Crenezumab

Tau is a protein that accumulates in Alzheimer's disease and damages brain cells including those essential for learning and memory. The effect of crenezumab on tau burden was assessed using \[18F\]GTP1 Tau PET. The annualized rate of change in tau burden from the first \[18F\]GTP1 scan of the standardized uptake ratio (SUVR) in the entorhinal cortex (Braak Stage 1) with an inferior cerebellum reference region was analyzed using a random coefficient regression model (RCRM). Braak staging classifies the degree of pathology in Alzheimer's disease. Braak stages 1 and 2 are used when neurofibrillary tangle involvement is confined mainly to the transentorhinal region of the brain, stages 3 and 4 when there is also involvement of limbic regions such as the hippocampus, and 5 and 6 when there is extensive neocortical involvement.

API ADAD Composite Cognitive Test is a combination of tests, most sensitive to detect cognitive decline \& progression. API ADAD Composite Cognitive Test total score were computed from: Consortium to Establish a Registry for AD (CERAD) Word List: Recall (score range=0-10); Multilingual Naming Test (score range=0-15); Mini-Mental State Examination (MMSE) for orientation to time (score range=0-5); CERAD Constructional Praxis (measure of visuospatial ability) (score range=0-11); Raven's Progressive Matrices (measure of nonverbal fluid reasoning \& visuospatial abilities), Set A (score range=0-12). ADAD-API Cognitive Composite Test total score = \[(Multilingual Naming Test Score/15)+(MMSE Score/5)+(Raven's Progressive Matrices Score/12)+(CERAD Word List Recall Score/10)+(CERAD Constructional Praxis Score/11)\]\*20. Total score ranges=0-100. Higher score=better results. Annualized rate of change in API ADAD Composite Cognitive Test was estimated using random coefficient regression model.

FCSRT assesses immediate \& delayed verbal episodic memory, using Controlled Learning to optimize encoding specificity for more effective recall. Participants were to remember a list of 16 items presented on cards. Participant's task was to learn \& attempt a free recall of the items, followed by a semantically cued recall of items not spontaneously produced during free recall. There were a total of three learning trials, each preceded by 20 seconds of interfering cognitive task. For first two trials, participants were reminded of any item not recalled in cued recall. Free recall (score range: 0-48) \& cued recall (score range: 0-64) assessment occurred immediately, after each of three learning trials, \& after a delay of approx. 30 minutes. Higher scores indicate better performance. FCSRT Cueing Index=(FCSRT Total Free Recall score-FCSRT Total Recall score)/(FCSRT Total Free Recall score-48). Score range for FCSRT Cueing Index is 0-1, with higher score=better results.

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. . An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

A serious adverse event (SAE) is any AE that meets any of the following criteria: fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect in a neonate/infant. Non-SAE of special interest for this study include the following: cerebral vascular edema, Superficial siderosis of central nervous system, cerebral micro-hemorrhages or macro-hemorrhages, pneumonia, liver injury.

AE severity grading scale for the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 was used for assessing adverse event severity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on the following general guideline: Grade 1) mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2) moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3) severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4) life-threatening consequences; urgent intervention indicated, Grade 5) death related to AE.

ATA is a measurement to explore the potential relationship of immunogenicity response with pharmacokinetics, safety and efficacy. Percentage of participants at post-baseline with positive results for ATA against crenezumab are reported.

Alzheimer's disease (AD) is associated with ARIA. The occurrence of imaging abnormalities believed to represent cerebral vasogenic edema, has been reported in association with the investigational use of compounds that are intended to treat Alzheimer's disease by reducing Abeta in the brain. Here, the percentage of participants with symptomatic and asymptomatic ARIA-E were reported.

AD is associated with ARIA. Cerebral micro-hemorrhages (microbleeds \[MBs\]) are radiologically defined as small dot-like foci of signal loss observed on magnetic resonance imaging (MRI) sequences sensitive for paramagnetic tissue properties. The occurrence of MBs has also been identified as an adverse event in anti-amyloid vaccination trials, and together with superficial siderosis, they have been termed ARIA-H.