Genetic Risk for Alzheimer’s Disease: What this Tells Us about Mechanism of Disease

Event Details

Type

Friday Lecture Series

Speaker(s)

Alison M. Goate, D.Phil., Jean C. and James W. Crystal Professor of Genomics, chair of the department of genetics and genomic sciences, professor of neuroscience and neurology, Icahn School of Medicine at Mount Sinai

Speaker bio(s)

Alzheimer’s disease is the most common form of dementia affecting more than 6.7 million Americans age 65 years and older. It is characterized clinically by slowly progressive memory loss and neuropathologically by the presence of extracellular ß-amyloid (Aß) plaques, intracellular accumulation of neurofibrillary tangles, and the presence of neurodegeneration and gliosis. Studies in genetic and sporadic forms of AD have demonstrated that both forms of the disease are characterized by a prodromal phase, lasting up to two decades, in which plaques and tangles accumulate leading to neurodegeneration. Inherited forms of AD are associated with mutations in the amyloid precursor protein (APP) gene or the presenilins (1 & 2) and directly implicate APP metabolism in disease pathogenesis. During the last year several antibody-based therapies targeting ß-amyloid have been approved by the FDA. However, although Aß accumulates in sporadic forms of the disease other mechanisms are likely to be important. The most common genetic risk factor in late onset AD, is apolipoprotein E (APOE) genotype. Both risk and protective alleles have been identified enabling mechanistic studies of the role of APOE in AD risk. Genome-wide association studies have implicated close to one hundred other loci in AD risk and integrative genomic studies demonstrate that these common alleles are largely non-coding and reside in microglial enhancers. Genomic, epigenomic and functional studies demonstrate that these risk genes influence microglial state and their response to Aß and/or neurodegeneration. Rare coding variants in TREM2, PLCG2 and ABI3 also highlight the importance of microglia and implicated TREM2 signaling as a central biochemical response of microglia to Aß or damage caused by Aß in the AD brain.

Dr. Alison Goate has worked on the genetics of neurodegenerative diseases including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) since 1987, and is the founding director of the Ronald M. Loeb Center for Alzheimer’s disease at ISMMS. She reported the first mutation to cause familial Alzheimer's disease. Dr. Goate is also a leader in the study of late onset AD genetics using both GWAS and sequencing approaches. Her team demonstrated the enrichment of AD risk variants in microglial enhancers, regulatory elements that control gene expression in immune cells of the brain. She is now building upon these insights using genome-editing in induced pluripotent stem cells to understand the molecular mechanisms of disease and to develop novel therapeutics. Dr. Goate has received many awards for her research including the Potamkin Award from the American Academy of Neurology, the Khalid Iqbal Lifetime Achievement Award from the Alzheimer’s Association, the MetLife Award and the Rainwater Prize for Innovation in Neurodegeneration. She was elected a fellow of AAAS in 2012 and a fellow of the National Academy of Medicine in 2016.

FLS lectures will take place in Caspary Auditorium and virtually via Zoom. We recommend virtual participants log out of VPN prior to logging in to Zoom. Please do not share the link or post on social media.

We recommend virtual participants log out of VPN prior to logging in to Zoom. Please do not share the link or post on social media. This lecture will be recorded for the RU community.

Open to

Tri-Institutional