Approved Research

Determine genetic factors that modulate the Alzheimer's disease risk effects of APOE-!4

Lay summary

Aging-associated diseases have become a leading threat to population health. Of note, Alzheimer's disease (AD) is one of the most prevalent aging-associated neurodegenerative diseases with no effective intervention strategy.

APOE-!4-a common missense mutation resulting in a mutated protein, is a leading genetic risk factor for many aging-associated diseases including AD. Particularly, individuals harboring APOE-!4 face a 3- to 15-fold higher risk for AD than the general population, and APOE-!4 presents in approximately half of all patients with AD.

However, no appropriate intervention strategies target APOE-!4. Even worse, some intervention strategies exert no effects or even unexpected outcomes in APOE-!4 carriers. Thus, there is an urgent need for developing more accurate genetic test solutions for AD risk forecasting as well as effective AD intervention strategies that specifically target APOE-!4. To accomplish this, a deeper understanding of the effects of APOE-!4 in AD pathogenesis is required.

Identifying factors that modulate APOE-!4 AD risk will shed light on the pathways on lowering APOE-!4 AD risk and boost the development of intervention strategies for APOE-!4 carriers (who are facing a higher AD risk). Recent studies suggested the roles of genetic factors in APOE surrounding regions in modifying APOE-!4 AD risk. While till now, it remained unknown which genetic factors modulate APOE-!4 AD risk and what would be the associated mechanism. Here we initiated a 3-year research project which was recently funded by the General Research Fund at Hong Kong, in which we will try to identify variants that can modify APOE-!4 AD risk, and further investigate their possible effects in modulating the expression of brain APOE/ APOE-!4 transcripts.

This study aimed to: (I) Identify the genomic variants that modify the risk effect of APOE-!4 in Alzheimer's disease; (II) Examine the effects of candidate variants on modulating APOE expression and Alzheimer's disease-associated endophenotypes; and (III) Examine the mechanisms of how the candidate variants modify APOE expression.

The successful completion of the captioned project will result in identification of genetic factors that can modify the APOE-!4 AD risk in the general population, with the results will provide a roadmap for an APOE-!4-guided solution for AD diagnosis and therapy, which will enable both a more accurate genetic-based risk assessment for AD, as well as a tailored AD intervention strategy that targets APOE-!4.