Israeli study reveals molecular basis for female Alzheimer’s patients’ rapid decline

Israeli research combining molecular and computational neuroscience has uncovered a molecular basis for why women living with Alzheimer’s disease experience more rapid cognitive deterioration than men.

A study, led by Prof. Hermona Soreq and Prof. Yonatan Loewenstein of the Edmond & Lily Safra Center for Brain Sciences at The Hebrew University of Jerusalem, points to a correlation between this accelerated cognitive decline and depletion of mitochondrial RNA fragments in the nucleus accumbens part of the brain.

The peer-reviewed study was published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Soreq told The Times of Israel that the study’s findings, together with other advances in RNA research and therapeutics, could lead to better treatments for women living with Alzheimer’s. With no known cure for the disease, the aim would be to significantly slow down its progression.

More than 55 million people worldwide are living with dementia, and 60-80% have Alzheimer’s disease. Twice as many women as men have the disease, with one reason being that women live longer. However, researchers are investigating possible biological and cultural reasons that may play a role.

Women with Alzheimer’s often experience negative side effects from drugs currently used to treat the disease, because they were developed using male animals and tested primarily on men.

“We’ve been looking for decades now at RNA and the molecular basis of how the brain functions,” Soreq said.

“You try to find what’s wrong when things are not functioning, and how the brain functions when everything is fine,” she said.

Soreq looked at brain functions regulated by acetylcholine, a neurotransmitter that plays a role in memory, learning, attention, arousal, and involuntary muscle movement. Alzheimer’s is one of several medical conditions associated with low levels of acetylcholine, or the malfunctioning of the cholinergic pathway.

Soreq also studied the extent to which acetylcholine regulation is associated with RNA metabolism.

“We bumped into the difference between men and women four years ago when we explored the differences in the pathway for acetylcholine in patients with mental disease and found massive differences between men and women,” Soreq said.

Hebrew University molecular neuroscience professor Hermona Soreq (right) and Tamara Zorbaz test cultured neurons in the lab. (Yosef Adest)

“At the same time, we were reading about women getting sick more often with Alzheimer’s disease, and when they do they deteriorate faster than men, even when you calculate for a longer life expectancy,” she said.

This prompted Soreq and her team to look at cholinergic regulation in men and women but from the perspective of small RNAs, particularly transfer RNA (t-RNA) molecules that play a key role in protein synthesis. After t-RNA has brought amino acids to growing protein chains, its job is done and it is cut up into pieces by enzymes.

It was thought that these t-RNA fragments were useless, but Soreq discovered that they could play a role in acetylcholine signaling. She studied RNA profiles of individuals — both men and women — to see how many and what kind of t-RNA fragments they had.

“This was not a study with mice. It was a human study in which we used postmortem brain tissue provided by our colleague David A. Bennett at Rush University in Chicago,” Soreq said.

“He’s been collecting these tissues for decades. He takes care of monks and nuns from a religious order. He gives them regular medical checkups and treats them, and they fill out questionnaires and agree to donate their brains to science after their deaths,” she explained.

This provides data, clinical information, and tissue, but it doesn’t necessarily help explain differences in RNA seen in the brain tissue. It is not clear whether they relate to general deterioration and shrinkage of the brain, or whether it reflects a change in cognition.

Illustrative image of an elderly patient with Alzheimer’s, dementia. (Chinnapong, iStock by Getty Images)

That is where RNA sequencing technology comes in. “You get a long list of sequences and you use computational biology to analyze and ask which of those sequences shows a difference between cognitively able and unable individuals. And if it does, would those be men or women?” Soreq said.

It turned out that women with cognitive decline lose the t-RNA fragments much earlier than men.

“These fragments have a job to do. And when they get lost, they don’t do their job. This is probably associated with the faster deterioration of women with Alzheimer’s cognition,” Soreq said.

These cut-up pieces are specifically of RNA from the mitochondria, rather than RNA from nuclear DNA. Mitochondrial RNA is inherited from a person’s mother. However, Soreq said she couldn’t yet say whether this indicates that Alzheimer’s disease is inherited from one’s maternal line.

Soreq hopes that therapeutics will be able to be developed based on these findings, but notes that the blood-brain barrier poses serious challenges.

“The good thing is that this came up at a time when RNA therapeutics is not a bad word anymore. Thanks to the (COVID) pandemic we now know that one can retrieve RNA and inject it, or inject the molecules that produce it,” Soreq said.

“This creates an opening for a future study that would ask whether we can retrieve those lost collections of t-RNA fragments. And if we did that, would it slow down — or even prevent — the deterioration in women with Alzheimer’s,” she said.