03 Sep 2015

The hormone estrogen has a long and fitful history in Alzheimer’s research, and at the recent Alzheimer’s Association International Conference, scientists grappled anew with its possible impact on amyloid-β deposition, brain structure, and risk. Perhaps unsurprisingly, mixed messages emerged at the meeting, held July 18-23 in Washington, D.C. On a positive note, a large epidemiological study found that estrogen given early in menopause reduced Alzheimer’s risk, and results from a small cohort indicated that early treatment with the hormone may have slowed amyloid accumulation. However, another study found that early treatment with the hormone shrank the brain. After many years of study and a batch of new data, the jury is still out on whether hormone replacement therapy is good or bad for the brain, and researchers agreed that the nature of estrogen’s effects likely come down to who is being treated, and when.

Women take supplemental estrogen to ease symptoms of menopause, which include hot flashes and insomnia. In model systems, estrogen has been reported to protect neurons and reduce the production of Aβ. Given that two-thirds of people with Alzheimer’s are women, researchers have wondered whether flagging estrogen was partly to blame, and if supplemental hormones could help. The answer is far from simple. The Women’s Health Initiative Memory Study (WHIMS) showed that hormone therapy increased the risk of dementia when initiated after age 65, but subsequent studies reported that the hormones seemed harmless or helped prevent dementia when taken during early menopause (see May 2003 news; Shao et al., 2012; Maki et al., 2011; Jun 2013 news). From this, the “critical window" hypothesis was born, which posits that early treatment with the hormone may be beneficial, while later treatment could be harmful. Roberta Diaz-Brinton, at the University of Southern California in Los Angeles, expanded on that with the “healthy cell bias of estrogen action” hypothesis, which claims that healthy neurons respond positively to estrogen, but that sickly neurons, which are more likely to be present in older age, respond negatively.

At AAIC, researchers discussed several batches of new human data. For one, a long-term, Finnish epidemiology study offered support for estrogen’s positive effects on cognition. More than 13,000 participants, who were aged 47 to 56 at the initiation of the Kuopio Osteoporosis Risk factor and Prevention (OSTPRE) study, answered questions about their use of hormone therapy as well as other health and lifestyle factors every five years from 1989 until 2009. Almost 9,000 women completed the study. In addition, researchers drew from prescription registries to corroborate the questionnaire data. They found that women who used some form of hormone therapy for more than 10 years halved their risk of Alzheimer’s disease. The study was led by Bushra Imtiaz of the University of Eastern Finland in Kuopio.

These OSTPRE results appear the opposite of the WHIMS finding that hormone therapy doubled dementia risk when it was started after age 65. However, Imtiaz told Alzforum that women in her study reported starting hormone therapy at an average age of 52, more than a decade younger than the women in the WHIMS trial. Thus she concluded that the findings supported the critical-window hypothesis.

The multicenter Kronos Early Estrogen Prevention Study (KEEPS) trial was designed in part to test the critical-window hypothesis. More than 700 participants in this study underwent four years of placebo or hormone therapy, either in the form of oral conjugated equine estrogens (CEE) or 17-β estradiol administered through a transdermal patch. Both estrogen treatments were accompanied by progesterone, which prevents the harmful uterine growth that can occur when estrogen is administered alone. KEEPS started all treatments between five months and three years after menopause onset (see Wharton et al., 2013). Recently published findings from KEEPS indicated that estrogen therapy did not alter cognition in women during the trial or within more than two years of follow-up (see Gleason et al., 2015).

In Washington, KEEPS leader Kejal Kantarci of the Mayo Clinic in Rochester, Minnesota, presented structural MRI data from a subset of 95 KEEPS participants who had scans at the beginning and end of the four-year treatment phase of the trial. Gray matter volume, as measured by expansion of the ventricles, fell in volunteers taking CEE compared to placebo. Transdermal estrogen had no effect on brain volume. Women who started their CEE treatment later in menopause had the largest ventricular volume expansion. The researchers are continuing to measure brain volume changes in this group of women longitudinally.

The findings, though from a small cohort of scanned women, were both fascinating and disturbing, Diaz-Brinton commented after the talk. However, neither of the treatment groups displayed signs of cognitive decline compared to placebo. Kantarci said the brain changes may be transient. She hopes to address this, as well as whether the structural changes ultimately have cognitive consequences later in life, in follow-up studies on this cohort. It is also important to note that use of transdermal estrogen did not significantly reduce brain volume as seen with CEE, she said.

Further evidence that estrogen can shrink the brain came from the WHIMS trial. Christina Hugenschmidt of Wake Forest School of Medicine in Winston-Salem, North Carolina, in collaboration with Diaz-Brinton, analyzed brain MRI scans of 1,400 women in the WHIMS trial more than two years after that study concluded. Half of them returned for an additional scan about five years after that. Hugenschmidt reported that during that five-year period, brain volume shrank by a decrement of -18.6 mL in women on estrogen therapy who were also diabetic. For women without diabetes, brain volume only decreased slightly (decrement of -0.4 mL) with estrogen treatment. The women in this study had initiated hormone therapy when they were all at least 65 years old. The researchers suggested that the results, published July 10 in Neurology, supported the healthy-cell-bias hypothesis, because the therapy had the strongest neurodegenerative effects on women with underlying metabolic problems. However, clearly future studies about the effects of estrogen in the diabetic brain will be needed to strengthen that support, Hugenschmidt said.

Val Lowe, also from the Rochester Mayo, reported on amyloid burden in a small subset of KEEPS participants. The researchers recruited 17 women who took CEE, 21 who took estradiol via the transdermal patch, and 30 women from the placebo arm, to undergo amyloid PET scans three years after the four-year treatment phase concluded. These women did not have a baseline PET scan at the beginning of the study. Women who had taken transdermal estradiol had lower levels of amyloid than the placebo group at this time. However, this finding was only statistically significant for ApoE4 carriers. In contrast, women who had taken CEE had comparable amyloid burden to controls three years after treatment.

The findings from this small pilot study mesh with animal studies, which have implicated estrogen in the reduction of Aβ production. CEE may not have affected amyloid because it contains a mix of non-human estrogens, including estrone, Kantarci said. That ApoE4 carriers appear to have responded more robustly to the transdermal treatment could reflect the fact that without treatment, they accumulate amyloid at a faster rate than non-carriers and thus had a bigger response to treatment, she said. Kantarci emphasized that the small numbers of participants in the study preclude any strong conclusions. She plans to test if the apparent dip in amyloid correlates with a reduction in AD risk.

Most researchers seem to accept the idea that a critical window exists during which estrogen treatment is most likely to be beneficial. “The question is, when is that window open, and when is it closed?” said Brinton. “When women have menopausal symptoms, we think that’s a good indication that it’s open.” Brinton proposed that menopausal symptoms are a sign of the ongoing bioenergetic transition in the brain that is caused by loss of estrogen (see Brinton et al., 2015). Estrogen promotes glucose metabolism in the brain, and loss of the hormone triggers the brain to go into starvation mode, which ultimately leads to compensation through metabolism of small molecules called ketone bodies. (Not to be confused with protein aggregates, ketone bodies are derivatives of fatty acids.) This ketogenic shift occurs in aging female mice as well as in AD mouse models (see Yao et al., 2010; Ding et al., 2013). Once the brain successfully starts using ketone bodies as a supplemental fuel, Brinton proposes, menopausal symptoms fade.

An extension of Brinton’s hypotheses would be that as long as estrogen therapy is started before the menopausal transition is complete, it could be continued indefinitely. However, currently physicians only recommend women take the therapy for a few years after menopause onset, then taper off. This is in part due to concerns of elevated breast cancer risk in some women with continued estrogen use. A form of estrogen that is only active in the brain could help solve that problem. One such therapy is currently in preclinical studies (see Aug 2015 news).—Jessica Shugart

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References

News Citations

1. Dementia Risk Increases, at Least in Those Who Start Hormone Therapy Late 28 May 2003
2. Early Hormone Therapy Does No Cognitive Harm 28 Jun 2013
3. Could “Brain-Only” Estrogen Treat Symptoms of Menopause? 5 Aug 2015

Paper Citations

1. Shao H, Breitner JC, Whitmer RA, Wang J, Hayden K, Wengreen H, Corcoran C, Tschanz J, Norton M, Munger R, Welsh-Bohmer K, Zandi PP, . Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology. 2012 Oct 30;79(18):1846-52. PubMed.
2. Maki PM, Dennerstein L, Clark M, Guthrie J, LaMontagne P, Fornelli D, Little D, Henderson VW, Resnick SM. Perimenopausal use of hormone therapy is associated with enhanced memory and hippocampal function later in life. Brain Res. 2011 Mar 16;1379:232-43. Epub 2010 Nov 13 PubMed.
3. Wharton W, Gleason CE, Miller VM, Asthana S. Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective sub study (KEEPS Cog). Brain Res. 2013 Jun 13;1514:12-7. Epub 2013 Apr 17 PubMed.
4. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G, Santoro NF, Taylor HS, Black DM, Budoff MJ, Hodis HN, Naftolin F, Harman SM, Asthana S. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015 Jun;12(6):e1001833; discussion e1001833. Epub 2015 Jun 2 PubMed.
5. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015 Jul;11(7):393-405. Epub 2015 May 26 PubMed.
6. Yao J, Hamilton RT, Cadenas E, Brinton RD. Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. Biochim Biophys Acta. 2010 Oct;1800(10):1121-6. PubMed.
7. Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PLoS One. 2013;8(11):e79977. Epub 2013 Nov 11 PubMed.

Further Reading

Papers

1. Fischer B, Gleason C, Asthana S. Effects of hormone therapy on cognition and mood. Fertil Steril. 2014 Apr;101(4):898-904. PubMed.

News

1. Hormone Replacement Therapy Still up on Balance Beam 22 Nov 2002