A Study to Learn About the Safety of BIIB080 Injections and Whether They Can Improve Symptoms of Participants With Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD Dementia Between 50 to 80 Years of Age

In this study, researchers will learn more about a study drug called BIIB080. The study will focus on participants with mild cognitive impairment or mild dementia due to AD.

The main question researchers are trying to answer is if BIIB080 can slow the worsening of AD more than placebo. It will focus on what dose of BIIB080 slows worsening of AD the most.

To help answer this question, researchers will use the Clinical Dementia Rating-Sum of Boxes, also known as the CDR-SB.

* Clinicians use the CDR-SB to measure several categories of dementia symptoms.
* The results for each category are added together for a total score. Lower scores are better.

Researchers will also learn more about the safety of BIIB080.

The study will be split into 2 parts. The 1st part is the Placebo-Controlled Period. The 2nd part is the Long-Term Extension (LTE) Period. The 2nd part of the study will help researchers learn about the long-term safety of BIIB080, and how it affects the participant's daily life, thinking, and memory abilities in the longer term.

A description of how the study will be done is given below.

* After screening, participants will first receive either a low dose or high dose of BIIB080, or a placebo, as an injection into the fluid around the spinal cord (cerebrospinal fluid). A placebo looks like the study drug but contains no real medicine.
* Participants will receive BIIB080 or placebo once every 12 weeks or 24 weeks.
* After 76 weeks of treatment in the Placebo-Controlled Period, eligible participants will move onto the Extension Treatment period, which will last 96 weeks.
* In the extension period, participants who received placebo will be switched to high dose BIIB080 every 12 or 24 weeks.
* Participants may be in the study for up to 201 weeks, or about 4 years. This includes the screening and follow-up periods.
* Participants can continue to take certain medications for AD. Participants must be on the same dose of medication for at least 8 weeks before the screening period.
* After the screening period, most participants will visit the clinic every 6 weeks.

BIIB080 is an investigational antisense therapy designed to target microtubule-associated protein tau (MAPT) messenger ribonucleic acid (mRNA) and prevent production of tau protein.

Eligibility Criteria:
Key Inclusion Criteria for Placebo-controlled Period:

* Must meet all the clinical staging criteria for MCI due to AD (Stage 3) or mild AD dementia (Stage 4) according to the National Institute on Aging at National Institutes of Health and the Alzheimer's Association (NIA-AA) and must have the following at Screening Visit 1:

  1. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index score of ≤85, indicative of objective evidence of memory impairment.
  2. CDR global score of 0.5 for MCI due to AD or 0.5 or 1 for mild AD dementia
  3. MMSE score of 21 to 30 (inclusive).
  4. CDR Memory Box score of ≥0.5.
* Evidence of amyloid pathology as measured by positive emission tomography (PET) or cerebrospinal fluid (CSF) sampling.
* Must have 1 care partner who, in the Investigator's judgment, has frequent and sufficient contact with the participant (at least 10 hours/week) to be able to provide accurate information about the participant's cognitive and functional abilities.

Key Inclusion Criteria for LTE Period

* Ability of the participant and/or his/her legally authorized representative (e.g., parent, spouse, or legal guardian), where local regulations and institutional practices permit, as appropriate and applicable, to understand the purpose and risks of the study, to provide informed consent, and to authorize the use of confidential health information in accordance with national and local privacy regulations. Incapacitated individuals will not be enrolled in the EU (European Union) and other countries where local laws, regulations, and practices do not permit their inclusion.
* Participants must have completed the placebo-controlled period of the study, including the Week 76 visit.
* Participants must have taken at least 5 doses of BIIB080 or placebo during the placebo-controlled period.
* Medically able to undergo the study procedures (including LP \[lumbar puncture\]) and to adhere to the visit schedule at the time of study entry into the LTE period, as determined by the Investigator.
* Apart from a clinical diagnosis of AD, the participant must be in good health as determined by the Investigator, based on medical history.
* Must have 1 care partner who, in the Investigator's judgment, has frequent and sufficient contact with the participant (at least 10 hours/week) to be able to provide accurate information about the participant's cognitive and functional abilities.

Key Exclusion Criteria for Placebo-controlled Period:

* Known allergy to BIIB080 or a history of hypersensitivity to any of the inactive ingredients in the drug product.
* Previous participation in this study or previous studies with BIIB080.
* Use of non-disease-modifying AD medications (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine) at doses that have not been stable for at least 8 weeks prior to Screening Visit 1 and during the screening period up to Day 1.
* Use of any commercially available disease-modifying AD medications such as anti-amyloid monoclonal antibodies.
* Prior participation in any active or passive immunotherapy study targeting Aβ, unless documentation of receipt of placebo is available.
* Prior participation in any passive immunotherapy study targeting tau, unless the last administration occurred 6 months or 5 half-lives, whichever is sooner, prior to Screening or documentation of receipt of placebo is available.
* Prior participation in any study involving an investigational treatment targeting tau that is not a passive immunotherapy, unless documentation of receipt of placebo is available.
* Prior participation in a study of any other agent(s) not included in exclusion criteria 5, 6, and 7 with a purported disease-modifying effect in AD within 12 months, unless documentation of receipt of placebo is available.
* Prior participation in a study of any gene therapy with a purported disease-modifying effect in AD, unless documentation of receipt of placebo is available.
* Current use or previous use of medications with a purported disease-modifying effect in AD, outside of investigational studies.
* Any vaccination given within 10 days prior to Day -1. Coronavirus disease 2019 (COVID-19) vaccinations using RNA or deoxyribonucleic acid (DNA) technology are allowed during the study, as well as other types of immunization/vaccination/booster, except during the 10 days before and after clinic visits.
* Contraindications to having a brain magnetic resonance imaging (MRI) \[e.g., MRI-incompatible pacemaker; MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed\]. If the MRI compatibility of implanted devices is unknown, the participant must be excluded from the study.
* Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 52 weeks prior to the Baseline Visit.

Key Exclusion Criteria for LTE Period

* Any medical or psychiatric contraindication or clinically significant abnormality that, in the opinion of the Investigator, will substantially increase the risk associated with the participant's enrollment in and completion of the study.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.