Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation (DIAN-TU)

To assess the safety, tolerability, biomarker, cognitive, and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug improves disease-related biomarkers and slows the rate of progression of cognitive or clinical impairment.

Alzheimer's disease (AD) is characterized pathologically by the presence of accumulation of amyloid plaques and tau-containing neurofibrillary tangles (NFTs) in the brain. Amyloid plaques can be detectable within the brain some years before symptoms manifest whereas tau-mediated toxicity has been hypothesized to appear later during the course of disease. Physiologically, tau is predominantly a neuronal microtubule-associated protein that plays a fundamental role in the stabilization of microtubules. Under pathological conditions however, short motifs in the microtubule binding region (MTBR) domains of tau adopt a beta-sheet conformation, inducing self-assembly with other tau molecules that lead to the formation of insoluble aggregates. Insoluble tau is also a feature of a number of different neurodegenerative diseases collectively termed tauopathies. The accumulation of insoluble deposits has been suggested to result in altered distribution and function of organelles to adversely affect neuronal cell function as well as causing synapse loss, ultimately leading to cell death. In AD, evidence also suggests a direct correlation between the number of NFTs found in the brain at postmortem and the degree of dementia observed in subjects with AD at the time of death. The microtubule-associated protein tau (MAPT) gene is located on chromosome 17 of the human genome. Through alternative splicing, 6 possible tau protein isoforms are expressed from this gene in the adult brain. A number of studies have suggested that pathological forms of tau protein transmit from neuron to neuron in human brain to cause disease, including AD. It has also been reported that tau can form seeds, which when applied extracellularly, can cause the initiation and propagation of intracellular tau aggregation. To form tau seeds, the MTBR of the protein is required. Furthermore, the tau MTBR is important in initiating the tau aggregation process and forming the core of fibrils pathologically associated with disease. Together, these observations suggest that therapeutic intervention with an antibody that binds to the MTBR region of tau in the brain, thereby disrupting tau aggregation may prevent initiation or slow down the neurodegeneration in AD or other tauopathies. Upcoming Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trials are designed to investigate therapies targeting tau in combination with amyloid as pre-specified in the approved and NIH-funded NexGen Prevention Trial grants. As with other amyloid lowering drug trials, clinical benefit was not definitively demonstrated in the symptomatic population after tau pathology has been established. Determining the role of tau in disease biology and progression is critically important. Based on beneficial effects on amyloid, tau, and neurodegeneration markers associated with amyloid removal in the gantenerumab trial arm in DIAN-TU, the DIAN-TU will now implement amyloid removal treatment in mutation carriers and add trial.show_full_description

Key Inclusion Criteria: * Between 18-80 years of age * Individuals who know they have an Alzheimer's disease-causing mutation. * Are within -10 to + 10 years of the predicted 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, participant 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. Key Exclusion Criteria: * Significant neurologic disease (other than AD) or psychiatric disease that may currently or during the course of the study affect cognition or participant's ability to complete the study. * At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months. Current stable mild depression or current use of antidepressant medications is not exclusionary. * History or presence of brain MRI scans indicative of any other significant abnormality * Substance or alcohol use disorder 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.