BIOLOGY AND PATHOBIOLOGY OF APOE IN AGING AND ALZHEIMER'S DISEASE - PROJECT SUMMARY (APOE U19: OVERALL) THE OVERARCHING GOAL OF THIS U19 PROJECT IS TO COMPREHENSIVELY UNDERSTAND THE BIOLOGY AND PATHOBIOLOGY OF APOLIPOPROTEIN E (APOE) IN AGING AND ALZHEIMER’S DISEASE (AD) TO INFORM THERAPEUTIC STRATEGIES. THE E4 ALLELE OF THE APOE GENE (APOE4) IS THE STRONGEST GENETIC RISK FACTOR FOR AD IMPACTING 50-70% OF ALL AD PATIENTS, WHILE THE E2 ALLELE IS PROTECTIVE COMPARED TO THE COMMON E3 ALLELE. APOE4 IS ALSO A STRONG RISK FACTOR FOR AGE-RELATED COGNITIVE DECLINE AND VASCULAR COGNITIVE IMPAIRMENT. TO INTEGRATE EXISTING KNOWLEDGE AND ADDRESS CRITICAL GAPS, WE PROPOSE A UNIFIED APOE CASCADE HYPOTHESIS THAT THE STRUCTURAL DIFFERENCES AND RELATED BIOCHEMICAL PROPERTIES AMONG THE THREE APOE ISOFORMS INITIATE THEIR DIFFERENTIAL EFFECTS ON A CASCADE OF EVENTS AT THE CELLULAR AND SYSTEMS LEVELS ULTIMATELY IMPACTING AGING-RELATED PATHOGENIC CONDITIONS INCLUDING AD. TOWARDS THIS, WE HAVE ASSEMBLED A MU

Summary

BIOLOGY AND PATHOBIOLOGY OF APOE IN AGING AND ALZHEIMER'S DISEASE - PROJECT SUMMARY (APOE U19: OVERALL) THE OVERARCHING GOAL OF THIS U19 PROJECT IS TO COMPREHENSIVELY UNDERSTAND THE BIOLOGY AND PATHOBIOLOGY OF APOLIPOPROTEIN E (APOE) IN AGING AND ALZHEIMER’S DISEASE (AD) TO INFORM THERAPEUTIC STRATEGIES. THE E4 ALLELE OF THE APOE GENE (APOE4) IS THE STRONGEST GENETIC RISK FACTOR FOR AD IMPACTING 50-70% OF ALL AD PATIENTS, WHILE THE E2 ALLELE IS PROTECTIVE COMPARED TO THE COMMON E3 ALLELE. APOE4 IS ALSO A STRONG RISK FACTOR FOR AGE-RELATED COGNITIVE DECLINE AND VASCULAR COGNITIVE IMPAIRMENT. TO INTEGRATE EXISTING KNOWLEDGE AND ADDRESS CRITICAL GAPS, WE PROPOSE A UNIFIED APOE CASCADE HYPOTHESIS THAT THE STRUCTURAL DIFFERENCES AND RELATED BIOCHEMICAL PROPERTIES AMONG THE THREE APOE ISOFORMS INITIATE THEIR DIFFERENTIAL EFFECTS ON A CASCADE OF EVENTS AT THE CELLULAR AND SYSTEMS LEVELS ULTIMATELY IMPACTING AGING-RELATED PATHOGENIC CONDITIONS INCLUDING AD. TOWARDS THIS, WE HAVE ASSEMBLED A MU