Alzheimer's Disease Neuroimaging Initiative: Two decades of pioneering Alzheimer's disease research and future directions

Abstract

This special issue of Alzheimer's & Dementia celebrates the accomplishments of the Alzheimer's Disease Neuroimaging Initiative (ADNI) project as it approaches its 20th anniversary in 2024, supported by funding from the National Institute on Aging. The earliest origins of ADNI lie in the groundbreaking discovery that antibodies targeting amyloid can remove amyloid beta (Aβ) plaques, sparking the advent of immunotherapy for Alzheimer's disease (AD).¹ At the same time, the importance of imaging and fluid biomarkers, particularly cerebrospinal fluid (CSF), in AD diagnosis gained recognition. ADNI was established in 2004 to validate and optimize biomarkers for AD clinical trials and freely share all the generated data with the scientific community without any restrictions.

Since then, ADNI has evolved through five sequential phases incorporating advancements in the field and contributing to significant breakthroughs such as standardizing and validating Aβ and tau positron emission tomography (PET) imaging and CSF biomarkers.^2-4 Moreover, ADNI data informed the design of clinical trials for aducanumab,⁵ lecanemab,⁶ donanemab,⁷ solanezumab,⁸ verubecestat,⁹ crenezumab,¹⁰ and gantenerumab,¹¹ facilitating the introduction of disease-modifying treatments into clinical practice. ADNI's open data sharing has led to over 6000 peer-reviewed publications, further highlighting the impact of the study.

Furthermore, ADNI's approach to conducting longitudinal observational studies and openly sharing data served as a model for similar initiatives globally, leading to the creation of consortia like the Parkinson's Progression Markers Initiative (PPMI),¹² Japanese ADNI,¹³ European ADNI,¹⁴ Korean Brain Aging Study (KBASE),^{15, 16} China ADNI,¹⁷ and South American initiatives.¹⁸ The following projects were also modeled on ADNI: the Dominantly Inherited Alzheimer Network (DIAN) studies,¹⁹ Alzheimer's Disease Research Center Consortium for Clarity in Alzheimer's Disease and Related Dementias Research Through Imaging (CLARiTI),²⁰ Longitudinal Early-Onset Alzheimer's Disease Study (LEADS),²¹ Australian Imaging Biomarker & Lifestyle Flagship Study of Ageing (AIBL),²² Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Longitudinal Frontotemporal Lobar Degeneration (ALLFTD),²³ Diverse Vascular Contributions to Cognitive Impairment and Dementia (VCID),²⁴ and Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID).²⁵

The strict enrollment criteria of ADNI were designed to specifically target AD pathology, aiming to enhance the efficiency of biomarker research, treatment development, and precision in clinical trials. However, this approach limits the inclusion of individuals with comorbidities. Furthermore, the study is an arduous and time-consuming experience for participants, requiring many brain scans, blood draws, lumbar punctures, and clinical assessments. As a result, the ADNI participant pool primarily consisted of non-Latinx White, older, well-educated adults, with disproportionally lower depiction of under-represented populations, including Black/African American, Latinx, Asian, Native Hawaiian/Pacific Islander, and Indigenous individuals. Moreover, enrollment rates have been notably low among individuals with lower levels of education and socioeconomic status and those who reside in rural areas. Consequently, like most clinical trials, the ADNI study cohort does not resemble the demographics of the United States. Therefore, its findings have yet to be generalizable to the entire US population.

In ADNI4, the latest phase of the ADNI project, several steps have been taken to improve previous limitations by establishing the Engagement Core, which leads ADNI's efforts to promote inclusive participation and engagement of ethnoculturally, socioeconomically, and geographically diverse groups. Additional steps are being taken to mitigate mistrust and improve public education about the importance of clinical research, to enhance diversity in participation, and to ensure findings are equally applicable to all Americans. Leveraging evidence-based, culturally informed community-engaged research (CI-CER) methods, including online social media campaigns and innovative recruitment pathways, ADNI aims to include 50% to 60% of new participants from underrepresented populations.

Looking ahead, we foresee a rise in clinical trials aimed at preventing mild cognitive impairment (MCI) and AD by including both symptomatic and asymptomatic individuals, often referred to as “prevention trials”.^{26, 27} Integrating new biomarkers and digital tools promises to enhance our understanding of AD while making clinical trials more accessible and less burdensome, thereby enhancing participation from diverse populations. This evolution in clinical trial methodology is timely, given the increasing importance of early intervention.

This special issue presents contributions from ADNI Core leaders and related submissions, particularly those using ADNI data. Alongside delineating ADNI's achievements, this special issue extensively explores its limitations and strategies for overcoming them. All submissions underwent a rigorous peer-review process. ADNI has made significant strides in the field over the past two decades, directly addressing the most critical questions and challenges in AD research. Moving forward, ADNI remains committed to tackling the most pressing issues in AD research by leading the development of innovative treatments and diagnostics to slow disease progression and prevent AD.

Dr. Weiner serves on editorial boards for Alzheimer's & Dementia, MRI, and TMRI. He has served on advisory boards for Acumen Pharmaceutical, ADNI, Alzheon, Inc., Biogen, Brain Health Registry, Cerecin, Dolby Family Ventures, Eli Lilly, Merck Sharp & Dohme Corp., National Institute on Aging (NIA), Nestle/Nestec, PCORI/PPRN, Roche, University of Southern California (USC), and NervGen. He has provided consulting to Baird Equity Capital, BioClinica, Cerecin, Inc., Cytox, Dolby Family Ventures, Duke University, Eisai, FUJIFILM-Toyama Chemical (Japan), Garfield Weston, Genentech, Guidepoint Global, Indiana University, Japanese Organization for Medical Device Development, Inc. (JOMDD), Medscape, Nestle/Nestec, NIH, Peerview Internal Medicine, Roche, T3D Therapeutics, University of Southern California (USC), and Vida Ventures. He has acted as a speaker/lecturer to The Buck Institute for Research on Aging, the China Association for Alzheimer's Disease (CAAD), the Japan Society for Dementia Research, and the Korean Dementia Society. He holds stock options with Alzheon, Inc., Alzeca, and Anven. The following entities have provided funding for academic travel: the University of Southern California (USC), NervGen, ASFNR, and CTAD Congress. Dr. Rivera Mindt receives support in the form of grants to Fordham University or the Icahn School of Medicine at Mount Sinai from NIH/NIA, The Alzheimer's Association, and Genentech Inc. Charitable Foundation. Dr. Okonkwo is supported by NIH grants to the University of Wisconsin-Madison. Author disclosures are available in the supporting information.

All human subjects provided informed consent.