The Friedman Brain Institute

Alzheimer's Disease Research

Alzheimer's disease research at The Friedman Brain Institute integrates basic, clinical, and translational research to better understand the molecular pathology of the disease and improve treatment.

Interdisciplinary research programs span genetics and genomics, preclinical cellular and animal models, patient-oriented research and clinical trials. Using state-of-the-art approaches, we continue to make breakthroughs in multiple aspects of dementia research. Our diverse team publishes more than 50 articles per year in peer-reviewed journals. Three interrelated centers focus on different aspects of Alzheimer’s disease including basic, translational, and patient-oriented research and clinical care. They are: the Loeb Center for Alzheimer’s Disease, the Alzheimer’s Disease Research Center, and the Center for Cognitive Health

Alzheimer’s Disease and Related Dementias

There are more than sixty causes of dementia, which is characterized by impairment of memory and thinking. Alzheimer’s disease is the most common cause and is characterized by gradual onset and progression of disease, usually in later life (age 60 and over).  Impairment of memory, particularly for recent events, is most often the initial symptom of disease. Death usually occurs within 5 to 20 years.  In Alzheimer’s, the brain is characterized by the abundant presence of beta-amyloid plaques and neurofibrillary tangles and substantial neuronal cell loss, particularly in the neocortex. It has recently been demonstrated that the disease also involves a substantial (10 to 20 years) presymptomatic phase in which first beta-amyloid plaques and then neurofibrillary tangles accumulate, leading to neurodegeneration and ultimately to clinical symptoms.

Investigators involved:  Dongming Cai, Joseph M. CastellanoJohn Crary, Fanny Elahi, Michelle EhrlichSamuel E. GandyAlison GoateKe HaoPatrick R. HofGiulio M. PasinettiStephen SaltonNikolaos K. RobakisEric SchadtAnne Schaefer, Merina T. Varghese, Herbert Wu, Bin Zhang

Frontotemporal Dementia (FTD) is characterized clinically by early and prominent changes in personality and behavior. Some forms are also associated with profound aphasia. This form of dementia usually has an onset between 55 to 65 years. Like Alzheimer’s, FTD is associated with protein deposits in the diseased brain. The most common form of FTD is associated with deposits of the RNA-binding protein TDP43. A second form of FTD is characterized by the presence of neuronal or glial tangles composed of tau protein (tauopathy). Genetic studies have demonstrated that FTD and amyotrophic lateral sclerosis (ALS) are etiologically related to one another. Mutations in several genes can lead to either FTD or ALS in family members.

Investigators involved: Alison GoateJohn Crary

Genetics and Genomics of Alzheimer’s Disease

Alzheimer’s disease is a complex genetic disorder. A small percentage of cases are inherited as an autosomal dominant trait (50% of the offspring of affected individuals develop disease).  Among these cases, three genes have been identified that can carry causative mutations: ß-amyloid protein precursor (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2).  Mutations in these genes are generally associated with an early age at onset (< 60 years).  Most cases of Alzheimer’s do not show such striking familial clustering and have an age at onset which is usually more than 60 years. Among this group, the strongest genetic risk factor is the apolipoprotein E4 allele.  Presence of a single E4 allele increases risk by approximately three-fold while two copies increases risk by as much as 10-fold. Genome-wide association studies have identified more than 20 loci, and next generation sequencing studies have identified rare variants in other genes that influence risk for late onset Alzheimer’s (LOAD). These studies have implicated lipid metabolism, innate immunity and endocytic trafficking in risk for LOAD

Investigators involved: Fanny Elahi, Alison Goate, Joseph M. Castellano, Ke HaoEric SchadtBin Zhang

Understanding the Molecular Basis and Mechanism of Alzheimer’s Disease

Mutations in APP and PSEN influence the cleavage of APP by beta and gamma secretases leading to higher levels of total Aß or Aß42, resulting in earlier amyloid aggregation and deposition.  In contrast APOE influences clearance of Aß, with the risk allele for Alzheimer’s, APOE4, being less efficient at clearing Aß. For most other genes and proteins linked to Alzheimer’s risk, the underlying mechanisms remain unclear and are the focus of our research. Our investigators use a diverse range of approaches to understand disease mechanism, including neuroimaging, genomics, cell-based studies including use of induced pluripotent stem cells and transgenic approaches.

Investigators involved:  Dongming Cai, Joseph M. Castellano, Fanny Elahi, Michelle EhrlichSamuel E. GandyAlison GoateKe HaoPatrick R. HofGiulio M. PasinettiNikolaos K. RobakisStephen SaltonEric SchadtAnne Schaefer, Merina T. Varghese, Bin Zhang

Advanced Clinical Care and Research

The Mount Sinai Alzheimer's Disease Research Center (ADRC), a leading center funded by the National Institute on Aging, supports state-of-the-art clinical care and research. Through the clinical resources of the ADRC, we conduct comprehensive neuropsychological, genetic, biomarker and diagnostic characterization on a clinical cohort. Our work is supported through a close collaboration with the Mount Sinai Center for Cognitive Health (CCH) and the Martha Stewart Center for Living. Within this infrastructure, we design and conduct innovative clinical trials and studies to treat or prevent cognitive loss within a wide range of conditions, including Alzheimer disease, mild cognitive impairment, diabetes and traumatic brain injury.  The core cohort is available for research studies, and the core faculty can provide expertise in developing evaluations for other settings and studies. We also maintain extensive historical databases of these resources, which are available for researchers. Finally, we offer post-mortem neuropathological analysis on brain tissue specimens from persons with Alzheimer’s disease and comparison groups. An extensive bank of this well-characterized material is available to qualified researchers.

Investigators involved: Dongming Cai, Fanny Elahi, Michelle EhrlichSamuel E. GandyAlison GoateKe HaoPatrick R. HofGiulio M. PasinettiNikolaos K. RobakisMary SanoEric SchadtBin Zhang

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