Efficacy and Safety of GSK4527226 [AL101] in Participants With Early Alzheimer's Disease

Inclusion Criteria:

Participant must be in the Alzheimer's continuum as defined by the 2018 National Institute on Aging and Alzheimer's Association (NIAAA) Research Framework corresponding to the clinical categories of MCI due to AD and mild AD dementia.

Participant must have evidence of amyloid positivity either by positive positron emission tomography (PET) result (Amyloid PET scans must be read by a central imaging lab) or cerebrospinal fluid (CSF) amyloid beta (Aβ) test result indicative of amyloid positivity

• Participants must also meet the following criteria for clinical severity:

1. MMSE score of between 21 and 29 points

2. CDR-global score (GS) of 0.5 to 1.0.

3. CDR Memory Box score greater than or equal to (≥) 0.5.

4. Participants with objective impairment in episodic memory as indicated by atleast 1 standard deviation below age-adjusted mean in the Wechsler MemoryScale-IV Logical Memory II (WMS-IV LMII)

• If the participant is receiving symptomatic AD medications such as anAcetylcholinesterase inhibitor (AChEI) or memantine, the dosing regimen must havebeen stable for at least 12 weeks prior to screening and is not expected to changeduring study participation.

• If the participant is receiving other medications for AD related symptoms orassociated conditions, the dosing regimen must have been stable for at least 4 weeksprior to screening and not expected to change during study participation. Symptomsmust be considered adequately and stably controlled by the investigator, withoutmarked changes in medication anticipated for the duration of the study.

• Body weight ≥ 45 kilogram (kg) to less than or equal to (≤)120 kg with body massindex (BMI) between 17 and 34.9 kilogram per meter square (kg/m^2), inclusive.

• A female participant is eligible to participate if she is not pregnant orbreastfeeding, and if of child-bearing potential follows contraception requirementsoutlined in the protocol

• A male participant is eligible to participate if he follows contraceptionrequirements outlined in the protocol

• Willing and able to give informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF).

• Availability of an adult person who has frequent and sufficient contact with theparticipant is able to provide accurate information regarding the participant'scognitive and functional abilities, agrees to provide information at clinic visits,and signs the ICF of the study partner.

Exclusion Criteria:

Participant has evidence of any neurological condition other than AD that may contribute to cognitive impairment.

• History or presence of vascular disease that has the potential to affect cognitivefunction.

• History or presence of stroke within the past 1 year or recent transient ischemicattack within 180 days before screening.

• History of severe, clinically significant central nervous system (CNS) trauma.

• History or presence of intracranial tumor.

• Presence of ongoing infection(s) that may affect brain function, or history ofinfections that resulted in neurologic sequelae.

• History of primary psychiatric diagnosis that the investigator considers mayinterfere with study assessments.

Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, suicidal behaviour or has been assessed to be at risk of suicide, in the opinion of the investigator within 6 months before screening, at screening, or at the Baseline visit, or has been hospitalized or treated for suicidal behaviour in the past 2 years.

• Participant has history of alcohol and/or moderate to severe substance use disorderwithin the past 2 years

• Magnetic resonance imaging (MRI) evidence based on central read of:

1. >3 lacunar infarcts.

2. Stroke involving a major vascular territory, severe small vessel, or whitematter disease.

3. Any territorial /cortical/other infarct >1 cubic centimetre (cm^3).

4. White matter hyperintense lesions on the FLAIR sequence that correspond to anoverall Fazekas score of 3

5. >4 microhaemorrhages.

6. Any areas of superficial (leptomeningeal) hemosiderosis.

7. A single macro-hemorrhage greater than 10 millimetres (mm) at greatestdiameter.

8. Vasogenic edema.

9. Cerebral contusion, encephalomalacia, aneurysms, vascular malformations, orinfective lesions.

10. Space occupying lesions or brain tumors.

11. Significant cerebral vascular pathology

12. Hydrocephalus/Normal pressure hydrocephalus.

13. Other MRI findings contraindicating participation in the study such assubarachnoid hemorrhage.

• History suggestive of exposure to, or past tuberculosis (TB) infection shouldundergo screening for TB disease.

• Chronic active immune disorder requiring systemic immunosuppressive therapy within 6months prior to Screening.

• Screening serum vitamin B12 concentration < Lower limit of normal (LLN) or in thelow normal range

• Folate <LLN or Thyroid-stimulating hormone (TSH) > Upper limit of normal (ULN)

• Hemoglobin A1c >8 percentage (%) or poorly controlled diabetes during the last 12weeks

• History of cancer

• Known history of severe allergic, anaphylactic, or other hypersensitivity reactionsto chimeric, human, or humanized antibodies or fusion proteins

• Planned surgery during the study which requires general, spinal, or epiduralanesthesia that would take place during the study.

• Known genetic predisposition for clotting disorder or hemorrhagic disease.

• Key exclusionary medications include:

• Antipsychotics, opiates/opioids, cannabinoids, hypnotics, antidepressants, moodstabilizers, or stimulants that are used on a chronic basis, are exclusionaryif not consistent with the following rule: treatment has to have been at astable dose for at least 4 weeks before screening and should remain stableduring the study

• Any biologic drugs with systemic exposure, whether investigational or approved,used within 6 months before screening Any disease modification drug for AD,such as aducanumab and lecanemab, whether investigational or approved, usedwithin 6 months before screening.

• Anticoagulation medications within 90 days of screening and during the study

• Systemic immunosuppressive therapy within 6 months before screening and duringthe study.