A Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease (AD)

Time from randomization to clinical progression to mild cognitive impairment or dementia due to Alzheimer's disease was based on the diagnosis of the independent Clinical Adjudication Committee (iCAC).

Time to onset of confirmed clinical progression was defined as the time from randomization to the first occurrence of two consecutive visits (approximately 6 months apart) with a Clinical Dementia Rating Global Score (CDR-GS) of > 0. CDR is a clinician reported (ClinRO) measure used to stage severity of AD dementia based on a semi-structured interview with participant \& a reliable informant. CDR characterizes participant's level of cognitive \& functional impairment across six domains (memory, orientation, judgment \& problem solving, community affairs, home \& hobbies, \& personal care) on a 5-point rating. CDR-GS is calculated based on the Washington University CDR-assignment algorithm \& characterizes a participant's level of global impairment/stage of dementia according to following categories: 0 (normal), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate dementia), \& 3 (severe dementia). Score ranges from 0 to 3 \& a high score on CDR-GS would indicate a high disease severity.

A-IADL-Q-SV=observer reported (ObsRO) measure assessing participant's ability to perform instrumental activities of daily living (including household/leisure activities, use of household appliances, management of finances, etc.). A-IADL-Q-SV includes 30 items rated by study partner. Each item is divided into 2 questions=1st question asks if activity was performed by participant during past 4 weeks (Yes/No/Don't know). If performed, 2nd question captures level of difficulty while performing activity on 5-point Likert scale (no difficulty to no longer able to perform the activity). If not performed, 2nd question captures why activity was not performed (never done before, no longer able to do so due to physical problems, no longer able to do so due to difficulties with memory/planning/thinking/other, including free text response). A-IADL-Q-SV=average of all scored responses multiplied by 25. Score range=0-100. Higher scores=better functioning. Negative change from baseline=worsening.

The CFIa is an outcome measure developed to assess memory-related cognitive and functional decline in non-demented elderly individuals. The CFIa is a modified version of the original CFI and differs in terms of recall period and item response options. The CFIa is computed as the sum of 14 items, rated on a 5-point Likert scale ranging from Never=0 to Always=4 and referring to the participant's current ability (most recent experience). Total scores range from 0 to 56. Higher scores indicate greater cognitive impairment. Negative change from baseline indicates improvement. The participant (PRO) and study partner (ObsRO) versions of the CFIa were used in this study.

The CFIa is an outcome measure developed to assess memory-related cognitive and functional decline in non-demented elderly individuals. The CFIa is a modified version of the original CFI and differs in terms of recall period and item response options. The CFIa is computed as the sum of 14 items, rated on a 5-point Likert scale ranging from Never=0 to Always=4 and referring to the participant's current ability (most recent experience). Total scores range from 0 to 56. Higher scores indicate greater cognitive impairment. Negative change from baseline indicates improvement. The PRO and ObsRO versions of the CFIa were used in this study.

The CDR is a ClinRO measure used to stage the severity of AD dementia based on a semi-structured interview with the participant and a reliable informant. The CDR characterizes the participant's level of cognitive and functional impairment across six domains (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care) on a 5-point rating scale in which 0 = None, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe (with the exception of personal care, which is rated on a 4-point rating scale and excludes the questionable impairment level). The CDR-SB is calculated by summing the ratings across each of the six domains (total score: 0 to 18), with higher scores indicating greater impairment. A negative change from baseline indicates improvement.

An AE is any untoward medical occurrence in a patient or clinical study participant temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity, and leads to congenital anomaly or birth defect. An AESI included drug induced liver injury and suspected transmission of infectious agent via medicinal products.

The number of ADA-positive participants after drug administration were determined for participants exposed to gantenerumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 4-fold higher in comparison to the titer at the baseline. As prespecified in the protocol, this outcome measure was applicable only to participants exposed to gantenerumab.

ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for edema or effusion), edema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD.

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Local injection reactions (or injection-site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection.

The C-SSRS is an assessment tool used to assess the lifetime suicidality of a participant (baseline) as well as any new instances of suicidality (since last visit). The structured interview prompts recollection of suicidal ideation (SI), including the intensity of the ideation, behavior, \& attempts with actual or potential lethality. Categories have binary responses (yes/no) \& include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active SI with Any Methods (Not Plan) without Intent to Act; Active SI with Some Intent to Act, without Specific Plan; Active SI with Specific Plan \& Intent, Preparatory Acts \& Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. SI or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates SI or behavior. Only categories with at least one participant with event are reported.

Brain amyloid load over time was planned to be assessed using [18F] florbetaben or [18F] flutemetamol tracers. These are PET radioligand selective to amyloid. Amyloid PET burden is measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The weighted composite target region are composed of (both left and right side): frontal lobe, parietal lobe, temporal lobe lateral, cingulum posterior and anterior cingulate gyrus. The reference region used to normalize the composite region is the whole cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan.

Change in tau load represents how much neurofibrillary tau pathology is present in brain assessed using PET scan. For the longitudinal tau PET assessment, [18F]-MK-6240 was used. Tau load is measured using SUVR in four composite target ROIs: Temporal composite target region included (both left \& right) anterior \& posterior superior temporal gyrus, posterior temporal lobe, fusiform gyrus, \& middle and inferior temporal gyrus; Medial temporal composite region not including hippocampus included (both left \& right): amygdala, parahippocampus \& anterior medial \& lateral temporal lobe; Frontal lobe (both left \& right) \& Parietal lobe (both left \& right). Inferior cerebellar grey matter = reference region for calculating median SUVRs for all four target regions.

Amyloid beta is a peptide fragment of the amyloid precursor protein.

Amyloid beta is a peptide fragment of the amyloid precursor protein.

NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in CSF proportionally to the degree of axonal damage in a variety of neurological disorders, including AD.

CSF pTau is an indicator of neuronal injury and neurodegeneration. An elevation in levels specific pTau species, is thought to be a marker for progressive cellular degeneration in AD.

CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of tau, is thought to be a marker for progressive cellular degeneration in AD.

Whole brain volume is measured by volumetric MRI (vMRI). Volumetric imaging is a three dimensional (3D) technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Whole brain volume represents a summary measure of total brain parenchyma which includes the cerebrum, basal ganglia, diencephalon, and cerebellum.

Total Ventricular Volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total ventricular volume represents a summary measure of total including right and left lateral ventricles, third ventricle and fourth ventricle of brain.

Total hippocampal volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total hippocampal volume is calculated by summing up right and left hippocampal volumes.