Inclusion Criteria:
Participants with MCI enrolling in the trial must meet all the following criteria:
1\. Diagnosis of MCI due to suspected CTE, and with age \>45 years, or AD, and with age \>50 years at the time of the Screening Visit (see Inclusion Criteria 9) 2. Participants must have a trial partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with trial procedures 3. Participants, or in the Investigator's opinion, participant's legally acceptable representative, and a trial partner provide informed consent as required by IRB 4. Female participants must be either surgically sterilized or post-menopausal, defined as at least 1 year without menses as reported by the participant or have a negative serum pregnancy test 5. Willing to comply with trial procedures 6. Willing to communicate with trial personnel 7. Willing to undergo longitudinal follow-up visits at 1 and 2 years after the Imaging Visit (only for Part B) 8. CDR global score of 0.5 9. Participants with MCI due to suspected CTE must meet the diagnostic standards of possible traumatic encephalopathy syndrome as all the following criteria:
a. All of the following features are required: i) Persistence of symptoms for longer than 2 years; no other neurologic disorder that is more likely to account for all the clinical features; history of head trauma exposure, progressive course; and at least 1 supportive feature ii) History of head trauma exposure, typically associated with history of concussion, although may be limited to subconcussive trauma iii) Head trauma exposure is repetitive in nature iv) Demonstrated progressive course v) Delayed symptom onset vi) Self-report or observer report of cognitive dysfunction, confirmed with objective cognitive decline documented by results of formal neuropsychological testing. Cognitive decline typically affects more than 1 domain (neuropsychological tests, visuospatial, memory, and language) b. Only 1 of the following supportive features is required: i) Emotional dysregulation: including depression, anxiety, agitation, aggression, paranoid ideation, deterioration of interpersonal relationships, or suicidality ii) Behavioral change: including violence, poor impulse control, socially inappropriate behavior, avolition, apathy, change in personality, or comorbid substance abuse iii) Motor disturbance: including bradykinesia, tremor, rigidity, gait instability, dysarthria, dysphagia, or ataxia 9. Participants with MCI due to suspected AD must meet all the following criteria:
1. Diagnosis of MCI due to suspected AD according to workgroups of the Diagnostic Guidelines of the National Institute on Aging and Alzheimer's Association (NIA-AA)
2. Documented evidence of memory decline with gradual onset and slow progression for at least 1 year. If medically documented evidence is not available, an informant may provide confirmatory evidence
3. An MMSE-2 score of 22 to 30, inclusive, at the Screening Visit
4. Biomarker positive based on predefined plasma p-tau cutoff
5. Modified Hachinski Ischemic Score of ˂4 at the Screening Visit
6. Cognitive deficits do not occur exclusively in the context of delirium
7. Cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia), or other medical condition (e.g., hypothyroidism)
8. Treated with a stable dosage regimen of acetylcholinesterase inhibitors (AchEI) and/or memantine for at least 4 months prior to the Screening Visit. Participants should be expected to remain on a stable dosage regimen of these medications for the duration of the trial. Participants who are not being treated with AchEI and/or memantine at the time of the Screening Visit due to contraindications or previous failed treatment with these medications are also eligible for inclusion, if it is expected that participants will not be treated with these medications for the duration of the trial.
Inclusion Criteria for Healthy Volunteers (Part A):
1. Medically healthy, at the age within 3 years of any participants with MCI due to suspected CTE or AD in Part A, and with no clinically relevant findings on physical examination or laboratory results
2. Participants must have a trial partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with trial procedures
3. No cognitive impairment based upon cognitive assessment and as evaluated by the Investigator
4. No first-degree family history of early-onset AD or other neurodegenerative diseases (prior to age 65)
5. An MMSE-2 score ≥27.
Exclusion Criteria:
1. Pregnant or breastfeeding
2. Unable to remain still for duration of imaging procedure or have an inability to tolerate neuropsychological, clinical, or PET scan studies (e.g., head tremor that may cause head motion artifact, uncontrollable psychosis, acute suicidality)
3. History of stroke, transient ischemic attack, seizures, or other condition of the head or neck within 12 months prior to the Screening Visit that, in the Investigator's opinion, might affect circulation to the head or image interpretation
4. Preexisting major neurologic or other physical illness that could confound results (e.g., multiple sclerosis, diabetes, cancer)
5. Psychiatric disorder such as mania, schizophrenia, anxiety, or depression (Geriatric Depression Scale ≥10), which in the Investigator's opinion, might interfere with completing trial procedures
6. Condition or personal circumstance that, in the Investigator's opinion, might interfere with the collection of complete, good quality data
7. History of significant prescription drug, non-prescription drug, or alcohol abuse, including but not limited to marijuana, cocaine, heroin, or derivatives
8. Previously received F-18 FNT at any time, or any other investigational product (IP) within the past 30 days
9. History of allergic reactions to albumin, or severe anemia or cardiac failure in which case the use of albumin would be medically contraindicated
10. Unstable cardiac disease or uncontrolled hypertension (systolic blood pressure \[BP\] \>170 mmHg or diastolic BP \>100 mmHg)
11. Any use of benzodiazepines within 24 hours prior to all trial visits
12. Plan to take ibuprofen or naproxen within 5 days before the PET scan
13. Received any radioactive drugs or scans within the previous month or 10 half-lives of the drug, whichever is longer, or participated in imaging or other clinical research studies that might confound trial results
14. Implants (e.g., implanted cardiac pacemakers or defibrillators, insulin pumps, metallic ocular foreign body, implanted neural stimulators, CNS aneurysm clips, or other medical implants that have not been certified for MRI), a history of claustrophobia in MRI, or any contraindication for MRI
15. History of any CT/MRI finding such as mass lesions or brain infection that are unrelated to the trial
16. Participated in another clinical trial for an investigational agent (other than monoclonal antibody) and taken at least one dose of trial drug, unless confirmed as placebo, within 90 days prior to the Screening Visit. The end of a previous investigational trial is defined as the date of the last dose of trial drug
17. Monoclonal antibody treatment within the previous 180 days prior to the Screening Visit
18. Plan to receive treatment of aducanumab, lecanemab, or other potentially approved treatment options for Early AD during the trial.
