If you can’t define the condition, how can you find a treatment?
though almost all of these patients are given a diagnosis of Alzheimer’s disease, nearly every one of them has a mixture of brain abnormalities.
For researchers trying to find treatments, these so-called mixed pathologies have become a huge scientific problem. Researchers can’t tell which of these conditions is the culprit in memory loss in a particular patient, or whether all of them together are to blame.
Another real possibility, noted Roderick Corriveau, who directs dementia research programs at the National Institute of Neurological Disorders and Stroke, is that these abnormalities are themselves the effects of a yet-to-be-discovered cause of dementia.
These questions strike at the very definition of Alzheimer’s disease. And if you can’t define the condition, how can you find a treatment?
In addition to plaques and tangles, other potential villains found in the brains of people with a diagnosis of Alzheimer’s include silent strokes and other blood vessel diseases, as well as a poorly understood condition called hippocampal sclerosis.
Potential culprits also include an accumulation of Alpha-synuclein, the abnormal protein that makes up Lewy bodies. And some patients have yet another abnormal protein in their brains, TDP-43.
No one knows how to begin approaching the multitude of other potential problems found in the brains of Alzheimer’s patients. So, until recently, they were mostly ignored.
“I wouldn’t say it’s a dirty little secret,” said John Hardy, an Alzheimer’s researcher at University College London. “Everybody knows about it. But we don’t know what to do about it.”
Some experts said they had been reluctant to talk much about mixed pathologies for fear of sounding too negative. But “at a certain point we have to be somewhat more realistic and rethink what we are doing,” said Dr. Albert Hofman, chairman of the epidemiology department at Harvard’s T.H. Chan School of Public Health.
The problem began with the very discovery of Alzheimer’s disease. In 1906, Dr. Alois Alzheimer, a German psychiatrist and neuroanatomist, described a 50-year-old woman with dementia. On autopsy, he found peculiar plaques and twisted, spaghetti-like proteins known as tangles in her brain. Ever since, they have been considered the defining features of Alzheimer’s disease.
But scientists now believe this woman must have had a very rare genetic mutation that guarantees a person will get a pure form of Alzheimer’s by middle age.
Patients with the mutation appeared to develop only plaques and tangles, and no other pathologies, so for decades, plaques and tangles were the focus of research.
The rare genetic mutations led to an overproduction of amyloid, it turned out, the abnormal protein in those plaques. To many scientists, that suggested that amyloid was the fundamental cause of Alzheimer’s.
More plaques usually meant more severe dementia, in both older and younger patients. So researchers tested drugs that could attack amyloid or stop its production in genetically engineered mice. The drugs worked beautifully.
Scientists recognized that mice were an imperfect model – they never develop dementia – but the studies were encouraging. So it was a huge disappointment when, over and over, those drugs failed in clinical trials in patients.
Tests of anti-plaque drugs continue, despite the increasing recognition that many factors may combine to cause dementia – or that, perhaps, the true cause has yet to be found.
What to do now? Scientists are struggling to reframe the problem. Some think research should be more focused on age.
“We can’t avoid the fact the number one risk factor for Alzheimer’s disease is age and many of these other pathologies are age-associated,” said Dr. John Morris, a professor of neurology at Washington University in St. Louis. “We don’t see them in younger people.”
Carol Brayne, an epidemiologist at Cambridge University, has been saying as much for decades. There is something significant, she has found, about the obvious fact that the older a person gets, the more likely he or she is to develop dementia. By their 90s, 1 out of 2 people has dementia.
A more optimistic view is that there may be something in the brain that sets off a cascade of multiple pathologies. If true, blocking that factor could stop the process and prevent dementia. Hofman is convinced the precipitating factor is diminished blood flow to the brain.
Supporting this view, he added, are data from nine studies in the U.S. and Western Europe consistently finding a 15 percent decline in the incidence of new Alzheimer’s cases over the past 25 years.
Or perhaps it really is amyloid that begins the avalanche of other problems.
Some researchers still hold out hope that if anti-amyloid drugs are started early enough, they might prevent dementia. Clinical trials are testing the idea now in people genetically disposed to get Alzheimer’s disease.