A Study to Evaluate Efficacy and Safety of Intravenous Sabirnetug in Participants With Early Alzheimer's Disease (ALTITUDE-AD)

iADRS is a validated composite of cognition and function made up of Alzheimer's Disease Assessment Scale - Cognitive Subscale 13-item (ADAS-Cog13) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living scale (ADCS-iADL). ADAS-Cog13 is a rater-administered instrument consisting of 13 items assessing cognitive function areas most typically impaired in AD. ADAS-Cog13 scores range from 0 to 85, with higher scores indicating a greater deficit of global cognition. The ADCS-iADL is a subset of the 23-item ADCS-ADL (items 6a and 7 to 23). The iADLs are more complex skills required to successfully live independently. iADL-items score ranges from 0 to 59 (lower scores indicating greater impairment). The iADRS is calculated as a linear combination of total scores from the ADAS-Cog13 and ADCS-iADL. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance.

The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire to be answered by a participant's study partner, where a participant's performance level is rated over the last 4 weeks, based on a set of performance descriptions. The ADCS-iADL is a subset of the 23-item ADCS-ADL (items 6a and 7 to 23). The iADLs are more complex skills required to successfully live independently, and include shopping, keeping appointments, traveling outside of the home, making a meal or snack, and reading and writing. The iADL-items score ranges from 0 to 59 with lower scores indicating greater impairment.

ADAS-Cog is a rater-administered instrument, designed to assess the severity of dysfunction in cognition, characteristic of persons with AD. The ADAS-Cog13, the cognitive subscale of the ADAS, consists of 13 items assessing cognitive function areas most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, and digit cancellation. The scores range from 0 to 85, with higher scores indicating a greater deficit of global cognition.

The CDR is obtained through semi-structured interviews of individuals with AD and informants. The ratings are obtained in six domains: memory, orientation, judgment & problem-solving, community affairs, home & hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. CDR-SB score is obtained by summing each of the domain scores, with scores ranging from 0 to 18. Higher scores reflect greater cognitive and functional impairment.

MMSE is a standard staging and assessment tool in AD, designed for grading the cognitive state of individuals with AD. The scale comprises tasks concerning orientation, memory, attention, language, and praxis to evaluate an individual's cognitive state. MMSE total score ranges from 0 to 30, with lower scores indicative of greater cognitive impairment.

The QOL-AD tool is a 13-item assessment with each question scored on a 4-point scale where 1 = poor quality of life and 4 = excellent quality of life. Scores range from 13 to 52 with higher scores indicating better quality of life.

NPI-Q is a validated questionnaire completed by informants about participants for whom they care. Each of the 12 NPI-Q domains contains a survey question (answered in Yes/No) that reflects the cardinal symptoms of that domain. If the domain response is "Yes," the informant then rates the severity of the symptoms present within the last month on a 3-point scale and the distress of the symptom using a 5-point scale. The total NPI-Q severity score is the sum of the individual severity scores for each symptom and ranges from 0 to 36, with higher scores indicating more severe behavioral impairment. The total NPI-Q distress score is the sum of the individual distress scores for each symptom and ranges from 0 to 60, with higher scores indicating greater caregiver distress.

EQ-5D-5L is a self-report survey that measures quality of life. The EQ-5D-5L consists of an EQ-5D descriptive system and EQ visual analog scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels, each assigned a unique 1-digit number: no problems, slight problems, moderate problems, severe problems, and extreme problems. The digits are combined into a 5-digit number that describes the participant's health state. The EQ VAS records the participant's health on a vertical visual analog scale, where the endpoints are labeled 0= the best health you can imagine, and 100= the worst health you can imagine.

The RUD questionnaire is a standardized tool and the most widely used instrument for resource use data collection in dementia, enabling comparison of costs of care across countries with differing health care provisions. It is designed to collect data on formal and informal care resource use and to be useful in different care settings, across different countries and care systems, and in both clinical studies and observational cost-of-illness studies.

ZBI consists of 22 items. Twenty-one of the items are designed to measure several aspects of burden, whereas Item 22 is a global measure of burden. Response options for each item range from 0-4, and total scores range from 0-88, with higher scores indicating greater self-reported burden.

No clinical progression in participants will be defined as no decline in CDR-SB score. The CDR is obtained through semi-structured interviews of individuals with AD and informants. The ratings are obtained in six domains: memory, orientation, judgment & problem-solving, community affairs, home & hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0 = no impairment; 0.5 = questionable impairment; 1 = mild impairment; 2 = moderate impairment; and 3 = severe impairment. CDR-SB score is obtained by summing each of the domain scores, with scores ranging from 0 to 18. Higher scores reflect greater cognitive and functional impairment.

The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). Greater lethality or potential lethality of suicidal behaviors (endorsed on the behavior subscale) indicates increased risk.

Correlation between sabirnetug exposure and clinical outcomes (including iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE) will be assessed in this study.

Assessment of the correlation between change in clinical outcomes (iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE) and change in biomarker (amyloid PET) will be determined by computing Pearson's correlation coefficient for each treatment group.