We’ve been trying to mount an effective response to Alzheimer’s disease for about a century now, but unfortunately we haven’t made a whole lot of progress in understanding it, let alone curing it. But a study whose very nature meant it would take decades to complete may finally be bearing some serious fruit.
Back in 1987 in Colombia, a large group of relatives over four generations — about 5,000 people total — were found to have very high rates of early symptoms of dementia, in a pattern that looked very much like autosomal dominant heredity — that is, when you only need to inherit one defective copy of the responsible gene to be affected, with the gene on a chromosome other than X or Y. So if either parent has just one copy of the responsible gene, each of their children will have a 50% chance of inheriting the disease. If both parents have one copy, that goes up to 75%. With symptoms only appearing after child-bearing age, you can see how a mutation like this could easily hang around.
Later it was found that all of the affected individuals did indeed have the exact same mutation in a gene on chromosome 14 that came to be aptly called presenilin-1 (PSEN1). Just a single “letter” in their DNA was “C” instead of the usual “A”, such that the 280th amino acid of the PSEN1 protein was alanine instead of glutamic acid. The mutation seems to have arisen in the first half of the 1600s, probably brought over from Spain by a single individual.
The initial broad diagnosis of dementia was narrowed down to early-onset Alzheimer’s disease, in part by doing autopsies. On average, the affected people would first get symptoms (headaches and memory loss) at an average age of just 47. This would progress over the next 8 years or so to behavior and personality changes, language impairment, gait disturbances, seizures, uncontrollable twitching, and finally death. It is still not clear why PSEN1 mutations trigger Alzheimer’s.
But among all the affected people, two have stood out because even though they had the PSEN1 mutation, they did not develop any symptoms until decades later than expected. One such woman was found in 2019 to have a second mutation in a gene called APOE that impaired its function. Interestingly, she had high levels of beta-amyloid protein accumulated in her brain, which has long been thought to be a cause of Alzheimer’s disease. Yet she didn’t get it. Why not?
And now we have a second individual, this time a man, who showed no symptoms for 20 years or so after the onset we’d expect from his PSEN1 mutation. Although he had a normal APOE gene, he had a mutation in a gene called reelin (RELN; known to affect neuron development but with no known role in Alzheimer’s) that caused the corresponding protein to be more potent than normal RELN protein. Same deal here: he had lots of beta-amyloid, yet he somehow fended off Alzheimer’s. His case is reported posthumously, after years of observation and analysis by researchers in Colombia, Boston, and elsewhere, in the May 15 issue of Nature Medicine.
We do know that RELN is important for neuropsychiatric health — after all, mice that lack functional RELN protein are called “reeler” mice because they have a staggering gait, with tremors and cognitive issues. Humans completely lacking RELN are rare because both copies of the gene need to be disrupted, but they have similar issues. The mouse and human versions of RELN look very much alike and seem to function similarly.
Brains from mice that don’t have functional RELN appear disorganized:
Comparative brain slices of normal (left) and Reeler mutant (right) mice
And that’s because even though all the types of neurons form properly, they don’t get placed correctly; all the layers get mixed up:
The two Colombian individuals had secondary mutations that were different, yes, but they’re connected. The APOE and RELN proteins, it turns out, both bind to the same types of receptors, called ApoER2 and VLDLR. When these receptors are activated, they trigger a process that helps newly developing neurons go to the right place so that neural networks can develop properly.
When APOE binds to these receptors, it inhibits this process, but when RELN binds to these same receptors, the process is promoted. So we have a competition here in which we need RELN to hold its own. The mutations that staved off Alzheimer’s for these two people were 1) a loss of APOE function and 2) a gain of RELN function. In other words, they were two alternative ways to accomplish the same thing: tip the balance toward RELN and away from APOE, and trigger the receptors that promote neural placement, or whatever other function it is that is preventing Alzheimer’s.
Out of the 5,000 or so Colombians with the PSEN1 mutation, about 1,200 had their genomes and medical histories analyzed over 35 years, and among all of them, just these two individuals with PSEN1 mutations held off Alzheimer’s disease, and the two mutations they accomplished that with turn out to affect the exact same target.
Ohhhh, boy.
“Reading that paper made the hair on my arms stand up,” says neuroscientist Catherine Kaczorowski at the University of Michigan in Ann Arbor. “It’s just such an important new avenue to pursue new therapies for Alzheimer’s disease.”
So here we have a new mechanism to prevent Alzheimer’s disease despite the presence of beta-amyloid, which has long been thought to be a primary cause. Can we find molecules that activate the ApoER2 and VLDLR receptors appropriately, to keep neural development and placement steady, even as we age? Can we develop and prescribe them as drugs? There’s no particular reason to think that we can’t, and so we need to try and implement that right away.
Indeed, there are already some experimental suggestions that the approach of tipping the RELN/APOE balance in the brain might indeed be a good path to take: for example, luring APOE away with a decoy receptor (to make things easier on RELN) seems to slow neurodegeneration in mice.
🔸 🔸
We’re still congratulating ourselves for approving drugs that try to reduce beta-amyloid accumulation, but that may just be rearranging the deck chairs on the Titanic. The Colombia-Boston study may very well have lit the way to a new approach. (And this is by no means to say there can’t also be others.) It took decades to accomplish, but this is real data from real people that we could not have ethically obtained any other way than years and years of patience, preparedness, and compassion.
“The person who recognizes his major mistakes is on the road to wisdom.”
– Colombian Proverb
Francisco Lopera of the University of Antioquia, Medellín, Colombia, who’s been involved with this research for no less than 40 years, had this to say:
“What we have done with the study of these two protected cases is to read Mother Nature.
The most exciting thing is that nature has revealed to us both the cause of Alzheimer’s and the cure for it. Mother Nature did an exceptional experiment with these two subjects: it endowed them both with a gene that causes Alzheimer’s and at the same time with another gene that protected them from the symptoms of the disease for more than two decades.
Therefore, the solution is to imitate nature by developing therapies that mimic the mechanism of protection of these genetic variants in subjects at risk of suffering from the disease.
A great door has been opened for the prevention and treatment of incurable diseases.”
When you look at Francisco Lopera, you see a life very well spent. We all stand to benefit.
