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Restrictions on existing  APOE  mouse models have impacted research toward understanding the strongest genetic risk factor contributing to Alzheimer’s disease (AD) and dementia,  APOE ε4  , by hindering observation of a key, common genotype in humans –  APOE ε3/ε4  . Human studies are typically underpowered to address  APOE ε4   allele risk as the  APOE ε4/ε4   genotype is rare, which leaves human and mouse research unsupported to evaluate the  APOE ε3/ε4   genotype on molecular and pathological risk for AD and dementia.    Methods  As a part of MODEL-AD, we created and validated new versions of humanized  APOE ε3/ε3   and  APOE ε4/ε4   mouse strains that, due to unrestricted breeding, allow for the evaluation of the  APOE ε3/ε4   genotype. As biometric measures are often translatable between mouse and human, we profiled circulating lipid concentrations. We also performed transcriptional profiling of the cerebral cortex at 2 and 4 months (mos), comparing  APOE ε3/ε4   and  APOE ε4/ε4   to the reference  APOE ε3/ε3   using linear modeling and WGCNA. Further,  APOE  mice were exercised and compared to litter-matched sedentary controls, to evaluate the interaction between  APOE ε4   and exercise at a young age.    Results  Expression of human APOE isoforms were confirmed in  APOE ε3/ε3 , APOE ε3/ε4   and  APOE ε4/ε4   mouse brains. At two mos, cholesterol composition was influenced by sex, but not  APOE  genotype. Results show that the  APOE ε3/ε4   and  APOE ε4/ε4   genotype exert differential effects on cortical gene expression.  APOE ε3/ε4   uniquely impacts ‘hormone regulation’ and ‘insulin signaling,’ terms absent in  APOE ε4/ε4   data. At four mos, cholesterol and triglyceride levels were affected by sex and activity, with only triglyceride levels influenced by  APOE  genotype. Linear modeling revealed  APOE ε3/ε4  , but not  APOE ε4/ε4  , affected ‘extracellular matrix’ and ‘blood coagulation’ related terms. We confirmed these results using WGCNA, indicating robust, yet subtle, transcriptional patterns. While there was little evidence of  APOE  genotype by exercise interaction on the cortical transcriptome at this young age, running was predicted to affect myelination and gliogenesis, independent of  APOE  genotype with few  APOE  genotype-specific affects identified.    Discussion   APOE ε4   allele dosage-specific effects were observed in circulating lipid levels and cortical transcriptional profiles. Future studies are needed to establish how these data may contribute to therapeutic development in  APOE ε3/ε4   and  APOE ε4/ε4   dementia patients.

The APOEε3/ε4 Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice