A Study to Assess the Effects of ACI-24.060 in Alzheimer's Disease and in Down Syndrome (ABATE Study)

Inclusion Criteria:

Study Part 1

1. Age ≥50 and ≤85 years at screening.

2. Diagnosis of prodromal AD: MCI due to AD according to National Institute on AgingAlzheimer's Association (NIA-AA) criteria.

3. PET scan at screening consistent with the presence of amyloid pathology.

4. Clinical Dementia Rating (CDR)-Global Score of 0.5.

5. Subjects either not taking any marketed treatment for AD or receiving a stable doseof an acetylcholinesterase inhibitor (ACHEI) and/or memantine for at least 2 monthsprior to baseline.

Study Part 2

1. Age ≥35 and ≤50 years at screening (subjects with DS with age ≥35 and ≤39 years maybe considered on the condition that there is prior evidence of amyloid resultscompatible with AD pathology at PET-scan and/or in biofluids).

2. Male or female subjects with DS with a cytogenetic diagnosis being either trisomy 21or complete unbalanced translocation of the chromosome 21.

3. PET scan at screening consistent with the presence of amyloid pathology.

4. Mild to moderate intellectual disability as per Diagnostic and Statistical Manual ofMental Disorders (DSM-5) classification.

5. Subjects must have a study partner who has direct and regular contact, at least 10hours per week, with the subject and who is able to provide reliable answers toquestions related to the subject, according to the study investigator.

Exclusion Criteria:

1. Any unstable and/or clinically significant medical condition likely to hamper theevaluation of safety and/or efficacy of the study vaccine (eg, moderate and/orsevere untreated obstructive sleep apnea, clinically significant reduction in serumB12 or folate levels, clinically significant abnormalities of thyroid function,stroke, or other cerebrovascular conditions), as per investigator's judgement.

2. DSM-5 criteria for drug or alcohol abuse or dependence currently met within the past 5 years.

3. History or presence of uncontrolled seizures. If history of seizures, they must bewell controlled with no occurrence of seizures in the 2 years before studyscreening. The use of antiepileptic medications is permitted.

4. Concomitant or past history psychiatric or neurologic disorder other than thoseconsidered to be related to AD (eg, head injury with loss of consciousness,symptomatic stroke, Parkinson's disease, severe carotid occlusive disease, transientischemic attacks [TIAs], hemorrhagic and/or non-hemorrhagic stroke).

5. History of meningitis or meningoencephalitis.

6. History of moderate or severe traumatic brain injury.

7. History of inflammatory neurological disorders.

8. History or presence of immunological or inflammatory conditions, includingneurological disorders, judged to be clinically significant by the investigator.

9. History of severe allergic reaction (eg, anaphylaxis) including, but not limited tosevere allergic reaction to previous vaccines, foods, and/or medications.

10. Significant risk of suicide, defined using the C-SSRS as the subject answering "yes"to suicidal ideation questions 4 or 5 or answering "yes" to suicidal behavior withinthe past 12 months.

11. MRI scan at screening showing a single area of cerebral vasogenic edema, superficialsiderosis, or evidence of a previous macro-hemorrhage or showing more than 4cerebral microhemorrhages (regardless of their anatomical location or diagnosticcharacterization as "possible" or "definite"). Evidence of space occupying lesionsother than benign meningioma of less than 1 cm diameter, more than 2 lacunarinfarcts, or 1 single infarct larger than 1 cm in diameter. Screening MRI scanshowing structural evidence of alternative pathology not consistent with AD and isconsidered to be at the origin of subject's symptoms.

12. Deviations from normal values for hematologic parameters, liver function tests, andother biochemical measures, judged to be clinically significant by the investigator.

13. Subjects with a positive Human Immunodeficiency Virus (HIV-1 and 2) test atscreening.

14. Subjects with clinical or laboratory evidence of active hepatitis B or C atscreening (eg, HBV or HCV antigens).

15. Subjects with positive syphilis serology consistent with active syphilis atscreening.

16. MRI examination cannot be done for any reason, including but not limited to metalimplants contraindicated for MRI and/or severe claustrophobia.

17. Any contraindication for PET scan imaging.

18. Any contraindication to lumbar puncture in subjects undergoing this procedure (note:lumbar puncture is optional in subjects with DS).

19. Previous treatment with ACI-24 or any other active immunotherapy against AD at anytime in the past unless there is firm evidence that the subject received placeboonly and the placebo formulation is not expected to induce any specific immuneresponse.

20. Previous treatment with any investigational and/or marketed passive immunotherapyagainst AD within 6 months before screening or 5 half-lives, whichever is longer,unless there is firm evidence that the subject received placebo only.

21. Ongoing treatment with any approved anti-amyloid passive immunotherapy forAlzheimer's disease.

22. Use of acetylcholinesterase inhibitor or glutamatergic drugs (eg, memantine,topiramate, lamotrigine) if not on stable dose for at least 2 months beforescreening.

23. Any vaccine received within the 2 weeks before screening, including ananti-influenza or anti-COVID 19 vaccine received within 4 weeks beforerandomization.

24. Subjects with treated hypothyroidism not on a stable dose of replacement medicationfor at least 2 months before screening and having clinically significant abnormalserum T4 and/or thyroid stimulating hormone at screening.

25. Subjects undergoing lumbar puncture and being treated with any anticoagulants orantiplatelet drugs, except aspirin at doses of 100 mg daily or lower.

26. Use of antidepressants (other than selective serotonin reuptakeinhibitors/serotonin-norepinephrine reuptake inhibitors at stable dose); typicalantipsychotics; γ-aminobutyric acid agonists (eg, gabapentin); or stimulants (eg,methylphenidate, modafinil). Stable doses of atypical antipsychotics orbenzodiazepines are only allowed if this is not considered to influence the safetyand the efficacy of the study vaccine according to the site investigator and thesponsor medical monitor.

27. Chronic use of opioid analgesics. A limited treatment duration for acute conditionsuntil 24 hours before cognitive assessment is allowed.

28. Current use of immunosuppressant or immunomodulating drugs or their use within the 6months before study screening. Current use of oral steroids or their use within the 3 months before study screening. Additional Exclusion Criteria in Study Part 2 The following are exclusion criteria at the time of randomization but will not beconsidered as exclusionary after treatment assignment:

29. Clinical diagnosis of AD dementia in DS as per International Classification ofDiseases 10 (ICD-10).

30. DSQIID >20.

31. Intelligence quotient score <40 (KBIT-2).