ADRC Research

The Stanford Alzheimer’s Disease Research Center (ADRC) supports internal research in the form of developmental projects. These are usually conducted over a two year period and are funded for up to $250,000 each. The Stanford ADRC selected two projects in 2020, and we anticipate new projects in 2021, 2022, and 2023. Developmental project grants are intended for junior faculty level investigators and for more senior investigators whose research lies in other areas and who now want to work in the field of Alzheimer disease and related disorders.

The Stanford ADRC contributes de-identified data and biological resources to registries and repositories supported by the National Institute on Aging. It supports other research at Stanford University and at other institutions. Center support can include de-identified data (clinical, neuropsychological, structural and molecular brain imaging, genetic, ‘omics, microbiome, and neuropathological), fluid biospecimens obtained from ADRC volunteers (plasma, CSF), fibroblast cell lines, autopsy tissues, biostatistical consultation, and research guidance.

The Stanford ADRC supports research training and education in a variety of ways. The ADRC Research Fellowship Program is described more fully in the Research Education Component. This program provides integrated clinical and basic science training opportunities and mentored research experiences. It is designed to prepare the next generation of researchers for careers in brain aging and in Alzheimer’s disease and related disorders.

ADRC Developmental Projects

Developmental research project (2020) 1.1

Principal investigator: Abu-Remailehm, Monther, PhD

Title: Molecular basis of lysosomal dysfunction in neurodegeneration

Project description: Neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia affect millions of people worldwide. With no cure available, they represent the world’s fifth-largest cause of death. Aging is the single biggest risk factor in developing neurodegenerative disorders. Thus, with expansion of the aging population the prevalence of these fatal diseases is on the rise. Recent evidence has implicated lysosomal dysfunction as a possible cause of various forms of Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia: 1) Several familial forms of these diseases are caused by mutations in genes encoding lysosome-associated proteins. 2) Almost 56% of sporadic Parkinson’s disease cases carry at least one damaging variant in a gene whose dysfunction leads to a lysosomal storage disease. 3) Abnormalities in endo-lysosomal system are among the earliest known cytopathologies in Alzheimer’s disease and mutations in genes that promote b-amyloidogenesis have direct primary effects on lysosomes. Lysosomes are cellular compartments that degrade macromolecules and clear damaged organelles. Lysosomes have also emerged as major regulators of cell signaling, metabolism and longevity. There is an urgent need to understand the molecular and biochemical basis of lysosomal dysfunction in age-associated neurodegenerative diseases to determine its role in disease pathology. This has been challenging because of lack of tools to probe protein, small molecule, and RNA contents of lysosomes. To overcome this hurdle, we have recently developed a method to rapidly immunopurify lysosomes from cells and tissues (LysoIP). Purified lysosomes are suitable for small molecule profiling using liquid chromatography/mass spectrometry. Using this innovative approach, we identified the biochemical basis of lysosomal dysfunction in Batten disease, a monogenic early-onset neurodegenerative disease. In this proposal we hypothesize that lysosomal dysfunction is a driver event in age-associated neurodegeneration. By profiling lysosomes from Alzheimer’s disease and Parkinson’s disease patient-derived cells, we will determine the exact biochemical basis of lysosomal dysfunction in these fatal diseases. To achieve this, we will:

Aim 1: Generate LysoTag Alzheimer’s disease and Parkinson’s disease patient-derived fibroblasts. We will leverage the precious resources at Stanford Alzheimer's Disease Research Center to acquire skin fibroblasts derived from healthy donors, Alzheimer’s disease or Parkinson’s disease patients to tag and study their lysosomes using our innovative technology.

Aim 2: Define the metabolomic, lipidomic, and proteomic landscape of the lysosome in Alzheimer’s disease and Parkinson’s disease patient-derived fibroblasts. To determine the biochemical basis of lysosomal dysfunction in Alzheimer’s disease and Parkinson’s disease, we will profile the metabolome, lipidome and proteome of lysosomes purified from engineered patients’ fibroblasts.

Aim 3: Determine the consequences of the lysosomal changes we discover and leverage them to understand the biochemical basis of neurotoxicity in Alzheimer’s disease and Parkinson’s disease. Using functional approaches, we will determine the role of altered lysosomal pathways in disease pathology.

Developmental research project (2020) 1.2

Principal investigator: Heather E. Moss, MD, PhD

Title: Retinal biomarkers of Alzheimer’s disease and related diseases

Project description: Development of effective therapies for Alzheimer’s disease and related diseases has been hampered by lack of biomarkers to facilitate early diagnosis of disease and measure early treatment response. The retina is a promising tissue in which to identify biomarkers of neurological diseases because the retina is comprised of neural tissue and can be imaged non-invasively in vivo with high resolution. Historical attempts to leverage in vivo imaging derived retinal measurements in patients with neurological diseases for clinical advantage has been stymied by lack of specificity, which we believe is due to low resolution of clinical retinal imaging modalities. Accordingly, this application seeks to apply state-of-the-art retinal imaging technology to discover features in the retinas of human subjects with mild cognitive impairment and Alzheimer’s disease that can be developed as biomarkers for early detection of Alzheimer’s disease and measurement of Alzheimer’s disease progression. We hypothesize that there are specific retinal changes associated with Alzheimer’s disease and that these can be detected using in-vivo ophthalmic imaging. Subjects with Alzheimer’s disease, mild cognitive impairment and healthy controls will undergo cellular-level retinal imaging with adaptive optics scanning laser ophthalmoscopy. Structural retinal features unique to Alzheimer’s disease and mild cognitive impairment subjects will be identified through comparison with control subjects. Categorical and continuous measures of retinal structural features will be correlated with baseline cognitive testing, neuroimaging and cerebrospinal fluid measures collected for Alzheimer’s disease and mild cognitive impairment subjects through the Alzheimer’s Disease Research Center as well as with changes in these measures during the year after retinal imaging. The immediate impact of this project will be to identify specific retinal features in living humans that are candidates for detection of neurodegeneration and progression of neurodegeneration in Alzheimer’s disease. The features will have direct translational potential as biomarkers that are relevant to human disease and practical for measurement in living humans. In the longer term these will serve as the foundation for new directions for Alzheimer’s disease research in humans, including developing interventions to prevent and treat Alzheimer’s disease.

ADRC Research, 2015-2019