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Mutations in Three Genes Protect Against Alzheimer’s

Clues to combatting a devastating disease can come from identifying people who have gene variants – mutations – that protect them, by slowing the illness or lowering the risk that it develops in the first place. Understanding how they do this may inspire treatment strategies for the wider patient population.

Rare variants of three well-studied genes appear to delay inherited forms of Alzheimer’s disease – by decades.

Gene #1: The Famous Case of Aliria from the Colombian Family

In 2019. researchers reported on a patient, Aliria Rosa Piedrahita de Villegas, who seemed to have fended off early-onset familial Alzheimer’s thanks to a variant of a second, apparently protective gene. The report appeared in Nature Medicine.

Aliria belongs to a 6,000-member family in Colombia, known for the many individuals who show signs of Alzheimer’s at about age 44, but have the telltale buildup of amyloid beta protein beginning in their twenties. About half the family has been affected. They have a variant of the presenilin-1 gene, PSEN1 E280A, which accounts for about 70 percent of cases of early-onset Alzheimer’s. Aliria inherited the variant, yet she didn’t begin to experience cognitive decline until age 72.

“Our work with this family allows us to track those earliest changes associated with Alzheimer’s disease and identify how those changes happen over time. This will help us identify, in people beyond those in Colombia, who may be at risk and who may be more resistant to Alzheimer’s, as well as learn which biomarkers are better predictors of disease progression,” Yakeel T. Quiroz, Ph.D., from Massachusetts General Hospital, told the Alzheimer’s Association. That’s where this special patient went for brain scans that revealed the very high levels of amyloid beta protein plaques characteristic of the disease.

But what, exactly, has protected Aliria? She’d also inherited two copies of the Christchurch mutation, a rare variant of the gene APOE, named for where it was discovered in New Zealand. The Christchurch gene variant reduces the density of tau tangles, the other type of protein that aggregates in an Alzheimer’s brain.

More recently, researchers at the Washington University School of Medicine used genetically modified “humanized” mice to show that the Christchurch mutation interrupts the interaction between amyloid beta and tau.

“As people get older, many begin to develop some amyloid accumulation in their brains. Initially, they remain cognitively normal. However, after many years the amyloid deposition begins to lead to the accumulation of the tau protein. When this happens, cognitive impairment soon ensues. If we can find a way to mimic the effects of the APOE Christchurch mutation, we may be able to stop people who already are on the path to Alzheimer’s dementia from continuing down that path,” explained David M. Holtzman, MD, from Washington University.

Could a treatment decouple formation of amyloid beta plaques from deposition of tau tangles? That’s what the researchers wanted to find out, publishing their findings in the January 2024 Cell. The switch from amyloid buildup to tau takeover is critical, and little understood. Aliria’s case may clarify matters.

“This woman was very, very unusual in that she had amyloid pathology but not much tau pathology and only very mild cognitive symptoms that came on late. This suggested to us that she might hold clues to this link between amyloid and tau,” Holtzman said.

But Aliria is the only person known in the world to have these dual mutations. Did they in fact interact, or is her unusual genotype – apparent protection from Alzheimer’s – just a coincidence?

To solve this puzzle, Holtzman and colleagues created mice genetically predisposed to overproduce amyloid, but that also have the human Christchurch mutation. Then, they injected human tau protein into the brains of the mice. Because the mouse brains were already brimming with amyloid “seeds,” the tau tangles should have glommed up the injection sites, and then spread to other brain regions – but they didn’t. Very little tau was found amongst the abundant amyloid choking the brains – modeling Aliria’s fortuitous double-mutation situation.

The mice revealed the mechanism of the Christchurch mutation’s protection: activity levels of microglia, the brain’s waste-disposal cells. Microglia cluster around amyloid plaques on brain cells. In Alzheimer mice with the APOE Christchurch mutation, the microglia surrounding the amyloid plaques went into overdrive in gobbling up and destroying tau aggregates.

“These microglia are taking up the tau and degrading it before tau pathology can spread effectively to the next cell. Without tau pathology, you don’t get neurodegeneration, atrophy, and cognitive problems. If we can mimic the effect that the mutation is having, we may be able to render amyloid accumulation harmless, or at least much less harmful, and protect people from developing cognitive impairments,” Holtzman said.

Gene #2: Reelin

The researchers investigating the large Colombian family that includes Aliria described “the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease” in the May 15, 2023 Nature Medicine. Like Aliria the man retained cognition until age 67, although he had the strong PSEN1 E280A mutation that causes very early onset Alzheimer’s.

By age 73, neuroimaging showed higher levels of amyloid beta plaques than in other family members with the Alzheimer’s mutation. And although his brain also had tau tangles, a memory center, the entorhinal cortex, was comparatively free of tau. Perhaps this unusual distribution enabled his cognitive abilities to persist despite drowning in amyloid beta.

But he didn’t share Aliria’s Christchurch mutation.

Instead, the man’s apparent protection came from a rare variant of another gene, RELN, which encodes the protein reelin. It is a well-studied signaling protein implicated in several neurological and psychiatric conditions, including schizophrenia, bipolar disorder, and autistic spectrum disorder.

In experiments with mice, the researchers showed that his form of reelin is a gain-of-function mutation, stronger than the more common variant of the gene. (“Gain-of-function” is a classic term in genetics, not something invented during the COVID pandemic.)

Like apolipoprotein E, reelin binds to receptors on certain lipoproteins, which carry cholesterol. This reduces activation of tau, which apparently disturbs the delicate balance between amyloid beta and tau in a way that slows Alzheimer’s.

Gene #3: Altering Fibronectin at the Blood-Brain Barrier

Even more recently, researchers at Columbia University have been focusing on another apparently protective gene variant, which encodes a protein, fibronectin. It’s a minor component in a healthy brain, but excess is associated with increased risk of developing Alzheimer’s.

Fibronectin is embedded in the blood-brain barrier. This 400-mile labyrinth of capillaries, the tiniest blood vessels, winds through the neurons and glial cells that constitute delicate brain matter.

The one-cell-thick capillary walls form a lining, called endothelium, that’s normally so tightly packed that it keeps toxins from the bloodstream, while allowing into the brain essential substances such as oxygen. The barrier also tempers biochemical fluctuations that would overwhelm the brain if it had to continuously respond, and oversees levels of neurotransmitters.

Understanding blood-brain barrier function has been at the heart of research into drug therapies for neurological diseases.

Working with zebrafish and mouse models of Alzheimer’s, the investigators have discovered that a variant of the fibronectin gene prevents the buildup of fibronectin at the blood-brain barrier. Excess amyloid beta can exit the brain into the bloodstream, lowering risk of developing Alzheimer’s, the investigators estimate. Their research appears in Acta Neuropathologica.

Caghan Kizil, PhD, explains the findings:

“Alzheimer’s disease may get started with amyloid deposits in the brain, but the disease manifestations are the result of changes that happen after the deposits appear. Excess fibronectin could be preventing the clearance of amyloid deposits from the brain. Our findings suggest that some of these changes occur in the brain’s vasculature and that we may be able to develop new types of therapies that mimic the gene’s protective effect to prevent or treat the disease.”

This strategy differs from directly targeting amyloid deposits and facilitating their removal, which may be too little too late. “We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream. That’s why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development,” said study co-leader Richard Mayeux.

After demonstrating the consequence of lowering fibronectin in zebrafish and mice, the researchers examined the protein in people who inherited a variant of the APOE gene, APOEe4, associated with Alzheimer’s, but who live a long time. Was a variant of the fibronectin gene protecting them?

To find out, the Columbia researchers sequenced the genomes of several hundred individuals with APOEe4 older than 70, from several ethnic backgrounds. Some had Alzheimer’s.

“These resilient people can tell us a lot about the disease and what genetic and non-genetic factors might provide protection,” said study co-leader Badri N. Vardarajan, PhD. A variant of the fibronectin gene is apparently protective.

When the researchers posted a preprint of their findings, other groups added data from other populations, supporting the association: fibronectin protects. Data from more than 11,000 people indicated that the mutation reduces the odds of developing Alzheimer’s in APOEe4 carriers by 71% and delays disease onset by about four years in those who do develop the disease.

Only about 1 to 3 percent of carriers for APOEe4 in the US also have the protective fibronectin mutation, but that’s 200,000 to 620,000 people, the researchers estimate. This inborn shield may inspire research that leads to development of new drugs that could help many more.

Summed up Kizil, “There’s a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer’s disease, independent of their APOEe4 status. Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition.”

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