Studies have shown that women are more likely to develop Alzheimer’s Disease (AD) than men, in the presence of certain indicators for the disease. There are two proteins in particular, that have been associated with Alzheimer’s Disease, the β-amyloid protein and the tau protein. Beta-amyloid and tau are important indicators of Alzheimer’s Disease.
The β-amyloid protein is produced naturally in our brain. However, in some cases, it can accumulate to clumps, known as plaques outside of nerve cells and thereby block the communication between these cells. Plaques can trigger inflammation and are associated with neurodegenerative diseases such as Alzheimer’s Disease.
Moreover, the β-amyloid-induced inflammation can contribute to the formation of neurofibrillary tau tangles inside nerve cells. Neurofibrillary tau tangles are depositions of the tau protein (abnormal accumulations) and are responsible for cognitive decline associated with Alzheimer’s Disease. Conclusively, high levels of β-amyloid and tau are indicators for an increased risk of developing Alzheimer’s Disease.
Biological mechanisms contributing to tau deposition in females
The mechanisms leading to a sex difference in Alzheimer’s Disease are subject of current research and not yet well understood. Early menopause has been linked to worse outcomes regarding Alzheimer’s Disease dementia, which could be related to tau deposition.
Furthermore, at first sight, the evidence on the relationship between HRT and cognitive impairments seems contradictory. While some trials reported that hormone replacement therapy (HRT) may ameliorate cognitive impairment in menopausal women, results from the Women’s Health Initiative trial suggest that HRT use (estrogen plus progestin) was associated with a 2-fold higher incidence of probable dementia when compared to placebo. However, the results from this study must be considered with caution (see Infobox below).
The contradiction between these studies could be explained by the timing of the initiation of HRT. Indeed, follow-up studies showed that the negative impact of HRT depends on whether HRT is initiated close to menopause onset or later in postmenopausal women.
Early Menopause onset and HRT use are associated with tau deposition in females with high b-Amyloid levels
A recent study published in JAMA investigated the biological mechanisms that might be exacerbating tau deposition, which has previously been shown to increase the risk of developing Alzheimer’s Disease, in female individuals. The study was conducted in adults without any diagnosed cognitive impairment or dementia and it aimed to determine whether female sex, younger age at menopause, and HRT use were associated with regional tau deposition.
Overall, 292 underwent clinical evaluation including positron emission tomography (PET) to determine levels of β-amyloid and tau. The median age was 67 years and 66% were female.
Influence of sex, age at menopause and HRT use on tau deposition
The study found that females exhibited a higher tau level compared to age-matched males, confirming the afore mentioned higher risk of females to develop Alzheimer’s Disease. As expected, this was especially pronounced in individuals with elevated β-amyloid levels.
In general, age at menopause in female individuals was not associated with a higher risk. However, in females with high levels of β-amyloid, early age at menopause was significantly associated with more tau deposition.
A similar association was found when comparing women using HRT to those who were not exposed to HRT. If the analyses were restricted to individuals already at an increased risk due to high levels of β-amyloid, women who had received HRT exhibited higher tau levels than non-users. When restricted to individuals not at an increased risk due to high levels of β-amyloid, both HRT users and non-users exhibited higher tau levels than men.
Furthermore, the study found that late initiation of HRT (> 5 years after menopause) was associated with tau deposition compared to early HRT (within 5 years after menopause).
Cognitive function according to questionnaire-based assessment
Finally, the cognitive function of the participants was assessed using a questionnaire-based assessment. The higher the score, the better the cognitive function of the tested individual.
In general, females had a better cognitive ability than age-matched males. When comparing female participants, early menopause was associated with lower cognitive abilities, especially in females with high β-amyloid levels. There was no difference between females who used HRT compared to those who did not, but timing of HRT did have an impact as those with late HRT initiation had a subtly lower cognitive function than those with early initiation of HRT.
What can we learn from this?
The study suggests that earlier menopause and HRT use in the presence of high β-amyloid may be associated with an exacerbation of tau deposition in the brain, and thereby with a higher risk for developing Alzheimer’s Disease. The association between HRT and tau deposition depends on the timing of HRT initiation. To fully understand sex differences in Alzheimer’s Disease development and progression more research is needed.
A potential limitation of this study is, since the collected data was self-reported by participants, factors like age at menopause might be unreliable. Moreover, the strong decline of HRT use after the publication of the WHI report (approximately 46% HRT use in menopausal women before to 14.6% after publication), significantly influenced the age profiles of HRT users versus non-users, hence biasing the relationsh ip.
In conclusion, these findings may have implications for Alzheimer’s Disease diagnostic treatment plans for postmenopausal women. Women who experienced early menopause and those with a therapy use are possibly at increased risk of developing Alzheimer’s Disease.
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