A Study of Donanemab, RG6289, or the Combination of Donanemab and RG6289 in Presenilin 1 (PSEN1) E280A Mutation Carriers for the Treatment of Autosomal-Dominant Alzheimer's Disease

Inclusion Criteria: * Membership in PSEN1 E280A mutation carrier kindred. * Agrees to conditions of, and is willing to undergo, genetic testing (e.g., APOE, PSEN1 E280A, and other genetic testing allowed by local regulatory requirements). * Males and females aged 25-65 inclusive. * Must meet one of the following criteria: a. Determined to be cognitively normal as defined by an MMSE of ≥24 for participants with less than 9 years of education or MMSE of ≥26 for participants with 9 or more years of education. b. Or determined to have MCI with amnestic presentation as defined by: 1\. Cognitive concern in the judgment of the Investigator, based in part on the: i. CERAD Word List: Recall \<3 for participants with less than 9 years of education. ii. CERAD Word List: Recall \<5 for participants with 9 or more years of education. iii. Preservation of independence in functional activities in the judgment of the Investigator. c. Or determined to have mild AD dementia as defined by: 1. Meets the 2011 National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria for probable AD, and 2. Has a CDR-GS of 0.5 or 1, with the memory box score ≥0.5. Exclusion Criteria: * Significant medical, psychiatric, or other neurological condition or disorder documented by history, physical, neurological, laboratory examinations that would place the participant at undue risk in the Investigator's judgment or impact the interpretation of efficacy. * History of stroke. * History of severe, clinically significant (persistent neurological deficit or structural brain damage) CNS trauma (e.g., cerebral contusion). * Current presence of bipolar disorder or other clinically significant major psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) or symptom (e.g., hallucinations, agitation, paranoia) that could affect the participant's ability to complete evaluations. * History of seizures (excluding febrile seizures of childhood, or other isolated seizure episodes that were not due to epilepsy in the judgment of the Investigator, and required at most time-limited anticonvulsant treatment, and which occurred more than 7 years prior to the screening visit). * Women who are pregnant or intend to become pregnant during the conduct of this study. * Women who are nursing infants or intend to nurse infants during the conduct of this study. * Known (or prior) hypersensitivity to donanemab, RG6289, or any excipients of RG6289. * History of or active inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis). * Medical history of malignancy in the past 5 years, with the following exceptions: 1. If considered to be cured or, 2. If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of the Investigator, is not likely to require treatment in the ensuing 5 years and, 3. For prostate cancer or basal cell carcinoma, no significant progression over the previous 2 years. 4. In-situ cervix carcinoma that has been successfully treated. 5. Fully excised non-melanoma skin cancers or in-situ melanoma. * Any surgery or hospitalization during the 4 weeks prior to screening or pre-planned/scheduled during the study period that, in the opinion of the Investigator, may compromise eligibility to the study. The Medical Monitor is available to the Investigator to advise and answer any questions. * Inability to tolerate MRI procedures or contraindication to MRI, including, but not limited to, presence of pacemakers not compatible with MRI, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an MRI scan, or any other clinical history or examination finding that, in the judgment of the Investigator, would pose a potential hazard in combination with MRI * Prior participation in an anti-amyloid therapy trial is allowed if it has been at least 1 year since the last study dose. * Any other investigational treatment, including anti-amyloid small molecules (i.e., BACEi and GSIs, other GSMs) within five half-lives or 16 weeks prior to screening (calculated from the last safety follow-up visit of the previous study), whichever is longer. Note: The participant may be eligible for this study if it can be documented that he/she was randomized to placebo