Allan Gallup, a retired lawyer and businessman, grew increasingly forgetful in his last few years. Eventually, he could no longer remember how to use a computer or the television. Although he needed a catheter, he kept forgetting and pulling it out. It was Alzheimer\u2019s disease, the doctors said. So after Mr. Gallup died in 2017 at age 87, his brain was sent to Washington University in St. Louis to be examined as part of a national study of the disease. But it wasn\u2019t just Alzheimer\u2019s disease, the researchers found. Although Mr. Gallup\u2019s brain had all the hallmarks \u2014 plaques made of one abnormal protein and tangled strings of another \u2014 the tissue also contained clumps of proteins called Lewy bodies, as well as signs of silent strokes. Each of these, too, is a cause of dementia. Mr. Gallup\u2019s brain was typical for an elderly patient with dementia. Although almost all of these patients are given a diagnosis of Alzheimer\u2019s disease, nearly every one of them has a mixture of brain abnormalities. [Like the Science Times page on Facebook. | Sign up for the Science Times newsletter.] For researchers trying to find treatments, these so-called mixed pathologies have become a huge scientific problem. Researchers can\u2019t 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 A. 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\u2019s disease. And if you can\u2019t 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\u2019s 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\u2019s patients. So, until recently, they were mostly ignored. \u201cI wouldn\u2019t say it\u2019s a dirty little secret,\u201d said Dr. John Hardy, an Alzheimer\u2019s researcher at University College London. \u201cEverybody knows about it. But we don\u2019t know what to do about it.\u201d In interviews, some experts said they had been reluctant to talk much about mixed pathologies for fear of sounding too negative. But \u201cat a certain point we have to be somewhat more realistic and rethink what we are doing,\u201d said Dr. Albert Hofman, chairman of the epidemiology department at Harvard\u2019s T.H. Chan School of Public Health. The problem began with the very discovery of Alzheimer\u2019s 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\u2019s 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\u2019s 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 into dementia. 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\u2019s disease. 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 \u2014 they never develop dementia \u2014 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 \u2014 or that, perhaps, the true cause has yet to be found. \u201cWhat motivates us is the depth of the unmet need,\u201d said Dr. Dan Skovronsky, chief scientific officer of the drug company Eli Lilly, which continues to investigate anti-amyloid treatments. \u201cThat\u2019s why we keep going forward. But it is such a tough, tough problem, and made tougher because of the mixed pathology.\u201d What to do now? Scientists are struggling the reframe the problem. Some think research should be more focused on age. \u201cWe can\u2019t avoid the fact the number one risk factor for Alzheimer\u2019s disease is age, and many of these other pathologies are age-associated,\u201d said Dr. John Morris, a professor of neurology at Washington University in St. Louis. \u201cWe don\u2019t see them in younger people.\u201d 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, one out of every two 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. Dr. Hofman is convinced that the precipitating factor is diminished blood flow to the brain. \u201cAlzheimer\u2019s disease is a vascular disease,\u201d he said. Supporting this view, he added, are data from nine studies in the United States and Western Europe consistently finding a 15 percent decline in the incidence of new Alzheimer\u2019s cases over the past 25 years. \u201cWhy is that? I think the only reasonable candidate is improved vascular health,\u201d Dr. Hofman said. The most important factor is the decline in smoking, he believes, but people in rich countries also are more likely to better control high blood pressure and cholesterol levels. Dr. Seth Love, professor of pathology at the University of Bristol in England, noted that a core feature of Alzheimer\u2019s is a reduction in blood flow through the cerebrum of the brain. That happens even in people with the genetic mutation that leads Alzheimer\u2019s in middle age. Fifteen to 20 years before these people have dementia, blood to their brains slows. \u201cWe don\u2019t know why,\u201d Dr. Love said. 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\u2019s disease. But even if the drugs work, will they work in the elderly patients who make up the bulk of those with an Alzheimer\u2019s diagnosis \u2014 but who don\u2019t have anything resembling a pure form of the disease? Perhaps those drugs will have only a small effect in patients with mixed pathologies, Dr. Hardy said. It would take gigantic trials going on for years to see such a tiny effect. \u201cThose aren\u2019t the kind of medicines we are looking for,\u201d said Dr. Skovronsky, of Eli Lilly. \u201cWe want something that has a big effect.\u201d Dr. Skovronsky has been forced to do some soul-searching. Trying anti-amyloid drugs in old people in the early or middle stages of Alzheimer\u2019s just is not working. But when is it best to intervene, and in whom? And do scientists need to find drugs for all the other pathologies in the brains of dementia patients, as well? \u201cIt\u2019s the right time to focus on these tough questions,\u201d Dr. Skovronsky said.