Maria C Carrillo

• Ph.D.
• Chief Science Officer at Alzheimer's Association

Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred n...

In the last two decades, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has significantly advanced our understanding, technologies, and methods for detecting and diagnosing Alzheimer's disease and related dementias. This perspective proposes repurposing ADNI to address emerging research and healthcare challenges. The focus would shift towar...

INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized co...

Background: As literature suggests that Early-Onset Alzheimer's Disease (EOAD) and late-onset AD may differ in important ways, need exists for randomized clinical trials for treatments tailored to EOAD. Accurately measuring reliable cognitive change in individual patients with EOAD will have great value for these trials. Objectives: The current...

The design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) ap...

Background The clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) described EOAD as predominantly amnestic, though this p...

INTRODUCTION The Alzheimer's Association Global Biomarker Standardization Consortium conducted a blinded case–control study to learn which phosphorylated tau (p‐tau) assays provide the largest fold‐changes in Alzheimer's disease (AD) versus non‐AD and show commutability in measuring patient samples and candidate certified reference materials (CRMs)...

Background LatAm‐FINGERS is a non‐pharmacological multicenter randomized clinical trial aimed at preventing cognitive impairment. The intervention advocates for a lifestyle change based on diet, exercise, risk factor control, cognitive training, and socialization. However, the baseline assessment lacks a evaluation of the participants sociability b...

Background LatAm‐FINGERS is the first non‐pharmacological multicenter randomized clinical trial aimed at preventing cognitive impairment in Latin America. It encompasses twelve countries that collectively represent 45% of the territory in the Americas. Its objective is to reach populations that, despite sharing commonalities such as language, are c...

Background The LatAm‐FINGERS trial marks a pioneering initiative as the first non‐pharmacological clinical trial encompassing participants from 12 Latin American countries, including Argentina, Brazil, Bolivia, Chile, Colombia, Costa Rica, Ecuador, Dominican Republic, Mexico, Peru, Puerto Rico, and Uruguay. This initiative represents a significant...

Real‐World data platforms for Alzheimer’s Disease (AD) offer a unique opportunity to improve health equity through better understanding of health disparities and inclusivity in research, which is critical to translatability of research findings. AD research in the US and globally remains largely inaccessible to many individuals due to individual‐le...

Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of t...

Background The variability in the regional distribution of Aß‐PET signal and its relation to clinical features is debated. We used data‐driven approaches to uncover heterogeneity in cortical Aß‐PET signal from a large representative sample collected through the IDEAS study. Methods We analysed cross‐sectional Aß‐PET collected from 10,361 patients...

Background Understanding how early‐onset Alzheimer’s disease (EOAD) differs from typical late‐onset AD (LOAD) is an important goal of AD research that may help increase the sensitivity of unique biomarkers for each phenotype. Building upon prior work based on small samples, here we leveraged two large, well‐characterized natural history study cohor...

Background Residence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.) is associated with greater dementia risk and possibly greater postmortem Alzheimer’s pathology. It remains unknown if neighborhood disadvantage is associated with in vivo beta‐amyloid positron emission tomography (PET) for Alzheimer’s. We examined thi...

Background Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age = 65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s...

Background The timing of tau‐PET accumulation and cognitive decline in sporadic early‐onset Alzheimer’s disease (eoAD, age‐at‐onset<65) has not been established and is needed to optimize tau‐PET as an outcome measure in clinical trials. Here we leverage large‐sample, longitudinal data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEA...

Background Diagnosing sporadic early‐onset AD (EOAD, age‐at‐onset<65) is challenging: in the multi‐center Longitudinal Early‐onset Alzheimer’s Disease Study, ∼25% of patients with clinically diagnosed EOAD are amyloid‐PET‐negative. Here we used FDG‐PET to characterize the heterogeneity of hypometabolic profiles in these patients and better identify...

Background Early‐onset Alzheimer’s disease (EOAD) occurs before age 65 and has more diverse disease presentations than late‐onset AD. To improve our understanding of phenotypic heterogeneity among EOAD individuals, we analyzed cognitive scores using data‐driven statistical analysis. Method Baseline cognitive data from 286 sporadic EOAD individuals...

Background The Institute on Methods and Protocols for Advancement of Clinical Trials in Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) (IMPACT‐AD) is a novel multi‐disciplinary training program funded by the National Institute on Aging (NIA) and the Alzheimer’s Association for individuals seeking expertise in designing and...

Background Previous studies on sex differences in amyloid burden have shown inconsistent findings. We examined the effect of sex on amyloid‐PET outcomes in a large, real‐world, cohort of individuals with cognitive impairment. Method The IDEAS study evaluated the clinical utility of amyloid‐PET in 18,295 Medicare beneficiaries age ≥65 years with MC...

Background Neurodegeneration in sporadic early‐onset Alzheimer disease (EOAD) is topographically heterogeneous, as suggested by variability in syndromic presentation. We performed an unsupervised clustering analysis of structural MRI data to identify anatomical subtypes of EOAD. We hypothesized that distinct clusters will be present but will: (1) s...

Background APOE‐ɛ4 is a major risk factor for Alzheimer’s disease (AD); its effects have been examined in late‐onset AD (LOAD) but less so in early‐onset AD (EOAD). In LOAD, APOE genotype has strong effects on episodic memory and medial temporal lobe (MTL) atrophy (Wolk & Dickerson, 2010). However, EOAD often presents with more cognitive impairment...

Background Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age≥65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s D...

Background Prior work has advanced our understanding of cortical atrophy in early‐onset Alzheimer’s disease (EOAD), but longitudinal data are sparse. Current longitudinal MRI studies point to progressive atrophy in cerebral cortex exhibiting a posterior‐to‐anterior gradient, but these studies include small samples with mostly amnestic EOAD. Here, w...

Background The variability in the regional distribution of Aβ‐PET signal and its relation to clinical features is debated. We used data‐driven approaches to uncover heterogeneity in cortical Aβ‐PET signal from a large representative sample collected through the IDEAS study. Methods We analysed cross‐sectional Aβ‐PET collected from 10,361 patients...

Background The timing of tau‐PET accumulation and cognitive decline in sporadic early‐onset Alzheimer’s disease (eoAD, age‐at‐onset<65) has not been established and is needed to optimize tau‐PET as an outcome measure in clinical trials. Here we leverage large‐sample, longitudinal data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEA...

Background There is a significant need for biomarkers of neurodegenerative burden in Early‐onset Alzheimer’s disease (EOAD). Evidence suggests that levels of specific CSF biomarkers (e.g., Neurofilament light (NfL), Synaptosomal‐Associated Protein (SNAP‐25), neurogranin, Visinin‐like protein 1 (VILIP‐1), Aß 42/40, phospho‐tau and total tau) index t...

Background Understanding how early‐onset Alzheimer’s disease (EOAD) differs from typical late‐onset AD (LOAD) is an important goal of AD research that may help increase the sensitivity of unique biomarkers for each phenotype. Building upon prior work based on small samples, here we leveraged two large, well‐characterized natural history study cohor...

Background Residence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.) is associated with greater dementia risk and possibly greater postmortem Alzheimer’s pathology. It remains unknown if neighborhood disadvantage is associated with in vivo beta‐amyloid positron emission tomography (PET) for Alzheimer’s. We examined thi...

Background The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study demonstrated that amyloid PET changes patient management in >60% of Medicare beneficiaries with MCI/atypical dementia. IDEAS had limited racial/ethnic diversity and excluded patients with “typical” amnestic clinical presentations. Here we present preliminary results from th...

Background The Centiloid framework was developed to harmonize amyloid‐PET quantification across radiotracers and processing pipelines to facilitate data sharing and merging; it is now widely used across research and clinical trials. As we just completed the quantification of 10,361 amyloid‐PET scans from the largest “real‐world” study of amyloid‐PE...

Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [¹⁸F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of t...

Background Diagnosing sporadic early‐onset AD (EOAD, age‐at‐onset<65) is challenging: in the multi‐center Longitudinal Early‐onset Alzheimer’s Disease Study, ∼25% of patients with clinically diagnosed EOAD are amyloid‐PET‐negative. Here we used FDG‐PET to characterize the heterogeneity of hypometabolic profiles in these patients and better identify...

INTRODUCTION The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS The workgroup identified key research questions that guided a systematic literature...

The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. Methods: The workgroup identified key research questions that guided a systematic literature review on cl...

Background Early‐onset Alzheimer’s disease (EOAD) manifests prior to the age of 65. Clinical presentation of EOAD is distinct from that of late‐onset Alzheimer’s disease, and is characterized as having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)...

Background Widespread cognitive impairments have previously been documented in Early‐Onset Alzheimer’s Disease (EOAD) relative to cognitively normal (CN) same‐aged peers or those with cognitive impairment without amyloid pathology (Early‐Onset non‐Alzheimer’s Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed wor...

Background Early‐Onset Alzheimer’s Disease (EOAD) is a rare condition that affects only 5% of patients with Alzheimer’s Disease (AD). At present, only basic information is known about the impact of AD risk variants on EOAD, and the effects of more subtle genetic contributions to cognitive decline have yet to be investigated. Genetic variants for br...

Background Early Onset Alzheimer’s Disease (EOAD) is a rare condition that manifests prior to the age of 65, and affects approximately 5% of patients with Alzheimer’s disease. The Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) is the largest prospectively‐evaluated cohort of participants with sporadic EOAD in the United States, initiate...

Background The Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) is analyzing the genetic etiology of early onset (40‐64 years) cognitive impairment, including amyloid‐positive early‐onset Alzheimer’s disease (EOAD) and amyloid‐negative early‐onset Alzheimer’s disease (EOnonAD). One goal of this investigation is to identify novel or under‐...

Background Currently, it is unclear to what extent late‐onset Alzheimer’s disease (AD) risk variants contribute to early‐onset AD (EOAD). One method to clarify the contribution of late‐onset AD genetic risk to EOAD is to investigate the association of AD polygenic risk scores (PRS) with EOAD. We hypothesize that in the Longitudinal Early‐Onset Alzh...

INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with...

INTRODUCTION Alzheimer's disease (AD) and related dementias (ADRD) present significant health challenges. Understanding their underlying biology, advancing existing and new therapies, and enhancing care for patients and caregivers are critical priorities. METHODS This article utilizes data from the International Alzheimer's and Related Dementias R...

INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐score cognitive‐domain composites for 311 am...

The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in...

The newly proposed revised criteria for diagnosis and staging of Alzheimer's disease (AD) by the Alzheimer's Association (AA) Workgroup represent a significant milestone in the field. These criteria offer objective measures for diagnosing and staging biological AD, bridging the gap between research and clinical care. Although implementation feasibi...

The Alzheimer's disease (AD) research field has entered a new era, where our fundamental understanding of the pathophysiology of AD and advances in biomarkers have not only allowed for earlier, timely, and accurate detection and diagnosis of the disease, but that amyloid removal has been shown to be associated with signals of slowing cognitive and...

The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta‐amyloid and tau. Recent clinical trial readouts implicate a variety of non‐amylo...

Amyloid-PET detects fibrillar β- amyloid deposits, a defining feature of Alzheimer's disease. This technology has been used in research for over 20 years, and is now used in clinical practice to guide patient diagnosis and management. However, the real-world use of amyloid-PET may differ from research settings due to less standardized acquisition p...

The emergence of the United States Food and Drug Administration (FDA)‐approved amyloid‐targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease‐modifying treatmen...

Here we highlight the Alzheimer's Association's role since its inception, as a strategic collaborator with National Institutes of Health–National Institute on Aging in the development of the modern era of the Alzheimer's Movement and in making Alzheimer's disease (AD) a national priority in the United States by developing several initiatives to adv...

INTRODUCTION The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid‐beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex‐dependent disease m...

Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer’s disease (AD) and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully i...

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Definin...

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer’s disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generate...

INTRODUCTION While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care. METHODS In 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and...

Two of every three persons living with dementia reside in low‐ and middle‐income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high‐income countries (HICs), with dementia research predominantly focusing on HICs. This imb...

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well‐resourced, non‐Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowl...

INTRODUCTION The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co‐organized and co‐sponsored by the Alzheimer's Association,...

Background Discordance between the clinical diagnosis of AD by experts after a comprehensive evaluation and AD pathology on autopsy remains common. We sought to identify clinical situations where amyloid‐PET would be most valuable as a diagnostic tool by identifying predictors associated with discordance between initial clinical diagnosis and amylo...

Background U.S. POINTER is a randomized, controlled, multi‐domain 2‐year clinical trial in 2000 older Americans to slow cognitive decline via culturally‐appropriate healthy lifestyle interventions. Participant diversity is essential, with targeted enrollment of 50% women and 23% enrollees from communities of color (reflecting the U.S. population in...

Background Historically, Alzheimer’s disease (AD) biomarkers have been used to identify the presence of pathology and have been shown to change well ahead of symptom onset. While previous research has evaluated plasma pTau231 and its associations with cognition, little to none of this research has focused on early‐onset AD (EOAD) populations. Here...

Background Multicentric initiatives to study brain cognition in the elderly offers us a unique collection of brain imaging data accompanied by detailed neuroclinical and neuropsychological evaluations. U.S. POINTER and LatAm‐FINGERS, part of the World Wide FINGERS, are both large‐scale investigations of lifestyle interventions and its impact on cog...

Background We aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures. Methods In December 2022, we selected patients...

Background U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two multidomain lifestyle interventions in 2111 older adults who are at increased risk of cognitive decline and dementia due sedentary lifestyle, poor diet, and other factors such as family history of memory impairment and suboptimum cardiovascular health. Metho...

Background The longitudinal progression of tau pathology in sporadic early‐onset Alzheimer’s disease (EOAD, age‐at‐onset<65) has not been well established and may be key to its understanding and treatment. We utilized in vivo PET imaging to characterize regional patterns of pathological tau accumulation in the Longitudinal Early‐onset Alzheimer’s D...

Background Aβ deposition is thought to start decades prior to symptom onset. Previous studies have shown that mathematical modeling enables reconstruction of Aβ‐PET trajectory and age estimation at Aβ‐PET positivity in Aβ‐positive patients. We aimed to apply this approach to determine Aβ duration and estimate age at Aβ‐PET positivity in sporadic ea...

Background In EOAD, the localization of neurodegeneration is often more prominent in posterior lateral temporal, lateral and medial parietal, frontal, or occipital cortex relative to the medial and ventral temporal cortical localization of typical LOAD. Convergently, neuropathological investigations have identified a “hippocampal‐sparing” form of A...

Background Increased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this pop...

Background Much of the genetic etiology of sporadic early onset Alzheimer’s disease and frontotemporal dementia is largely unknown. Genetic investigation using whole exome sequencing (WES) data in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) aims to address this gap, with the hypothesis that some individuals with early onset cogni...

Background The Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in t...

Background Fewer than 5% of patients with Alzheimer’s disease are diagnosed between 40‐64 years old, making “early‐onset Alzheimer’s disease” (EOAD) an uncommon phenomenon (Zu et al., 2015). To date, only basic knowledge on EOAD is known, no uniform criteria for EOAD have been implemented, and sample sizes in research have been small. The Longitudi...

Background We examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) particip...

Background Multidomain lifestyle interventions hold great promise world‐wide as interventions to slow cognitive aging, and delay and prevent Alzheimer’s Disease and Related Disorders (ADRD). To have the greatest reach, they must be tailored for and assessed within local cultures in clinical trials. For trials to have the greatest impact, it’s impor...

Background The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a two‐year randomized controlled trial designed to evaluate the effects of lifestyle interventions on older adults aged 60‐79 years. The POINTER Imaging ancillary study employs arterial spin labeling (ASL) magnetic resonance imaging (MR...

Background Tau positron emission tomography (PET) is increasingly used in the clinical evaluation of patients and as an outcome measure in Alzheimer’s disease (AD) clinical trials. Due to differences in tracer properties, instrumentation, and methods of analysis, however, tau‐PET outcome data cannot currently be meaningfully compared or combined. H...

Background Approximately 10‐25% of amnestic early‐onset dementia are negative for amyloid (Early‐onset non‐Alzheimer’s Disease, EOnonAD). EOnonAD is a heterogenous group with various etiologies. In order to better understand the traits of EOnonAD, we clustered amnestic EOnonAD individuals according to cognitive patterns. Method Cognitive data of 6...

Background Only a small percentage of early‐onset Alzheimer’s disease (EOAD) participants are known to carry autosomal dominant pathogenic variants in the amyloid beta precursor protein (APP) gene or in presenilin 1 or 2 (PSEN1/2); more research is needed to identify additional causative genetic variants. This study presents results of the initial...

Background Amyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans. Method Randomly selected amyloid P...

Background Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amylo...

Background The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological test used for assessing episodic memory impairment. The sequence of the RAVLT consists of five learning trials, an intrusion list recall, a subsequent recall (short delay), and a delayed recall (approximately thirty minutes after the short delay recall). The RAVLT has...

Background Age‐related cognitive declines are well‐documented in cognitively normal adults (van der Willik et al., 2021), as are greater cognitive impairments with advancing age in traditional‐ (or “late‐”) onset Alzheimer’s disease (LOAD; Davis et al., 2018). Early‐onset Alzheimer’s disease (EOAD; diagnosis ≤65 years old) possesses a unique diseas...

Background Amyloid‐PET quantification was developed in research settings using highly selected samples, harmonized acquisition protocols, and MRI‐based preprocessing. We aimed to analyze scans from IDEAS, a large‐scale, real‐world study of amyloid‐PET. Major challenges lie in scans being acquired on various PET/PET‐CT/PET‐MR scanners without standa...

Background LatAm‐FINGERS is the first non‐pharmacological multicenter randomized clinical trial to prevent cognitive impairment in Latin America (LA). The trial congregates the effort of 12 Countries, including Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Peru, Puerto Rico, and Uruguay. The main aim...

Background The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neu...

Background The Rey Auditory Verbal Learning Test (RAVLT) is a common neuropsychological test for characterizing episodic memory deficits. Performance of the RAVLT has been described in numerous presentations of cognitive impairment. However, there is limited research for analyzing the predictive value of RAVLT scores. We examine the ability of the...

Background Female sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐ε4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐ε4 on plasma and cerebrospinal fluid (CS...

Background Increased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this pop...

Background Discordance between the clinical diagnosis of AD by experts after a comprehensive evaluation and AD pathology on autopsy remains common. We sought to identify clinical situations where amyloid‐PET would be most valuable as a diagnostic tool by identifying predictors associated with discordance between initial clinical diagnosis and amylo...

Background Tau positron emission tomography (PET) is increasingly used in the clinical evaluation of patients and as an outcome measure in Alzheimer’s disease (AD) clinical trials. Due to differences in tracer properties, instrumentation, and methods of analysis, however, tau‐PET outcome data cannot currently be meaningfully compared or combined. H...

Background Amyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans. Method Randomly selected amyloid P...

Background Negative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amylo...

Background Aß deposition is thought to start decades prior to symptom onset. Previous studies have shown that mathematical modeling enables reconstruction of Aß‐PET trajectory and age estimation at Aß‐PET positivity in Aß‐positive patients. We aimed to apply this approach to determine Aß duration and estimate age at Aß‐PET positivity in sporadic ea...

Background Female sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐e4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐e4 on plasma and cerebrospinal fluid (CS...

Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well‐defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the...

INTRODUCTION Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early‐onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS We analyzed MRI scans to define the sporadic EOAD‐signature atrophy in a...