The study will be conducted in 2 blinded parts (Part 1 and Part 2). In Part 1, study participants who are mutation carriers will receive active donanemab and non-mutation carriers will receive placebo-donanemab for up to 18 months (76 weeks), with a minimum treatment period of 9 months. Amyloid PET scans will be conducted at screening, 9, and 18 months in Part 1. Participants who are at or below 11 CL at screening or reach complete amyloid plaque clearance as measured by florbetapir F18 PET (defined as ≤11 CL) at 9 months will initiate Part 2. Participants who are ≤11 CL at screening may delay their entry into Part 2 for up to 6 months at the discretion of the Investigator. All remaining participants will start Part 2 after completing 18 months (76 weeks) in Part 1 independent of amyloid results. Non-carriers will receive placebo in both Parts 1 and 2.

In Part 2, study participants who are mutation carriers will be randomized 1:1:1:1 in a full factorial design to receive either RG6289 + placebo-donanemab (RG6289 alone group), donanemab + placebo-RG6289 (donanemab alone group), the combination of RG6289 and donanemab (combination group), or placebo-RG6289 and placebo-donanemab (placebo group). All non-carriers will be assigned to the placebo group. CDR-GS at the end of Part 1 and the amyloid level using the last completed amyloid PET scan in Part 1 will be used for stratification. All study participants will participate in a double-dummy design for the duration of Part 2 receiving both an intravenous (IV) infusion at the required interval for the donanemab or matching placebo as well as a daily oral treatment of RG6289 or matching placebo.

An exploratory outcome of Part 1 is a comparison of the amyloid clearance between this ADAD cohort and historical controls using propensity score matching. The primary outcome in Part 2 is change from the start of Part 2 through the end of Part 2 in brain amyloid load in PSEN1 E280A mutation carriers as measured by amyloid PET imaging. Other endpoints will include fluid and imaging biomarkers and measures of cognition and functioning. The maximum study duration for any individual participant will be 3 years, not including the screening or follow-up periods

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