III
IN NOVEMBER 1901, at a psychiatric hospital in Frankfurt am Main, Germany, a woman named Auguste Deter presented herself to the pathologist and psychiatrist Alois Alzheimer (1864–1915) complaining of persistent and worsening forgetfulness. She could feel her personality draining away, like sand from an hourglass. “I have lost myself,” she explained sadly.
Alzheimer, a gruff but kindly Bavarian with pince-nez spectacles and a cigar perpetually plugged into the side of his mouth, was fascinated and frustrated by his inability to do anything to slow the unfortunate woman’s deterioration. This was a sad time for Alzheimer himself. His wife of just seven years, Cäcilia, had died earlier in the year, leaving him with three children to raise, so when Frau Deter came into his life, he had to deal with his profoundest grief and greatest clinical impotence at the same time. Over the following weeks, the woman became increasingly confused and agitated, and nothing Alzheimer tried provided even slight relief.
Alzheimer moved to Munich the following year to take up a new post but continued to follow Frau Deter’s decline from a distance, and when at last she died in 1906, he had her brain sent to him for autopsy. Alzheimer found that the poor woman’s brain was riddled with clumps of destroyed cells. He reported these findings in a lecture and a paper, and in so doing became permanently associated with the disease, though in fact it was a colleague who first called it Alzheimer’s disease in 1910. Remarkably, the tissue samples Alzheimer took from Frau Deter survived and have been restudied using modern techniques, and it turns out that she was suffering from a genetic mutation unlike any ever seen in another Alzheimer’s patient. It appears that she might have been suffering not from Alzheimer’s at all but rather from another genetic condition known as metachromatic leukodystrophy. Alzheimer didn’t live long enough to fully understand the importance of his findings. He died from complications of a severe cold in 1915 aged just fifty-one.
We now know that Alzheimer’s begins with an accumulation of a protein fragment called beta-amyloid in the sufferer’s brain. Nobody is quite sure what amyloids do for us when they are working properly, but it is thought they may have a role in forming memories. In any case, they are normally cleared away after they have been used and are no longer needed. In Alzheimer’s victims, however, they aren’t flushed away but accumulate in clusters known as plaques and stop the brain from functioning as it should.
Later in the disease, victims also accumulate tangled fibrils of tau proteins, which are invariably referred to as tau tangles. How tau proteins relate to amyloids and how both relate to Alzheimer’s are also uncertain, but the bottom line is that sufferers experience steady, irreversible memory loss. In its normal progression, Alzheimer’s first demolishes short-term memories, then moves on to all or most memories, leading to confusion, shortness of temper, loss of inhibition, and eventually loss of all bodily functions, including how to breathe and swallow. As one observer has put it, in the end “one forgets, on a muscular level, how to exhale.” People with Alzheimer’s, it could be said, die twice—first in the mind, then in the body.
This much has been known for a century, but beyond that nearly all is confusion. The bewildering fact is that it is possible to have dementia without having buildups of amyloid and tau, and it is equally possible to have amyloid and tau buildups without having dementia. One study found that about 30 percent of elderly people have substantial beta-amyloid accumulations but no hint of cognitive decline.
It may be that plaques and tangles aren’t the cause of the disease but simply its “signature”—the detritus left behind by the disease itself. In short, nobody knows if amyloid and tau are there because the victim is making too much of them or is simply failing to clear them adequately. The absence of consensus means that researchers fall into two camps: those who principally blame beta-amyloid proteins (and who are wryly known as baptists) and those who blame tau (known as tauists).
One thing that is known is that plaques and tangles accumulate slowly and begin their buildup long before signs of dementia become evident, so clearly the key to treating Alzheimer’s will be to get to accumulations early, before they start doing real damage. So far we lack the technology to do so. We can’t even definitively diagnose Alzheimer’s. The only certain way to identify the condition is postmortem—after the patient dies.
The greatest mystery of all is why some people get Alzheimer’s and others don’t. Several genes have been found to be associated with Alzheimer’s, but none has been directly implicated as a root cause. Just getting old vastly increases your susceptibility to Alzheimer’s, but then the same could be said of almost all bad things. The more education you have had, the less likely you are to get Alzheimer’s, though having an active and questing mind, as opposed to just racking up a lot of classroom hours in one’s youth, is almost certainly what keeps Alzheimer’s at bay. Dementias of all types are considerably rarer in people who eat a healthy diet, exercise at least moderately, maintain a sound weight, and don’t smoke at all or drink to excess. Virtuous living doesn’t eliminate the risk of Alzheimer’s, but it does reduce it by about 60 percent.
Alzheimer’s accounts for between 60 and 70 percent of all dementia cases and is thought to affect some fifty million people around the world, but Alzheimer’s is only one of about a hundred types of dementias, and it is often difficult to distinguish among them. Lewy body dementia, for instance, is highly similar to Alzheimer’s in that it involves a disturbance of neural proteins. (It’s named for Dr. Friedrich H. Lewy, who worked alongside Alois Alzheimer in Germany.) Frontotemporal dementia arises from damage to the frontal and temporal lobes of the brain, often because of a stroke. It is often highly distressing to loved ones because victims frequently lose inhibitions and the ability to control impulses, so they tend to do embarrassing things—shed clothes in public, eat food abandoned by strangers, steal from supermarkets, and so on. Korsakoff’s syndrome, named for a nineteenth-century Russian investigator, Sergei Korsakoff, is a dementia that arises most often from chronic alcoholism.
Altogether, one-third of all people over the age of sixty-five will die with some form of dementia. The cost to society is huge, yet almost everywhere research is curiously underfunded. In Britain, dementias cost the National Health Service £26 billion a year, but receive only £90 million annually in research funding, compared with £160 million for heart disease and £500 million for cancer.
Few diseases have been more resistant to treatment than Alzheimer’s. It is the third most common cause of death among older people, exceeded only by heart disease and cancer, and we have no effective treatment for it at all. In clinical trials, Alzheimer’s drugs have a 99.6 percent failure rate, one of the highest in the whole field of pharmacology. In the late 1990s, many researchers were suggesting that a cure was imminent, but that proved premature. One promising treatment was withdrawn after four people taking part in trials developed encephalitis, an inflammation of the brain. Part of the problem, as mentioned in chapter 22, is that Alzheimer’s trials must be done on laboratory mice, and mice don’t get Alzheimer’s. They must be bred to grow plaques inside their brains, and that means they respond to drugs in different ways than humans would. Many pharmaceutical companies have now given up altogether. In 2018, Pfizer announced that it was withdrawing from research into Alzheimer’s and Parkinson’s disease and cutting three hundred jobs from two research facilities in New England. It is a sobering thought that poor Auguste Deter, if she presented herself to a doctor today, would be no better off now than she was with Alois Alzheimer almost 120 years ago.