This is a Phase 1b, multicenter, randomized, placebo-controlled, double-blind, multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL628 in participants with early Alzheimer's disease (AD), defined as mild cognitive impairment, or mild AD with biomarker evidence of amyloid positivity.

Note: In the Netherlands, this study includes an open-label extension.

Key Inclusion Criteria:

• BMI of ≥18 to < 32 kg/m2 and body weight of ≥45 kg

• Have a diagnosis of probable AD dementia based on NIA AA 2011 criteria, including amnestic or nonamnestic presentation at screening

• Have supportive evidence of AD pathology via historical records or laboratory testing at screening for amyloid positivity

• Have AD severity defined as the following at screening:

  • A Clinical Dementia Rating global score of 0.5 or 1
  • A Mini-Mental State Examination score of 20 to 30 (inclusive)

Key Exclusion Criteria:

• Have clinically significant neurological or cognitive disorders affecting the CNS other than AD, as determined by the investigator

• Have clinically significant psychiatric conditions

• Have any history of unstable or poorly controlled endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, hematological, or other significant medical condition that, in the opinion of the investigator, may interfere with the completion or interpretation of study assessment

• Have had a malignancy within 5 years before screening, except fully resected basal cell carcinoma or other malignancies (such as prostate cancer) at low risk of recurrence, depending on investigator and medical monitor agreement

• Have had previous anti amyloid or anti tau immunotherapy (including active immunization)

  • Note: ADAD participants who have participated in previous passive anti-amyloid immunotherapy > 6 months previously will be allowed, contingent on investigator and Sponsor agreement

• Have had previous exposure to gene therapy

Sponsor staff directly interacting with the site (clinical operations and medical monitor) will be blinded but may be unblinded if necessary to ensure participant safety.