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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AG042791-02S1
Application #
8913356
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Silverberg, Nina B
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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