15 February 2013. White blood cells age quickly in post-menopausal women who carry the ApoE4 gene, but estrogen slows that decline, scientists report February 13 in PLoS ONE. Natalie Rasgon at Stanford University School of Medicine, California, and colleagues found that telomeres, the protective chromosome ends that are trimmed during DNA replication, shrank faster in aging women who carry at least one copy of this Alzheimer’s disease (AD) risk allele. Because shorter telomeres reflect more rounds of DNA replication, they are seen as an indirect measure of a cell’s age, though shrinking telomeres can also be an indication of oxidative stress or inflammation. Interestingly, women on hormone replacement therapy maintained longer telomeres. “It appears that ApoE4 carriers are at risk for accelerated cellular aging,” Rasgon told Alzforum. Further, she added, “Women receiving hormone therapy may have [ApoE] genotype-dependent responses.”
Some studies point to accelerated cell aging in AD. Patients have shorter white blood cell telomeres (see Honig et al., 2006) that dwindle further as the disease progresses (see Panossian et al., 2003). Other studies suggest this is only true in ApoE4 carriers (see Takata et al., 2012).
Rasgon previously reported that post-menopausal women who reported more years—and thus more estrogen exposure—between menarche and menopause have longer telomeres (see Lin et al., 2011), as do women on long-term hormone replacement therapy (see Lee et al., 2005). These were cross-sectional studies. No one had determined if the association holds up over time or if ApoE4 status influences it.
First author Emily Jacobs, University of California, San Francisco, and colleagues addressed both questions in a randomized, longitudinal trial. The research team measured the length of telomeres in white blood cells of 63 cognitively healthy, post-menopausal women, all of whom had started hormone replacement therapy at menopause and had been taking it for at least one year—one decade on average. Therapy consisted of either conjugated equine estrogen, estradiol, or either of those plus progesterone. Twenty-four participants carried at least one copy of the ApoE4 allele. Researchers randomized half the participants to continue hormone treatment and the other half to suspend it at the start of the trial.
Two years later, the scientists measured the chromosome ends again. ApoE4 carriers lost significantly more base pairs than did non-carriers. When estrogen entered the equation, it further divided the women. On average, those who remained on hormone therapy maintained their telomeres regardless of allele status. However, if the women stopped their treatments, ApoE4 carriers lost an average of 322 base pairs per telomere while non-carriers gained 490. The results imply that ApoE4 speeds up cell aging through loss of telomeres, and that estrogen’s impact depends on allele status. The mechanism of action is still unclear, wrote the authors.
The findings jibe with “numerous previous studies [that] suggest ApoE4 promotes oxidative stress and inflammation,” Mark Mattson, National Institute on Aging, Baltimore, Maryland, told Alzforum in an e-mail. Further studies will be needed to determine if the apolipoprotein exerts a direct influence on telomeres, and whether shorter telomeres in immune cells might mediate ApoE4’s effects on the aging brain and other organs, he wrote.
Results also indicate that if women with ApoE4 begin estrogen therapy as soon as menopause starts, they may be able to protect themselves against cell decline. “I find that fascinating,” said Phyllis Wise, University of Illinois at Urbana-Champaign. “We are learning that estrogen’s effects are pleiotropic, and this paper suggests they are even broader than we had appreciated before—they can get into the arena of chromosomal structure.” Estrogen’s precise influence on telomeres is unclear, wrote the authors, but previous studies reported that the hormone stimulates expression of part of the telomerase complex and raises the activity of telomerase, the enzyme that adds DNA to telomere ends (see Misiti et al., 2000, and Calado et al., 2009). Estrogen also has antioxidant properties (see Wong et al., 2008), which could indirectly stabilize telomeres.
Treatment does not seem to help non-carriers maintain their telomeres. In fact, stopping the treatment actually led to their growth, a phenomenon still under investigation by scientists, wrote the authors. Why might estrogen affect ApoE4 carriers and non-carriers differently? Rasgon and colleagues are unsure, but write that it could relate to ApoE gene expression. A previous study reported that estradiol boosts ApoE translation (see Srivastava et al., 1997).
Regardless of the mechanism, these findings may help experts make sense of contradictory evidence about the benefits and dangers of hormone replacement therapy. For example, some studies suggested that it decreases risk for dementia (see ARF related news story), while others indicated the opposite (see ARF related news story). ApoE status seems to define subsets of women who respond differently to estrogen, said Rasgon. “This study moves us a step closer to understanding which groups of women may benefit from hormone therapy versus those who will not.”
Because of the small sample size, this study was unable to tease apart whether different types of estrogen replacement have different effects. Rasgon said she plans to address that issue in future work, in addition to testing whether her findings hold up in a larger sample. As of now, results are too preliminary to make clinical recommendations about genetic testing for ApoE4, or about which subgroups should take supplemental estrogen, Rasgon told Alzforum.—Gwyneth Dickey Zakaib.
Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL. Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use. PLoS One. 2013;8(2):e54713. Abstract