The Effect of ApoE Genotype, Plasmalogen Biosynthesis, and Reverse Cholesterol Transport Biomarkers on Cognition and Odds of Alzheimer’s Disease in Elderly Persons Dayan Goodenowe 1, Tara Smith 1, Vijitha Senanayake 1, Bassirou Chitou 1, Asuka Mochizuki 1, Sue E. Leurgans 2, David A. Bennett 2 1 Phenomenome Discoveries Inc., Saskatoon, Saskatchewan, Canada. 2 Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA Reduced cholesterol transport, Apolipoprotein E (ApoE) ε4 and depleted plasmalogens (PlsEtn) are hypothesized to be mechanistically involved in the etiology of dementia and AD pathology. Serum biomarkers of PlsEtn biosynthesis were measured in 862 elderly subjects and the relationships between cholesterol transport biomarkers, ApoE allele status, cognition and incident AD was determined. Plasmalogens and Cognition – Mechanism and Post-Mortem Studies Plasmalogens and AD Pathology – Mechanism and Post-Mortem Studies Plasmalogens and Cholesterol Regulation Plasmalogen Biosynthesis – Associations with Age and Cognition Plasmalogens and Cognition – Serum Studies Higher age and ApoE ε4 genotype were associated with lower cognition and higher odds of AD ApoE ε2 genotype, higher PBV, and a higher HDL-C/TC ratio were associated with higher cognition ApoE ε2 genotype and higher PBV were associated with lower odds of AD The PBV association with cognition was 2.5-times larger than the ApoE association with cognition PlsEtn-20:4 Serum PlsEtn Level CNLowModSevere -DHA-PlsEtn Cognitive Impairment Amyloid plaques are formed when APP is metabolized by β- secretase. β-secretase is located in the cholesterol-rich lipid raft region of the membrane Normal/healthy APP metabolism occurs via α- secretase. α-secretase is located in the phospholipid rich region of the membrane When membranes are enriched with DHA-plasmalogens, in vitro, α-secretase levels are increased and the formation of pathological amyloid (Aβ1-42) peptides is reduced Post-mortem human brain analyses reveal that persons with high levels of DHA-plasmalogens have low levels of Alzheimer’s pathology (Rush University, n=100, corrected for age, education, and gender) The fusion and release of neurotransmitters from presynaptic vesicles is critical for normal neuron function PlsEtn-18:1 PtdEtn-20:4 PtdEtn-18:1 In vitro studies have shown that adequate membrane levels of polyunsaturated fatty acid (PUFA) containing plasmalogens (PlsEtn) are needed for membrane fusion Post-mortem human brain analyses reveal that persons with high levels of DHA-plasmalogens have higher cognition (Rush University, n=100, corrected for age, education, and gender) Background and Introduction Serum levels of DHA-PlsEtn are decreased in cognitively impaired subjects. Subjects with severe cognitive impairment have lower levels than subjects with mild cognitive impairment (Goodenowe et al., 2007) ApoE is the predominant cholesterol transport protein in the brain. The different ApoE isoforms have significantly different cholesterol efflux activity (ε2> ε 3> ε4, Michikawa, 2000) When membranes are enriched with DHA- plasmalogens, sterol-O-acetyltransferase (SOAT) levels are increased, resulting in increased cholesterol esterification and increased cholesterol efflux, which results in decreased cellular cholesterol levels (Mankidy et al., 2011) -ε2-ε2 -ε3-ε3 -ε4-ε4 Overall plasmalogen biosynthesis is stable from age and then decreases; Plasmalogen Biosynthesis is decreased in subjects with cognitive impairment; Subjects with severe cognitive impairment have lower PBV than subjects with mild cognitive impairment (Goodenowe et al, 2015) Serum PBV An overall Plasmalogen Biosynthesis Value (PBV) can be generated by determining the ratio of key plasmalogen precursors and products (Goodenowe et al., 2015) Plasmalogens are synthetized in peroxisomes by specialized enzymes Average age: 71+/-9 Clinical VariablesOutcome Analysis: Cognition and AD Outcome Analysis: Contribution of Variables Results – ApoE, RCT, PBV, and AD ApoE - PBV Interaction Analyses Conclusions Low PBV is the largest contributor (other than age) to reduced cognition in the elderly with an overall effect size 2.5-times larger than ApoE genotype; High PBV or ApoE ε2 genotype is associated with increased RCT (HDL-C/TC ratio); High PBV neutralizes the increased probability of AD associated with the ApoE ε4 genotype independent of its effect on RCT. ε4ε4 ε3ε3 ε2ε2 ε4ε4 ε3ε3 ε2ε2 Probability of AD Global Cognition HDL-C / Total Cholesterol PBV significantly affected the probability of AD in ApoE e3 and e4 carriers; PBV significantly affected the cognition level in ApoE e2, e3 and e4 carriers; Both ApoE and PBV were associated with HDL-C/TC ratio; PBV affected the HDL-C/TC ratio in e2 and e3 carriers but not e4 carriers; The PBV effect on HDL-C/TC is not a viable mechanism to explain the PBV effect on e4 carriers. ApoE and Cholesterol Regulation