- Alzheimer’s disease is more prevalent in women than in men, with women accounting for more than two-thirds of all dementia cases.
- Studies have shown that the early onset of menopause before the age of 45 years and starting hormone therapy late after menopause are associated with an increased risk of Alzheimer’s disease.
- A new study suggests that women, compared to men, showed higher levels of tau deposits in the brain that may contribute to the increased risk of Alzheimer’s disease.
- Women undergoing menopause at a younger age and initiating hormone therapy at a later age were especially susceptible to showing greater tau levels in the brain, potentially exacerbating the risk of Alzheimer’s disease in this group of women.
Previous studies have shown that younger age at menopause and late initiation of hormone therapy after menopause onset can increase the risk of dementia. However, the impact of age at menopause and hormone therapy on the accumulation of β-amyloid and tau proteins, which are considered to underlie Alzheimer’s disease development, is not well understood.
A recent study published in
Speaking to Medical News Today, the study’s author Dr. Rachel Buckley, a neurologist at Massachusetts General Hospital, said the study was “one of the first to report a link between women’s age at menopause and tau in the brain.”
“We found that in multiple areas of the brain that tend to be most likely to show higher tau in women than men, women with earlier age at menopause and elevated levels of amyloid showed higher levels of tau than those who reported an average age at menopause (~50 years in the United States). Women who reported premature menopause (<40 years at menopause onset) exhibited a much higher risk of tau in the brain. This supports the notion that longer exposure to estrogen throughout life might be protective against Alzheimer’s disease.”
— Dr. Rachel Buckley
Alzheimer’s disease is characterized by the abnormal aggregation of misfolded β-amyloid and tau proteins in the brain.
The β-amyloid aggregates, referred to as plaques, accumulate in the space between neurons, whereas the aggregates of tau protein, known as
Studies have shown that Alzheimer’s disease is more prevalent in older women, with postmenopausal women accounting for over
For instance, among individuals with high levels of amyloid beta deposits in the brain, females tend to show higher levels of
The mechanisms underlying these sex differences in the accumulation of tau protein are not well understood. Previous studies have shown that earlier onset of menopause is associated with an increased risk of accumulation of β-amyloid plaques in the brain and cognitive decline.
Premature menopause and hormone therapy
Premature menopause refers to the occurrence of menopause before 40 years, whereas early menopause describes the cessation of the menstrual cycle before 45 years. Early or premature menopause may occur spontaneously or due to surgical intervention and is linked to dementia risk.
Hormone therapy is commonly used for ameliorating the symptoms of menopause. Studies have shown that hormone therapy, especially a combination of estrogen with progestin, used for the treatment of menopause symptoms, is also associated with an increased risk of dementia.
Further research revealed that the initiation of hormone therapy more than 5 years after menopause onset was associated with an increased risk of dementia. In contrast, cases involving the initiation of hormone therapy close to the onset of menopause may not increase the risk of dementia.
The present study examined whether sex, age at menopause, the use of hormone therapy, and the timing of hormone therapy initiation influenced the accumulation of tau in individuals with identical levels of β-amyloid protein.
The study consisted of 292 individuals without a diagnosis of mild cognitive impairment or dementia.
These individuals were participating in the Wisconsin Registry for Alzheimer’s Prevention, one of the largest studies aimed at understanding factors associated with the development of Alzheimer’s disease. One of the salient features of the Wisconsin Registry for Alzheimer’s Prevention is that it contains data on the age of menopause, the use of hormone therapy, and positron emission tomography (PET) scans.
Specifically, the study included 193 females and 99 males with a mean age of 67 years. The female participants included 98 females who had used hormone therapy either in the past or were using it at the time of the study, whereas the remaining 95 were hormone therapy non-users. Based on the timing of menopause onset, the women were classified as having undergone premature menopause (before the age of 40 years), early menopause (between the age of 40-45 years), or regular-onset menopause (after 45 years of age).
These participants underwent positron emission tomography (PET) brain scans to assess the levels of β-amyloid and tau protein in seven brain regions. The brain scan to detect tau levels was conducted at an average age of 67 years. The researchers specifically examined brain regions that show sex differences in the accumulation of tau protein.
Consistent with previous studies, the brain scans revealed that female participants were more likely to show higher tau levels than their age-matched male counterparts. Female participants with high β-amyloid levels were especially more likely to show higher tau levels than male participants with similar β-amyloid levels.
Younger age at menopause and the use of hormone therapy were not associated with increased tau levels in the brain than regular menopause age and absence of use of hormone therapy, respectively.
However, in female participants with higher β-amyloid levels, undergoing menopause at a younger age and the use of hormone therapy were individually associated with increased tau levels in the brain than those who underwent menopause at regular age and the lack of hormone therapy use, respectively.
Among female participants who used hormone therapy, initiation of hormone therapy more than 5 years after menopause onset was associated with increased tau levels in the brain than those who initiated hormone treatment sooner.
Individuals who initiated hormone therapy at a later stage and had earlier onset of menopause also showed a modest increase in cognitive decline compared with females who initiated hormone therapy at an earlier stage and had regular menopause onset.
The researchers note that these findings could inform guidelines about the use of hormone therapy after menopause. Dr. Verna Porter, neurologist and director of the Dementia, Alzheimer’s Disease and Neurocognitive Disorders at Providence Saint John’s Health Center in Santa Monica, California, told MNT:
“The findings of this study may inform AD risk discussions relating to female reproductive health and treatment. Further, these findings are consistent with clinical guidelines that suggest HT is relatively safe when used close to the onset of menopause but may pose an increased risk for progression to AD dementia if initiated later.”
“[These results show that] earlier age at menopause and later initiation of HT following menopause, may be important sex-specific risk factors for AD due to sex differences in tau deposition.”
— Dr. Verna Porter
The strengths of the study included the large sample size and the carefully gather data on hormone therapy and menopause onset.
“A major strength of this study is the focus on reproductive factors in this large observational study. It is, unfortunately, extremely unusual to have such a comprehensive study of Alzheimer’s disease that also includes detailed measures of menopause, surgical history, and hormone therapy use,” Dr. Buckley said.
“Studies just don’t often think to ask women about their menopause,” she added.
The authors acknowledged that the study had a few limitations. For instance, the data on menopause onset and hormone therapy were based on self-reports that can be unreliable.
“The participants in this study were not representative of the general population in the United States, so we cannot extrapolate our findings to women from a range of socioeconomic, racial, and ethnic backgrounds or education levels,” Dr. Buckley said.
She also pointed out that the study was observational and does not prove a causal link, saying “[T]hat is, we cannot say with any certainty that menopause or hormone therapy was the direct cause of higher tau in the brain.”
“Finally, we only report data from one-time point, which is problematic because a lot of biases and confounding factors can make it seem as if the association between menopause and AD risk is important. It is far more powerful to say that premature menopause is associated with faster rates of tau accumulation in the brain than simply saying that it is higher at a single time point. This is another next step in our investigation,” she added.
Dr. Porter also noted, “There was an absence of data on what precipitated premature/early menopause in some female participants, and the reasons why female participants chose to initiate HT. Future studies should also investigate the potential differential effects of past and current HT use in a larger sample size.”
The study’s authors intend to further examine the role of hormones and genetic factors on β-amyloid and tau accumulation in their subsequent work.
“We’re taking a multi-pronged approach with our next studies. We’re exploring the direct impact of midlife levels of sex hormones (namely, estradiol, estrone, and testosterone) on amyloid and tau burden in the brain in both men and women. But we don’t think the whole story is just about the reproductive side of things,” Dr. Buckley said.
In addition, Dr. Buckley noted that genetic factors could also influence β-amyloid and tau accumulation in the brain.
“No one really wants to touch the X chromosome because it is so hard to measure, but we believe there are some compelling reasons to roll up our sleeves and get to work to better understand the X. Firstly, genes on the X chromosome are associated with better immune responses in women,” she said.
“It is entirely possible that we’ve been thinking of women as ‘more vulnerable’ to AD, but there might also be a very interesting story of genetic resilience out there that is yet to be aligned with the hormone findings.”
— Dr. Rachel Buckley