Research Overview

My research aims to uncover the biological principles that govern adaptation, plasticity, and resilience across aging and disease. Using the aging brain as a model system, I investigate how immune signaling, lipid metabolism, lysosomal biology, and cellular state transitions coordinate adaptive responses that preserve function or drive dysfunction. By integrating genetics, multi-omics, spatial biology, and longitudinal analyses, I aim to define the molecular and cellular mechanisms that shape biological aging and identify opportunities for therapeutic intervention.

A central goal of my research program is to understand why some biological systems remain resilient while others transition toward dysfunction, and how these adaptive trajectories can be measured, predicted, and ultimately reprogrammed. Looking forward, I aspire to uncover universal principles of adaptive biology, including those found in exceptional human aging and natural models of extreme adaptation, and translate these discoveries into innovative strategies that promote healthy aging, preserve brain health, and improve human resilience.

Core Scientific Questions

1. Adaptation - What determines biological adaptation and resilience?

• How do cells and tissues adapt to aging, environmental stress, and disease?

• Which adaptive programs preserve function, and which lead to dysfunction?

• How do genetic variation and environmental factors shape resilience across the lifespan?

2. Plasticity - How do biological systems change across aging and disease?

• How do lipid metabolism, lysosomal function, and proteostasis regulate cellular resilience?

• Why do some cells, tissues, and brain regions remain resilient while others become vulnerable?

• How do metabolic and cellular state transitions influence aging, regeneration, and disease progression?

3. Transformation - Can aging be measured, predicted, and reprogrammed?

• How can we move beyond chronological age to quantify dynamic biological states?

• What biomarkers best capture adaptation, resilience, and reversibility?

• Can aging trajectories be redirected through targeted biological interventions?

4. Translation - Can nature's adaptive strategies improve human health?

• How has evolution shaped exceptional resilience to aging and environmental stress?

• What can we learn from hibernation, exceptional longevity, regeneration, and natural resistance to extreme environments?

• Can these adaptive programs be translated or engineered to promote healthy aging and disease resistance?

Research Support 

Ongoing

Project: Identifying Resilience Mechanisms in Aging and AD through Microglial Intervention

Project Period: 09/11/2026 - 08/31/2028

Principal Investigator: Tsai AP

Sponsor: K99/R00 NIH Pathway to Independence Award, National Institute on Aging

Project Description: Microglial dysfunction, characterized by lipid droplet accumulation, lysosomal deficits, and impaired debris clearance, is a shared hallmark of brain aging and Alzheimer’s disease (AD), yet the mechanisms that sustain microglial resilience remain poorly understood. These studies will advance our understanding of the molecular and spatial mechanisms that underlie microglial resilience and may reveal novel therapeutic targets to preserve brain health and cognitive function in aging and AD.

Project: Uncovering Alzheimer’s and Parkinson’s disease-specific transcripts through single-cell long-read sequencing

Project Period: 10/15/2025 - 03/31/2027

Principal Investigator: Tsai AP

Sponsor: Stanford Alzheimer’s Disease Research Center

Project Description: The objective of this project is to identify Alzheimer’s disease- and Parkinson’s disease-specific immune transcript isoforms using single-cell long-read RNA sequencing. By integrating genetic risk variants, transcript isoform diversity, and disease-relevant immune states, this work aims to uncover previously unrecognized molecular mechanisms underlying neurodegeneration and to establish a foundation for immune-targeted therapeutic and biomarker development.

Completed

Project: The role of an AD protective- and longevity-associated variant of PLCG2 in brain aging

Project Period: 07/01/2023 - 06/30/2026

Principal Investigator: Tsai AP

Sponsor: Larry L. Hillblom Foundation

Project Description: The primary objective of this project is to define how the Alzheimer’s disease protective and longevity-associated PLCG2 P522R variant preserves brain resilience during aging. This work investigates genetic, cellular, and molecular mechanisms by which PLCG2 signaling maintains microglial function, limits age-associated neuropathology, and promotes healthy brain aging.

Project: An effective therapeutic approach for Alzheimer's disease by targeting phospholipase C gamma 2

Project Period: 01/01/2021 - 12/31/2021

Principal Investigator: Tsai AP

Sponsor: Indiana Clinical and Translational Sciences Institute

Project Description: The objective of this project was to elucidate the role of PLCG2-mediated microglial signaling in Alzheimer’s disease pathogenesis. This study focused on the regulation of microglial function through the BTK-PLCG2 signaling axis, providing mechanistic insight into how AD-associated genetic variation influences neuroinflammation and disease progression.

Future Directions

My independent research program will expand in three directions:

(1) uncovering the adaptive mechanisms that govern resilience across aging, neurodegeneration, and extreme biological conditions; 

(2) developing integrative models that capture biological plasticity, aging trajectories, and the potential for reprogramming; and 

(3) translating these principles into biomarkers, engineered biological systems, and therapeutic strategies that promote healthy aging and improve human health.

Together, these efforts aim to establish the principles of adaptive biology and transform them into next-generation approaches for precision medicine, regenerative biology, and healthy longevity.