Each year, millions of people are exposed to repetitive head impacts (RHI) through contact sports. RHI can result in concussions and asymptomatic non-concussions to confer risk for Alzheimer's disease (AD) and related dementias (ADRD) including chronic traumatic encephalopathy (CTE). Presently, a diagnosis of CTE can only be rendered at autopsy and it has been neuropathological diagnosed in several hundreds of American football players particularly those who played at elite levels (college and professional). The ability to make an accurate diagnosis of CTE is needed to facilitate research on risk factors, mechanisms, prevention, and treatment.

In 2015, the investigators were awarded a NINDS funded 7-year U01 known as the DIAGNOSE CTE Research Project (NCT02798185) designed to develop biomarkers, characterize the clinical presentation, and examine genetic and RHI risk factors for CTE. This current 5-year NIH funded multicenter study DIAGNOSE CTE Research Project-II will build on and extend those findings.

The aims of the DIAGNOSE CTE Research Project-II are to:

• retain and grow DIAGNOSE-I and examine the clinical and biomarker course of Traumatic Encephalopathy Syndrome (TES);
• investigate risk and resilience factors of TES; and
• compare biomarkers of amyloid (Aβ), p-tau, neurodegeneration, neuroinflammation, and white matter (WM) injury between TES and AD.

The investigators hypothesize that TES has unique clinical and biomarker profiles, and RHI and non-RHI risk factors influence the development of TES.

There will be 3 study groups:

1. Retention, 150 former football players and 50 controls retained from DIAGNOSE-I;
2. Expansion, the investigators will grow DIAGNOSE-I by newly recruiting 75 former college and professional football players and 25 controls;
3. AD, 50 Aβ+ participants with cognitive impairment. In total, the investigators will study 225 former football players, 75 controls, and 50 AD.

Participants will complete a single visit, including clinical exams, social determinants of health (SDOH) measures, MRI, blood draw, and tau PET, at 1 of 5 P30 AD Research Centers (ADRCs): Boston University (BU), University of California, San Francisco (UCSF), Arizona/Banner Alzheimer's Institute (BAI), University of Florida (1Florida), and University of Texas Health Science Center at San Antonio (South Texas).

The Retention Cohort will have 18F-Flortaucipir (18F-AV-1451, Tauvid (FTP)) PET to study its longitudinal value. The Expansion Cohort will have 18F-MK-6240 (MK-6240) PET to build on the investigators' preliminary data. A subset of the Retention Cohort (n=20) will have FTP and MK-6240 for tracer comparison. Blood will be analyzed for 6 p-tau epitopes, Aβ40/42, neuroinflammation, and WM injury. DIAGNOSE-I participants were asked to pledge to donate their brain.

This study will permit continued brain donation and clinical-pathological validation studies. Results will provide insight into the detection, diagnosis, and prognosis for people living with CTE, paving the way for treatment trials.

Inclusion Criteria:

1. Former college or professional football players (n=225) will include those retained from DIAGNOSE-I (n=150) and newly recruited (n=75). Criteria will include

   1. Former college football players must have played more than 6 years of football including 3 or more years at the college level. They must not have played organized football or other contact sports following college.
   2. Former professional football players must have played 12 or more years of total football including 3 or more years in college and at least 1 season professionally where they played in at least 1 game (as corroborated by https://www.pro-football-reference.com)

2. Control (n=75) will include those retained from DIAGNOSE-I (n=50) and newly recruited (n=25). Inclusion criteria for control include:

   1. Asymptomatic at screening
   2. Never been diagnosed with, or treated for, any of the following: depression, manic-depressive or bipolar disorder, anxiety, or other psychiatric or mental health problems
   3. No known traumatic brain injury (TBI) and/or moderate/severe concussion (severity determined on phone screening).
   4. No history of RHI including participation in contact and collision sports (i.e., football, ice hockey, rugby, soccer, lacrosse, wrestling, boxing gymnastics, martial arts, kickboxing), or military service (refers to active combat experience or combat training involving exposure to IED blasts or combatant stick training). These are examples and there might be instances of other RHI sources that could be exclusionary as determined by investigators.
   5. BMI of 24 or higher to be similar in body habitus to former professional and college football players.
   6. Must have at least 2 years of post-secondary education at a 4-year accredited college or university or have an associate's degree if they did not attend a 4-year accredited college or university.

3. AD-CI (n=50) will come from the local ADRCs where Clinical Dementia Rating (CDR) and amyloid biomarker status are known for most participants being followed annually. Inclusion criteria include:

   1. CDR of 0.5-1.0 within 6-12 months of study visit
   2. Positive amyloid PET or CSF AD biomarker within 12 months of study visit (done as part of their participation in the local ADRCs and/or clinical care).
   3. No history of RHI including participation in contact and collision sports (i.e., football, ice hockey, rugby, soccer, lacrosse, wrestling, boxing gymnastics, martial arts, kickboxing), or military service (refers to active combat experience or combat training involving exposure to IED blasts or combatant stick training). These are examples and there might be instances of other RHI sources that could be exclusionary as determined by investigators.
   4. BMI of 24 or higher to be similar in body habitus to former professional and college football players.
   5. If possible, baseline visit should be conducted before the initiation of anti-amyloid monoclonal antibody treatments or therapeutic trials targeting amyloid; however, will allow participants that recently started treatment. Baseline must be completed within 3-months of treatment initiation.
   6. No prior therapeutic trials targeting amyloid or tau prior to initiating study

4. Tracer comparison sub-sample: 20 professional football players from DIAGNOSE-I will have FTP and MK-6240 tau PET (done at the same site, scanner). The 20 participants at highest risk for having CTE pathology will be selected based on the following:

   1. 60+ years old to increase likelihood of meaningful pathology
   2. Must have played professionally
   3. Participant was amyloid PET negative at the baseline DIAGNOSE-I evaluation to rule out potential confounding from AD

To further enrich the sample, we will also use the following to guide selection of participants:

1. Must have TES-Cognitive Impairment (from baseline DIAGNOSE-I consensus conference) and participant QDRS >=2 (consistent with CDR diagnosis of mild cognitive impairment ) with a prioritization of individuals who have a QDRS >= 6.0 (equivalent to a CDR=1 or mild dementia) AND/OR
2. Must have evidence of tau (FTP) PET uptake from their baseline DxCTE-1 scan, as determined by Dr. Rabinovici's lab.

For newly recruited, those individuals who meet any of the following criteria are not eligible for enrollment as study participants.

Exclusion Criteria:

1. Unstable medical conditions that confound our ability to diagnose neurodegenerative disease accurately (e.g., active cancer with recent chemotherapy or radiation treatments, unstable heart disease particularly if oxygen dependent, kidney disease requiring dialysis)
2. Neurological conditions that confound our ability to diagnose neurodegenerative disease accurately (e.g., acute clinical stroke, severe traumatic brain injury with ongoing symptoms [post-football for football players])
3. Serious mental Illnesses that confound our ability to diagnose neurodegenerative disease accurately (e.g., active psychosis)
4. Inability to fulfill research protocol requirements due to physical, visual, or hearing impairment
5. English is not primary language
6. Unable to travel to 1 of the five study sites to participate
7. Lack of an adequate informant to be available in-person or by telephone for each annual research evaluation. Informant must be 18 years or older, speaks/visits with the participant at least 1X per week for a minimum of 6 months, agree to complete questionnaires about participant, able to travel to study visit if determined it is needed, and is knowledgeable regarding changes to the participant's cognition, mood and behavior
8. Lack of capacity to provide informed consent (IC) or does not have a legal authorized representative or guardian who can provide surrogate IC
9. Unwilling to attempt to have an MRI
10. If willing to complete MRI, contraindications to 3T MRI (e.g., pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.)

For all participants (retention and expansion), the following will be exclusionary for participating in PET scan activities:

1. Medical radiation exposure will be assessed by the study physician. If the candidate participant has had more than one research nuclear medicine study in the prior 12 months, study inclusion will require joint PI approval.
2. Investigational agents are prohibited 30 days prior to entry
3. Initiated medication (via participation in clinicaltrials) against tau proteins prior to their baseline study visit
4. History of a relevant severe drug allergy or hypersensitivity
5. Inability to urinate
6. Any serious illness that, in the study physician's opinion could interfere with the completion of the PET scans or post a potential safety risk

Former National Football League Players, Former Varsity Level College Football Players, Healthy Controls, Alzheimer's Disease with cognitive impairment.