2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

ApoE4-Specific Biomarker Cut-offs for Accelerated Alzheimer’s Progression

How do certain gene variations impact biological markers of Alzheimer’s at different stages?

Nicolai Franzmeier. Ph.D.
LMU University Hospital Munich (LMU Klinikum)
Munich, Germany

Background

Genes play an important role in Alzheimer’s. The apolipoprotein E (APOE) gene provides instructions for making ApoE protein. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. In some populations, the APOE-e4 variation is thought to increase a person’s risk of developing Alzheimer’s. However, it is not known precisely how APOE-e4 increases the risk of Alzheimer’s disease.

Characteristic features of early Alzheimer’s disease in the brain include buildup of beta-amyloid protein fragments into amyloid plaques, in a process known as amyloidosis. It is thought that beta-amyloid buildup promotes clumping of tau proteins. Tau clumps lead to the formation of neurofibrillary tangles, ultimately causing neuronal dysfunction and cell death, and this process is called tauopathy. The hallmarks of the transition from amyloidosis to tauopathy are not known. It is also not known how APOE gene variations may affect sease progression.

Research Plan

Dr. Nicolai Franzmeier and colleagues will use data gathered from people with and without Alzheimer’s disease. The dataset includes amyloid brain scans, tau tangle brain scans, APOE genotyping, brain MRI, blood biological markers (biomarkers), and clinical data for each individual. To study the transition from amyloidosis to tauopathy, they plan to study the biomarkers in the absence of tau build up, as well as the biomarkers that may signal at the start of tau build up in people with and without APOE-e4 variations. 

Moreover, they will use the dataset to determine if there are specific changes in amyloid brain imaging and tau blood levels in individuals with APOE-e4 that can predict the onset of cognitive decline.

Impact

Results of this study could improve our understanding of the biological mechanisms that drive changes that are observed in Alzheimer’s, especially those linked to APOE gene variations. It may also identify biological markers of Alzheimer’s-related changes that could be used to help diagnose Alzheimer’s at earlier stages.