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

Prior treatment

• 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.
• Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.
• 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.
• Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.

Other illness

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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
• History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.
• 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.
• A centrally read MRI demonstrating presence of ARIA-E, \> 4 cerebral microhemorrhages, any superficial siderosis, any macrohemorrhage, or severe white matter disease at screening.

Lab values

• 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

Other

• Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.
• Hepatic or renal abnormalities that in the opinion of the investigator would interfere with participation in or analysis of the trial.
• 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.
• Morbid obesity with significant comorbidities or that would preclude MRI imaging.
• Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban). Daily use of low dose (\< 325 mg) aspirin is not exclusionary.
• Lack of sufficient venous access.
• Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
• Participants with the "Dutch" APP E693Q mutation.
• Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility
• Exposure to lecanemab, donanemab, or other investigational amyloid lowering agents within the past 6 months or five half-lives from screening, whichever is longer.
• 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
• 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

• Provide written informed consent, signed, and dated by the participant and study partner, or by the participant's legally authorized representative if applicable, according to local regulations for the ICF and, if applicable, country specific ICFs.
• Participant is at least 18 years old.
• People of childbearing potential
  • Must have a negative serum pregnancy test at screening (V1)
  • Must agree not to try to become pregnant from the time of signed ICF until twenty (20) weeks after the last dose of any study drug.
  • Must agree not to breastfeed from the time of signed ICF until twenty (20) weeks after the last dose of any study drug.
  • If partner is not sterilized, must agree to use highly effective contraceptive measures, methods that can achieve a failure rate of less than 1% per year when used consistently and correctly from screening (V1) until twenty (20) weeks after last dose of any study drug.
  • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal ii. progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable iii. intra-uterine device (IUD) iv. intrauterine hormone-releasing systems (IUS) v. bilateral tubal occlusion vi. vasectomized partner (only when this is the only partner) vii. true sexual abstinence when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\], declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of contraception)
• Mutation Status:
  • Participant is a carrier of a mutation in an APP, PSEN1, or PSEN2 gene that is associated with DIAD or does not know their mutation status and there is a mutation in their family pedigree that puts them at a direct risk of inheriting the known mutation;
  • Participant is -25 to -11 years from predicted age of cognitive symptom onset based on their mutation type or family pedigree Note: If the at-risk parent is deemed a non-carrier through confirmed genetic testing at any time during the study, the participant will be withdrawn.
• Cognitive status of participant is normal (CDR-SB 0).
• Fluency in DIAN-TU trial approved language and evidence of adequate premorbid intellectual functioning. Participants must be fluent in languages for which cognitive and clinical measures have been translated and validated for use in the DIAN-TU. Fluency is generally defined as daily or frequent functional use of a language generally from birth or a young age. In cultures where multiple languages are spoken or for participants who are multilingual, determination as to whether a participant's level of fluency in languages for which clinical and cognitive measures are available meets qualification for the study should be made by the site PI.
• Adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
• Receiving stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to baseline visit (V2) with the exceptions of medications taken for episodic conditions (e.g., migraine abortive therapy, antibiotics, and other medications for upper respiratory and gastrointestinal ailments).
• Has a study partner who in the PI's judgment can provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits that require study partner input for scale completion, and who signs the necessary ICF, if applicable.
• Agrees not to donate blood or blood products for transfusion from the time of Screening (V1) for a study drug arm, for the duration of the study, and for 5 half lives after the final dose of study drug.
• In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.
• Willing to complete all study-related testing, evaluations, and procedures.