What Does it Mean to be ‘Amyloid Positive?’


by Jim Schnabel

November 11, 2014

Brain scans for Alzheimer’s-related amyloid beta (Aβ) deposits began to be available a few years ago, and could someday be as routine for older people as angiograms and colonoscopies are now. An amyloid scan uses an injected, mildly radioactive tracer that seeps into the brain, binds to the insoluble Aβ deposits—also known as plaques—and “lights them up” for a positron emission tomography (PET) scanner.

Amyloid scans are not yet covered by Medicare in the US. Even so, neurologists sometimes recommend them so they can distinguish Alzheimer’s-type dementia or mild cognitive impairment (MCI), which typically are associated with a heavy plaque load, from impairments caused by small strokes or other factors.

But some clinical trial researchers have been using amyloid scans on cognitively normal elderly people, to select those who are at higher risk of Alzheimer’s—and thereby shorten the necessary duration of the trial. Elderly people who don’t mind spending several thousand dollars also can arrange to have amyloid scans simply for their own information.

People who are scanned that way will wonder what it means if they have dense enough Aβ plaques to qualify as “amyloid positive.” Does it mean that the steep cognitive slide of Alzheimer’s is imminent? Or is their risk only mildly increased? Can one be “amyloid positive” at 80 and still have a fair chance of staying dementia-free for another decade?

Naturally the risk will depend on the extent of the plaque burden—there is a wide range between the “amyloid positive” threshold and the higher levels typically seen in people with Alzheimer’s dementia. But even an Alzheimer’s-level plaque burden, in a cognitively normal person, doesn’t mean that dementia must be near.

“From post-mortem and amyloid imaging studies we are starting to have a little bit clearer picture of the role of Aβ in Alzheimer’s, and it seems that it is a necessary but not sufficient cause of cognitive decline,” says Victor Villemagne, a researcher at the University of Melbourne.

A gradual accumulation

An 80-year old who is found to be “amyloid positive” on a PET scan certainly can live to 90 and beyond and stay dementia-free. The transition from “amyloid negative” to what scientists have agreed to call “amyloid positive,” and then to heavy amyloid consistent with Alzheimer’s dementia, seems to occur very slowly for the average person.

One of the clearest findings in this regard was published by Villemagne and his colleagues last year in Lancet Neurology. As part of the Australian Imaging, Biomarkers, and Lifestyle Study of Aging, they scanned 200 elderly people—19 with Alzheimer’s at the outset, 35 with MCI, and 145 with no evident cognitive impairment—at 18-month intervals for a few scans each.

The resulting plots of amyloid density and clinical impairments over time suggested a very prolonged phase of plaque buildup prior to the appearance of cognitive signs: Someone who had just reached the “amyloid positive” threshold could expect to wait about 14 years before showing signs even of mild cognitive impairment. They then could expect a further three-year interval before the onset of dementia—if their MCI progressed that far; it often doesn’t. Moreover, according to these data, a healthy elderly person with a barely detectable level of amyloid, well below the “positive” threshold, would require 12 years, on average, to reach that first positive threshold—implying that a total of almost three decades of detectable Aβ deposition normally occurs before Alzheimer’s dementia manifests.

A study by Mayo Clinic researchers, published at virtually the same time, came to nearly the same conclusion: Aβ deposition takes about three decades, including about 15 years between passing the “amyloid positive” threshold and tailing off at levels consistent with Alzheimer’s.

Similarly, in a study published last year, Villemagne, Christopher Rowe and their colleagues at the University of Melbourne found that only 17% of healthy elderly subjects who were initially found to be in the “mild” amyloid-positive range, and only 37% in the heavy, AD-like range, progressed to MCI or Alzheimer’s dementia over the following three years.

In short, an 80-year old just reaching the threshold of positivity—which is close to the average amyloid burden for that age—would be most likely to die of something else before developing Alzheimer’s dementia.

Amyloid plaques don’t drive the progress of dementia

Aβ plaques aren’t an absolute determinant of Alzheimer’s risk because, despite being among the most visible signs of the disease to pathologists at autopsy, they are not strong drivers of the disease process.

Plaque levels on average start to plateau years before dementia occurs, and, after dementia starts, do not show much of a relationship to the degree of cognitive impairment. Clinical trials also have found that various anti-Aβ compounds, including a vaccine that demonstrably cleared plaques, did not significantly slow the progress of Alzheimer’s dementia. In recent years, scientists have found that smaller clumps (“oligomers”) of Aβ seem much more toxic to brain cells, and correlate better with cognitive decline. Many now suspect that the Aβ plaques are protective, in the sense that they sequester Aβ that might have aggregated into toxic oligomers. Certainly many elderly people are found to have heavy Aβ plaque loads at autopsy despite having shown no sign of cognitive impairment when alive.

According to a disease model that is popular at present, the initial, decades-long, symptom-free stage of Alzheimer’s is dominated by accumulating Aβ, in fibril (tiny fiber-like aggregate) and oligomer forms. The symptomatic stage of disease, on the other hand, involving mass brain cell loss and eventually dementia and death, is dominated by more powerful degenerative processes—for which Aβ (principally oligomers, not plaques) serves as a trigger.

One of these other processes involves the neuronal protein tau; its oligomers and fibrils eventually spread in an infection-like manner through the Alzheimer’s-afflicted brain. That spread correlates better (than the spread of Aβ plaques) with the loss of brain cells and the descent into dementia, and the toxicity of oligomeric Aβ has been found to depend upon the presence of tau.

Conceivably, though, a brain that can resist tau aggregation and spread, or even the downstream effects of those processes, would remain amyloid-positive indefinitely without showing signs of cognitive impairment. Such brains are not uncommon. As noted above,autopsy studies have frequently reported extensive Aβ plaques and even tau-based neurofibrillary tangles—at levels that would satisfy traditional diagnostic criteria for Alzheimer’s—in the brains of people who seemed cognitively healthy while they were alive. Now with amyloid PET scanning, researchers have been able to track these amyloid-positive but seemingly Alzheimer’s-resistant people while they are alive.

“A main focus of investigation today is to understand why these individuals with amyloid in their brains do not decline cognitively,” says Anders Fjell, a researcher at the University of Oslo. The possibilities include a greater “cognitive reserve” from higher IQ or more education, as well as a greater supply of genetic, environmental and/or lifestyle factors that help brain cells resist the specific harm instigated by Aβ.“And then of course there is a big debate about whether these individuals are really ‘normal’ or will get Alzheimer’s eventually,” Fjell adds.

Recently Bruce Yankner and colleagues at Harvard reported finding a neuron-protecting protein, REST, that may help explain such neural resilience. “Our working model at this point is that the human brain can tolerate quite a bit of pathology, including Alzheimer’s pathology [i.e., plaques and tangles] because it has very robust stress response mechanisms, and we think that REST is part of that,” says Yankner. He and his lab are working on ways to boost REST levels in the aging brain, in the hope of preventing Alzheimer’s and other neurodegenerative conditions.

“Amyloid positive” status means less, the older you get

One of the less-publicized implications of autopsy and amyloid-scan studies is that Aβ plaque buildups become steadily more likely as you age, even if you remain cognitively healthy. Researchers have found that about one in eight cognitively healthy people in their 60s, one in three in their 70s, and at least half of those in their 80s are “amyloid positive.”

Thus, until medicines come along that can change the picture, Aβ buildup is a normal part of modern human aging, and scoring “amyloid positive” on a PET scan distinguishes a person less and less from his peers as he ages.

That doesn’t mean that the Aβ plaque burden is irrelevant to Alzheimer’s risk—more Aβ is still indicative of higher risk on average. But there is evidence that the later in life Alzheimer’s dementia hits (implying a later Aβ buildup) the slower the associated cognitive decline will be. Therefore, at advanced ages, when brain amyloid becomes more and more normal, Alzheimer’s dementia also becomes more and more “normal”—in other words, less distinguishable from ordinary age-related cognitive decline.

Scientists hypothesize that later-onset Alzheimer’s dementia moves more slowly essentially for the same reasons it never afflicts some elderly brains at all: because those brains have better defense mechanisms, which delayed the onset of dementia in the first place.

There is still much for researchers to learn in this area. More precise analyses of where Aβ plaques have formed in the brain could yield more useful and predictive information, for example. PET tracers that highlight tau pathology also are coming soon, and will surely complement amyloid PET technology. But at present, although “amyloid positive”status on average means a higher risk of cognitive decline, it is clearly not as bad a label as it probably looks at first glance.