A woman with a genetic mutation thought to inevitably cause Alzheimer’s disease in people’s 50s escaped that fate, living into her 70s before she developed mild dementia — and researchers think they know why.
In addition to the Alzheimer’s mutation, they reported on Monday, she has a rare form of a gene best known for producing molecules that help carry cholesterol through the bloodstream. Somehow, the second gene prevented the devastating consequences of the first, a finding that might one day open up new approaches to treating or preventing Alzheimer’s.
“This is an excellent and thought-provoking study,” said Dr. Michael Greicius of Stanford University School of Medicine, an expert in Alzheimer’s genetics who was not involved in the research. He emphasized, however, that because the patient’s combination of genes is “exceedingly uncommon and possibly unique,” the study — published in Nature Medicine — is “hypothesis-generating” but far from definitive.
He and five other Alzheimer’s researchers cautioned that this is a single case report, not a large study, and the rarity of the woman’s genetics may well make it impossible to prove that the supposedly protective gene really did keep her from developing early-onset Alzheimer’s.
The woman (unnamed, to protect her privacy) belongs to a large extended Colombian family. Descended from a Basque couple who migrated to Colombia 300 years ago, roughly 1,200 of its 6,000 living members carry a mutation in a gene called PSEN1, discovered in 1987. The mutation (known as E280A) causes the brain to overproduce the protein fragment beta-amyloid, which forms sticky plaques between neurons and is a diagnostic hallmark (though not necessarily the cause) of Alzheimer’s.
Because the Colombian family is the largest single group with mutations that cause early-onset Alzheimer’s — half of those with the gene develop mild cognitive impairment by age 44 and dementia by 49 — they have been a key part of studies of the disease.
Through one such study, the woman came to the attention of neuropsychologist Yakeel Quiroz of Massachusetts General Hospital. The woman’s memory and thinking had been basically fine well into her 50s and 60s, her family said. Although brain imaging revealed extremely high levels of amyloid — as is expected with PSEN1 — only in her 70s did she develop mild cognitive impairment, three decades after relatives who also have the amyloid-superproducing PSEN1 mutation.
In fact, she has more amyloid plaques than relatives whose cognition began crashing in their 40s. She also has relatively low brain levels of tau, also a protein fragment but one that accumulates inside (and kills) neurons. She also has little neurodegeneration.
To figure out how the woman avoided early-onset Alzheimer’s, Quiroz and her colleagues sequenced her genome. One of her genes, APOE3, was extremely unusual: Both copies (one from her mother and one from her father) carried the rare “Christchurch mutation,” named for the New Zealand city where it was discovered in 1987. Despite that history, it is found almost exclusively in Latinos; Stanford’s Greicius estimates that only about 1 in 100 million people have two copies.
Like every other human, the woman has thousands of other unusual genetic variants. But Quiroz zeroed in on the Christchurch mutation based on an algorithm that ranks variants for their role in particular diseases. Different forms of APOE have long been associated with Alzheimer’s: APOE4 raises the risk of developing the disease, APOE2 lowers the risk, and APOE3 is neutral (there is no APOE1). “We felt confident the Christchurch variant of APOE3 was of interest,” Quiroz said.
To test that hunch, she and her team studied how the Christchurch form of the APOE3 molecule interacts with other molecules that play a role in Alzheimer’s. In lab dishes, the Christchurch form didn’t bind as well as ordinary APOE3 to sugar molecules (called heparan sulphate proteoglycans). Those sugars, previous studies showed, are critical enablers of tau, the neuron-killing Alzheimer’s-related molecule: Bound to APOE, the sugars allow tau to spread from one neuron to another, jumping around the brain in a dance as lethal as glowing embers in a wildfire.
The Christchurch mutation, Quiroz and her team concluded, dampens tau formation and neuronal death even when the brain is awash in amyloid.
If they’re right, it might be possible to prevent or treat Alzheimer’s through a route very different from removing brain amyloid, as most experimental drugs have (in virtually every case, without success). Instead, antibodies or other molecules that keep APOE from binding to the tau-spreading sugars “could reproduce [the] potentially protective effect” of the Christchurch mutation, including in people with ordinary genes, Quiroz and her colleagues wrote. That “could have a profound impact on the treatment and prevention of Alzheimer’s disease.”
Other scientists weren’t so sure. The main doubt: This patient, like everyone, has tens of thousands of other rare variants, any one of which might be why she did not develop early-onset Alzheimer’s as her PSEN1 mutation should have caused.
“There are thousands of variants in our genome,” said Nikolaos Robakis of the Icahn School of Medicine at Mount Sinai, who discovered one of the first mutations for early-onset Alzheimer’s. “So, from the get-go, it’s unlikely that this is the one” that let the woman escape what would have otherwise been her genetic fate.
One reason for doubt: Having one copy of the Christchurch variant (as seven of 117 members of the patient’s extended family do) rather than two (as she does) has apparently no benefit, Stanford’s Greicius pointed out. Four of the seven also have the early-onset Alzheimer’s mutation, and all developed the disease.
“It would have been most convincing to show that while two copies of the Christchurch variant move the age of onset from early 40s to early 70s, one copy had a middling effect, moving the age to the early 50s,” he said. “But there was no ‘dose effect.’” That, agreed Robakis, “is evidence against” the claim that this rare form of APOE3 acts as an anti-Alzheimer’s talisman.
But even skeptics agreed on one thing: The role of APOE in Alzheimer’s is vastly understudied. Remedying that could be the Colombian woman’s most valuable contribution to Alzheimer’s research.