title: Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use.
abstract: Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean  = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR  = 6.26, 95% CI  = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.
authors: Robert Wood Johnson Foundation Health and Society Scholars Program, Center for Health and Community, University of California San Francisco, San Francisco, California, United States of America. egjacobs@nmr.mgh.harvard.edu
authors: Emily G
authors: EG
authors: Jacobs
authors: Candyce
authors: C
authors: Kroenke
authors: Jue
authors: J
authors: Lin
authors: Elissa S
authors: ES
authors: Epel
authors: Heather A
authors: HA
authors: Kenna
authors: Elizabeth H
authors: EH
authors: Blackburn
authors: Natalie L
authors: NL
authors: Rasgon
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D020249:Hormone Replacement Therapy; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D009483:Neuropsychological Tests; D017698:Postmenopause / Q000235:genetics*; D012307:Risk Factors; D059506:Telomere Shortening
chemical_list: D053327:Apolipoprotein E4