Alzheimer’s disease research has long been beset by a religious war of sorts: “BAPtists” ardently believe that plaques formed by beta-amyloid proteins drive the disease by gumming up and ultimately killing neurons. “TAUists” believe that the real culprits are the neurofibrillary tangles, or twisted tau proteins, that accumulate within neurons. And “ATHIEsts” believe that while both of these factors play a role, anything else may ultimately be to blame for advancing the disease.
As I mentioned in Monday’s post (“Why the Latest Alzheimer’s Drug Has So Many People Confused”), the BAPtists have drawn the greatest number of disciples for a generation or more—on both the academic research and drug development fronts. And amyloid hypothesis backers even have a new biological model to explain how this pathological process might begin—and accelerate. The idea, as writer Laura Beil explains in a wonderfully clear feature in Science News, is called the “clean cycle”:
During normal sleep, the brain actively clears out stray beta-amyloid (also called A-beta), protein remnants that are discarded by neurons themselves. But when sleep is disrupted, the trash removal is stalled: “[T]he brain doesn’t get the chance to mop up all the A-beta that the neurons produce, according to a developing consensus,” Beil writes. “A-beta starts to collect in the small seams between cells of the brain, like litter in the gutter. If A-beta piles up too much, it can accumulate into plaques that are thought to eventually lead to other problems such as inflammation and the buildup of tau, which appears to destroy neurons and lead to Alzheimer’s disease.”
Indeed, thanks to PET scans, we can see that, even in healthy brains, the amount of this stray protein increases dramatically—by as much as 5% in certain brain regions—after only a single night of sleep deprivation. The fact that Alzheimer’s itself disrupts sleep serves only to speed up and amplify this vicious cycle. But there are gaps in the theory, too. One is a chicken-and-egg conundrum, says Beil: “If Alzheimer’s both affects sleep and is affected by it, which comes first?”
Another gap—or at least a confounder—is the fact that amyloid-clearing agents have been tested again and again in investigative clinical trials and have never been shown to halt the disease. As I wrote on Monday, the recent results from the Phase II trial of BAN2401, an anti-amyloid drug from Biogen and Eisai didn’t exactly break this record. Though patients who received the experimental antibody may have had some improvement in cognition, the outcomes appeared to fall short of what many had hoped for, and even expected.
On top of that comes another weighty question: Call it the seven-ton mystery—or the elephant in the room of Alzheimer’s oddities: Why don’t elephants experience the same kind of brain deterioration with aging?
The brains of Loxodonta africana, or African elephants, are nearly three times larger than their human counterparts—holding as many as 257 billion neurons compared to our feeble 100 billion or so (though the vast majority of the elephant’s supply reside outside the cerebral cortex). But elephants seem to have extraordinary memory capacity late into life, as Michael Garstang, an emeritus distinguished research professor at the University of Virginia, details in his book Elephant Sense and Sensibility—with herd matriarchs remembering discrete faraway locations visited many decades earlier, for example, and transferring that knowledge to the next generations.
Moreover, to the extent it can be known (It’s hard to ask an elephant what they had for breakfast yesterday), there seems to be little evidence that older elephants suffer from mental decline. So far, in the handful of brains of older elephants that have been examined post-mortem, there’s also no evidence of a buildup of amyloid plaques.
As for the sleep-brain-cleaning thesis, that too runs into a snag with elephants: The creatures, on the whole, sleep very little. (Wild elephants may sleep as little as two hours a day, according to one study, though captive animals tend to sleep longer.) But in any case, if elephants are clearing any amyloid buildup during the course of their zzz’s, there isn’t much time to get it done.
One possible explanation is that elephant brains may have some other biological mechanism for keeping their neurons firing brightly through the decades.
But then, another theory isn’t mechanistic at all—rather, it goes to the heart of elephant life itself: They’re deeply social. The animals congregate for life in tight-knit extended family networks, one generation alongside another. Could that have something to with keeping aged brains humming?
As it turns out, there’s actually a fair amount of research to suggest it might. Several studies in humans have appeared to demonstrate that strong social connections reduce the risk of cognitive impairment in older adults—and that the opposite circumstance (social disengagement) makes mental deterioration worse.
Unfortunately, such evidence might offer one clue as to why Alzheimer’s deaths have been rising in this U.S., increasing 123% between the years 2000 and 2015. In the end, such a sad stat may reflect our frayed social fabric—and the lack intergenerational contact among families today—as much, perhaps, as it does some biological or chemical driver of the disease.
So while the BAPtists and TAUists and ATHIEsts debate the murky science among themselves, give your mom or dad, or aunt, or older neighbor a call this weekend and shoot the breeze. Who knows? You may end up doing more to fight Alzheimer’s than many pharma execs.
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