Principal Investigator: Dr. Roberta Brinton
University of Southern California, Pharmacology and Pharmaceutical Science, 1985 Zonal Avenue, Los Angeles, CA 90033, United States
Collaborating leads –
Nophar Geifman – University of Manchester, Manchester, UK
Roberta Brinton – University of Arizona, Tuscon, USATags: 19923, Alzheimer's, APOE, Precision Medicine, Statins
Lead Collaborators: 1) Dr. Roberta Brinton,
2) Dr Nophar Geifman
Collaborating Institutions and Addresses: 1) University of Arizona, Pharmacology and Neurology, 1501 North Campbell Avenue, Tucson, AZ 85724, United States
2) University of Manchester,Institute of Population Health, Vaughan House, Portsmouth Street, Manchester, M13 9GB, United Kingdom
1a: Alzheimer’s disease (AD) has reached global epidemic proportions. Therapeutics to prevent, delay and treat AD are urgently needed.
Significant emerging evidence links cholesterol, Aβ and AD, and several studies have shown a reduced risk for AD and dementia in populations treated with statins. The ApoE4 allele of the apolipoprotein E gene, is associated with higher cholesterol levels and increased risk for AD. Preliminary results of our own meta-analysis of clinical trial data indicate that the use of statins may delay or slow down the progression of the disease and cognitive decline, to a greater extent in ApoE4 carriers.
1b: Despite substantial research and development investment in Alzheimer’s disease, effective therapeutics remain elusive. Our precision medicine approach will generate scientific evidence needed to drive the development of therapies that treat the right person, with the right treatment at the right time.
1c: We propose the use of a precision medicine approach, which takes into account people’s individual variations in genes, environment and lifestyle, for analysis of data from the UK BioBank, in order to further examine the effect that the use of statins may have on the onset and cognitive decline of Alzheimer’s disease.
1d: Full cohort
Project extension – January 2020
We used an apoE-genotype-specific drug repositioning approach to screen for drugs to treat apoE4-related AD. From a meta-analysis of 214 human temporal lobar samples from public databases, we established apoE-genotype-specific transcriptomic signatures of AD and applied them to a validated Connectivity Map (CMap) database containing transcriptomic perturbation signatures of 1300 existing drugs to identify those capable of perturbing an entire gene-expression network away from the apoE-genotype-driven disease state towards a normal state. The loop-diuretic bumetanide was the top predicted drug candidate for apoE4/4 AD. Treating aged apoE4 knock-in (apoE4-KI) mice with bumetanide rescued cognitive deficits, warranting further efficacy tests in human EMR Data. We propose to analyze the rate of Alzheimer’s disease among apoE4-carriers who have taken bumetanide as compared to a demographic and genotype matched control group to answer the question of whether bumetanide exposure lower the incidence of apoE4-related AD. We would like to expand the scope of the original proposal using the same method we applied to genotype apoE4 carriers from the available genetic data, as well as similar methods to probe the effect of the FDA-approved compound Bumetanide on apoE4-related AD.
Last updated Jan 28, 2020