Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer's disease: A 31Phosphorus MR spectroscopy study

Abstract

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Fig 1. Effects of sex and APOE4 status on brain high-energy phosphates.

Plots show mean high-energy phosphate (HEP) in frontal cortex for each pairwise comparison, with 95% confidence intervals (C.I.). *P<0.05, corrected for multiple comparisons. Abbreviations: APOE4-, non-carriers; APOE4+, carriers; ATP, total adenosine triphosphate; PCr, phosphocreatine; Pi, inorganic phosphate.

Fig 2. Effects of sex and APOE4 status on brain membrane phospholipids.

Plots show mean PME/PDE measures in frontal cortex for each pairwise comparison, with 95% confidence intervals (C.I.). Abbreviations: APOE4-, non-carriers; APOE4+, carriers; PDE, phosphodiesters; PME, phosphomonoesters.

Fig 3. Effects of APOE4 dose on PCr/ATP and PCr/Pi.

Plots show mean PCr/ATP and PCr/Pi measures in frontal cortex by APOE-dose group in men and women, with 95% confidence intervals (C.I.). *P<0.05, corrected for multiple comparisons. Abbreviations: APOE4-, non-carriers; APOE4-/+, heterozygous carriers; APOE4+/+, homozygous carriers; ATP, total adenosine triphosphate; PCr, phosphocreatine; Pi, inorganic phosphate.

Fig 4. Schematic representation of sex and APOE4 status effects on midlife mitochondria phosphorus metabolites measured with ³¹P-MRS.

All panels: Phosphorus metabolites assessed with ³¹P-MRS include phosphocreatine (PCr) rephosphorylated from creatine (Cr) using adenosine triphosphate (ATP) derived from chemical exchange of inorganic phosphate (Pi) and adenosine diphosphate (ADP) in mitochondria. Membrane phosphodiesters (PDE) and phosphomonoesters (PME) are also shown. Left panel: PCr/ATP and PCr/Pi are lower in women vs. men in frontal, temporal, medial temporal and posterior cingulate cortex (blue). Middle panel: PCr/ATP and PCr/Pi are lower in APOE4 carriers (APOE4+) vs. non-carriers (APOE4-) in frontal cortex (red). Right panel: PCr/ATP and PCr/Pi are lower in females and male APOE4 carriers vs. male non-carriers in frontal cortex (purple).