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.

The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein
(APP) that are associated with dominantly inherited Alzheimer's disease have very high
penetrance (near 100%). This study will target individuals who are either known to have a
disease-causing mutation or who are at risk for such a mutation (the child or sibling of a
proband with a known mutation) and unaware of their genetic status. Because the age at onset
of cognitive changes is relatively consistent within each family and with each mutation
(Ryman, Acosta-Baena et al. 2014), an age at onset is determined for each affected parent or
mutation. This study will enroll subjects who are either asymptomatic and are within a
specific window of time of expected age at onset for their family and/or mutation or who have
symptoms of mild Alzheimer's disease.

The ability to identify individuals destined to develop Alzheimer's disease (AD) within the
next 10-15 years with a high degree of confidence provides a unique opportunity to assess the
efficacy of therapies while individuals are asymptomatic and/or very early stages of
dementia. Families with known disease-causing mutations are extremely rare and are
geographically dispersed throughout the world. These constraints necessitate a specialized
study design. Many of the subjects in this study will not yet have any cognitive symptoms of
AD; they will be "asymptomatic" carriers of mutations that cause dominantly inherited
Alzheimer's disease and would be expected to perform normally on standard cognitive and
functional testing. Imaging and fluid biomarkers will be used to demonstrate that the
treatment compounds have engaged their therapeutic targets. A set of cognitive measures
designed to assess the very earliest and most subtle cognitive changes will be collected.
Additionally, because many at-risk individuals decide not to know whether they have the
disease-associated mutation or not, some of the at-risk individuals enrolled in this study
will not have the disease causing mutations; they will be "mutation negative". It is
important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be
pressured into genetic testing to learn their genetic status in order to be eligible for the
trial). These mutation negative individuals will be assigned to the placebo group; and will
not be included in the primary efficacy or futility analyses. Subjects and site study staff
will remain blinded as to these individuals' active or placebo group assignment and mutation
status. Thus, the study will be double blinded for placebo and for mutation status, except
for mutation positive subjects who are aware of their genetic status. There may be
exceptional circumstances when required by local regulation or health authorities where
enrollment may be restricted to mutation carriers only but such mandates will be thoroughly
documented and agreed upon by the governing regulatory agency and sponsor. Several different
therapies (each referred to as a study drug arm) will be tested in order to increase the
likelihood that an effective treatment will be discovered. The compounds are selected for
this trial based on mechanism of action and available data on efficacy and safety profile.

The study design includes a pooled placebo group shared by all study drug arms. Mutation
positive subjects will be assigned to a study drug arm and subsequently randomized within
that arm in an overall 3:1 ratio to active drug:placebo. Mutation negative subjects will all
receive placebo treatment. Importantly, subjects and study staff will not be blinded as to
which study drug arm (gantenerumab or solanezumab) each subject has been assigned; they will
be blinded as to whether subjects have been randomized to active drug or placebo. Biomarker
data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of
action and known effects on the tested biomarkers. The primary cognitive endpoint will be the
same for all study drug arms. This study is an adaptive platform based study. Interim
analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study
drug engages its biological targets. This biomarker approach is particularly important in
this study as most study subjects will be cognitively normal at baseline and most will remain
cognitively normal during the first 2 years of the study. The cognitive composite is designed
to assess subtle cognitive changes that may be detectable before the onset of dementia. The
cognitive disease progression model (CDPM) endpoint design will allow for detection of these
subtle cognitive changes.

A cognitive run-in (CRI) period may open for recruitment if no study drug arm is available
for immediate enrollment, or if a treatment arm is stopped prior to the planned completion
(e.g., at biomarker interim, drug toxicity). The CRI period will enhance study enrollment by
identifying eligible subjects and engaging them with the cognitive process, and can reduce
fluctuations in practice effects by allowing subjects to become accustomed to the testing
process.

For the solanezumab and gantenerumab drug arms: Primary Completion Anticipated= Sep 2019 and
Study Completion= Jan 2020

Inclusion Criteria:

- Between 18-80 years of age

- Individuals who know they have an Alzheimer's disease-causing mutation or are unaware
of their genetic status and have an autosomal dominant Alzheimer's disease (ADAD)
mutation in their family.

- Are within -15 to + 10 years of the predicted or actual age of cognitive symptom onset
for treatment arms. For Cognitive Run-In (CRI): includes participants who are younger
than 15 years prior to the expected age of cognitive symptom onset, in addition to
those 15 years younger and no more than 10 years older than expected or actual age of
cognitive symptom onset.

- Cognitively normal or with mild cognitive impairment or mild dementia, Clinical
Dementia Rating (CDR) of 0-1 (inclusive)

- Fluency in DIAN-TU trial approved language and evidence of adequate premorbid
intellectual functioning

- Able to undergo Magnetic Resonance Imaging (MRI), Lumbar Puncture (LP), Positron
Emission Tomography (PET), and complete all study related testing and evaluations.

- For women of childbearing potential, if partner is not sterilized, subject must agree
to use effective contraceptive measures (hormonal contraception, intra-uterine device,
sexual abstinence, barrier method with spermicide).

- Adequate visual and auditory abilities to perform all aspects of the cognitive and
functional assessments.

- Has a Study Partner who in the investigator's judgment is able to provide accurate
information as to the subject's cognitive and functional abilities, who agrees to
provide information at the study visits which require informant input for scale
completion.

Exclusion Criteria:

- History or presence of brain MRI scans indicative of any other significant abnormality

- Alcohol or drug dependence currently or within the past 1 year

- Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or
foreign metal objects in the eyes, skin or body which would preclude MRI scan.

- History or presence of clinically significant cardiovascular disease, hepatic/renal
disorders, infectious disease or immune disorder, or metabolic/endocrine disorders

- Anticoagulants except low dose (≤ 325 mg) aspirin.

- Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the
past six months.

- History of cancer within the last 5 years, except basal cell carcinoma, non-squamous
skin carcinoma, prostate cancer or carcinoma in situ with no significant progression
over the past 2 years.

- Positive urine or serum pregnancy test or plans or desires to become pregnant during
the course of the trial.

- Subjects unable to complete all study related testing, including implanted metal that
cannot be removed for MRI scanning, required anticoagulation and pregnancy.