The Ronald M. Loeb Center for Alzheimer's Disease

We employ cutting-edge induced pluripotent stem cell (iPSC) technology to create sophisticated human cellular models of Alzheimer's disease. Our researchers develop specialized 3D stem cell models that replicate critical aspects of the human brain, allowing for detailed examination of disease mechanisms in a controlled environment. These include innovative blood-brain barrier models that enable the study of cerebrovascular dysfunction and its contribution to neurodegeneration, particularly in cerebral amyloid angiopathy—a common Alzheimer's comorbidity.

Our scientists engineer iPSC-derived neurons, microglia, and hypothalamic organoids to investigate how genetic variants associated with Alzheimer's disease affect cellular function and contribute to pathology. Using advanced genetic and molecular tools, researchers observe, record, and manipulate neuronal activity while examining its impact on glial states. This work focuses particularly on how disease-associated mutations in genes such as SPI1, APOE, MS4A4A/MS4A6A, LACTB, and MAPT influence microglial behavior and their transition between different functional states in response to Alzheimer's pathology.

The Center's teams utilize high-throughput screening and CRISPR-based approaches to prioritize noncoding variants that may contribute to functional changes in Alzheimer's disease. By investigating how these variants influence alternative gene expression and splicing events, our researchers aim to identify regulatory elements that could become targets for gene therapy or modulation of gene expression. This patient-specific approach leverages iPSC technology to generate personalized cellular models, providing insights into both the molecular mechanisms of the disease and potential therapeutic interventions tailored to individual genetic profiles.

The Ronald M. Loeb Center for Alzheimer's Disease utilizes diverse animal models to investigate the fundamental mechanisms of Alzheimer's disease (AD) progression and potential therapeutic interventions. Through genetically engineered mouse models, Center scientists examine how mutations in presenilin 1, presenilin 2, apolipoprotein E, and amyloid precursor protein contribute to both familial and sporadic forms of the disease.

Investigations at the Center focus on memory formation, storage, and updating across the lifespan. Our teams combine in vitro and in vivo recording approaches to examine changes at the molecular, cellular, and network levels that may contribute to memory deficits during normal aging and in age-related disorders. One significant finding revealed that middle-aged mice show impaired ability to update spatial memories, correlated with their inability to decrease hippocampal ensemble connection—suggesting that weakening connections of prior memory ensembles to create "space" for new ones may be crucial for memory updating.

Our researchers employ sophisticated techniques like in vivo gene transfer with adeno-associated virus (AAV) vectors and nanoparticles to investigate genetic and metabolic contributions to neurodegeneration. Comprehensive metabolic assessments examine food intake, activity levels, indirect calorimetry, and gene expression to understand how metabolic architecture influences disease progression. Additionally, we study the impact of chronic intermittent hypoxia (mimicking obstructive sleep apnea) on tau pathology and explore how PSEN1 mutations damage brain blood vessels, potentially contributing to early AD pathology. Lipid nanoparticles (LNPs) represent an important technological frontier for drug delivery to the brain, and Center investigators are using LNPs to deliver gene therapies targeting APOE. These multifaceted approaches aim to identify novel therapeutic targets and interventions.

Our investigators conduct extensive research into various dementia forms beyond Alzheimer's disease. Current efforts include a family-based study recruiting patients with a family history of dementia for genetics, blood biomarkers, and transcriptomic analysis.

A major focus at The Ronald M. Loeb Center for Alzheimer’s Disease involves integrating Lewy body dementia and amyotrophic lateral sclerosis genome-wide association study datasets with brain cell type-specific omics data. This integration helps functionally map disease common variant loci and nominate candidate causal genes. The Center is actively expanding its recently published genome-wide association analysis of progressive supranuclear palsy, already the largest study to date, with the goal of doubling its size.

Innovative approaches at the Center include integrating machine learning-derived traits from whole slide images of paired brain tissue with genetic data in progressive supranuclear palsy. This methodology moves beyond conventional case-control approaches. Additional work examines CADASIL and other white matter disorders, studying monogenic conditions affecting vasculature through genes like NOTCH3, HTRA1, COL4A, TREX1, and GLA. Through detailed microscopic examination, investigators have contributed to the classification and staging of primary age-related tauopathy, chronic traumatic encephalopathy, aging-related tau astrogliopathy, and progressive supranuclear palsy.

The Ronald M. Loeb Center for Alzheimer's Disease also focuses on Parkinson's disease and related synucleinopathies. Studies focus on the molecular mechanisms of dopamine neuron degeneration and autophagy-lysosome dysfunction that contribute to protein aggregation disorders in the central nervous system.

A key area of investigation at the Center involves the development of spinal fluid biomarkers for Parkinson's disease, which could enable earlier and more accurate diagnosis. Our teams are also exploring the intersectional pathogenesis of LRRK2 mutations in both Crohn's disease and Parkinson's disease, seeking to understand how this genetic factor contributes to these seemingly distinct conditions.

Our research includes tandem repeat analysis, investigating how short DNA sequences repeated in direct succession may influence gene expression, genome stability, and protein function in neurological diseases. Using advanced whole genome sequencing and novel bioinformatic pipelines, scientists systematically profile short tandem repeats and variable number tandem repeats across the genome to detect variations and expansions. This work is complemented by phenome-wide association studies linking tandem repeat variants with clinical traits such as cognitive symptoms or disease onset, helping define how repeat expansions contribute to disease heterogeneity. Additionally, the Center is developing diagnostic and therapeutic nanobodies for both Parkinson's disease and Alzheimer's disease.

Researchers at The Ronald M. Loeb Center for Alzheimer's Disease are at the forefront of translating genetic insights into novel therapeutic approaches. Utilizing computational and experimental models, the Center prioritizes gene targets for precision medicine, including RNA-based therapeutics and drug repurposing strategies for brain disorders.

Scientists at the Center have predicted and validated multiple gene regulatory network key regulators—including TYROBP, VGF, ATP6V1A, and PLXNB1—that drive Alzheimer's disease pathology. These discoveries offer new insights into disease complexity and direct new therapeutic development efforts. Our multidisciplinary approach incorporates artificial intelligence and high-throughput screening in C. elegans and microglia to discover small molecules with therapeutic potential.

As a key contributor to major research consortia, we develop and apply advanced bioinformatics pipelines to integrate diverse datasets and accelerate discoveries in neurodegeneration. Current development projects include novel algorithms for repurposing drugs and drug combinations, an AI-powered structure-based platform for drug discovery, and specialized compounds for treating complex conditions, including Alzheimer's and Parkinson's disease. Many studies have demonstrated that drug targets with human genetic support are more likely to survive the pharmaceutical industry drug development pipeline and become an FDA-approved drug. Based on this knowledge, an important therapeutic strategy at The Ronald M. Loeb Center for Alzheimer’s disease is to target Alzheimer’s disease risk genes to understand the underlying mechanisms and develop novel therapies. For example, lower levels of AD associated proteins, MS4A4A/MS4A6A and LACTB in microglia, are known to be protective. We are devising novel therapeutics that mimic these protective mechanisms.