ score for characterizing the pr...
The Cognitive Function Index (CFI) is an evaluation of participants’ cognitive and functional decline. Alzheimer’s disease (AD) clinical trials, including Preclinical trials, require participants to have a study partner (SP) to help evaluate participant cognitive and functional performance. Past studies in early AD dementia and Mild Cognitive Impai...
Genetic studies of Alzheimer’s disease (AD) have focused on the clinical or pathological diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. Our goal was to identify the underlying genetic bases for brain amyloidosis during the preclinical phase of AD. We performed genome‐wide assoc...
In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer’s disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize t...
Introduction:
The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported.
Methods:
APECS (verub...
Introduction:
We examined the associations among instrumental activities of daily living (IADL), cortical amyloid, and cognition in cognitively normal (CN) older adults.
Methods:
CN participants screening for the A4 Study (n = 4486) underwent florbetapir (amyloid) positron emission tomography. IADL were assessed using the Alzheimer's Disease Coo...
Despite negative findings from numerous clinical trials of potential disease-modifying therapies for Alzheimer disease, amyloid remains the most compelling therapeutic target. Advances in biomarker methods now enable accurate monitoring of Alzheimer disease progression from the earliest stages of the disease. We must therefore redouble efforts to f...
Dr. Umbricht suggests that the two examples we cite in our viewpoint (1) support rather than call into question the value of interim futility analyses in Alzheimer’s disease (AD) trials. He points out that the first example, the Phase 3 trials of aducanumab, the futility analyses did indeed indicate a trend toward a beneficial treatment effect in o...
BACKGROUND: The Trial-Ready Cohort for Preclinical/ Prodromal Alzheimer’s Disease (TRC-PAD) Informatics Platform (TRC-PAD IP) was developed to facilitate the efficient selection, recruitment, and assessment of study participants in support of the TRC-PAD program.
OBJECTIVES: Describe the innovative architecture, workflows, and components of the TRC...
Importance
The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure.
Objective
To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive i...
Background:
The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy.
Objectives:
To remotely enroll a cohort of individuals into a web-based longitudinal observational study....
Background:
The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD) aims to accelerate enrollment for Alzheimer's disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluatio...
Background:
Screening to identify individuals with elevated brain amyloid (Aβ+) for clinical trials in Preclinical Alzheimer's Disease (PAD), such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) trial, is slow and costly. The Trial-Ready Cohort in Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) aims to accelerate and red...
The Trial-Ready Cohort for Preclinical/prodromal Alzheimer's Disease (TRC-PAD) project is a collaborative effort to establish an efficient mechanism for recruiting participants into very early stage Alzheimer's disease trials. Clinically normal and mildly symptomatic individuals are followed longitudinally in a web-based component called the Alzhei...
Background
Evidence on preventing Alzheimer’s disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention.
Methods
Electronic databases and re...
Importance
Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer’s disease dementia remains to be examined in a multi-site trial.
Objective
To examine the feasibility,...
In the standard, orderly progression of drug development trials, a moderately-sized Phase 2 trial demonstrates safety and efficacy of one or more doses of the investigational product, followed by large confirmatory Phase 3 trials of one or two doses leading to regulatory approval. The large and lengthy Phase 3 trials often include interim futility...
In clinical trials in populations with mild cognitive impairment, it is common for participants to initiate concurrent symptomatic medications for Alzheimer's disease after randomization to the experimental therapy. One strategy for addressing this occurrence is to exclude any observations that occur after the concurrent medication is initiated. Th...
Importance
The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity...
While amyloid-targeting therapies continue to predominate in the Alzheimer's disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease...
The termination of many clinical trials of amyloid-targeting therapies for the treatment of Alzheimer's disease (AD) has had a major impact on the AD clinical research enterprise. However, positive signals in recent studies have reinvigorated support for the amyloid hypothesis and amyloid-targeting strategies. In December 2019, the EU-US Clinical T...
With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer’s disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representa...
background evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. we completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. Methods electronic databases and rel...
Background:
Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH.
Methods:
EPOCH was a randomized, doub...
Introduction:
We aimed to estimate the frequency of each AT(N) (β-amyloid deposition [A], pathologic tau [T], and neurodegeneration [N]) profile in different clinical diagnosis groups and to describe the longitudinal change in clinical outcomes of individuals in each group.
Methods:
Longitudinal change in clinical outcomes and conversion risk of...
Importance
Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease.
Objective
To...
Introduction:
Clinical trials on preclinical Alzheimer's disease are challenging because of the slow rate of disease progression. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently than models of time to progression.
Methods:
Multivariate continuous data are simulated...
The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ a...
