The Friedman Brain Institute

There are more than 60 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 the disease, usually in later life (age 60 and over). Impairment of memory, particularly for recent events, is most often the initial symptom of disease.

With Alzheimer’s disease, 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 in the research area include:

• Joel Blanchard, PhD
• Joseph M. Castellano, PhD
• John Crary, MD, PhD
• Michelle Ehrlich, MD
• Fanny Elahi, MD, PhD
• Samuel E. Gandy, MD, PhD
• Alison Goate, DPhil
• Ke Hao, PhD
• Julius (Trey) Hedden III, PhD
• Patrick R. Hof, MD
• Edoardo M Marcora, PhD
• Giulio M. Pasinetti, MD, PhD
• Ana Pereira, MD
• Towfique Raj, PhD
• Alan E Renton, PhD
• Nikolaos K. Robakis, PhD
• Panagiotis Roussos, MD, MS, PhD
• Stephen Salton, MD, PhD
• Eric Schadt, PhD
• Anne Schaefer, MD
• Merina T. Varghese, PhD
• Mat Victor, PhD
• Herbert Wu, PhD
• Bin Zhang, PhD

Frontotemporal Dementia

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 disease, FTD is associated with protein deposits in the diseased brain. The most common form of frontotemporal dementia is associated with deposits of the RNA-binding protein TDP43. A second form is categorized by the presence of neuronal or glial tangles composed of tau protein (tauopathy). Genetic studies have demonstrated that frontotemporal dementia 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 in this research area include:

• John Crary, MD, PhD
• Fanny Elahi, MD, PhD
• Alison Goate, DPhil

Alzheimer’s disease is a complex genetic disorder. A small percentage of cases are inherited as an autosomal dominant trait (50 percent 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 disease 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 increase risk by as much as 10-fold in people of European ancestry. APOE4 risks differ across ancestry considerably with APOE4 conferring lower risk in people of African ancestry but higher risks in people of Asian ancestry relative to the figures provided for European ancestry. Genome-wide association studies have identified more than 100 loci, and next generation sequencing studies have identified rare variants in other genes that influence risk for Late Onset Alzheimer’s Disease (LOAD). These studies have implicated myeloid cell enhancers as the site of most AD risk alleles suggesting that regulation of microglial/macrophage gene expression and response to ß-amyloid and/or cellular damage caused by ß-amyloid is key to the development to LOAD. Pathway analyses implicate lipid metabolism, innate immunity and endocytic trafficking in risk for LOAD. In microglia/macrophages this suggests that efferocytosis or clearance on lipid rich debris/apoptotic cells is a central pathway for disease.

Investigators in this research area include:

• Joseph M. Castellano, PhD
• Fanny Elahi, MD, PhD
• Alison Goate, DPhil
• Ke Hao, PhD
• Edoardo M Marcora, PhD
• Towfique Raj, PhD
• Alan E Renton, PhD
• Panagiotis Roussos, MD, MS, PhD
• Eric Schadt, PhD
• Bin Zhang, PhD

Mutations in the amyloid precursor protein (APP) and presenilin genes 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 disease, APOE4, being less efficient at clearing Aß.

For most other genes and proteins linked to Alzheimer’s disease risk, the underlying mechanisms remain unclear and are the focus of research. Our investigators use a diverse range of approaches to understand disease mechanisms, including neuroimaging, genomics, cell-based studies, including use of induced pluripotent stem cells and transgenic approaches.

Investigators in this research area include:

• Joel Blanchard, PhD
• Joseph M. Castellano, PhD
• John Crary, MD, PhD
• Michelle Ehrlich, MD
• Fanny Elahi, MD, PhD
• Samuel E. Gandy, MD, PhD
• Alison Goate, DPhil
• Ke Hao, PhD
• Julius (Trey) Hedden III, PhD
• Patrick R. Hof, MD
• Edoardo M Marcora, PhD
• Giulio M. Pasinetti, MD, PhD
• Ana Pereira, MD
• Towfique Raj, PhD
• Alan E Renton, PhD
• Nikolaos K. Robakis, PhD
• Panagiotis Roussos, MD, MS, PhD
• Stephen Salton, MD, PhD
• Eric Schadt, PhD
• Anne Schaefer, MD
• Merina T. Varghese, PhD
• Mat Victor, PhD
• Herbert Wu, PhD
• Bin Zhang, PhD

The Mount Sinai Alzheimer's Disease Research Center, 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 Alzheimer's Disease Research Center, we conduct comprehensive neuropsychological, genetic, biomarker, and diagnostic characterization on a clinical cohort. Our work is supported through a close collaboration with the Barbara and Maurice Deane Center for Wellness and Cognitive Health and the Martha Stewart Centers 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’s 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 in this research area include:

• John Crary, MD, PhD
• Michelle Ehrlich, MD
• Fanny Elahi, MD, PhD
• Samuel E. Gandy, MD, PhD
• Alison Goate, DPhil
• Hillel T Grossman, MD
• Ke Hao, PhD
• Vahram Haroutunian, PhD
• Julius (Trey) Hedden III, PhD
• Patrick R. Hof, MD
• Judith A Neugroschl, MD
• Giulio M. Pasinetti, MD, PhD
• Towfique Raj, PhD
• Nikolaos K. Robakis, PhD
• Stephen Salton, MD, PhD
• Mary Sano, PhD
• Eric Schadt, PhD
• Margaret Sewell, PhD
• Bin Zhang, PhD
• Carolyn W Zhu