Like wrinkles and a slower metabolism, Alzheimer’s disease appears to be an inevitable part of the aging process, according to prominent brain researcher George Bartzokis.
The “myelin model” Bartzokis has developed attributes Alzheimer’s and other forms of neurodegeneration to the failure of the aging brain to keep up with the increasingly difficult task of repairing myelin, the fatty white insulation that wraps around nerve axons like wax paper around its tube.
Myelin facilitates transmission of signals along axons, the fibers that link neurons to each other. When myelin breaks down, signals don’t travel as quickly and may stop altogether. Inadequate repair may put so much stress on neurons that they eventually die.
Since myelin repair tends to slow as we age, we’d all probably get Alzheimer’s if we lived long enough, says Bartzokis, a professor of psychiatry at the University of California, Los Angeles’s Semel Institute for Neuroscience and Human Behavior. That’s why promoting myelin repair becomes so important with age.
The role of new brain connections
Brain cells known as oligodendrocytes produce myelin and wrap it around axons. This process continues throughout childhood and into adulthood. The frontal lobes—the seat of judgment, planning and other distinctly human functions—are among the last brain regions to myelinate.
According to Bartzokis, the average human brain achieves maximum myelination by about 45. After that, myelin begins to break down, and the brain starts to produce more oligodendrocytes to repair the damage.
In a long article in the journal Neurobiology of Aging, which editor-in-chief Paul D. Coleman called “monumental,” Bartzokis lays out the process by which myelin breakdown gradually exceeds the ability of the brain to repair it, resulting in a cascade of dysfunction that leads to Alzheimer’s and other disorders.
In contrast, the prevailing explanation for Alzheimer’s blames the disease on toxic forms of two proteins: Amyloid fragments clump together into plaques between neurons, triggering inflammation that irritates the brain, while tau protein fibrils accumulate within neurons, apparently contributing to their death.
This explanation, known as the amyloid cascade hypothesis, has several shortcomings. First, although the genes most closely linked to Alzheimer’s disease involve the production of toxic amyloid in the brain, the correlation between amyloid plaques and dementia remains weak. People with lots of plaques may not have dementia at all, while others who have a mild plaque burden may be severely demented.
Conversely, the incidence of Alzheimer’s tracks well with the presence of tau fibrils within neurons. But “there is almost no known genetic relationship between tau and Alzheimer’s disease,” says Marsel Mesulam, a professor of neurology and psychiatry at Northwestern University who has been pondering this inconsistency of the amyloid cascade hypothesis for more than a decade. Mesulam also is a member of the Dana Alliance for Brain Initiatives.
So what’s going on? Mesulam suspects that the cause of neurodegeneration in Alzheimer’s involves neuroplasticity—the ability of neurons to create and strengthen connections with other neurons. Every sensation, memory, thought and emotion produces modifications of neural connections.
Amyloid precursor protein, which breaks down into the toxic amyloid fragments, promotes the creation of new synapses, Mesulam says. But the toxic fragments disrupt synaptic function, stressing neurons and possibly causing the breakdown of tau within individual neurons. The hippocampus, severely damaged in Alzheimer’s, is particularly vulnerable to this process because it promotes the creation of short-term memories—a relentless and demanding job that produces a great deal of neuroplasticity stress.
“So Alzheimer’s disease can be conceptualized as a state of neuroplasticity failure in which the brain is no longer able to keep itself in good repair to respond to new experience and learning,” Mesulam says, “and we don’t quite know how to enhance neuroplasticity in the brain of elderly individuals.”
Bartzokis agrees that neuroplasticity fails in Alzheimer’s disease and other disorders, but he places the blame farther upstream in the disease process. He believes that the process of myelin repair gradually fails as we age, and this in turn leaves the synapse at the end of each axon more vulnerable to breakdown.
“Plasticity—the creation and loss of synapses—does not consume exorbitant amounts of energy,” Bartzokis says. “However, the release and reabsorption of neurotransmitters at the synapse consumes a lot of energy. So the myelin repair process shuts off a neuron’s transmission down that particular axon and starves the synapse until the myelin is fixed, rather than spend a lot of energy transmitting distorted information.”
Bartzokis believes that poor myelin repair precedes the stress of creating and maintaining connections among neurons. “If repair fails, the synapses starve, and are thus sacrificed,” Bartzokis says.
In other words, they die—a familiar phenomenon in advanced Alzheimer’s disease.
Myelin and other brain disorders
The failure of myelin repair may explain other aging-related brain changes, Bartzokis says. For example, elderly people who show no signs of memory loss or dementia may nevertheless display poor judgment, falling victim to obvious scams or giving away their life savings to con artists.
Natalie Denburg, an assistant professor at the University of Iowa, attributes this to the problems in the prefrontal cortex—one of the regions most vulnerable to age-related myelin breakdown, according to Bartzokis.
“There is evidence that the frontal lobes age disproportionately to the rest of the brain,” Denburg says. “The frontal lobes are particularly vulnerable to white matter (myelin) changes from several medical conditions that promote microvascular change, such as high blood pressure, migraine and mini-strokes.”
Brain scans she performed on elderly people whose decision-making ability appeared to be impaired showed cortical thinning in an area of the prefrontal cortex critical for judgment. (Denburg co-authored the essay “Why So Many Seniors Get Swindled” for the Dana journal Cerebrum in August 2009.)
This makes sense to Bartzokis. “Your highest form of judgment is a late-myelinating function,” he says. “That’s why adults show better judgment than teenagers. But when myelin becomes thinner in older people, they slow down and don’t think as quickly. As a result, their cognitive processing speed declines, undermining functions like decision-making.”
A disturbance in the initial development of myelin may also cause brain disorders that appear in youth, such as autism and schizophrenia, Bartzokis adds.
“You can have very different types of diseases that have in common the problem of myelination,” he says. “Aberrant myelination in youth, or myelin breakdown in Alzheimer’s, will cause the same psychiatric symptoms, such as paranoia, depression and so on, because the same brain circuitry is malfunctioning.”
Wrong direction for research?
Bartzokis also believes that a failure to consider myelin repair might take Alzheimer’s research in the wrong direction. For example, one approach to treating Alzheimer’s involves inhibiting BACE1, an enzyme that cleaves amyloid precursor protein (APP).
“But BACE inhibitors reduce myelin thickness,” Bartzokis says. “BACE cleaves APP, but also cleaves neuregulin, one of the principal myelination signaling paths in the brain. It controls the thickness of myelin. When they gave BACE inhibitors to mice, they found that the myelin was reduced, but the mice seemed pretty much OK. But they’re mice. They don’t have as much myelin as humans. If you reduce the thickness of a mouse’s myelin it probably won’t make much difference, but we’re much more myelinated than mice, and reducing the thickness of our myelin could be a huge problem.”
Besides, attempting to treat Alzheimer’s by reducing the amount of toxic amyloid in the brain has not produced impressive results. In his opinion, this is because the treatment deals only with a byproduct of the myelin repair process.
“It’s not that amyloid is not involved—it’s clearly involved,” Bartzokis says, “but it’s involved at a late point in the disease process. We need to intervene before then. Treating amyloid may be akin to treating tombstones instead of treating people before they need one.”
Luckily, while genetics affects when the disease begins, lifestyle choices also are significant, he says, providing an opportunity for people to reduce their risk of developing the disease.
“First, make sure your brain doesn’t get damaged,” he suggests. “Hypertension, diabetes, cholesterol—all of those things damage the brain by interfering with normal maintenance. Also, people need fish oil as they get older because the omega-3 fatty acids provide the bricks for rebuilding myelin. The third thing is exercise, which provides a powerful pro-myelinating effect.”