Reelin as an Important Factor in the Development of Alzheimer's Disease
This popular science article touches on some of the research indicating that the protein Reelin may be an important protective factor in the aging brain. Alzheimer's disease reduces its production, which may contribute to the neurodegeneration and dementia produced by the underlying biochemistry of protein aggregation characteristic of the condition. As is often the case, the lynchpin for the assembly of accumulated scientific evidence emerges from the examination of an individual who bears a variant form of the protein and is thus protected from much of the consequences of Alzheimer's disease pathology.
A key protein that helps assemble the brain early in life also appears to protect the organ from Alzheimer's and other diseases of aging. A trio of studies published in the past year all suggest that the protein Reelin helps maintain thinking and memory in ailing brains, though precisely how it does this remains uncertain. The studies also show that when Reelin levels fall, neurons become more vulnerable. The research has inspired efforts to develop a drug that boosts Reelin or helps it function better, as a way to stave off cognitive decline.
Reelin became something of a scientific celebrity in 2023, thanks to a study of a man who should have developed Alzheimer's in middle age but didn't. The man was part of a large family that carries a very rare gene variant known as Paisa. Family members who inherit this variant are all but certain to develop Alzheimer's in middle age. But this man, despite having the variant, remained cognitively intact into his late 60s and wasn't diagnosed with dementia until he was in his 70s. After he died at 74, an autopsy revealed that the man's brain was riddled with sticky amyloid plaques, a hallmark of Alzheimer's. Scientists also found another sign of Alzheimer's - tangled fibers called tau, which can impair neurons. But oddly, these tangles were mostly absent in a brain region called the entorhinal cortex, which is involved in memory. That's important because this region is usually one of the first to be affected by Alzheimer's
The researchers studied the man's genome. And they found something that might explain why his brain had been protected. He carried a rare variant of the gene that makes the protein Reelin. A study in mice found that the variant enhances the protein's ability to reduce tau tangles. Another team published an analysis of the brains of 427 people. It found that those who maintained higher cognitive function as they aged tended to have more of a kind of neuron that produces Reelin.
A more recent study included a highly detailed analysis of post-mortem brains from 48 people. "The neurons that are most vulnerable to Alzheimer's neurodegeneration in the entorhinal cortex, they share one feature. They highly express Reelin." In other words, Alzheimer's appears to be selectively damaging the neurons that make Reelin, the protein needed to protect the brain from disease. As a result, Reelin levels decline and the brain becomes more vulnerable. The finding dovetails with what scientists learned from the man whose brain defied Alzheimer's. He had carried a variant of the Reelin gene that seemed to make the protein more potent. So that might have offset any Reelin deficiency caused by Alzheimer's.