Assessing polygenic risks for Alzheimer's diseases in National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) cohort.

Objectives of the proposed research: Alzheimer's disease (AD) is a progressive neurological disorder that affects millions globally. Despite significant strides in developing treatments aimed at specific neuropathological markers, a substantial subset of individuals retains normal cognitive function even in the presence of AD-related neuropathology. This phenomenon suggests the existence of "cognitive resilience" factors that help preserve cognitive function independently of the disease's typical pathological processes. The primary objective of our proposed research is to conduct a comprehensive secondary analysis of the extensive genotype and phenotype data curated within the National Institute on Aging Genetics of NIAGADS. We aim to identify genetic and molecular signatures of individuals with high resilience to AD.
Study design: To achieve our objectives, we will develop a novel computational framework that integrates polygenic risk scores (PRS), incorporating additional clinical variables into clinical risk scores. This will allow for a more precise measurement of AD risk at the individual level within the ADSP and provide a comprehensive assessment of AD risk and resilience factors.
Analysis plan: Following our previous GRPa-PRS framework [1], we will identify participants within the top quantile of AD risk who, despite their elevated risk, do not develop AD. These individuals will be classified as highly resilient. Given that the effects of resilience are generally subtle, we will aggregate genetically regulated effects at the pathway level, enabling us to characterize resilience at the individual level. Following this, we will conduct a comparative analysis of the identified resilient vs AD individuals to further understand the underlying genetic and molecular basis of their resilience. To further validate our findings, we will link these results with additional molecular evidence from the ROS/MAP cohort.
1. GRPa-PRS: A risk straticifcation method to identify genetically regulated pathways in polygenic diseases. Alzheimers Dement.
2. Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease. Translational psychiatry, 12(1), 296

Alzheimer's disease (AD) is a progressive neurological disorder that poses substantial societal and economic challenges, affecting over 55 million people worldwide. Significant research efforts and therapeutic developments have focused on addressing AD's neuropathological features, such as beta-amyloid plaques and neurofibrillary tangles. Despite these efforts, clinical-pathological studies have revealed that a notable proportion of individuals maintain normal cognitive function even in the presence of these neuropathological markers. Through our GRPa-PRS framework, we aim to stratify individuals with high resilience and identify factors associated with cognitive resilience—the ability to preserve cognitive function despite a high genetic risk for developing AD. The success of this project will help to uncover these resilience factors could pave the way for innovative therapeutic strategies that enhance resistance to AD.