Identification of an APOE 4-specific blood-based molecular pathway for Alzheimer's disease risk

INTRODUCTION: The precise apolipoprotein E (APOE) epsilon 4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear.METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype.RESULTS: The Green Module was associated with AD diagnosis in APOE epsilon 4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE epsilon 4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE epsilon 4 homozygotes. A Framingham Heart Study validation study supported the findings for AD.DISCUSSION: The study identifies the APOE epsilon 4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease. Identification of an APOE epsilon 4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD. CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE epsilon 4 homozygotes. Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE epsilon 4 carriers. HighlightsDISCUSSION: The study identifies the APOE epsilon 4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease. Identification of an APOE epsilon 4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD. CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE epsilon 4 homozygotes. Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE epsilon 4 carriers. Highlights