EFFICACY AND SAFETY OF GSK4527226 [AL101] IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE

Prior treatment

• Evidence of any neurological condition other than AD that may contribute to cognitive impairment 2. History or presence of vascular disease that has the potential to affect cognitive function. 3. History or presence of stroke within the past 1 year or recent transient ischemic attack within 180 days before screening. 4. History of severe, clinically significant CNS trauma. 5. History or presence of intracranial tumor. 6. Presence of ongoing infection(s) that may affect brain function, or history of infections that resulted in neurologic sequelae. 7. History of primary psychiatric diagnosis that the investigator considers may interfere with study assessments 8. Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, suicidal behaviour or participant has been assessed to be at risk of suicide, in the opinion of the investigator within 6 months before Screening through the Baseline Visit, or has been hospitalized or treated for suicidal behaviour in the past 2 years

Lab values

• Participant has history of alcohol or moderate to severe substance use disorder within the past 2 years. 10. MRI evidence based on central read of: a. >3 lacunar infarcts. b. Stroke involving a major vascular territory, severe small vessel, or white matter disease. c. Any territorial/Cortical/Other infarct >1 cm3. d. White matter hyperintense lesions on the FLAIR sequence that correspond to an overall Fazekas score of 3. e. >4 microhemorrhages. f. Any areas of superficial hemosiderosis. g. A single macrohmorrhage greater than 10 mm at greatest diameter. h. Vasogenic edema. i. Cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions. j. Space occupying lesions or brain tumors. k. Significant cerebral vascular pathology. l. Hydrocephalus/Normal pressure hydrocephalus. m. Other MRI findings contraindicating participation in the study such as subarachnoid hemorrhage. 11. Unable to tolerate MRI procedures or has a contraindication to MRI. 12. History suggestive of exposure to, or past tuberculosis (TB) infection should undergo screening for TB disease 13. Chronic active immune disorder requiring systemic immunosuppressive therapy within 6 months prior to Screening 14. Serum vitamin B12 concentration < LLN or in the low normal range 15. Folate < LLN or TSH > ULN 16. Hemoglobin A1c >8% or poorly controlled diabetes during the last 12 weeks.
• History of cancer 18. Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. 19. Planned surgery during the study which requires general, spinal, or epidural anesthesia that would take place during the study. 20. Key exclusionary medications include: a. antipsychotics, opiates/opioids, cannabinoids, hypnotics, antidepressants, mood stabilizers, or stimulants that are used on a chronic basis, are exclusionary if not consistent with the following rule: treatment has to have been at a stable dose for at least 4 weeks before screening and should remain stable during the study b. Any biologic drugs with systemic exposure, whether investigational or approved, used within 6 months before screening. c. Any disease modification drug for AD, such as aducanumab and lecanemab, whether investigational or approved, used within 6 months before screening. d. Anticoagulation medications within 90 days of screening and during the study e. Systemic immunosuppressive therapy within 6 months before screening and during the study 21. Impaired coagulation or platelet count <50,000/uL. 22. Participant resides in a skilled nursing facility, convalescent home, or longterm care facility. 23. If at screening, a participant with comorbidities that are likely to require non-study related medical procedures with additional radiation exposure is identified, the investigator must discuss with the medical monitor to determine if the total radiation exposure would be deemed to exceed maximum radioactive exposure allowed by country-specific regulations or 40 mSv for the study (whichever is the lower value). 24. Known genetic predisposition for clotting disorder or hemorrhagic disease.

• Participant must be 50 to 85 years of age, inclusive. 2. Participant must be in the Alzheimer’s continuum as defined by the 2018 NIA-AA Research Framework corresponding to the clinical categories of MCI due to AD and mild AD dementia. 3. Participant must have evidence of cerebral amyloidosis (A+) by either positive amyloid PET scan read by central imaging lab or CSF amyloid beta test result indicative of amyloid positivity. 4. Participant must meet the following inclusion criteria to define clinical severity: a. MMSE score of between 21 and 29 points b. CDR-GS of 0.5 to 1.0. c. CDR Memory Box score >0.5 d. WMS-IV LMII score at least 1 standard deviation below age-adjusted mean i. ≤ 15 for age 50 to 64 years ii. ≤12 for age 65 to 69 years iii. ≤11 for age 70 to 74 years iv. ≤9 for age 75 to 79 years v. ≤7 for age 80 to 90 years 5. If the participant is receiving symptomatic AD medications such as an acetyl choline esterase inhibitor, (e.g. donepezil, rivastigmine, galantamine), or memantine, the dosing regimen must have been stable for at least 12 weeks prior to screening and is not expected to change during study participation. 6. If the participant is receiving other medications for AD related symptoms or associated conditions, the dosing regimen must have been stable for at least 4 weeks prior to screening and not expected to change during study participation. Symptoms must be considered adequately and stably controlled by the investigator, without marked changes in medication anticipated for the duration of the study.
• Body weight ≥45 kg to ≤120 kg with BMI between 17 and 34.9 kg/m2, inclusive. 8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and if she is of child-bearing potential follows contraception requirements outlined in the protocol. 9. A male participant is eligible to participate if he follows contraception requirements outlined in the protocol. 10. Participant is willing and able to give informed consent which includes compliance with the requirements and restrictions listed in the ICF. 11. Availability of an adult person who has frequent and sufficient contact with the participant is able to provide accurate information regarding the participant’s cognitive and functional abilities, agrees to provide information at clinic visits, and signs the ICF of the study partner.