Boston University Alzheimer's Disease Research Center Clinical Core: Infrastructure to facilitate research on post‐traumatic Alzheimer's disease and related dementias

Abstract

We describe the rationale, methodology, and design of the Boston University Alzheimer's Disease Research Center (BU ADRC) Clinical Core (CC). The CC characterizes a longitudinal cohort of participants with/without brain trauma to characterize the clinical presentation, biomarker profiles, and risk factors of post‐traumatic Alzheimer's disease (AD) and AD‐related dementias (ADRD), including chronic traumatic encephalopathy (CTE). Participants complete assessments of traumatic brain injury (TBI) and repetitive head impacts (RHIs); annual Uniform Data Set (UDS) and supplementary evaluations; digital phenotyping; annual blood draw; magnetic resonance imaging (MRI) and lumbar puncture every 3 years; electroencephalogram (EEG); and amyloid and/or tau positron emission tomography (PET) on a subset. As of 3/2025, the CC consists of 467 participants (mean age: 65.6, 50.1% female), including 163 RHI and 302 TBI who completed a UDS 3.0 baseline visit. Common sources of RHI included football (n = 95), soccer (n = 26), ice hockey (n = 17), and military service (n = 46). Most TBIs were mild (97.7%). Eighty‐nine percent agreed to brain donation. The BU ADRC CC will facilitate research, education, and training on post‐traumatic AD/ADRD.

Highlights

• The Boston University Alzheimer's Disease Research Center (ADRC) Clinical Core facilitates unique research, education, and training on Alzheimer's disease and Alzheimer's disease‐related dementias (AD/ADRD) with a focus on post‐traumatic AD/ADRD, including chronic traumatic encephalopathy (CTE).

• We summarize the rationale, mission, study design, and recent updates for the Clinical Core.

• As of March 2025, the Clinical Core includes a longitudinal cohort of 467 participants enriched for repetitive head impacts (∼1/3) and traumatic brain injury (∼1/3) exposure who span the cognitive continuum, with most having available fluid and neuroimaging biomarker data and agreeing to brain donation (89%).

1. BACKGROUND

The P30 National Institute on Aging (NIA) funded Boston University Alzheimer's Disease Research Center (BU ADRC) (P30AG072978) has seven closely integrated Cores and a Research Education Component (REC) that create an infrastructure to facilitate research, education and training on Alzheimer's disease (AD) and AD‐related dementias (ADRD) with a focus on post‐traumatic AD/ADRD including chronic traumatic encephalopathy (CTE) (Figure 1). The unique mission of the BU ADRC Clinical Core (CC) is to establish and characterize a longitudinal cohort of participants with and without brain trauma, including repetitive head impacts (RHIs), to facilitate research comparing post‐traumatic AD/ADRD, including CTE, with other forms of AD/ADRD. The objective of this paper is to describe the rationale, methodology, and design of the BU ADRC CC. In so doing, this paper will inform the scientific community on the resources available from the BU ADRC that can be accessed and used to facilitate collaboration, research, and training, including but not limited to post‐traumatic AD/ADRD. We begin with a brief overview of the history of the BU ADRC CC, followed by a summary of its current objectives, specific aims, and endpoints. A detailed description of the CC infrastructure, participants, methods, and design is provided. We provide updates on the status of the CC and conclude with methodological considerations of the CC and a discussion of the expected impact from the infrastructure and resources created.

FIGURE 1.

BU ADRC infrastructure overview. Cores are highly interactive and synergistic while maintaining specific aims and responsibilities. Each core collaborates uniquely with the REC to accomplish REC goals. BU ADRC, Boston University Alzheimer's Disease Research Center; DMS, data management and statistics; GMP, genetics and molecular profiling; ORE, outreach, recruitment and engagement; REC, research education component.

1.1. BU ADRC CC: History

The BU ADRC was established through funding by the NIA in 1996. Since its inception, the BU ADRC has sustained a mission to facilitate leading‐edge research on AD/ADRD. When the BU ADRC was founded, the Center focused on late‐stage dementia. As AD/ADRD research evolved, the Center's focus shifted to early‐stage disease detection, resulting in a longitudinal cohort of participants who span the continuum of AD (normal cognition [NC], mild cognitive impairment [MCI], and dementia). This longitudinal CC cohort has served as the catalyst for new research, including identification of novel neuropsychological measures and in vivo biomarkers for detecting and monitoring AD. ¹ , ² , ³ The BU ADRC has made significant contributions to the study of blood‐based biomarkers. We began to collect blood in 2008, and blood draws became annual in 2015. These blood samples have been analyzed to show the utility of plasma biomarkers of p‐tau across many different epitopes, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and total tau (t‐tau) for the detection and diagnosis of AD dementia, as well as AD neuropathology for a subset who had blood and brain tissue. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹

1.2. BU CTE Center: RHI, traumatic brain injury, and AD/ADRD

In 2008, the CTE Center was founded at BU and co‐existed alongside the BU ADRC. The BU CTE Center and its investigators have gained international recognition for research on the long‐term consequences of RHI and traumatic brain injury (TBI), including CTE. ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Research from the CTE Center and others has highlighted the pronounced heterogeneity of brain trauma, and how various forms of brain trauma affect risk for AD/ADRD. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ TBI has historically been viewed as a risk factor for AD. Yet, in vivo biomarker and neuropathological studies have provided limited evidence for TBI as a specific risk factor for AD neuropathology. ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Existing research supports TBI as a potential risk factor for Lewy body pathology, TDP‐43 pathology, infarcts, white matter injury, and atrophy. ²¹ , ²⁵ , ²⁶ The distinct AD/ADRD process that head trauma triggers seems to be dependent on the severity, frequency, and source(s). ²⁷ , ²⁸ , ²⁹ , ³⁰ Exposure to RHI and resulting symptomatic concussions and asymptomatic non‐concussive impacts is associated with the neurodegenerative disease known as CTE. ¹⁰ , ¹¹ , ¹² , ¹⁵ , ¹⁶ , ³¹ , ³² , ³³ The history of CTE dates back to 1928 through descriptions of neurological disturbances in boxers. ³⁴ CTE has now been neuropathologically diagnosed in hundreds of deceased American football players ¹¹ , ³¹ , ³² , ³⁵ , ³⁶ in addition to other contact and collision sport athletes (e.g., ice hockey, soccer, boxing). ³⁵ , ³⁷ , ³⁸ , ³⁹ CTE has also been neuropathologically diagnosed in military veterans ³⁵ , ⁴⁰ and those exposed to intimate partner violence. ⁴¹ , ⁴² The neuropathology of CTE is well‐characterized ¹² , ¹⁵ , ³⁷ , ⁴³ and unique from AD and other tauopathies. ⁴⁴ , ⁴⁵ Research supports a dose‐response relationship between cumulative exposure to RHI (particularly from American football) and risk and severity for CTE neuropathology. ¹⁰ , ¹⁶

Characterization of the clinical presentation and in vivo biomarkers of CTE lags behind the neuropathological advancements. The current clinical and biomarker investigations of CTE are limited by focus on male former American football players, cross‐sectional designs, retrospective interviews with informants of brain donors, and lack of disease comparison groups. ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ Consequently, methods to diagnose CTE during life have not yet been established. To make an accurate clinical diagnosis of CTE possible, the clinical presentation needs to be better characterized, in vivo biomarkers need to be developed and validated, and diagnostic criteria need to be validated.

1.3. BU ADRC CC: Characterization of participants with brain trauma

To advance our ability to accurately diagnose CTE during life requires prospective characterization of participants across the RHI exposure continuum who are followed at regular intervals and who agree to brain donation to permit clinical‐biomarker‐pathological validation studies. Through supplemental funding to the BU ADRC from the NIA in 2018, our Center began to integrate examination of participants exposed to RHI with emphasis on the comparison of those with and without RHI, vis‐à‐vis clinical presentation, biomarker profile, genetic and other risk factors, and clinical–pathological correlations. The supplement funding led to implementation of detailed assessment and characterization of all forms of head trauma to allow for the broad study of its association with AD/ADRD. Concurrently, the CC continued to recruit and longitudinally follow participants across the AD continuum who did not have brain trauma. This foundational change to the BU ADRC CC was in response to the scientific needs of the AD/ADRD community and knowledge gaps in the literature. The supplement allowed for alignment of the BU ADRC and the BU CTE Center. Studying the late effects of RHI and TBI and comparing AD, CTE, and other ADRDs has become a Center‐wide mission for the BU ADRC.

In addition, in 2018, the NIA also awarded a supplemental grant entitled “The Clinical Applications of Digital Technology in Alzheimer's Disease Dementia” which had the primary objective to evaluate and longitudinally examine the utility and feasibility of a range of smartphone applications and devices that assess various lifestyle factors and cognitive function in relation to the clinical manifestation of AD/ADRD. The secondary objective was to create a strong data infrastructure (e‐health platform) that could potentially serve as a national model for the ADRC network.

1.4. BU ADRC CC: Specific aims and endpoints

The specific aims of the BU ADRC CC are listed in Table 1. The BU ADRC CC will sustain, augment, and characterize the clinical presentation of an established CC cohort that is demographically diverse and representative of the sampled catchment area, including those who present to Boston Medical Center (BMC), Boston neighborhoods surrounding BMC, and greater Boston. CC evaluations are closely integrated with the BMC Memory and Aging Clinic, and the Boston Veterans Administration (VA) Memory Disorders Clinic. The CC cohort oversamples those with brain trauma to be able to compare those with and without TBI and RHI exposures. The CC plays a central role in the BU ADRC by engaging research participants and driving activities that reflect the Center's overall themes, including the systematic comparison of AD, CTE, and other ADRDs. Achieving the specific aims will support the larger goals of the BU ADRC and advance the priorities identified in the National Alzheimer's Project Act (NAPA) recommendations. Next, we provide a detailed description of the design and methods of the BU ADRC CC.

TABLE 1.

Specific aims of the Boston University Alzheimer's Disease Research Center Clinical Core.

Aim 1: Sustain, augment, and characterize the clinical phenotypes and trajectories of an established CCC	1A: Collaborate with the ORE Core to sustain and augment the CCC, ensuring appropriate representation of the targeted population 1B: Characterize the neurological, neuropsychological, neuropsychiatric, and consensus diagnostic profiles of CC participants 1C: Characterize profiles of CC participants using novel phenotyping approaches, including digital and EEG phenotyping 1D: Obtain brain donation consent from CC participants and work with the Neuropathology Core to facilitate brain donation
Aim 2: Obtain brain imaging, biospecimens, and novel biomarkers from the CCC	2A: Obtain traditional structural and functional research‐quality brain imaging, and PET amyloid and tau on a subset 2B: Collect cerebrospinal fluid and blood products
Aim 3: Share data and biospecimens and provide a source of well‐characterized participants for local and national research studies on AD and ADRD and post‐traumatic AD/ADRD.	3A: Facilitate reciprocal transmission of CC‐generated data and biospecimens between cores 3B: Submit high quality UDS data to NACC and biospecimens to NCRAD 3C–3D: Share data and biospecimens and provide a source of well‐characterized participants for local investigator‐driven research (3c), and for cross‐ADRC and national AD/ADRD research (3d)
Aim 4: Educate trainees to develop the next generation of AD/ADRD clinical investigators	4A: Work with the Research Education Component to train students, residents, fellows, and investigators on the clinical manifestations of and methods for conducting clinical research on AD/ADRD, including CTE

Abbreviations: AD, Alzheimer's disease; ADRD, Alzheimer's disease‐related dementia; CC, Clinical Core; CCC, Clinical Core Cohort; EEG, electroencephalogram; ORE, Outreach, Recruitment, and Engagement; CTE, chronic traumatic encephalopathy; NACC, National Alzheimer's Coordinating Center; NCRAD, National Centralized Repository for Alzheimer's Disease and Related Dementias; PET, positron emission tomography; UDS, Uniform Data Set.

2. PARTICIPANTS AND STUDY DESIGN

2.1. Infrastructure overview

The Director of the BU ADRC is Dr Ann McKee. The CC is one of seven Cores at the BU ADRC (Figure 1). The BU ADRC CC is led by Drs Michael Alosco (leader, neuropsychology) and Jesse Mez (co‐leader, behavioral neurology). Eric Steinberg (nurse practitioner) is the program manager and has served in this role since 2004, and has substantial experience in the assessment, diagnosis, and patient care of AD/ADRD. He leads the day‐to‐day operations and oversees the collection of participant history and the conduct of neurological exams (supervised by Dr Mez). A study coordinator serves as a liaison between Mr Steinberg and a team of research assistants who schedule, coordinate, and conduct study visits. In addition to staff, many faculty investigators, particularly junior‐level faculty, are part of the CC and play integral roles in patient evaluation and care, biomarker assessment and collection, participation in the multidisciplinary diagnostic consensus conferences (MDCCs), training, and education. The BU ADRC CC includes post‐doctoral PhD fellows, behavioral neurology MD fellows, PhD and MD students, and undergraduate students. These trainees participate in various ADRC didactic and research activities.

2.2. Definitions of RHI and TBI

Participants are considered to have RHI if they have “substantial” exposure as defined by the 2021 Traumatic Encephalopathy Syndrome (TES) research diagnostic criteria. ¹⁴ Sources of exposure to RHI are diverse and include: (1) contact and collision sports including but not limited to boxing, American football, ice hockey, mixed martial arts, men's lacrosse, Greco‐Roman wrestling, rugby; (2) military service including combat, blast exposure or combatant or breach training; and/or (3) physical violence including intimate partner violence and child abuse. Participants with RHI exposure are further divided into those with “substantial” versus “extensive” exposure as defined by the TES criteria and football versus non‐football sources of RHI exposure. The current TES research diagnostic criteria differentiate substantial from extensive by providing empirically‐derived cutoffs for the number of years of American football play required to confer risk for CTE. ¹⁰ Substantial exposure to RHI from American football is defined by 5 or more years of organized American football, with at least two played at the high school level. ¹⁴ There are no established cutoffs for other sources of exposure to RHI. Per the TES research diagnostic criteria, determination of substantial exposure to other sources of RHI requires judgment of whether the exposure is equivalent to 5 or more years of American football with at least two at the high school level. Participants exposed to RHI (e.g., contact and collision sport play), but at a lower level than substantial as defined by the TES research diagnostic criteria (e.g., less than 5 years of American football), are not considered part of the RHI exposure group. Participants are considered to have TBI if a past event meets American Congress of Rehabilitation Medicine and Veterans Affairs/Department of Defense criteria, based on self‐report, informant report and/or review of medical records.

2.3. Recruitment and retention strategies

Active recruitment efforts are made for participants with and without RHI and/or TBI to be demographically similar and representative of the target population, including those who present to BMC, Boston neighborhoods surrounding BMC, and greater Boston. Because recruitment is based on brain trauma exposure, AD/ADRD‐related outcomes are not considered in recruitment to avoid selection bias. Nonetheless, as most participants are recruited through our memory clinics or have concerns related to cognition, behavior, family history, or brain trauma exposure, they represent a clinic‐based sample and span the cognitive continuum. All participants must be 50 years or older. Age 50 was chosen to capture pre‐clinical biomarker changes and earlier neurodegenerative symptom onset that may arise after brain trauma. There are no exclusions for sex, race, or ethnicity. Exclusion criteria include: (1) language barriers; (2) inability to fulfill research protocol requirements due to physical, visual, or hearing impairment; (3) lack of an informant who is knowledgeable about the participants mood, behavior and cognition; and (4) any condition or disorder that confounds our ability to diagnose neurodegenerative disease accurately including unstable medical conditions (e.g., active cancer with recent chemotherapy, unstable heart disease and oxygen dependent), neurological conditions (e.g., multiple sclerosis, brain tumor involving the parenchyma, active seizure disorder, acute TBI or stroke with ongoing symptoms), serious mental illness (e.g., schizophrenia), or neurodevelopment conditions (e.g., intellectual disability, autism spectrum disorder). Exclusions are determined on a case‐by‐case basis based on clinical severity. Inclusion and exclusion criteria are intentionally broad to limit participation bias and maximize a representative sample.

Recruitment goals include enrolling approximately one‐third of the CC to have RHI exposure, one‐third to have TBI without RHI, and one‐third to have neither TBI nor RHI exposure. Most participants with RHI exposure have also had a TBI. These sample sizes provide statistical power to make group comparisons, while allowing for sufficient participants for non‐RHI related research. We aim our recruitment strategy to ensure that exposure groups are similar in age and race, particularly in the proportion of Black or African American participants. Regarding age, we aim for a similar relative frequency by age bins (50–64, 65–79, and 80+) as in our target population. Our goal is to have at least 20% with RHI exposure who are females, based on the fraction of women who have participated in contact and collision sports at the college level since Title IX was implemented. Because Title IX was only implemented in 1972, there are far fewer females in the target population who are older and played contact sports at a high level. The BU ADRC has historically had a recruitment goal of 26% Black or African American participants based on representation of our target population. Importantly, the overall goal is to expand and augment the CC across brain trauma exposure groups and all age, sex, and race recruitment bins that will allow researchers to use the large pool of participants to identify demographically matched (e.g., 1:1, 2:1, etc.) groups to test their a priori hypotheses.

Recruitment is strategic and based on filling the aforementioned age, sex, and race recruitment bins. As bins are filled, recruitment into those bins stops, and individuals are referred to other research opportunities within and/or ancillary to the BU ADRC. We aim to recruit all participants using similar recruitment strategies, though additional efforts are needed to oversample for participants with brain trauma. Directed by Drs. Andrew Budson and Katherine Turk, the Outreach, Recruitment, and Engagement (ORE) Core of the BU ADRC, lead recruitment and retention efforts. Recruitment and retention goals are met through a wide variety of outreach methods, including robust partnerships with local organizations, community science partnership boards, as well as the use of websites, social media, brochures, newsletters, in person and webinar talks, memory screenings, seminars and/or participation at community events, and a regular “thank you” brunch for participants. Drs. Christopher Nowinski and Robert Cantu, founders of the Concussion Legacy Foundation (CLF), are members of the ORE Core. The CLF, a non‐profit advocacy, education, and policy development organization dedicated to advancing the study, treatment, and prevention of the effects of brain trauma, has a central role in recruitment. The CLF has tremendous experience and knowledge pertaining to communication and outreach about concussion, non‐concussive impacts, post‐concussion syndrome, and the neurodegenerative disease, CTE. The CLF and Dr. Nowinski have the largest social media presence in the sports concussion and CTE field.

2.4. Study design and procedures

Figure 2 provides an overview of the CC workflow. Participants are evaluated at one of three sites: (1) the BMC Memory and Aging Clinic (MAC) is led by Drs. Mez and Alosco, where evaluations are concurrently conducted for clinical care and CC participation. The BMC MAC attracts patients from across the country because of the unique expertise of the BU ADRC CC leaders in post‐traumatic AD/ADRD; (2) Boston VA Memory Disorders and TBI Clinics are longstanding clinics led by Drs. Budson and Turk, ORE Core leaders, who also conduct combined clinical care and CC participation evaluations; and (3) General Clinical Research Unit (GCRU), which is part of the Clinical and Translational Science Institute at BU Medical Center (BUMC) and provides exam rooms, nursing staff, and laboratory facilities for research visits only. Participants complete evaluations (Table 2) that include the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) exams, non‐UDS supplemental cognitive and neuropsychiatric tests, the BU RHI Exposure Assessment, blood draw (for blood biomarkers, DNA extraction, and multi‐omics), neuroimaging (structural, functional, and molecular), lumbar puncture (LP), and digital phenotyping. All evaluations are performed annually except for MRI and LP, which are performed at baseline and every 3 years. LP is also optional. EEG and digital phenotyping are completed every 1–3 years, depending on ancillary funding, with the intention to evolve toward annual sessions. Depending on ancillary funding, a subset also undergoes amyloid and/or tau PET. PET imaging will become routine in Summer of 2025 through our participation in the CLARiTI study. Results of the evaluations and the participants’ histories are presented at weekly MDCCs at which syndromal and etiological diagnoses are adjudicated for each participant. All participants are asked for brain donation. The integration of data collection between the seven multidisciplinary Cores is represented in Figure 3.

FIGURE 2.

Overview of clinical core recruitment and enrollment. BMC, Boston Medical Center; CLF, Concussion Legacy Foundation; GCRU, General Clinical Research Unit; VA, Veterans Affairs.

TABLE 2.

Annual clinical assessments and neuropsychiatric instruments.

Domain	Test/Instrument
Uniform Data Set (UDS) 3.0 and supplementary tests
Neurologic exam	Semi‐structured clinical examination of cranial nerves, sensory functions, muscle strength, fasciculations, and reflexes
Motor	International Parkinson and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) 50 (UPDRS with UDS 4.0)
Performance validity	UDS Reliable Number Span 51
	Test of Memory Malingering (TOMM) 52
Premorbid intelligence	Wide Range Achievement Test‐Fourth Edition (WRAT‐4) Word Reading Subtest 53
Cognitive screening	Montreal Cognitive Assessment (MoCA) (National Alzheimer's Coordinating Center [NACC] UDS) 51 , 54 , 55
Attention, visual scanning, and psychomotor speed	Symbol Digit Modalities Test 56
	Trail Making Test Part A (NACC UDS) 51 , 57
	Number Span (NACC UDS) 51
Executive function	TabCAT Flanker Task 58
	Delis‐Kaplan Executive Function System (D‐KEFS) 59 Color Word Interference (administration began with UDS 4.0)
	F + L Phonemic Fluency (NAC UDS) 51 , 60
	Trail Making Test Part B 51 , 57 (NACC UDS)
Learning and memory	Benson Complex Figure Test Delayed Recall 51 (NACC UDS)
	Neuropsychological Assessment Battery (NAB) List Learning 61 (replaced by Rey Auditory Verbal Learning Test with UDS 4.0)
	Craft Story 51 (NACC UDS)
Language	Category (Semantic) Fluency – Animals 51 , 60 (NACC UDS)
	Category (Semantic) Fluency – Vegetables 51 , 60 (NACC UDS)
	Multilingual Naming Test (MINT) 51 , 62 (NACC UDS)
Visuospatial ability	Benson Complex Figure Test Copy 51 (NACC UDS)
	Judgment of Line Orientation (JOLO) 63
Dementia severity	Clinical Dementia Rating (CDR) 51 , 64 (NACC UDS)
	Functional Activities Questionnaire (FAQ; Informant) 51 , 65 (NACC UDS)
Subjective cognitive concerns	Behavior Rating Inventory of Executive Function‐Adult Version (BRIEF‐A) Global Executive Composite (GEC; Participant and Informant) 66 ; BRIEF‐A Metacognition Index (MI; Participant and Informant) 66
	Cognitive Change Index (Participant and Informant) 67 , 68
Sleep	Mayo Sleep Questionnaire (MSQ; Participant and Informant) 69
	Epworth Sleepiness Scale 70
Pain	Headache Impact Test (HIT‐6) 71
Neuropsychiatric instruments
Affective lability	Center for Neurologic Study—Lability Scale (CNS‐LS) 72
Behavior	Barratt Impulsivity Scale‐11 (BIS‐11) 73
	BRIEF‐A Behavioral Regulation Index (BRI; Participant and Informant) 66
	Buss‐Durkee Hostility Inventory (BDHI) 74
	Neuropsychiatric Inventory—Questionnaire (NPI‐Q; Informant) 75 (NACC UDS)
Depression, anxiety, apathy, other	Apathy Evaluation Scale (AES) 76
	Beck Anxiety Inventory (BAI) 77
	Beck Depression Inventory‐II (BDI‐II) 78
	Beck Hopelessness Scale (BHS) 79
	Geriatric Depression Scale (GDS‐15) 80
	Sheehan‐Suicidality Tracking Scale (S‐STS) 81

Note: At the time of this manuscript, UDS version 3.0 was still being administered and transitioning to UDS 4.0, where the BU ADRC CC will add the Rey Auditory Verbal Learning Test as the list learning verbal memory task.

Abbreviation: BU ADRC, Boston University Alzheimer's Disease Research Center; CC, Clinical Core.

FIGURE 3.

Dynamic study flow and data collection: Integration of multidisciplinary clinical cores. NACC, National Alzheimer's Coordinating Center; NCRAD, The National Centralized Repository for Alzheimer's Disease and Related Dementias; SCAN, Standardized Centralized Alzheimer's & Related Dementias Neuroimaging.

2.5. Institutional review board approval and consent

The BUMC Institutional Review Board approves all study procedures. Consent forms are mailed to all participants for review before in‐person evaluation visits. At evaluation visits, the consent forms are discussed with the participant. Prior to consenting, participant decisional capacity is evaluated. If the participant is not able to provide key points that demonstrate understanding of these study concepts, then a legally authorized representative (LAR) will be used to consent on the participant's behalf. If a LAR consents on behalf of a participant, the participant must provide assent and a willingness to participate. No cognitively impaired subjects are enrolled if there is any evidence of dissent. Participant dissent is always honored.

3. MEASURES AND METHODS

3.1. In‐person clinical assessments

Annual in‐person study visits take place over a 1–2 day period. Table 2 lists the clinical exams and measures that are administered. Evaluations are comprised of the NACC UDS exams and non‐UDS supplemental cognitive and neuropsychiatric tests that assess clinical domains of interest as they pertain to post‐traumatic AD/ADRD. The normative data used for UDS neuropsychological tests have changed over time. Since recruitment of participants with RHI was initiated in 2019, the September 2020 means and standard deviations of UDS 3.0 tests from people with NC (by age, sex, and education) who are part of the NACC data set have been consistently applied to generate standardized scores and determine cognitive impairment. These data can be found online at naccdata.org. Normative data used for non‐UDS tests are in Table 2. The BU ADRC CC administers standalone and embedded performance validity measures. These tests are administered in part because the CC includes several former elite athletes who are part of litigation (which is also documented), such as the National Football League (NFL) Concussion Settlement. Neuropsychiatric manifestations, particularly neurobehavioral dyregulation, have long been described in the setting of post‐traumatic AD/ADRD, including CTE. We deploy a comprehensive battery of neuropsychiatric assessments (Table 2). Although significant efforts are made to maintain a consistent CC battery, additions and changes may be implemented depending on priorities, interests, and funding. For example, we have launched a caregiving battery in the BU ADRC under the direction of Dr. Maureen O'Connor, which has been administered at least one time, with expectations of continued administration once ancillary funding is established.

Extensive training procedures are employed to ensure standardization of the administration and scoring of clinical evaluations across examiners. Those administering the Unified Parkinson's Disease Rating Scale (UPDRS) complete formal online training. A comprehensive neuropsychological test administration and scoring manual has been developed. Neuropsychological tests are double‐scored for quality control. All staff administering the cognitive, mood, and behavior measures are certified in test administration and scoring by the CC Leader and/or a trained neuropsychology delegate.

3.2. Abbreviated remote clinical assessments

Remote visits are offered to prioritized participants who would not otherwise be assessed, including (1) brain donors no longer willing/able (e.g., out of state) to come to an in‐person visit, (2) brain donors too cognitively or physically impaired for an in‐person visit or cognitive testing, and (3) participants of high priority to Center goals (e.g., those at high risk for CTE, under‐represented groups). An annual abbreviated remote protocol is administered by video [NACC Video T‐Cog battery]. ⁸² This protocol also includes consent and participant and study partner interviews. Participants who are no longer assessed in person, but do not meet the above criteria become part of our research registry and may participate in ancillary studies that leverage and continue their legacy data.

3.3. Head trauma exposure

Unique to the BU ADRC CC is our focus on the assessment of lifetime head trauma exposure. We developed the “Boston University Repetitive Head Impact Exposure Assessment” ⁸³ , ⁸⁴ (BU RHIEA), which has been described in detail elsewhere. This evaluation tool is used to determine RHI and TBI status and is completed by the participant at their baseline visit. Interim RHI and TBI changes are assessed at follow‐up. The BU RHIEA is used to obtain self‐reported RHI and TBI history through detailed questions pertaining to contact and collision sport experience (e.g., positions, number of seasons at each level, ages played), military experience, other experiences with RHI (e.g., intimate partner violence), and estimated total number of concussions. The Ohio State University TBI Identification Method‐Interview Form is included in the assessment. ⁸⁵ The BU RHIEA and the associated published data generated informed the assessment questions of RHI exposure being used in UDS version 4.0.

3.4. Social determinants of health

The CC will be enhancing social determinants of health (SDoH) assessments by adopting UDS version 4.0. Independent initiatives are also underway. In collaboration with Dr. Robert Turner, we serve as a site for the Black Men's Brain Health study, which is recruiting 200 Black men (100 football players, 100 non‐football players). Hundreds of these participants will be evaluated and co‐enrolled into the BU ADRC CC. This initiative involves comprehensive assessments of SDoH that will be administered. We also serve as a site for the Neighborhoods Study.

3.5. Novel digital phenotyping

Digital phenotyping at the BU ADRC began in 2019 with the collection of digital audio recordings of spoken responses to neuropsychological tests and has been expanded to multiple internet‐connected devices beginning in July 2021 to present. Digital data acquisition is conducted during in‐person clinic visits and remotely using tablet and smartphone applications, wearables, and, most recently, in‐home sensors. Technologies for our digital platform are described in Table 3 and were selected using four major criteria: (1) access to raw digital data (e.g., in its native format) from the device or application, (2) operating systems compatible with both iOS and Android, (3) demonstrated use with older age participants, and (4) scientific validation of clinical measure of interest.

TABLE 3.

Ongoing digital data collection in BU ADRC cohort.

Device/category	Components	Measures
DANA Digital Testing	Code Substitution, Go No Go, Insomnia Severity Index, Match to Sample, Memory Search, Patient Health Questionnaire, Procedural Reaction Time, Simple Reaction Time, and Spatial Processing	Executive function, visuospatial skills, processing speed, psychomotor function
Digital Voice NP tests	Picture description, category naming, store recall, object recall, letter fluency, category fluency, sentence reading	Linguistic features – language complexity (measures of lexical, semantic, syntactic complexity), unique words, word‐frequency, neighborhood density; semantic coherence (measures to analyze language patterns)
		Acoustic features – articulatory precision, vocal quality, respiratory support, prosody, nasality, proxy measures for cognitive processing
Digital Pen tests	Clock Drawing Test	Attention, executive function, processing speed, visuospatial and visuoperceptual skills, psychomotor function
Non‐DANA Digital Testing	Lumosity application (various memory, attention, problem‐solving, flexibility, speed, and language tasks) Mezurio application (Flashcards task, tilt task, gallery game)	Executive function, long‐term episodic memory
Gait and Balance Measurement	APDM mobility lab Hebrew Senior Life smartphone gait and balance assessment	Stride variability, stride length, gait cadence, gait cycle duration, gait symmetry
Wrist Wearable Activity Monitoring	Fitbit, Verisense	Daily light, moderate, vigorous physical activity, inactivity, steps, heart rate, sleep duration, sleep staging.
Sleep Monitoring	Dreem headband, SleepImage PO2 ring	EEG, sleep movement, respiration, sleep staging, periodicity, fragmentation, pulse oxygen, apnea, hypopnea
Passive Typing Monitoring	NeuraMetrix computer application, Longevity smartphone application	Typing speed, consistency, and fluctuations in daily activities
Home Monitoring	Emerald device	Radio signal for derivation of sleep, gait, activity, and breathing

Abbreviation: EEG, electroencephalogram.

Participants are allowed to choose which technologies they want to use and at what frequency over a 2+ year period. During technology selection sessions, study staff introduce all available technologies. Study staff describe what the technology measures, how it is used, and any benefits or risks of each device. Participants are allowed to pick as many or as few technologies as they want.

Although study staff describe a preferred schedule of use, participants are invited to adjust the schedule to their preference. For the preferred schedule, participants are asked to use their selected technologies within 2‐week assessment periods and do so every 3 months. Before each 2‐week assessment window, participants are queried on the usability of each technology and their feelings about testing burden. These data are used at the next assessment period to allow participants to modify their technology use protocol by adding and/or removing technologies to ensure participants are not frustrated or overburdened by ongoing use of any technology. Participants able and willing to come for an in‐clinic visit are asked to use three in‐clinic technologies during an estimated 1‐h in‐clinic visit. The only exclusion criteria for participation are inability to come for an in‐clinic visit and no internet connectivity for remote data acquisition.

3.6. Neuroimaging

Baseline and 3‐year neuroimaging protocols are acquired on a SCAN‐certified Philips 3T MR 7700 system. Data were acquired on a Philips 3T Achieva prior to a complete magnet replacement with an Ingenia Elition in March 2020. The MRI scanner was upgraded in 2023 to the MR 7700 system. Sequences currently acquired include structural 3D T1‐weighted, T2‐weighted, and T2‐weighted fluid‐attenuated inversion recovery (FLAIR) sequences, multi‐shell diffusion MRI (dMRI), resting‐state functional MRI (rs‐fMRI), quantitative susceptibility mapping (QSM), pseudo‐continuous arterial spin labeling (pCASL) and T2*‐weighted sequences. High resolution (1 × 1 × 1 mm³) 3D T1‐weighted images using magnetization‐prepared rapid gradient echo (MPRAGE) are acquired in the sagittal orientation using repetition time/echo time (TR/TE) = 6.5/2.9 ms with a flip angle of 9 degrees, and field of view (FOV) = 256 × 256 mm. High resolution (1 × 1 × 1.2 mm³) 3D T2 FLAIR sequences are acquired sagittally using TR/TE/TI = 4800/271/1650 ms, and FOV = 256 × 256 mm. High resolution (1 × 1 × 1 mm³) 3D T2‐weighted images are acquired sagittally using TR/TE = 2500 / 251.6 ms with a flip angle of 90 degrees and FOV 256 × 256 mm. The diffusion MRI is acquired axially and is spread over three shells (500, 1000, and 2500 s/mm²). The resting‐state fMRI is an eyes‐open echo planar imaging (EPI) acquisition with 3.4 × 3.4 × 3.4 mm³ resolution, with a TR/TE = 3000/30 ms and 197 dynamics. QSM scans are acquired axially with 1 × 1 × 1.5 mm³ acquired resolution that is reconstructed to 0.5 × 0.5 × 1.5 mm³ resolution, with TR 47 ms. pCASL is performed using a 3D GRASE sequence with the following parameters: TR/TE = 4250/9.0 ms, FOV = 240 × 240 mm, post‐label delay of 2000 ms with reconstructed resolution of 2.5 × 2.5 × 4.0 mm. Axial T2*GRE with TE = 20, TR = 650, FOV = 250 × 200 mm, and 4 mm slice thickness. The total scan time for the protocol is approximately 55 min.

PET: A subset undergoes amyloid (18F‐florbetaben) and tau (18F‐MK‐6240) PET at BMC on the Alzheimer's Disease Neuroimaging Initiative (ADNI)‐certified GE Discovery 710. Our goal is to acquire amyloid and tau PET on all CC participants, if funds and resources permit. CLARiTI will facilitate this goal as well as permit longitudinal acquisition. ADRC participants are co‐enrolled in other tau and amyloid PET studies, and these PET scans and associated processed data are also returned to the BU ADRC to facilitate participant characterization and wider sharing. Regarding 18F‐MK‐6240 procedures, 70 min after a 185 MBq (5 mCi) bolus injection, the participant undergoes brain scans consisting of 85 min frames. Regarding 18F‐florbetaben procedures, 90 min after a 300 MBq (8.1 mCi) bolus injection, the participant completes a dynamic 20‐min brain scan (four frames, 5 min each). If a participant completes both PET scans, they are performed at least 24 h apart. Amyloid and tau PET images are visually assessed and reported out by collaborators at the University of California, San Francisco ADRC, based upon United States Food and Drug Administration (FDA) ‐approved visual read methods for 18F‐florbetaben and the current clinical interpretation standard for 18F‐MK‐6240 (18F‐MK‐6240 results are not disclosed to participants).

EEG: All participants are offered to complete an EEG session using both a dry‐electrode system as well as a more traditional gel‐based EEG system on separate days. The Cumulus platform uses a dry sensor, wireless EEG headset that records brain activity, accompanied by gamified versions of cognitive tasks presented via a tablet‐based app. ⁸⁶ The wireless EEG headset consists of dry, flexible Ag/AgCl‐coated polymer sensors at 16 channels. The left and right mastoids are used for reference with single‐use, snap‐on electrodes attached to wires extending from the headset. The electronics and sensors are mounted on flexible neoprene and incorporate anatomical landmarks to encourage consistent placement in line with the 10–20 sensor system. The analog headset has a high input impedance of 1 GΩ, a configurable driven bias function for common‐mode rejection, built‐in impedance checking, and configurable gain and sampling rates. An onboard processor and Bluetooth module transmit 250 Hz EEG data to the tablet, from where it is transferred to a cloud server for storage and processing. EEG recording and behavioral events are timestamp synchronized to ±2 ms. The gamified tasks are based on well‐known paradigms from experimental electrophysiology and cover a range of core cognitive functions. Each session is comprised of 2 min of eyes closed resting state, a continuous recognition old/new memory task using images and varying lags of 2, 8, and 20 items, a two‐tone auditory oddball paradigm, and a visual oddball paradigm. Behavioral measures, including correct button presses, misses, false alarms, and reaction times, are collected for later analysis.

On a separate day, an EEG session is administered using an FDA‐approved EEG device, g.Nautilus PRO headset (G‐Tec) flexible eight‐electrode system and the software includes Cognitive Health Assessment Management Platform software (CHAMP), manufactured by VoxNeuro. The system has eight channels and gel electrodes with a common spatial pattern (CSP) layout on predefined positions. The event‐related potentials (ERP)/EEG System is an FDA 510(k) approved device intended for the acquisition, display, analysis, storage, reporting, and management of EEG and auditory evoked potentials using 24‐bit accuracy at a 500 Hz sampling rate. During this EEG session, participants complete an Auditory Oddball, Continuous Visual Memory Test, Auditory Evoked Potential, Visual Evoked Potential, Eriksen Flanker 1 and Flanker 2 Task, the Go/No‐Go task, the Hayling Test, and 3 min of eyes open resting EEG measurement. Behavioral measures, including correct button presses, misses, false alarms, and reaction times, are collected for later analysis.

3.7. Fluid biomarkers and multi‐omics

Blood is collected annually, and a lumbar puncture is optional and discussed at baseline and every 3 years. The collection, tracking, banking, and distribution of all fluid biospecimens follow the manual of procedures from the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD). Samples are processed immediately, aliquoted, frozen, and stored at −80°C in the BU Biomarker Core, led by Drs. Wendy Qiu and Lee Goldstein. ∼100 mL of blood is collected by a trained phlebotomist, and 30 mL is shared with NCRAD as part of the AD Center Fluid Biomarker (ADCFB) Initiative. Buffy coat is extracted for DNA analysis, and whole blood is collected in PAXgene tubes for RNA extraction at the initial visit. The BU ADRC Genetics and Molecular Profiling Core, led by Drs. Lindsay Farrer and Gyungah Jun perform multi‐omic assays on select blood and brain samples in batch. To date, this includes transcriptomics (RNAseq) and proteomics (Somascan), focused on deceased brain donors where both blood and brain tissue are available. The ADCFB study returns standard plasma biomarker results back to ADRCs that are integrated into the data sets and used to inform etiological diagnostics. Lumbar puncture is performed by a trained MD using a 22 g Sprotte atraumatic spinal needle to acquire cerebrospinal fluid (CSF). Banked and analyzed CSF (and blood) products are and/or will be made available to outside investigators.

3.8. Brain donation

All study participants are asked to consider brain donation at annual BU ADRC evaluations. The value of brain autopsies is discussed with study participants, including that (1) brain autopsy is the only definitive way to diagnose AD or other neurodegenerative conditions, (2) clinicopathological studies utilizing clinical data collected during annual evaluations and brain autopsy data are crucial for improved diagnosis in life, and (3) brain tissue is critical for investigating disease mechanisms and identifying therapeutic targets. The Neuropathology Core, led by Drs. Thor Stein and Ann McKee provide a report of the autopsy findings that can be shared with family members.

If study participants agree to brain donation, they are asked to sign a brain donation consent form indicating their intent for donation at death. Participants are also asked to sign an updated brain donation consent form at each annual evaluation. Important logistics of brain donation are discussed. Participants are informed that brain donation will not interfere with any traditional or religious arrangement, such as an open casket viewing, and that it will not delay or complicate funeral arrangements. Study participants are asked to discuss their intent to donate with close family members, such as their adult children. The importance of involving close family members in this decision for brain donation is emphasized.

All study participants who agree to brain donation are provided with a card that includes information on how family members are to contact BU ADRC staff at the time of death, and they are encouraged to provide the information annually to close family members. After death and with consent of the family, brain, eyes, cerebrospinal fluid, and blood are collected and delivered on wet ice to the Neuropathology Core. The tissue is immediately processed to optimize neuropathological and molecular workups and to facilitate long‐term storage for current and future approved research projects. A standardized neuropathological evaluation is completed and compatible with Version 11 of the NACC neuropathology data‐collection form as well as the Federal Interagency TBI Research (FITBIR) core and supplemental chronic TBI‐related neurodegeneration common data elements.

4. MULTIDISCIPLINARY DIAGNOSTIC CONSENSUS CONFERENCES

Weekly MDCCs are held with a required minimum of one faculty‐level neuropsychologist (M.L.A., M.L., C.A.) and one faculty‐level behavioral neurologist (S.L., J.M.). There is representation from neuroradiology by C.W.F., who provides a read of all MRIs, and geriatric psychiatry by W.Q.Q. At each MDCC, all clinical data are first presented in narrative form, and Clinical Dementia Rating (CDR) Staging Instrument scores are reviewed. CDR scores are determined by a single clinician before MDCC and independent of the neuropsychological data. Following presentation of the history, course, and neuropsychological test score summaries, consensus syndromal diagnoses (e.g., NC, MCI, dementia) are made following NACC UDS diagnostic criteria guidelines. Neuropsychological test scores that fall > 1.5 SD below the normative mean are considered to fall in the impaired range. To maintain consistency, there is a manual of procedures to guide interpretation of scores, though clinician judgment is also considered. In addition, TES proposed to encapsulate the clinical syndrome of CTE, diagnoses are made following the 2021 Katz et al research diagnostic criteria. ¹⁴ Consensus on the individual items of the TES criteria (e.g., cognitive impairment, neurobehavioral dysregulation) is also done in order to guide improvements to the criteria in future iterations. Panel members make all syndromal diagnoses blinded to biomarkers.

MRI and amyloid and tau biomarkers (if available) are then presented to inform etiological diagnoses. Recently, the ADFCB lab began returning plasma ptau217 (ALZPATH) at no cost, and we have begun utilizing this value as a universal approach for all participants to characterize AD status. Cutoffs to define positivity currently being used adhere to Ashton et al., ⁸⁷ but this will likely change as the evidence evolves. As a Center focused on characterizing signs, symptoms, and biomarkers of CTE, we prioritize acquiring gold standard biomarkers (e.g., amyloid and tau PET, CSF analysis of amyloid and tau) on participants exposed to RHI. To date, this has been supported by ancillary funding. However, as a participating site in the CLARiTI initiative and with new P30 requirements, acquiring amyloid and tau PET across most participants (including longitudinally) will become more feasible.

5. DISCLOSURE OF RESULTS

Participants have the opportunity to learn the results of their neuropsychological, structural MRI, neurological, neuropsychiatric, and amyloid PET data. If they are cognitively normal, there are no abnormal MRI findings, and have not had an amyloid PET, participants receive a letter. Otherwise, results are returned by telephone or Zoom with an ensuing letter. All structural MRI scans are read by the study neuroradiologist (C.W.F.). Amyloid PET results are returned via Zoom video or in‐person by a trained doctoral‐level clinician. Before amyloid PET disclosure, participants’ cognitive and psychiatric data are disclosed, and readiness to receive results is assessed. Education is provided when results are returned using PowerPoint visuals, including showing the participant their amyloid PET scan. Visual read and quantification are both disclosed. Experimental procedures, including 18F‐MK‐6240 tau PET, are not currently disclosed to participants. There is also added sensitivity to the disclosure of tau PET results in participants at risk for CTE. The usefulness of these current tracers to detect CTE may be limited and is still under investigation. Blood‐based biomarkers (e.g., plasma ptau217) are also not disclosed at the time of this manuscript, but this may change as the field evolves. Finally, participants who are seen as part of the BMC MAC receive results of CSF analysis of amyloid and tau when clinically ordered. However, participants who are only involved in research and do not receive clinical care do not receive CSF results, as CSF research biomarkers are generated in batches from a non‐CLIA‐certified research lab. DNA is extracted from blood samples for genotyping for research activities, but research results are not returned to participants because they are generated from a non‐CLIA‐certified lab. For participants also receiving clinical care in the BMC MAC, genetic results, including APOE (for anti‐amyloid therapy management) and pathogenic variants, are returned.

6. DATA MANAGEMENT AND SHARING

The Data Management and Statistics Core (DMSC), led by Dr. Yorghos Tripodis and Joseph Palmisano, performs data management, database and web development, and data analysis. Data collection strategies include Web‐based assessments using REDCap, or similar data collection software, as well as customized forms for complex data. A web‐based tracking system has been developed to track participants, data, and specimens. Data collection and management systems include assessments, clinical data, summary data for imaging, biomarkers, and genetics, reporting for MDCCs, and study management. When possible, data are collected on tablets or laptops via direct electronic capture. Electronic forms include required fields, skip logic, and ranges, resulting in more complete and “cleaner” data at capture. All data, regardless of capture method, are processed using SAS, reviewed for logic, skip patterns, response ranges, and inconsistencies, and curated to analytic datasets.

Boston University Information Systems and Technology group (BU IS&T) provides computing services, network infrastructure, and technical support to all departments across the Boston University Charles River and Medical Campuses. Data collected are electronically encrypted via IPSec tunnel or secure socket layering (SSL) encryption technology. Websites, applications, and databases are protected by network firewalls that restrict access to designated users and hosts, and BU 2FA VPN is required as an additional security measure. All data collected is stored on a secure server to which only designated individuals have access. Data are transferred via secure and encrypted mechanisms.

The DMSC works closely with NACC on data sharing protocols and procedures. All data obtained in the study is shared with the research community via NACC, associated initiatives (e.g., SCAN, CLARiTI, NCRAD), or directly from the DMSC. There is an internal web‐based portal where data and biosamples can be requested. All requests are sent to the BU ADRC Executive Committee, where they are evaluated for scientific merit and rigor, feasibility, and overlap in shared priorities.

7. RESULTS

7.1. Participants

Because enrichment for RHI began in 2019 during UDS version 3.0 administration, the data presented hereafter are from the participant's first UDS 3.0 visit. Furthermore, the data presented include those who have completed their entire NACC UDS 3.0 visit, including the diagnostic consensus conference. Many of the data presented might not reflect the entire cohort of participants at the BU ADRC (i.e., participants who preceded UDS 3.0 were excluded). As an example, if the entire BU ADRC CC is considered, we have enrolled approximately 26% Black or African American participants. The data set also includes participants who are active and those lost to attrition (i.e., inactive, n = 109). As of the March 2025 master data set freeze, the sample included 467 participants (234 [50.1%] female, 72 [15.4%] Black or African American, mean age at baseline of 65.6 years [8.8 SD]) who completed a baseline UDS version 3.0 exam (Table 4). The mean number of UDS 3.0 visits was 6.93 (5.7 SD). Participants were well educated, with >75% having at least an associate's or bachelor's degree.

TABLE 4.

Demographic summary of BU ADRC CC at baseline UDS 3.0 visit.

Parameter	Total in‐person sample (N = 467)
Demographics
Sex, n (%) female	234 (50.1)
Age, mean (SD) years at baseline	65.6 (8.8)
Age by decade, n (%) years at baseline
50–64	222 (47.5)
65–79	223 (47.8)
80+	22 (4.7)
Race, n (%)
American Indian or Alaska Native	2 (0.4)
Asian	9 (1.9)
Black or African American	72 (15.4)
Native Hawaiian or other Pacific Islander	1 (0.2)
White	382 (81.8)
Other	1 (0.2)
Ethnicity, n (%) (n = 466)
Hispanic	9 (1.9)
Unknown	1 (0.2)
Years of education, mean (SD)	16.4 (2.3)
Level of education, n (%)
Some high school	6 (1.3)
High school diploma/GED	32 (6.9)
Some college, no degree	75 (16.1)
Bachelor's or associate's degree	156 (33.4)
More than a bachelor's degree, no other degree	13 (2.8)
Graduate degree	185 (39.6)
Cognitive diagnosis, n (%)
Normal cognition	207 (44.3)
MCI/non‐MCI cognitively impaired	207 (44.3)
Amnestic MCI, single domain	44 (9.4)
Amnestic MCI, multiple domain	73 (15.6)
Non‐amnestic MCI, single domain	18 (3.9)
Non‐amnestic MCI, multiple domain	10 (2.1)
Cognitively impaired, not MCI	62 (13.3)
Dementia	53 (11.3)
Dementia severity
Global CDR = 0	252 (54.0)
Global CDR = 0.5	169 (36.2)
Global CDR = 1.0	34 (7.3)
Global CDR = 2.0	12 (2.6)
Neuroimaging, n (%)
MRI	356 (76.2)
EEG	24 (5.1)
Amyloid PET	37 (7.9)
18F‐Florbetaben	14 (3.0)
18F‐Florbetapir	23 (4.9)
Tau PET	43 (9.2)
18F‐MK‐6240	33 (7.1)
18F‐PI‐2620	10 (2.1)
Biofluids collected, n (%)
Cerebrospinal fluid	111 (23.8)
Blood (plasma, serum, whole blood)	452 (96.8)

Note: Because enrichment for RHI began in 2019 during UDS version 3.0 administration, the data presented are from the participant's first UDS 3.0 visit. Furthermore, the data presented include those who have completed their entire NACC UDS 3.0 visit, including the diagnostic consensus conference. Therefore, many of the data presented might not reflect the entire cohort of participants at the BU ADRC (i.e., participants who preceded UDS 3.0 were excluded). As an example, if the entire BU ADRC CC is considered, we have enrolled approximately 26% Black or African American participants. Biomarkers do not necessarily correspond to baseline visit and represent what is available for participants who had a baseline UDS 3.0 visit.

Abbreviations: BU ADRC, Boston University Alzheimer's Disease Research Center; CC, Clinical Core; CDR, Clinical Dementia Rating scale; EEG, electroencephalogram; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography; UDS, Uniform Data Set.

Table 5 provides RHI and TBI characteristics. There were 163 participants with RHI exposure, with a mean of 2.9 (3.2 SD) visits, including 91 with one follow‐up visit, 59 with two follow‐ups, and 22 with three follow‐ups. There were 302 participants with TBI, with a mean of 5.9 (5.3 SD) visits, including 195 with one follow‐up visit, 168 with two follow‐ups, and 115 with three or more follow‐ups. There were 304 participants without RHI exposure with a mean of 7.7 (5.8 SD) visits. Table 4 provides demographic descriptions of the cohort at UDS 3.0 baseline. Of those with RHI, 95 (58.3%) participants played American football as their primary sport. Of these football players, 30 (31.6%) played professionally, 6 (6.3%) played semi‐professionally, 50 (52.6%) played collegiately, and 8 (8%) played in high school as their highest level of play. The most common positions were offensive line (21, 22.1%), followed by linebacker (17, 17.9%) and defensive back (16, 16.8%). Other frequent sources of exposure to RHI included participation in soccer (n = 26, 16.0%) and ice hockey (17, 10.4%). Of the cohort, 295 (97.7%) had mild TBI and 7 (2.3%) had moderate/severe TBI.

TABLE 5.

RHI and TBI exposure history and TES diagnoses.

	In‐person sample
Total N	467
RHI exposure status, n (%) yes	163 of 467 (34.9)
Contact & collision sports (primary sport, years played longest), n (%)	159 of 163 w/ RHI (97.5)
American football	95 (58.3)
Soccer	26 (16.0)
Ice hockey	17 (10.4)
Boxing	7 (4.3)
Rugby	7 (4.3)
Lacrosse	4 (2.5)
Wrestling	1 (0.6)
Martial arts/mixed martial arts	2 (1.2)
Football characteristics, n (%)	95 of 159 (59.7)
Years of American football played, mean (SD)	13.02 (5.3)
Highest level of football played, n (%)
Professional	30 (31.6)
Non‐pro/semi‐professional/juniors	6 (6.3)
College	50 (52.6)
High school	8 (8.4)
Youth	1 (1.1)
Position played at highest level of American football, n (%)
Offensive line	21 (22.1)
Tight end	3 (3.2)
Quarterback	3 (3.2)
Running back	15 (15.8)
Wide receiver	2 (2.1)
Defensive line	13 (13.7)
Linebacker	17 (17.9)
Defensive back	16 (16.8)
Other (includes special teams)	5 (4.2)
Unknown	1 (1.1)
Age of first football exposure, mean (SD)	10.91 (2.7)
Age of last football exposure, mean (SD)	24.2 (5.5)
Military service available data, n (%)	438 of 467 (93.8)
Military service history, n (%) yes	46 of 438 (10.5)
Physical violence available data, n (%)	112 of 467 (24.0)
Physical violence history, n (%) yes	29 of 112 (25.9)
TES diagnostic data available, n (%)	467 (100)
No TES	396 (84.8)
TES‐CTE suggestive	20 (4.3)
TES‐CTE possible	25 (5.4)
TES‐CTE probable	26 (5.6)
TBI, n (%) yes	302 of 467 (64.7)
Mild	295 of 302 (97.7)
Moderate/severe	7 of 302 (2.3)

Abbreviations: CTE, chronic traumatic encephalopathy; RHI, repetitive head injury; TBI, traumatic brain injury; TES, traumatic encephalopathy syndrome.

MDCCs have been completed for all participants, with 207 (44.3%) having NC, 62 (13.3%) being impaired, not MCI, 145 (31.0%) having MCI, and 53 (11.3%) having dementia at baseline. Among those with RHI exposure, 73 (44.8%) had NC, 9 (5.5%) were impaired without MCI, 65 (39.9%) had MCI, and 16 (9.8%) had dementia. Additionally, 71 (of 467) (15.2%) met criteria for TES, including 20 (4.3%) with TES‐CTE suggestive, 25 (5.4%) with TES‐CTE possible, and 26 (5.6%) with TES‐CTE probable. Among those without RHI exposure, 134 (44.1%) had NC, 53 (17.4%) were impaired without MCI, 80 (26.2%) had MCI, and 37 (12.2%) had dementia. The most commonly suspected primary etiological diagnoses for those with RHI exposure were CTE (n = 45), followed by AD (n = 11). The most common suspected etiologies for those without RHI exposure were AD (n = 76), followed by vascular brain injury (n = 7), TBI (n = 7), and depression (n = 7). Note that etiological diagnoses are informed by biomarkers when available. However, only a small subset has AD‐specific biomarkers available at this time (e.g., amyloid PET). This is expected to change rapidly with our new implementation of plasma ptau217 into the MDCCs for all participants.

7.2. Digital phenotyping

The BU ADRC has screened 256 participants and enrolled 235 participants thus far, surpassing the original goal of 200 participants. In the last 6 months, 33 participants have been screened, resulting in recruitment of 31 participants. Forty participants have completed 2‐year follow‐up visits. On the analysis side, we have successfully established interoperability with the American Heart Association Precision Medicine Platform and the Alzheimer's Disease Data Initiative.

7.3. Neuroimaging

Three hundred fifty‐six participants, including 126 with RHI exposure, have completed the structural and functional MRI protocol. Among participants with RHI exposure, 34 have completed 2 MRI scans, and 3 have completed 3 MRI scans. Among participants without RHI exposure, 58 participants have had 2 MRI scans, and 7 have completed 3 MRI scans. The BU ADRC has several ancillary studies investigating PET tracers for the detection of CTE. Among participants with RHI exposure, 21 have completed 18F‐florbeapir PET, 10 have completed 18F‐florbetaben PET, 28 have completed 18F‐MK‐6240 tau PET, and 11 have completed 18F‐PI‐2620 tau PET. Additionally, 25 participants have undergone EEG, 20 RHI, and 5 non‐RHI participants.

7.4. Fluid biomarkers

A total of 96 RHI and 15 non‐RHI participants have completed lumbar puncture; 160 RHI and 292 non‐RHI have completed blood draw.

7.5. Brain donation

Eighty‐nine percent of participants have agreed to brain donation. Thus far, the brain bank consists of 441 brain donations.

8. DISCUSSION

Here, we describe the rationale, mission, study design, and recent updates for the BU ADRC CC. This well‐characterized longitudinal cohort of 467 participants enriched for RHI (∼1/3) and TBI (∼1/3) exposure spans the cognitive continuum, with most participants agreeing to brain donation (89%). The CC provides a unique resource to the TBI and AD/ADRD research communities to advance research on post‐traumatic AD/ADRD. The BU ADRC CC is distinct from other ADRC CCs in its emphasis on recruitment and retention of participants exposed to RHI and TBI and the study of post‐traumatic AD/ADRD, including CTE. Recruitment and assessment were devised to address current knowledge gaps in the field, several of which serve the larger goal of accurately diagnosing CTE during life. These knowledge gaps include: (1) lack of objective clinical assessments to characterize signs and symptoms of CTE, (2) lack of longitudinal clinical characterization of individuals at risk for CTE to understand disease progression, (3) absence of validated biomarkers for CTE, and (4) lack of comparison between post‐traumatic AD/ADRD and other forms of AD/ADRD. Data from the BU ADRC CC will be instrumental for understanding disease distinctions between CTE and AD/ADRD, as well as advancing knowledge on how brain trauma of all types may impact clinical outcomes. These research objectives are facilitated through BU ADRC internal investigations and local data sharing portals, in addition to our participation in national data sharing initiatives. The unique focus of the BU ADRC CC has led to many cross‐ADRC collaborations, including a recently funded R01 that will involve the collaboration of five ADRCs to continue and expand on the DIAGNOSE CTE Research Project. BU ADRC investigator research on post‐traumatic AD/ADRD has also prompted UDS version 4.0 to incorporate a new assessment of RHI exposure, a more granular assessment of TBI, and TES as a syndromic diagnosis. Finally, the BU ADRC CC is uniquely positioned to train next‐generation scientists on post‐traumatic AD/ADRDs, including CTE. These newly trained and uniquely qualified clinician‐scientists will be ideally suited to conduct research and provide care for post‐traumatic AD/ADRD across the United States.

There are several methodological considerations of the BU ADRC CC. Those with and without brain trauma exposure have demographic differences. This is partly due to fewer women playing contact sports. We have a female RHI recruitment goal of 20% to match the NCAA post‐Title IX frequency. Further, recruitment of those with TBI and RHI is still underway, particularly for older, female, and non‐White participants. Past recruitment goals prior to 2019 did not include oversampling for RHI/TBI, and the decision was made to continue following willing participants even if demographic recruitment goals had been exceeded because legacy data had already been collected. Attrition plus active recruitment will lead to more balanced groups in the future. The large number of participants without brain trauma exposure still provides a rich pool to identify a matched group or to appropriately adjust for potential confounding. Because we recruit across the continuum of exposure to RHI, investigators can also examine exposure to RHI proxies as continuous variables instead of using the dichotomized groups. There is a sufficient number of participants to examine football and non‐football sources of RHI exposure as broad categories. However, the sample sizes by the different sources in the non‐football group are small at this time. Because oversampling for TBI/RHI was initiated in 2019, most participants with exposure have shorter follow‐up times than those without exposure. The current data set is most suited for baseline analyses at this time. To capture executive function impairment that has been described in the literature for people with TBI/RHI exposure, we have recently introduced new non‐UDS tests (e.g., TabCAT Flanker Task ⁵⁸ ) for which data is more sparse. Investigators should also be mindful that normative data for neuropsychological tests have changed over time, but have remained consistent since 2019 with enrichment for TBI/RHI.

In conclusion, the BU ADRC CC includes a longitudinal cohort of participants with and without RHI and TBI exposure that is ideally suited to facilitate research comparing post‐traumatic AD/ADRD, including CTE, with other forms of AD/ADRD. Investigators interested in collaborating and/or accessing BU ADRC CC data are encouraged to visit our website (bu.edu/alzresearch), where they can also request access to the Center's resources.

CONFLICT OF INTEREST STATEMENT

M.L.A.: Received honorarium from the Michael J Fox Foundation Inc as well as research support from Life Molecular Imaging Inc. M.M., E.G.S., J.M., M.L., C.A., S.L., M.A., M.K.O., Y.T., J.P., D.D., B.M., G.S., J.R.G., A.E., D.S., C.W.F., R.C.C., K.W.T., L.F., G.J., L.E.G., W.Q.Q., T.D.S., A.E.B., J.M.: None to report. R.A.: A scientific advisor to Signant Health and NovoNordisk. C.J.N.: A volunteer member of the Mackey‐White Committee of the National Football League Players Association, for which he receives travel support; an advisor and options‐holder with Oxeia Biopharmaceuticals, LLC, and StataDx; and has received travel support from the NFL, NFL Players Association, World Rugby, WWE, and AEW for lectures or conferences. C.J.N. has served as an expert witness in cases related to concussion and CTE and is compensated for speaking appearances and serving on the Players Advocacy Committee for the NFL Concussion Settlement. CJN is employed by the Concussion Legacy Foundation, a 501(c)(3) non‐profit which receives charitable donations. A.C.M.: A member of the Mackey‐White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the National Institutes of Health and Department of Veteran Affairs, and other funding from the Buoniconti Foundation and MacParkman Foundation during the conduct of the study. Author disclosures are available in the supporting information.

Consent Statement

All human subjects provided necessary informed consent to participate in this research study.

Supporting information

Supporting information

Alosco ML, Morrison M, Au R, et al. Boston University Alzheimer's Disease Research Center Clinical Core: Infrastructure to facilitate research on post‐traumatic Alzheimer's disease and related dementias. Alzheimer's Dement. 2025;21:e70654. 10.1002/alz.70654