Autosomal dominant Alzheimer's disease (AD) has informed the field of AD research about the molecular and biochemical mechanisms that are believed to underlie the pathological basis of AD. Further, mutations from autosomal dominant AD have provided animal and cellular models that are utilized to develop anti-A? drugs. Due to the rarity of autosomal dominant AD, the Dominantly Inherited Alzheimer Network (DIAN;U01 AG032438) was launched in 2008 to establish an international, multicenter registry of individuals at risk or with a known causative mutation of AD in the amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2) genes. DIAN evaluates participants at entry and longitudinally thereafter with clinical and cognitive batteries, structural, functional, metabolic,and amyloid imaging protocols, and biological fluid (blood;cerebrospinal fluid) collection with the goal of determining the sequence of imaging and biomarker changes in presymptomatic gene carriers who are destined to develop AD. Because the clinical and pathological phenotypes of dominantly inherited AD appear similar to those for the far more common late-onset "sporadic" AD, the nature and sequence of brain changes in dominantly inherited AD are also likely relevant for sporadic AD. The trial design is a randomized, blinded placebo controlled four arm trial of a fibrillar anti-A? antibody, a soluble anti-A? antibody, and a beta-secretase inhibitor i 160 (n=40 per arm) asymptomatic to mildly symptomatic ADAD mutation carriers. Subjects will receive either drug of placebo for two years to determine engagement of the CNS mechanism of action and downstream AD biomarkers.
The proposed grant will initiate a trial of 3 anti-amyloid drugs in individuals with known causative mutations for dominantly inherited Alzheimer's disease (AD). Although this dominantly inherited form of AD is rare, the symptoms and brain changes are similar to those observed in the far more common late-onset sporadic AD. The results of the trial provides a test of the amyloid hypothesis, and may delay, prevent or reverse cognitive impairment from AD.
|Bateman, Randall J; Benzinger, Tammie L; Berry, Scott et al. (2016) The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement :|
|Raman, Mekala R; Schwarz, Christopher G; Murray, Melissa E et al. (2016) An MRI-Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease. J Neuroimaging 26:264-8|
|Weninger, Stacie; Carrillo, Maria C; Dunn, Billy et al. (2016) Collaboration for Alzheimer's Prevention: Principles to guide data and sample sharing in preclinical Alzheimer's disease trials. Alzheimers Dement 12:631-2|
|Roe, Catherine M; Barco, Peggy P; Head, Denise M et al. (2016) Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals. Alzheimer Dis Assoc Disord :|
|Wang, Fen; Gordon, Brian A; Ryman, Davis C et al. (2015) Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease. Neurology 85:790-8|
|Nedelska, Zuzana; Schwarz, Christopher G; Boeve, Bradley F et al. (2015) White matter integrity in dementia with Lewy bodies: a voxel-based analysis of diffusion tensor imaging. Neurobiol Aging 36:2010-7|
|Dobrowolska, Justyna A; Kasten, Tom; Huang, Yafei et al. (2014) Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system. PLoS One 9:e89998|
|Frost, Shaun M; Kanagasingam, Yogesan; Sohrabi, Hamid R et al. (2013) Pupil response biomarkers distinguish amyloid precursor protein mutation carriers from non-carriers. Curr Alzheimer Res 10:790-6|
|Mills, S M; Mallmann, J; Santacruz, A M et al. (2013) Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris) 169:737-43|