RNA sequencing data for APOE2 mice, to compare differences in gene expression related to age and sex. Data was generated with the Illumina NovaSeq600 S2 platform provided by the Duke Sequencing and Genomic Technologies Shared Research Core.
Successfully predicting risk and resilience to aging associated decline would allow for preventive strategies to be implemented before irreversible brain changes, and reveal new targets for therapies to enhance aging quality. APOE allelic variation modulate brain vulnerability during aging, neurodegeneration in AD, and to cognitive decline. The APOE4 allele carriage confers the most risk, and has been intensely studied with respect to the control APOE3 allele. The APOE2 variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, APOE2 has been less studied compared to APOE3 and APOE4, and the mechanisms by which it confers cognitive resilience and neuroprotection remain largely unknown. Mouse models replicating the human APOE alleles through targeted replacement of the murine APOE gene provide useful tools to address such questions on the role of APOE genes in aging.  We aimed to identify changes during middle to old age transition, and to examine the role of female sex during this period. We have introduced a novel metric, the absolute winding number to complement the existing learning and memory estimates provided by the Morris water maze test. We tested the ability of this marker to detect changes during aging. We used diffusion MRI to reveal atrophy and microstructural changes during this period, and supplemented the most widely used measure of tissue integrity, fractional anisotropy with estimates of cellularity from MAP MRI.  We detected a small but significant 3% brain atrophy due to aging, exemplified by atrophy in the hippocampal commissure (15%), fornix, and cingulate cortex areas 24 (9%). Females had larger volumes relative to males for the bed nucleus of stria terminalis, subbrachial nucleus, postsubiculum (~10%), and claustrum (>5%), while males had larger volumes for the brachium of the superior colliculus, orbitofrontal cortex, frontal association cortex, and the longitudinal fasciculus of pons >9%). Age related atrophy was noted in white matter (anterior commissure, corpus callosum, etc.), as well as gray matter, in particular in olfactory cortex, frontal association area 3, thalamus, hippocampus and cerebellum. The amygdala was associated with both age and sex related vulnerability to aging, showing a faster decline in females. A negative age by sex interaction was also noted for the olfactory areas, right piriform cortex, bilateral amygdala, ventral hippocampus and entorhinal cortex, and cerebellum. Some brain subgraphs were favored in males e.g. for the secondary motor cortex and superior cerebellar peduncle), and other in females (e.g. hippocampus and primary somatosensory cortex, trunk region). Age effects were indicative of connectivity loss during transition from middle age to old age e.g. (e.g. hippocampus and primary somatosensory cortex, trunk region). Whole blood based transcriptomics revealed that the largest positive fold change with aging, was for Cpt1c, which encodes a protein that regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria. Arg1 also showed age specific changes, and is a critical regulator of innate and adaptive immune responses (FC~30). Amongst the age related genes surviving FDR correction, the largest FC was for Cpt1c (log2FC=7.1, adjusted p= 0.04). Cpt1c  encodes a member of the carnitine/choline acetyltransferase family, and its encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria. GO annotations point to its role in lipid metabolic processes (GO:0006629), transport (GO:0006810), small molecule metabolic processes (GO:0044281), and nitrogen compound metabolic processes (GO:0034641). Amongst the sex related genes the largest FC were observed for Maoa involved in catabolic processes and cellular nitrogen compound metabolic processes, and in the breakdown of the neurotransmitters serotonin, epinephrine, norepinephrine, and dopamine.  . Gene Ontology (GO) annotations related to this gene include oxidoreductase activity and primary amine oxidase activity. We propose modeling approaches that integrate through canonical correlation the ability to relate blood based to brain based changes, as well as with memory related traits, providing blood gene expression biomarkers that help track brain and behavior phenotypes. Our study aims to test the sex specific APOE2 impact on neurocognition, modulation of brain networks, and biological pathways during aging.