Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) and is primarily driven by obesity, another AD risk factor. The mechanism by which IR predisposes to AD is unknown. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus contributing to an improved understanding of the biological and regulatory mechanisms of IR in AD.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We conducted an epigenome‐wide association study of IR, quantified using the homeostasis model assessment of IR, in 3,167 Framingham Heart Study (FHS) participants without diabetes. We selected epigenetic markers (outcome) associated with IR at the genome‐wide level (<jats:italic>P</jats:italic><10<jats:sup>‐7</jats:sup>: 0.05/450,000) and evaluated their association with AD, vascular dementia, dementia, and brain volumes (hippocampal, total brain‐TBV, intracranial‐ICV, and lateral ventricular) in up to 3,040 FHS participants. We defined significant associations using <jats:italic>P</jats:italic><0.002 (0.05/3/7). All analyses were performed using blood DNA methylation measured using the Illumina HumanMethylation450 BeadChip and linear mixed‐effects models adjusted for age, sex, and batch, while allowing for heterogeneous variance across batches and accounting for familial relatedness. Models including IR or brain volume as a covariate were additionally adjusted for body mass index or ICV respectively.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>We confirmed the association of blood DNA methylation with IR at three loci (1p32:cg17901584‐<jats:italic>DHCR24</jats:italic>, 11q13:cg17058475‐<jats:italic>CPT1A</jats:italic>, and 21q22:cg06500161‐<jats:italic>ABCG1</jats:italic>). Blood DNA methylation at cg17058475‐<jats:italic>CPT1A</jats:italic> was significantly associated with TBV (<jats:italic>P</jats:italic>=0.0007). The carnitine palmitoyl transferase (CPT) system, crucial for the mitochondrial beta‐oxidation of long‐chain fatty acids, is involved in metabolic syndrome, type 2 diabetes, cardiovascular and neurological diseases including AD. Blood DNA methylation levels at cg17901584‐<jats:italic>DHCR24</jats:italic> and cg06500161‐<jats:italic>ABCG1</jats:italic> were nominally associated with AD (<jats:italic>P</jats:italic>=0.03) or vascular dementia (<jats:italic>P</jats:italic>=0.04) respectively. Both <jats:italic>DHCR24</jats:italic> and <jats:italic>ABCG1</jats:italic> are involved in cholesterol synthesis or transport. Reduced expression of <jats:italic>DHCR24</jats:italic> occurs in AD patient’s temporal cortex while CSF capacity to promote cell cholesterol efflux via ABCG1 is specifically impaired in AD and this impairment correlates with the main AD neurobiochemical markers.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our methylation analysis has shed light on genes potentially implicated in both IR and AD. Future work includes association analyses using brain omics from the AD Knowledge Portal.</jats:p></jats:sec>