Study reveals potential Alzheimer’s risk in women using hormone replacement therapy

Hormone Replacement Therapy involves giving women synthetic estrogen to replace depleting hormone levels and thus alleviate menopausal symptoms.

But several studies suggest HRT is a risk factor in various conditions.

A discovery in Liverpool that a gene could be ‘firing’ the progression of Alzheimer’s in women undergoing HRT further calls into question National Institute for Health and Care Excellence (NICE) support for HRT in managing menopausal symptoms.

“We decided to examine the effects of HRT on cerebrospinal fluid biomarkers linked to Alzheimer’s. What we found is that the disease’s fluid pathology is high when HRT use is paired with presence of a gene variant APOE e4, but not otherwise” explained Dr Ainara Jauregi-Zinkunegi, post-doctoral researcher in neuroscience at Liverpool John Moores University and first author.

The gene variant is present in approximately 1 in 4 people and has previously been linked to the development of dementia.

The team, which today (January 9, 2025) - publishes its findings in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, examined fluid biomarkers data from 136 women - mean age: 66 - with no cognitive problems, and compared HRT users with non-users, including whether they carried the APOE e4 variant.

While average levels of phosphorylated tau by amyloid beta-42, a measure of AD pathology, were comparable across HRT users and non-users, regardless of APOE e4, women reporting HRT use who had at least one APOE e4 allele had levels of the same biomarker that were over 60% higher.

They concluded that elevated levels of these biomarkers are likely to indicate increased Alzheimer’s Disease-related pathology in these women and, thus, a higher risk of developing dementia. HRT was not associated to higher biomarkers levels in the absence of APOE e4.

If our results are confirmed (in further studies), they would caution against HRT use in women at elevated risk for Alzheimer’s due to genetic susceptibility.

People who are already at elevated risk of AD, such as those with the e4 variant of APOE, even if currently asymptomatic, may be more susceptible to possible negative effects of hormone replacement.

There is still a lot we don’t know but it may be prudent to test women for presence of the APOE e4 variant before HRT administration, at least until more knowledge on this matter is acquired.”

Dr Davide Bruno, Reader in neuropsychology, Liverpool John Moores University

And he added: “We think this may be a scenario whereby exposure to estrogen might be beneficial for healthy neurons, but in contrast estrogen might worsen damage in ‘sick’ neurons.”