Premium
Human APOE4 carriers show different metabolic signatures than APOE3 carriers throughout Alzheimer’s disease development
Author(s) -
Yanckello Lucille M.,
Hammond Tyler C.,
Ham Stephanie,
Lin AiLing,
Nelson Peter T.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.040423
Subject(s) - apolipoprotein e , genotype , disease , allele , medicine , endocrinology , alzheimer's disease , biology , genetics , gene
Background Apolipoprotein ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). In contrast, ε3 allele of APOE (APOE3), is neutral and doesn’t alter ones risk for AD. As AD is increasingly being viewed as a metabolic disease, the goal of this study was to investigate the metabolic differences between APOE 3/3 or APOE 3/4 in post‐mortem human brain tissue at different stages of AD progression as determined by Braak staging (BS). Method Brain samples were obtained from the Alzheimer’s Disease Center Brain Bank at the University of Kentucky Sanders Brown Center on Aging. Samples included APOE 3/3 genotype at BS 0‐3 (n = 64) and 4‐6 (n = 36) and APOE 3/4 genotypes at BS 0‐3 (n = 17) and 4‐6 (n = 41). Samples were sent to Metabolon Inc. to determine metabolic profiles using non‐targeted UPLC‐MS/MS and GC‐MS. Result 218 Metabolites were detected to be different between genotypes throughout disease progression. More specifically, 179 of the 218 differ between genotypes at BS 0‐3, whereas only 41 were different at BS 4‐6. This shows that APOE genotype differences in metabolism are much more evident in early stages of disease progression. For example, increases were seen in metabolites implicated in oxidative stress such as gamma‐glutamylthreonine in early stage APOE4 carriers compared to non‐carriers. Changes in amino acid and lipid metabolism are also seen in APOE4 carriers early in disease stages, including higher levels of histamine , tryptophan , sphainganine , and sphingadienine . The release of histamine is related to responses to brain disease and altered tryptophan levels have been correlated to intensity of dementia in AD subjects. Altered sphingolipid metabolism has also been found in AD patients. Conclusion This study helps shed light on biochemical trends based on AD stage and APOE genotype differences. We found that APOE4 carriers had earlier changes in metabolism related to oxidative stress, amino acid metabolism and lipid metabolism, which all have all been implicated in AD progression. The findings from this study may facilitate future therapeutic development for AD prevention of asymptomatic APOE4 carriers with a precision medicine approach.