A Study of a Potential Disease Modifying Treatment in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation

Exclusion Criteria

• •1. Significant neurologic disease (other than AD) or psychiatric disease that may currently or during the study affect cognition or the participant's ability to complete the study. This would include disorders such as: recent or severe head trauma causing cognitive change, seizure disorder, neurodegenerative disease other than DIAD, hydrocephalus, cerebral/spinal hematoma, inflammatory disease, CNS infection (e.g., encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes) or endocrine disorder; psychiatric disorders such as schizophrenia, schizoaffective disorder, bipolar disorder or major depression, or any other psychiatric condition/disorder which could significantly interfere with the participant's cooperative participation (e.g., prominent anxiety, agitation or behavioral problems). Disorders that are controlled medically or remote history of these disorders (e.g., history of febrile seizures in childhood) that are not likely to interfere with cognitive function and compliance with study procedures are not exclusionary.
• •2. At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months, current major depression (as defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition \[DSM-V\]), or increased suicide risk based on screening Columbia Suicide Severity Rating Scale (C-SSRS). Current stable mild depression or current use of antidepressant medications are not exclusionary.
• •3. History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral hemorrhage (including atrial fibrillation and anticoagulation, documented transient ischemic attack \[TIA\] in the last 12 months) that may be interfering with cognition or is likely to impact with the participant's ability to complete the study. Low dose aspirin (≤ 325 mg daily) is not exclusionary.
• •4. Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.
• •5. History of or Baseline (V2) visit brain MRI scan indicative of any other significant abnormality, definite microhemorrhages, evidence of a cerebral contusion, encephalomalacia, or aneurysms. Minor or clinically insignificant imaging findings are not exclusionary.
• •6. Presence of certain implanted medical devices, such as some pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body which would preclude MRI scan.
• •7. Cardiovascular complications such as uncontrolled hypertension, history of myocardial infarcts, heart failure, atrial fibrillation, long QT interval on ECG likely to interfere with participation in or analysis of the trial in the opinion of the investigator
• •8. Hepatic or renal abnormalities that in the opinion of the investigator would interfere with participation in or analysis of the trial.
• •9. History of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B infection within the past year, history of Hepatitis C infection which has not been adequately treated, history of spirochete infection (e.g., syphilis, Lyme) of the CNS or history of other infection with high risk for interfering with participation or interpretation of the study in the opinion of the investigator.
• •10. History of clinically significant multiple or severe drug allergies, significant atopy, or severe post-treatment hypersensitivity reactions (including but not limited to erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and/or exfoliative dermatitis) or sensitivity to study-drug specific PET imaging agents with a high risk for interfering with participation or interpretation of the study in the opinion of the investigator.
• •11. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within 90 days prior to Baseline (V2) visit (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
• •12. Current clinically significant abnormalities of thyroid function, or clinically significant deficiency in vitamin B12. Vitamin B12 less than the lower limits of normal with normal methylmalonic acid (MMA)/homocysteine is not deemed clinically significant, therefore not exclusionary.
• •13. Unstable or poorly controlled diabetes which the investigator believes may interfere with participation in or analysis of the study protocol. Participants may be rescreened after 3 months to allow optimization of diabetic control
• •14. Morbid obesity with significant comorbidities or that would preclude MRI imaging.
• •15. Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban). Daily use of low dose (\< 325 mg) aspirin is not exclusionary.
• •16. Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.
• •17. Received any other investigational pharmacological treatment within 3 months of Screening or 5 half-lives, whichever is longer.
• •Note: Use of approved treatments for AD and other medications may be permitted in this study.
• •18. Lack of sufficient venous access.
• •19. Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
• •20. History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.
• •21. Any other medical condition that could be expected to progress, recur, or change to such an extent that it could bias the assessment of the clinical or mental status of the participant to a significant degree or put the participant at special risk.
• •22. Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.
• •23. Participants with the "Dutch" APP E693Q mutation.
• •24. Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility
• •25. A centrally read MRI demonstrating presence of ARIA-E, \> 4 cerebral microhemorrhages, any superficial siderosis, any macrohemorrhage, or severe white matter disease at screening.
• •26. Exposure to lecanemab, donanemab, or other investigational amyloid lowering agents within the past 6 months or five half-lives from screening, whichever is longer.
• •Note: Use of approved treatments for AD and other medications may be permitted.
• •27. Investigator site personnel directly affiliated with this trial and/or their immediate families, defined as a spouse, parent, child, or sibling, whether biological or legally adopted
• •28. Lilly employees or employees of a third-party organization (TPO) involved in this study that requires exclusion of their employees or have study partners who are Lilly employees or are employees of TPOs involved in this study that require exclusion of their employees