Gene Linked to Alzheimer's Disease Predicts Who Benefits from Hormone Replacement Therapy

“There have been very limited drug options for Alzheimer’s disease for 20 years,” explains Dr. Rasha Saleh, a researcher at the University of East Anglia in the UK. To address this “urgent need for new treatments,” Saleh and collaborators presented new evidence that the cognitive decline associated with Alzheimer’s Disease (AD) can be delayed with a drug therapy already popular with older women: Hormone Replacement Therapy (HRT).

No new clinical trials necessary.

The connection between estrogen and memory is firmly established in the neuroscience literature, and estrogen is linked to increased neuronal spine formation and better auditory processing. Dr. Saleh’s recent research sought to clear up previous conflicting results concerning HRT’s ability to prevent cognitive decline in peri- and post-menopausal women. The researchers discovered that an important genetic distinction might determine the effectiveness of HRT.

By considering various versions of the APOE gene, the authors identified a sub-group of older women who specifically benefit from HRT.

APOE4 is a variation of the APOE gene linked to an increased risk of dementia. Carriers of APOE4 are at a 3- to 15-fold higher risk of cognitive decline and AD later in life. Additionally, the negative cognitive effects linked to APOE4 are more prevalent in females with the variant, known as an increase in gene penetrance.

Dr. Saleh’s study included 1,178 European women from the European Prevention of Alzheimer’s Dementia initiative. The study’s multiple linear regression models allowed the scientists to pair individual participants to their measures of MRI activity, cognitive test results, the time they each began HRT, and APOE genotype.

These scientists found heterogeneity in the AD population, with HRT specifically benefiting those with the APOE4 variant.

Some improvements in cognitive test scores for HRT users were only observed in the APOE4 carrier group. When participants were both APOE4 carriers and HRT users, they received higher (better) scores on the Repeatable Battery for the Assessment of Neuropsychological Status, which measures attention, delayed memory, immediate memory, language skills, and visuo-construction.

Individuals with the APOE4 and HRT combo also had larger entorhinal and amygdala volumes,  two brain regions affected in AD. The loss of the sense of smell is an early sign of AD linked to the entorhinal cortex. The amygdala experiences changes in its microstructure during the course of AD, which can result in decreased volumes. It’s possible that for APOE4 carriers, HRT might prevent atrophy in these brain regions. Researchers stopped short of interpreting their concerning discovery that there was a decrease in the size of the amygdala volume in non-APOE4 carrying HRT users.

Earlier start time for HRT use in APOE4 carriers was also associated with larger right and left hippocampal volumes, another brain region known for memory formation affected by AD.

These findings provide clinicians with a genetic marker identifying groups who would most benefit from a previously established and approved drug therapy used by older women. It also supports the critical window hypothesis for the earlier introduction of HRT for protection against neuronal damage.

“The effects of HRT in this observation study, if confirmed in an intervention trial, would equate to a brain age that is several years younger,” predicts Dr. Shaleh. This work was conducted in the laboratory of Dr. Anne Marie Minihane, partnered with Dr. Craig W. Ritchie at the University of Edinburgh.

Sources:  Alzheimer’s Research & Therapy, Learning and Memory, Hormones and Behavior, Steroids, Behavioral Neuroscience