Center for Memory Disorders Research Programs
At the Stanford Center for Memory Disorders, we are as passionate about research as we are about taking care of patients. Our research spans a full spectrum, from bench to bedside: In basic science labs, we investigate the fundamental causes of Alzheimer's disease and creating novel treatments. Other faculty of the Center study advanced neuroimaging technologies and lab-based studies of blood samples, in an effort to make early diagnosis possible. Finally, we enroll interested patients in clinical trials of new therapies.
Discovering the cure for Alzheimer's disease will require good ideas from unexpected places. The Stanford Center for Memory Disorders benefits from being a part of Stanford University, a world-class research university with an enviable track record of discoveries, inventions, and ground-breaking contributions to virtually every area of human knowledge dating back to 1891.
Memory Disorders Research Programs
We are interested in understanding how immune responses promote neurological disease. Recent advances in human genetics, particularly for neurodegenerative disorders like Alzheimer’s disease, have highlighted a causal role of disrupted immune responses in disease pathogenesis. An injurious immune response may be a common denominator across many neurological disorders, both acute (brain trauma or stroke) and chronic (epilepsy, Parkinson’s disease, Alzheimer's for eg.). An understanding of how innate immune responses cause neurological disease will be essential if we are to develop disease-modifying therapies for our patients. Using systems biology approaches, we are identifying immune pathways that regulate immune metabolism and immune responses at the brain interface. Our objectives are (1) to understand how aberrant brain and/or peripheral innate immune responses cause synapse loss and contribute to the vulnerability of selected circuits in different neurologic disorders, and (2) to develop preventive and therapeutic strategies targeting these inflammatory pathways in patients with neurologic diseases.
The Greicius lab uses imaging, genetics, and imaging genetics to better understand Alzheimer’s disease and related disorders from the level of molecular pathways to large-scale distributed brain networks and behavior. Recent and ongoing work leverages the APOE4 genetic variation that increases risk for Alzheimer’s disease. In the Stanford Extreme Phenotypes in Alzheimer’s Disease (StEP AD) study, the lab is looking for protective genetic variants in healthy older subjects that have 1 or 2 copies of the high-risk APOE4 gene but do not show signs of Alzheimer’s disease. The StEP AD study is also looking at the for novel causal genetic mutations in patients with early-onset Alzheimer’s disease who do not have the APOE4 variant. All participants undergo “deep phenotyping” including molecular imaging, immunophenotyping, and blood/spinal fluid biomarkers. The expectation is that novel protective or causal variants identified in the StEP AD study will provide novel targets for drug development.
The primary aim of the James Lab is to improve the diagnosis and treatment of brain diseases by developing translational molecular imaging agents for visualizing neuroimmune interactions underlying conditions such as Alzheimer’s disease, multiple sclerosis, and stroke. We are researching how the brain and its resident immune cells interact with the peripheral immune system at very early, through to late, stages of disease. Our approach involves the discovery and characterization of clinically relevant immune cell biomarkers, followed by the design of imaging agents specifically targeting these biomarkers. After preclinical validation, we translate promising imaging probes to the clinic to enable precision targeting of immunomodulatory therapeutics and real-time monitoring of treatment response.
Within the population health sciences, our research agenda encompasses cognitive change that occurs as a usual concomitant of normal aging and the debilitating cognitive impairment that accompanies Alzheimer’s disease and other forms of dementia. Pathological changes of Alzheimer’s disease are believed to begin years, if not decades, before the onset of mental symptoms. For this reason, a key aspect of our research includes the investigation of factors that affect cognitive skills at midlife, a time when therapeutic interventions offer the greatest potential of forestalling late-life impairment. Our approach includes both investigator-initiated randomized clinical trials and population-based observational research. One important platform for our work is the Stanford Alzheimer’s Disease Research Center, a congressionally-mandated NIH center of excellence funded by the National Institute on Aging. We have also partnered with clinical epidemiologists at the University of Aarhus, Denmark, to examine risk factors for Alzheimer’s disease using linked Danish medical registries.
Dr. Longo and his research team are focused on elucidating mechanisms underlying neurodegenerative disorders and developing small molecule therapeutic strategies that target these mechanisms. Neurotrophin proteins bind to multiple receptors (p75, TrkA-C) to modulate survival, functional and degenerative intracellular signaling and synaptic function. The Longo laboratory and collaborators pioneered the mechanistic principle that non-peptide small molecules targeting individual receptor epitopes can activate or modulate neurotrophin receptors to produce distinctive biological effects capable of inhibiting disease mechanisms. This work has led to successful efficacy trials in many mouse models of neurodegenerative disorders including Alzheimer’s, Huntington’s, and Parkinson’s diseases as well as spinal cord injury, traumatic brain injury, chemotherapy-induced neuropathy, ischemic stroke recovery, Rett syndrome, and epilepsy. One of our small molecules, the p75NTR ligand, LM11A-31, has progressed through a human phase 1 safety trial and is in a phase 2a Alzheimer’s disease trial ongoing in Europe. We have been fortunate to execute the rare full translational spectrum of: identifying novel basic mechanisms, creating novel entities to target those mechanisms, moving these therapeutic candidates through mouse and other pre-clinical studies, progressing one of these candidates to first-in-human safety studies and testing of the first-in-class therapeutic entity in neurodegenerative disease subjects.
Our overall research objective is to understand the risk of Alzheimer’s disease before clinical symptoms of dementia are present. To study the earliest stages of Alzheimer’s disease, we take a multimodal approach to deeply phenotype our human research volunteers. Our studies integrate information from molecular PET imaging (especially Amyloid and Tau PET), MRI scans that provide information about brain structure and function, lumbar puncture to investigate the biomarkers in the cerebrospinal fluid, sensitive neuropsychological measurements, and genetics. Our hope is that the combination of these data types will improve our ability to predict who is most at risk for dementia decades before clinical symptoms are present.
At the Poston Lab, we seek understand the cognitive and other non-motor impairments that develop in patients with alpha-synuclein pathology, such as Parkinson’s disease, Lewy body dementia, and Multiple System Atrophy. Our lab uses functional and structural imaging, along with biological and genetic biomarkers, to determine the underlying pathophysiologies that cause these impairments, with the ultimate goal of aiding the development of new therapies.
The Skylar-Scott Lab is interested in assessing how cognitive, social, and physical activity affect cognitive performance and Alzheimer’s biomarkers cross-sectionally and longitudinally in a healthy older adults The lab is interested in exploring what biomarkers, demographic features, and lifestyle factors serve as “resilience factors” that correlate with superior cognitive performance. In the future, the lab hopes to investigate which lifestyle interventions prove most effective across the entire clinical continuum, from cognitively normal healthy adults to Alzheimer’s disease patients with dementia.
The Wyss-Coray research team studies brain aging and neurodegeneration with a focus on age-related cognitive decline and Alzheimer’s disease. The team is studying how circulatory blood factors can modulate brain structure and function and how factors from young organisms can rejuvenate old brains. We are trying to understand the molecular basis of the systemic communication with the brain by employing a combination of genetic, cell biology, and –omics approaches in killifish, mice, and humans and through the development of bio-orthogonal tools for the in vivo labeling of proteins.