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Could HRT stop dementia?

Thursday 14 February 2013

Taking hormone replacement therapy (HRT) could delay the onset of Alzheimer's disease for millions of women, a number of newspapers have reported today.

The reports overextrapolate the findings of a study involving 63 postmenopausal women who had been taking HRT. The research looked at the relationship between the genetic variant APOE-e4, HRT and telomere length, which is an indicator of cell ageing (see below for more information). 

The APOE-e4 gene is known to increase the risk of developing Alzheimer's disease, and previous studies have suggested a possible link between telomere length, cognitive decline and Alzheimer's disease. A possible relationship between oestrogen exposure and longer telomeres has also been found.

The researchers looked at two related questions. First, is carrying the APOE-e4 gene associated with accelerated cell ageing indicated by telomere length? Second, if so, can using HRT protect against that damage?

They found that:

  • post-menopausal women who carried APOE-e4 had about six times higher odds of telomere shortening 
  • women who carried APOE-e4 showed less reduction in telomere length if they stayed on HRT
  • women who did not carry APOE-e4 showed less reduction in telomere length if they stopped taking HRT

It should be stressed that this was a very small study that looked at an indicator of cell ageing, not whether women developed Alzheimer's or cognitive decline.

A previous review found that HRT did not prevent cognitive decline. This current research may excite interest in whether the effect of HRT may differ in women carrying different gene variants.

Where did the story come from?

The study was carried out by researchers from the University of California and other academic centres in the US. It was funded by the US National Institute on Aging and the National Institutes of Health.

It was published in the peer-reviewed open access journal, PLOS ONE.

The study's findings were over-interpreted by both The Daily Telegraph and the Daily Mail. Both newspapers reported that taking HRT may reduce the risk of developing Alzheimer's disease in women with the gene variant APOE-e4.

However, the study did not look at the potential effect of HRT on the risk of developing Alzheimer's, only at a biological sign of cell ageing. While it may be the case that this could have a knock-on health effect, this was not proven by this study.

The Independent provides the more appropriate headline, "HRT 'protects' against rapid ageing that may be linked to Alzheimer's disease, study finds."

What kind of research was this?

This research was a randomised study that involved 63 post-menopausal women. It looked at whether there was an association between the genetic variant APOE-e4 that was found in some of the women, and certain biological changes linked to cell ageing. Everyone carries the gene APOE but, like other genes, it has several variants.

Cellular ageing was measured by looking at telomeres – regions of DNA at the end of chromosomes that protect the DNA as cells divide. With each division, the length of the telomeres becomes a little shorter, so telomere length is often used as a measure of biological age. Put simply, the older the cell, the shorter the telomere tends to be.

The study also looked at whether taking HRT modified any association found between APOE-e4 and changes in the length of telomeres. The researchers say there is increasing evidence that there is a link between telomere length and neurodegenerative diseases such as Alzheimer's and cognitive (mental) decline.

APOE-e4 is recognised as a genetic risk factor for Alzheimer's disease. According to the Alzheimer's Society, people with one copy of this genetic variant (estimated to be around one in four people) have a fourfold increase in risk of developing Alzheimer's disease, and people with two copies of the APOE-e4 gene variant (around 1 in 50) have a tenfold increase.

They also say there is some evidence that carriers of APOE-e4 have shorter telomeres than non-carriers, but more research is needed to establish a direct relationship.

The researchers suggest that exposure to the female sex hormone oestrogen may be associated with telomere length, but few studies have looked at the potential effect of HRT on cellular ageing.

What did the research involve?

Participants in the study were 63 healthy post-menopausal women with an average age of 57. All had been using HRT for one year or more. The women were mainly white, except for one Asian American woman. 

Genotyping (looking at people's genetic make-up) performed at the start of the study found that 24 of the women carried the APOE-e4 variant.

The women were randomly divided into two groups. One group (31 women) were taken off HRT for the two-year study period. The other 32 women remained on HRT. 

Blood samples were taken from the women at the start of the study and again after two years. Using specialist laboratory techniques, researchers measured the telomere length in their white blood cells both at the start of the study and again after two years.

What were the basic results?

The researchers found that, overall, women who carried the APOE-e4 variant had six times greater odds of telomere shortening over the two years than non-carriers (odds ratio 6.26, 95% confidence interval 1.02 to 38.49).

The analysis took into account factors (confounders) that could affect results, such as the women's age, education, their use of HRT and how long their telomeres were at the start of the study. Overall, if APOE-e4 was taken into account, HRT use did not affect odds of telomere shortening.

The researchers then looked within the individual treatment groups for differences between APOE-e4 carriers and non-carriers. Among the group who remained on HRT, there was no significant difference in telomere length between carriers of the APOE-e4 gene and non-carriers. But in the group who stopped HRT, carriers of APOE-e4 had more telomere shortening than non-carriers, who actually showed an increase in telomere length.

How did the researchers interpret the results?

The researchers say the study demonstrates an association between APOE-e4 and telomere length, with carriers of APOE-e4 having "marked telomere attrition" during the two years of the study.

They calculate that in two years, the telomeres of these carriers shortened by an amount equivalent to what might be expected to take a decade in non-carriers.

In addition, they suggest that HRT may "buffer" against accelerated cell ageing in post-menopausal women at risk of dementia. 

They point out that, importantly for women who do not carry the APOE-e4 gene, there was no evidence that HRT had a "protective effect" on telomeres.

They also suggest that HRT may have different effects on cell ageing across different genetic subgroups, as stopping HRT had "beneficial effects" on telomere length for non-carriers of the gene variant.


This small study appears to have found an association between the gene variant APOE-e4 and the rate at which telomeres become shorter, which is usually regarded as a biological sign of cell ageing.

It does not show that HRT can help prevent Alzheimer's in women who carry the APOE-e4 gene variant. This analysis is an exaggeration of the researchers' findings by the press.

A systematic review from the Cochrane Collaboration in 2008 suggested that, at the time, there was good evidence that HRT did not prevent cognitive decline in older postmenopausal women when given in the short or longer term (up to five years). However, the Cochrane review did not look at whether the effect differed in women with different genotypes.

It is possible that, with only 24 carriers of the gene included, the findings are not representative of what would be seen in a larger group of women. A far larger trial that follows women for several years and looks at clinical outcomes is required in order to find out what the effects of HRT are on this group.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

HRT 'protects' against rapid ageing that may be linked to Alzheimer's disease, study finds

The Independent, 14 February 2013

HRT could help delay onset of dementia

The Daily Telegraph, 14 February 2013

HRT cuts Alzheimer risk

Daily Express, 14 February 2013

Links to the science

Jacobs EG, Kroenke C, Lin J, et al.

Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use

PLOS ONE. Published online February 13 2013