**Background:** Alzheimer's disease and related dementias (ADRD) affect approximately 55 million individuals worldwide, with prevalence projected to rise. While recent monoclonal antibody treatments (e.g., aducanumab, lecanemab, donanemab) have shown ability to remove amyloid plaques and slow cognitive decline in early AD, no treatments are available to prevent incipient ADRD. The Lancet Commission identified 12 modifiable risk factors accounting for about 40% of dementias globally, but estimates were based on UK samples and may not apply to diverse populations. There is a critical need for studies focusing on protective factors, cognitive reserve, and resilience, particularly in minoritized and disadvantaged groups who are 1.5 to 2 times more likely to develop ADRD. The Healthy Brain Initiative (HBI) was established to fill these gaps by following a racially/ethnically diverse cohort with deep phenotyping and novel biomarkers.
**Methods:** HBI is a longitudinal, observational cohort study that will recruit 500 participants aged ≥50 years with no, subjective, or mild cognitive impairment (Clinical Dementia Rating ≤1) and a study partner, who are medically eligible for MRI. Recruitment is community-based via advertisements, word-of-mouth, community events, and physician referrals. At baseline, participants complete web-based surveys (demographics, health history, risk/resilience factors), followed by two half-day visits including neurological exams, cognitive assessments (e.g., MoCA, HVLT, Trail Making Test, Craft Story, Benson Complex Figure Test, Cognivue®), physical function tests (e.g., gait analysis on Zeno Walkway, Timed Up and Go, Limits of Stability), overnight sleep study (Watch PAT), audiometry, spirometry, ankle-brachial index, optical coherence tomography (OCT), and neurobehavioral markers (eye tracking, speech). Blood and saliva are collected for plasma biomarkers (e.g., Aβ42/40, p-tau181, p-tau217, neurofilament light, GFAP, TDP-43), comprehensive metabolic panel, APOE ε4 status, and DNA methylation. All participants undergo structural and functional MRI at baseline and every 2 years; a subset consents to amyloid PET with 18F-Florbetaben. Annual follow-up visits repeat most assessments, with MRIs every other year. Telephone follow-ups occur at 3 and 6 months post-baseline and 6 months after annual visits.
**Key Results:** As of September 21, 2023, 156 participants completed baseline visits (68% women, 10% Black, 87% White, 3% Asian/mixed, 10% Hispanic). The study began recruitment on March 24, 2022. Primary outcomes include the Brain Health Platform (Resilience Index, Vulnerability Index, Number-Symbol Coding Task) and ATN staging (amyloid, tau, neurodegeneration) using Gaussian mixture modeling for amyloid PET. Secondary outcomes include continuous biomarker changes and cognitive/functional test scores. Planned statistical analyses include generalized linear mixed effects models, ordinal logistic Markov chain transition models, and competing risk models, with a target of 80% power for Black participants based on 20% racial distribution. Attrition is conservatively estimated at 15%.
**Clinical Implications:** HBI will provide an evidence base for precision medicine approaches to dementia prevention by identifying modifiable risk and resilience factors across the life course, particularly in diverse populations. The deep phenotyping and novel biomarkers (e.g., neurobehavioral markers, OCT, epigenetics) may lead to less invasive, more accessible diagnostic tools for early ADRD detection. Findings will inform individualized treatment plans and interventions targeting sociodemographic, lifestyle, and environmental factors. The data and biospecimen repository will be shared with the research community via NCRAD, facilitating future studies. Limitations include potential lack of generalizability due to volunteer bias and participant burden from extensive assessments, but targeted recruitment and retention efforts (e.g., transportation costs, newsletters) aim to mitigate these issues.