Veitch, Dallas P.

Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high‐impact studies using ADNI data or biospecimens from 2023 to mid‐2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co‐pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.

Abstract Alzheimer's disease (AD) continues to pose a major public health challenge. Since its launch in 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has played a pivotal role in advancing the field by providing a comprehensive, open‐access, longitudinal dataset that integrates neuroimaging, biomarker, genetic, and clinical data related to AD. We used standard literature search methods to identify ∼1830 publications from 2023 to mid‐2025 that used ADNI data or samples. This review highlights key ADNI studies with direct clinical applications. We describe how these have impacted the development and validation of plasma biomarkers, improved clinical trials, assessed AD therapies, and developed methods for diagnosis and prediction using clinical, fluid, and imaging biomarkers. These contributions are underlain by an improved understanding of biological mechanisms of disease progression in AD and highlight ADNI's central role in advancing translational research and accelerating progress toward more effective, individualized care for patients with AD.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA‐approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNI's promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer “the clinical trial of the future” focusing on demographic inclusivity. Highlights The Alzheimer's Disease Neuroimaging Initiative (ADNI) introduced a novel model for public‐private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimer's disease. ADNI generated and disseminated vital data for designing AD clinical trials.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

AbstractThe Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co‐pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI‐4 aims to address by enrolling a diverse cohort.

AbstractThe poor generalizability of clinical research data due to the enrollment of highly educated, non‐Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health‐care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under‐represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally‐informed digital research methods, community‐engaged research strategies, leadership from under‐represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under‐represented populations into US‐based clinical studies, thereby increasing the generalizability of their results.

AbstractIntroductionThe 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 National Institute on Aging beginning September 2022.MethodsADNI4 will recruit URPs using community‐engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50‐60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in‐clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials.Results and DiscussionADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

AbstractIntroductionEpidemiological 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.MethodsWe identified 289 non‐demented veterans with TBI and/or PTSD and controls who underwent clinical evaluation, cerebrospinal fluid (CSF) collection, magnetic resonance imaging (MRI), amyloid beta (Aβ) and tau positron emission tomography, and apolipoprotein E testing. Participants were followed for up to 5.2 years.ResultsExposure groups (TBI, PTSD, and TBI + PTSD) had higher prevalence of mild cognitive impairment (MCI: P < .0001) and worse Mini‐Mental State Examination scores (PTSD: P = .008; TBI & PTSD: P = .009) than controls. There were no significant differences in other cognitive scores, MRI volumes, Aβ or tau accumulation, or in most longitudinal measures.DiscussionTBI and/or PTSD were not associated with elevated AD biomarkers. The poorer cognitive status of exposed veterans may be due to other comorbid pathologies.

Abstract Introduction Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods Within 248 Aβ‐positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ‐positron emission tomography [PET] uptake, regional tau‐PET uptake, and regional magnetic resonance imaging–based atrophy) and risk‐factors (age, sex, education, apolipoprotein E [ APOE ], and white‐matter lesions) on cross‐sectional cognitive impairment and longitudinal cognitive decline. Results Sixteen percent of variance in cross‐sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ–tau–atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. Discussion These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.