Bioenergetic and inflammatory systemic phenotypes in Alzheimer's disease APOE ε4-carriers

We examined the impact of an APOE epsilon 4 genotype on Alzheimer's disease (AD) subject platelet and lymphocyte metabolism. Mean platelet mitochondrial cytochrome oxidase Vmax activity was lower in APOE epsilon 4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. Proteins that mediate mitophagy and energy sensing were higher in APOE epsilon 4 lymphocytes which could represent compensatory changes and recapitulate phenomena observed in post-mortem AD brains. Analysis of the lipid synthesis pathway found higher AceCSI, ATP CL, and phosphorylated ACC levels in APOE epsilon 4 lymphocytes. Lymphocyte ACC changes were also observed in post-mortem brain tissue. Lymphocyte RNAseq showed lower APOE epsilon 4 carrier sphingolipid Transporter 3 (SPNS3) and integrin Subunit Alpha 1 (ITGA1) expression. RNAseq pathway analysis revealed APOE epsilon 4 alleles activated inflammatory pathways and modulated bioenergetic signaling. These findings support a relationship between APOE genotype and bioenergetic pathways and indicate platelets and lymphocytes from APOE epsilon 4 carriers exist in a state of bioenergetic stress. Neither medication use nor brain-localized AD histopathology can account for these findings, which define an APOE epsilon 4-determined molecular and systemic phenotype that informs AD etiology.

Automated summary

The study revealed that the APOE ε4 genotype affects platelet and lymphocyte metabolism in Alzheimer's disease patients, showing lower platelet mitochondrial activity and higher lymphocyte apoptosis markers in APOE ε4 carriers. Proteins related to mitophagy and energy sensing were elevated in APOE ε4 lymphocytes, possibly representing compensatory changes. RNA sequencing also indicated activation of inflammatory pathways and modulation of bioenergetic signaling in APOE ε4 carriers.