R21 Roche: 3-Way Tau Tracers in AD

This is an open label study to compare three new generation TAU radioligands, 18F-RO948 (formerly known as 18F-6958948), 18F-MK6240, and \[18F\]GTP1for imaging of taupathy and demonstrate their absence of off-target binding in patients with Alzheimer disease (AD) and older healthy controls (OC). The study will directly compare AD and OC with these three next-generation TAU radioligands and compare each of them with historical data of the current most widely used first generation radioligand, 18F-AV1451. Upto38 (30 AD (Amyloid +)and 8 OC (Amyloid -), matched for age and sex with A+ subjects) male and female subjects aged 50-100 will be enrolled in this study protocol: up to 8 for Cohort 1, up to 8 for Cohort 2, and up to 22 for Cohort 3. The study consists of three cohorts: Cohort 1: Up to8 AD subjects (A+; CDR 0.5 and 1)will receive two PET scans in random order, with receiving either18F-RO948 or18F-MK6240 at the first scan. A third scan with 18F-GTP1is possible, depending on timing and radiotracer availability Cohort 2:Up to8 OC (A-; CDR=0)subjects will receive two PET scans in random order, with receiving either18F-RO948or 18F-MK6240 at the first scan. A third scan with 18F-GTP1is possible, depending on timing and radiotracer availability Cohort 3:Up to 22 (A+; CDR = 0, .5 and 1) subjects will receive three PET scans in random order, with receiving 18F-RO94818F-MK6240 or18F-GTP1at the first scan. Efforts will be made to include about 1/3 CDR = 0, 1/3 CDR .5, and 1/3 CDR 1 in Cohort 3.


Eligibility Criteria:
Inclusion Criteria:

* Male and female subjects 50 to 100 years of age: Female subjects must be either surgically sterile or post-menopausal for at least 1 year or, Women of child bearing potential must commit to use a barrier contraception method for the duration of the study in addition to either an intra uterine device or hormonal contraception started at least 1 month prior to the first dose of radiotracer and until follow-up. Male subjects and their partners of childbearing potential must agree to use an effective method of contraception and will not donate sperm during the study. Barrier method must include use of a spermicide.
* Subjects who sign an IRB approved informed consent prior to any study procedures. Subjects deemed incapable of informed consent must have informed consent provided by a legally authorized representative. For AD subjects, capacity for consent will be determined using the Alzheimer Disease Research Center's questions
* Subjects who in the opinion of the investigator based on medical history and physical exam can tolerate the PET scan procedures,and can safely tolerate tracer administration and the scanning procedures.
* If subjects are on any concomitant medication, the indication and dosage of these medicines should be stable for at least 4 weeks prior to study start with the expectation that no relevant changes in use or dose will occur throughout the trial.
* Body mass index BMI between 18 and 32 kg per m2, Body weight less than 300 pounds
* Older Controls must have normal cognitive function, including a normal CDR = 0 as judged by the investigator for OC.
* AD subjects must have a diagnosis of probable AD, according to the National Institute of Neurological and Communicative Disorders and Stroke Alzheime rDisease and Related Disorders Association criteria with a CDR \>0 to 1 and positive CSF or amyloid PET Scan.
* AD subjects must have a reliable person able to accompany the subject to all visits and answer questions about the subject.
* AD subjects must have a positive florbetapiro, amyloid blood-based biomarkers(BB BM), or amyloid-beta and tau CSF levels, which in the opinion of the principal investigator is consistent with a diagnosis of AD.

Exclusion Criteria:

* History or presence of a neurological diagnosis other than AD that may influence the outcome or analysis of the scan results; examples include but are not limited to stroke, traumatic brain injury, space occupying lesions, non-Alzheimer tauopathies, and Parkinson's disease.
* Subjects with a medical history that includes known autosomal dominant AD mutations in amyloid precursor protein APP or presenilin PS1, PS2 or mutations in genes that cause other types of autosomal dominant familial dementia, e.g., tau MAPT
* History or presence of any clinically relevant hematological, hepatic, respiratory, cardiovascular, renal, metabolic, endocrine, or CNS disease or other medical conditions that are not well controlled, may put the subject at risk, could interfere with the objectives of the study, or make the subject unsuitable for participation in the study for any other reason in the opinion of the principal investigator.
* Clinically relevant pathological findings in physical examination, ECG, or laboratory values at the screening assessment that could interfere with the objectives of the study.
* Known history of clinically significant infectious disease including AIDS or serological indication of acute or chronic hepatitis B or C or HIV infection.
* Women of childbearing potential must not be pregnant, or nursing and serum human chorionic gonadotropin HCG must be negative at the time of Screening Visit, and urine HCG must be negative on all subsequent visits.
* Loss or donation of more than 450 mL blood in the 4 months before screening or donation of plasma within 14days of screening or history of bleeding disorder or presence of anticoagulants
* Current symptoms of allergy and or severe allergy to drugs in medical history.
* History of drug or alcohol abuse or positive result from urine screen for drugs of abuse. AD subjects on prescribed narcotics medications will not be excluded if urine drug screen is positive for the documented narcotic drugs.
* Have received an investigational medication within the last 3 months or 5 elimination half-life, whichever is longer, prior to administration of the radiotracer.
* Has had or is planning to have exposure to ionizing radiation that in combination with the study related tracer administrations and scanning procedures would result in a cumulative exposure that exceeds 5.0 rem over a 12-month period of time.
* Contraindications of previous or study screening MRI
* History of, or suffers from, claustrophobia or feels that he or she will be unable to lie still on their back in the MRI or PET scanner.
* Subjects with hearing impairment, illiteracy, non-English speakers, or English as a second-language (since there is no direct medical benefit to participants).
* Subjects who have not completed at least 2 COVID-19 vaccination injections.16. Subjects who will not wear mask over nose and mouth during all visits except