A Study to Assess Safety and Target Engagement of E2814 in Participants With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease

An Open-Label Phase 1b/2 Study to Assess Safety and Target Engagement of E2814 in Subjects With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease

The primary objective of the study is to assess the safety and tolerability of intravenous (IV) infusions of E2814 in participants with dominantly inherited Alzheimer's disease (DIAD), and to evaluate target engagement (TE) of E2814 on microtubule binding region (MTBR)-tau species in cerebrospinal fluid (CSF) in participants with DIAD.

Inclusion Criteria:

1. Male or female, age 18 to 80 years at the time of informed consent
2. Individuals who are confirmed to be mutation positive for presenilin 1 (PSEN1), amyloid precursor protein (APP), or presenilin 2 (PSEN2) gene that is associated with DIAD
3. Clinical Dementia Rating - Sum of Boxes (CDR-SB) score 5 to 12 at Screening
4. Able to undergo magnetic resonance imaging (MRI), lumbar puncture (LP), PET, and complete all study-related testing and evaluations
5. Has a study partner who in the investigator's judgment is able to provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion

Exclusion Criteria:

1. Clinically significant illness that required medical treatment within 8 weeks before the 1st dose or a clinically significant infection that required medical treatment within 4 weeks before 1st dose

2. Females who are breastfeeding or pregnant at Screening or Baseline

3. Females of childbearing potential who:

   Within 3 months before screening, did not use a highly effective method of contraception

4. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's Alzheimer's disease (AD)

5. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening

6. History of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral haemorrhage (including atrial fibrillation and anticoagulation). Low dose aspirin (less than or equal to [<=] 325 milligram [mg] daily) is not exclusionary

7. Any current psychiatric diagnosis or symptoms, (example, hallucinations, major depression, or delusions) that could interfere with study procedures in the participant

8. Geriatric Depression Scale (GDS) score greater than or equal to 8 at Screening

9. Contraindications to MRI scanning, including but not limited to pacemaker/cardiac defibrillator, neurostimulators, ferromagnetic metal implants (example, in skull and cardiac devices other than those approved as safe for use in MRI scanners)

10. Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD

11. Other significant pathological findings on brain MRI at Screening

12. Hypersensitivity to E2814 or any of the excipients, or to any monoclonal antibody (mAb) treatment

13. Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study

14. With a bleeding disorder of current chronic use of anticoagulants (example, warfarin, dabigatran, rivaroxaban or apixaban) or of clopidogrel is exclusionary. Limited (occasional or isolated) use of anticoagulants/antiplatelet compounds in cases such as surgical procedures

15. Have thyroid stimulating hormone outside of normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator

16. Hemoglobin A1c (HgbA1c) greater than (>) 8 percent (%) (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (including hypoglycemic episodes). Participants may be rescreened after 3 months to allow optimization of diabetic control

17. Abnormally low serum vitamin B12 levels for the testing laboratory

18. 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, or history of spirochete infection of the central nervous system (example, syphilis, Lyme, or borreliosis)

19. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the investigator require further investigation or treatment or which may interfere with study procedures or safety

20. Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participant, or localized breast cancer in female participants)

21. Answers "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for any suicidal behavior in lifetime

22. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening

23. Any other medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator could affect the participant's safety or interfere with the study assessments

24. Concurrent participation in a clinical study involving any anti-amyloid therapies (including any mAb therapies) within 6 months before Screening

25. Concurrent participation in a clinical study involving any anti-tau therapies

26. Participated in any other investigational medication or device study in the 3 months or 5 half-lives (whichever is longer) of the medication before Screening

27. Planned surgery which requires general anesthesia that would take place during the study

28. Visual or hearing impairment that would prevent the participant from performing psychometric tests accurately