Development of a non-fibrillic amyloid-beta oligomer selective positron emission tomography imaging diagnostic for Alzheimer.

In the United States in an estimated million people suffered from Alzheimer s disease AD
with as many as being undiagnosed Alzheimer s Association Three stages of AD are proposed
National Institute on Aging and the Alzheimer s Association preclinical AD mild cognitive impairment
MCI due to AD and dementia due to AD The preclinical stage is proposed to begin or more years before
symptoms appear Today many researchers believe that treatments to slow or stop AD will be most effective
if administered during the preclinical or MIC stages However new biomarker tests are needed to identify
individuals at these early stages These biomarker tests will also be essential for monitoring treatment effects
Current biomarker tests for AD are based on the levels of total amyloid beta A mainly monomer in
cerebrospinal fluid CSF levels of tau and phosphorylated tau in CSF or the levels of fibrillic amyloid plaques
in the brain However many researchers now regard non fibrillic A oligomers A o in contrast to
monomeric or fibrillic A as the primary A toxins that cause acute cognitive deficits and induce the chronic
neuronal degeneration of AD tau abnormalities synapse loss oxidative damage etc A non invasive
method to detect and quantify A o could provide a valuable biomarker test to identify early stage AD patients
and for monitoring the effect of therapies Preliminary studies suggest that an A o selective antibody positron
emission tomography PET probe may enable the in vivo detection and quantification of A o
ACU is a proprietary affinity matured humanized monoclonal antibody exhibiting high selectivity
for A o versus monomeric and fibrillic A In AD mouse models ACU crosses the blood brain barrier and
forms complexes with A o in the brain ACU exhibits excellent pharmacokinetics biodistribution and brain
penetration in four animal species Protein binding studies show excellent selectivity for A o Exploratory
toxicity studies in monkeys reveal an excellent safety profile for ACU Thus ACU is an ideal candidate
for testing the potential utility of an A o antibody PET probe for the in vivo detection and quantification of A o
The objective of this Phase STTR application is to prepare and optimize an ACU PET probe and
demonstrate that it provides a sensitive and selective in vitro A o dependent signal from transgenic AD mouse
model tissues and human AD brain tissues The underlying hypothesis is that a sensitive and highly A o
selective PET probe can be made using ACU labeled with Cu If in vitro sensitivity and selectivity are
achieved the Phase study will also evaluate the sensitivity of the probe in vivo in a transgenic AD mouse
mode Overall success in this program would provide a non invasive method for detecting and quantifying
A o in vivo and support its development as an AD diagnostic tool for monitoring disease progression and the
effects of treatment and as a research tool that would enable a better understanding of the etiology of AD The proposed research is relevant to public health and the mission of the National Institute on Aging NIA
because it is expected to provide a first of its kind Alzheimer s disease PET probe that has broad application for
both early stage diagnosis and assessing the experimental efficacy of investigational new drugs Early diagnosis
of Alzheimer s disease is crucial for the most effective treatment and is not possible with current technology The
PET probes characterized in the proposed research targets toxic amyloid beta oligomers which are biomarkers
that develop years before currently measured pathology