Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation.

Multivariate Disease Progression Model adjusted for Estimated Years to Onset (EYO)and includes all timepoints up to treatment discontinuation. The treatment effect is reported relative to the mutation positive placebo arm. Multivariate Cognitive Endpoint comprising: (i) Wechsler Memory Scale-Revised Logical Memory Delayed Recall Test (MEMUNITS), (ii) Wechsler Adult Intelligence Scale Digit Symbol Substitution Test (WAIS), (iii) Mini-Mental State Examination (MMSE), and (iv) International Shopping List Task (ISLT). Measurements for each test were normalized using the mean (SD) at DIAN-TU-001 baseline for mutation negative subjects. Higher scores indicate more favourable cognitive performance.

Time frame: Baseline through Week 260

Population: The endpoint itself is a ratio based on feeding z-scores for four separate parameters into a model, with programming providing the ratio under model assumptions rather than providing a treatment-specific value this is used to generate the ratio. The four individual parameters are described in other outcomes. There are no by-arm values for any MDPM analysis.

In vivo quantification of β-amyloid deposition using positron emission tomography. This measure is a composite of brain regions. Higher scores indicate worse disease stage.

Time frame: Baseline, Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

CDR-SB score is considered a more detailed quantitative general index of cognition and function, and provides more information than the global CDR score in patients with mild dementia Scores range from 0-18 with lower scores showing more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

The Functional Assessment Scale is to be administered and completed by the study partner about subjects for whom they care. This scale measures instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS is to assess change in an individual's functional activities, relative to previously attained abilities, that are caused by cognitive dysfunction. If the study partner indicates that the subject no longer performs a particular task, it is reasonable to probe further and ask if they think the subject could still do the task. This will help tease out the relevant cognitive impairment

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of neurofilament light chain in cerebrospinal fluid using SIMO

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

CDR-SB score is considered a more detailed quantitative general index and provides more information than the global CDR score in patients with mild dementia Scores range from 0-18 with lower scores showing more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Clinical Dementia Rating - Global Score - Number of Subjects with an Increase from Baseline by Visit

Time frame: Baseline and Weeks 52, 104, 156, and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

The Functional Assessment Scale is to be administered and completed by the study partner about subjects for whom they care. This scale measures instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS is to assess change in an individual's functional activities, relative to previously attained abilities, that are caused by cognitive dysfunction. If the study partner indicates that the subject no longer performs a particular task, it is reasonable to probe further and ask if they think the subject could still do the task. This will help tease out the relevant cognitive impairment Scores range from 0-30 with lower scores indicate more favorable cognitive performance

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

The Geriatric Depression Scale (GDS) is a self-report measure of depression in older adults. Users respond in a Yes/No format. Of the 15 items, 10 indicate the presence of depression when answered positively while the other 5 are indicative of depression when answered negatively. Scores range from 0-15 for completed questionnaires. A score of 88 is recorded for participants unable to complete the test. Lower scores show more favorable outcome.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

MMSE is a brief, quantitative measure of cognitive status in adults used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual's response to treatment. Scores range from 0-30 and higher scores indicate more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

The questionnaire is to be administered and completed by the study partner about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are Yes(present) or No (absent). If the response to the domain question is No, the study partner goes to the next question. If Yes, the study partner then rates both the Severity of the symptoms present within the last month on a 3-point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a 5-point scale. The NPI-Q provides symptom 'Severity' and 'Distress' ratings for each symptom reported, and total 'Severity' and 'Distress' scores reflecting the sum of individual domain scores. Scores range from 0-36 with lower scores indicating more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Category Fluency is a widely used measure of semantic memory (verbal fluency, language). The subject is asked to name different exemplars of a given semantic category (animals), and the number of unique exemplars named is scored. Higher scores indicate more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Category Fluency is a widely used measure of semantic memory (verbal fluency, language). The subject is asked to name different exemplars of a given semantic category (vegetables), and the number of unique exemplars named is scored. Higher scores indicate more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Multivariate Disease Progression Model adjusted for estimated years from symptom onset (EYO) and includes all time points up to treatment discontinuation. The treatment effect for Solanezumab is reported relative to the mutation positive placebo arm. This alternative multivariate endpoint includes four tests: Logical Memory Immediate Recall, Digit Span Backward Recall, Category Fluency (Animals), Trailmaking Test Part B. Measurements for each test will be normalized using the mean (SD) at DIAN-TU-001 baseline among mutation negative subjects before being analyzed. For the Trailmaking Test B, the scores will be multiplied by -1 as higher scores indicate worse performance; whereas for the other three, lower scores indicate worse performance. Therefore, on the standardized endpoints, lower scores indicate worse performance.

Time frame: Baseline through Week 260

Population: The endpoint itself is a ratio based on feeding z-scores for four separate parameters into a model, with programming providing the ratio under model assumptions rather than providing a treatment-specific value this is used to generate the ratio. The four individual parameters are described in other outcomes. There are no by-arm values for any MDPM analysis.

The Groton Maze Learning Test 30 minute delayed recall measures episodic memory. The primary outcome is the number of errors made during recall of the previously memorized pathway from the Groton Maze Learning Test. The minimum score is 0 errors and the max is 999. Lower scores indicate better cognitive performance.

Time frame: Baseline, Week 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end). Tasks are only included where assessed for subjects with a baseline Clinical Dementia Rating Global Score less than 1.

The Groton Maze Learning Test measures executive function using a maze learning paradigm. A 10 x 10 grid of tiles is presented to the participant on the screen. A 28-step pathway is hidden among these tiles. A blue tile indicates the start and a tile with red circles indicates the finish. The participant must move one step at a time from the start toward the end by touching a tile next to their current location. If the correct move is made a green checkmark appears and if the move is incorrect a red cross is revealed. Once completed, they are returned to the start location to repeat the test and must try to remember the pathway they have just completed. Delayed Reverse Recall measures spatial working memory. The outcome is the number of errors made with the range of 0-999. Lower scores indicate better cognitive performance.

Time frame: Baseline, Week 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end). Tasks are only included where assessed for subjects with a baseline Clinical Dementia Rating Global Score less than 1.

Classic list-learning test that measures verbal learning & memory. Scores range from 0-12 with higher scores indicating more favorable cognitive performance.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

This is a measure of fluid intelligence. This test is used to get an estimate of the subjects IQ at baseline. Subjects are asked to complete a visual pattern by circling one of six response choices. Scores range from 0-12 with higher scores indicating more favorable cognitive performance.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Trail Making test taps attention, processing speed, and executive function. Part A consists of 25 circles numbered 1 through 25 distributed over a white sheet of standard document-sized paper. The subject is instructed to connect the circles with a drawn line as quickly as possible in ascending numerical order without lifting their pen. The subject's performance is judged in terms of the time, in seconds, required to complete each trail (Max time 150 seconds). Lower scores indicate more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

This test taps attention, processing speed, and executive function and depends on visuo-motor and perceptual-scanning skills and also requires considerable cognitive flexibility in shifting from number to letter sets under time pressure. Part B consists of 25 circles, but these circles contain either numbers (1 through 13) or letters (A through L). The subject must connect the circles while alternating between numbers and letters in an ascending order (e.g., A to 1; 1 to B; B to 2; 2 to C). The subject's performance is judged in terms of the time, in seconds, required to complete each Trail (Max of 300 seconds). Lower scores indicate more favorable cognitive function.

Time frame: Baseline, Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

This test engages multiple cognitive abilities, including attention, psychomotor speed, complex scanning, visual tracking, and immediate memory. Scores range from 0-93 with higher scores indicate more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Widely used measure of working memory (or attention) in which the subject is read number sequences of increasing length and then asked to repeat each sequence backward. The primary measure of performance is the number of digit sequences correctly reversed. The unit of measure is number of digit sequences correctly recalled and ranges from 0-12. Higher scores indicate more favorable cognitive function.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

This is a widely-used test of working memory in which the subject is read number sequences of increasing length and asked to repeat them. The total score is the number of sequences correctly repeated. The unit of measure is number of digit sequences correctly recalled and ranges from 0-12. Higher scores indicate more favorable cognitive function.

Time frame: Baseline, Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measure of delayed recall (episodic memory) of a story read to the subject at the beginning of the testing session and subject is asked to relay the story 20 minutes later. Scores range from 0-25 with higher scores indicating more favorable cognitive performance.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

This test assesses the ability to recall a short story. The subject is read a short story and immediately after hearing the story, the subject is asked to retell the story from memory. Scores range from 0-25 with higher scores indicating more favorable cognitive performance.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of the drug bound and free soluble Aβ1-40 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of the total soluble Aβ1-40 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of the total soluble Aβ 1-42 peptide in cerebrospinal fluid using ELISA

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of the total soluble Aβ1-42 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of phosphorylated tau at threonine-181 in cerebrospinal fluid

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data was not collected for all participants at each time point for various reasons

Measured concentration of the soluble Tau peptide in cerebrospinal fluid

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data was not collected for all participants at each time point for various reasons

Measurement of the presence or absence of anti-drug antibodies in serum Note: Mutation Negative Placebo subjects are not displayed as anti-drug antibody testing was not to be evaluated for these subjects. Note: Treatment Emergent Anti-Drug Antibody Positive subjects are defined as those with either (a) a baseline status of ADA Not Present and at least one post-baseline ADA present with a titer \>= 1:20 or (b) both a baseline and post-baseline status of ADA Present with the post-baseline titer being 2 dilutions (4-fold) greater than the baseline titer. Note: Treatment Emergent Anti-Drug Antibody Inconclusive subjects are defined as those for whom \>=20% of the subject's post-baseline ADA results are ADA Inconclusive and all remaining post-baseline samples are ADA Not Present. Note: Treatment Emergent Anti-Drug Antibody Negative subjects are defined as those who are evaluable for TE ADA but are neither TE ADA Positive nor TE ADA Inconclusive.

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Measured concentration of neurofilamnet light chain in plasma using Single Molecule Array (SIMOA)

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data was not collected for all participants at each time point for various reasons

Measured concentration of the total soluble Aβ 1-40 peptide in cerebrospinal fluid using ELISA

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data was not collected for all participants at each time point for various reasons

Measured concentration of the total soluble Aβ 1-42 peptide in cerebrospinal fluid using ELISA

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

PiB Standardized Uptake Value Ratio (\[11C\]PiB SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions dervived via automated segmentation using FreeSurfer) with respect to a reference region. In amyloid and tau imaging, SUVR is typically generated using some portion or the entire cerebellum as a reference because cerebellum is not affected until late in the progression of AD.

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Florbetapir Standardized Uptake Value Ratio (\[18F\]AV-45 SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions derivved via automated segmentation using FreeSurfer) with respect to a reference region. In amyloid and tau imaging, SUVR is typically generated using some portion or the entire cerebellum as a reference because cerebellum is not affected until late in the progression of AD.

Time frame: Weeks104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was notcollected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. For the clinical trial we examined cortical thickness values in prespecified regions of interest known to show atrophy in autosomal dominant Alzheimer Disease. Higher measurements are more favorable.

Time frame: Baseline and Weeks 52, 104, 156 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Rather than looking at how tissue in the brain changes, it is also possible to quantify how the ventricles, fluid filled spaces in the brain, change. Increasing ventricular volume represents greater amounts of cerebral spinal fluid which suggests atrophy of the brain. Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequences were processed using the Freesurfer software suite. Total ventricular volume was calculated from the ventricular volumes generated by this program.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. A whole brain volume measure was generated to represent global atrophy across the cortical and subcortical regions.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

FDG Standardized Uptake Value Ratio (\[18F\]FDG SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions derivved via automated segmentation using FreeSurfer) with respect to a reference region. In amyloid and tau imaging, SUVR is typically generated using some portion or the entire cerebellum as a reference because cerebellum is not affected until late in the progression of AD.

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).

This variable represents how much neurofibrillary tau pathology is present in brain as assessed using positron emission tomography (PET). Scans were conducted using \[F18\] Flortaucipir, a commonly used tracer in the field.

Time frame: Baseline and Weeks 52, 104 and 208

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end). In addition, the tau tracer was not introduced in the trial until after baseline for most participants.

Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. For the clinical trial we examined volume values in prespecified regions of interest known to show atrophy in autosomal dominant Alzheimer Disease.

Time frame: Baseline and Weeks 52, 104, 156, 208 and 260

Population: Number analyzed represents actual data collections at each collection time point. Data unavailable at any time point was not collected for various reasons i.e. participant attrition or common close design (participants did not reach that time point before trial end).