Bringing back memories

A new drug promises a breakthrough in Alzheimer’s treatment. Vicky Allan meets those living in hope, and those offering it

MARJORIE ALLAN often feels as though she has lost her mum. It happened slowly and gradually, starting with her mother's anxieties about the whereabouts of her keys on a Mallorca holiday, and has reached a stage where, sometimes, Jean Rankin does not seem to recognise her own daughter. These days, caring for her feels rather like looking after a difficult child. She can be awkward and irritable, prone to storming off. The frail woman sitting on the sofa of her Stenhousemuir home, dressed in the same mauve polyester suit she likes to wear every day, is not really Allan's mum. Here is her mother, captured in an old gilt-framed photograph: younger, fleshier, brighter, pink-lipped and groomed.
Conversation is difficult. Rankin seems distant and distracted. When she does engage, it is often to discuss events from long ago, as though she were constantly returning to her few clear remaining memories. She frequently talks about "the children". But these are not her own now grown-up son and daughter, nor her four grandchildren, nor anyone present in her life now. They are the family that lived in the big house where she worked as nanny before her marriage. It's as if that time and place were where she still exists.
When I arrive at her home with my own one-year-old, she lights up and begins to sing, clapping along as she trills out the tune, but not the words, of Coming Through The Rye. She used to sing this song for the children in the big house. In an instant, she is back there in her youth.

For her daughter, this is clearly heart-breaking. Tears dampen Marjorie Allan's eyes. There is something brutally random about which of Rankin's memories have been kept and which lost. Not only does Allan's childhood appear forgotten; Rankin barely ever mentions her late husband.
Alzheimer's is often described as a condition in which the sufferer is lost, little by little. Author Terry Pratchett, who was recently diagnosed with the disease, described how Alzheimer's "strips away your living self a bit at a time". This capacity for emotional as well as physical cruelty makes Alzheimer's one of the most disturbing diseases of Western society. And at the moment, Alzheimer's, along with other forms of dementia, is a disease that demands that we sit up and take notice. Given our ageing population, the number of dementia cases is predicted to increase from the current 700,000 to 1.7 million by 2051, with the associated NHS costs running into billions of pounds. Worldwide, cases of the disease are expected to quadruple to 106m by 2050. For this reason, a bill is currently going through the US congress pushing for the investment needed to fund a breakthrough in Alzheimer's treatment. The panic is on.
The memory loss associated with senility was once considered a normal part of ageing: Granny has gone "soft in the brain"; great-uncle has "lost his marbles". Only in the past half-century have we begun properly to treat it as a disease. In fact, back in the early 20th century when Alois Alzheimer originally defined the condition, it was pertinent only for those rare "pre-senile" dementias occurring before old age. By the 1970s, however, with the emergence of a growing older population, the senile form of the disease was also given the name.
Dementia has ceased to be a condition that is hidden away in the family closet. Former prime minister Margaret Thatcher's descent into forgetfulness has been publicly charted by her daughter, while Terry Pratchett has described his own as an "embuggerance" but carried on writing. We also live in an era when all aspects of ageing are considered worth fighting.
Does this mean we are any closer to real hope for sufferers? For Jean Rankin, now entering the severe stages of the disease, perhaps not. The carers at her day centre recently told her daughter she was losing more of her personal skills. Her independent life at her Falkirk home is "hanging by a thread". The future for her is only further deterioration.
But there is hope. Ongoing research at the University of Aberdeen by Professor Claude Wischik and his company TauRx suggests that within five years a drug that stems the development of the disease may be on the market. Currently undergoing trials, the drug - remberTM - has so far been found to reduce memory loss by 80%. Effectively, it is halting the progress of the condition. What is remarkable about remberTM is that it came from left-field. Most other scientists had been pursuing the theory that the culprit - and, therefore the target for drugs - was protein deposits in the brain called "amyloid plaques". Meanwhile, Wischik had been examining another set of protein formations known as "tau tangles". He believed that if those tangles could be broken down, the disease could be halted.
The announcement of Wischik's findings last July, at the International Con-ference for Alzheimer's Disease in Chicago, came at a time of despondency, following a series of failed trials for a drug that, it was hoped, would affect the progress, rather than merely the symptoms, of the disease. Meanwhile, the limitations of existing drugs used to treat symptoms were becoming apparent. A report earlier this year in the US Annals Of Internal Medicine declared that the five main drugs currently approved in the US (four of which are approved in the UK) produced only "marginal" improvements in cognitive levels.
Wischik insists that his motivation for telling the world about the optimistic findings of the remberTM trials was the need for $150 million (£84m) additional funding to take the drug through Phase III trials. "I had to make a big splash," he tells me. "My purpose really was not to get on the front pages of newspapers. The people I needed to get through to were 100 analysts in New York who will determine whether we can raise this money or not. I needed to do this with a big noise, so they would come knocking on my door."
The remberTM story is one of maverick promise. Its central character, Wischik, is eccentric by nature, bloody-minded yet self-deprecating, with a flair for colourful metaphor. He tells me he is not a brilliant scientist (and he's worked with a few, including Nobel prize winners Aaron Klug and Cesar Milstein), but that he has "the right combination of bullshit skills and technical skills".
His is also a tale of persistence coming good. For Wischik, remberTM has been just another stage on a quarter-century-long journey, which began when he left his Australian home for a research post at Cambridge University under the late Professor Martin Roth. Roth, then Britain's most eminent psychiatrist, had come to believe that the tau formation was "the most important lesion for explaining dementia". What was needed, he told Wischik, was "to seize the tangle by the throat".
Alzheimer's lies at the centre of a battle for the human mind that raged throughout the 20th century. Roth played a role in this fight. Wischik credits him with having "guided a generation of psychiatrists through a period of post-Freudian thought into the age of drugs, when psychiatry understands mental illness biologically".
But the battle began long before Roth - in 1910, just nine years after a woman in her 40s arrived at the Frankfurt Mental Institute exhibiting many of the symptoms associated with what was then called senile dementia. Auguste D, as she was called, had memory loss and delusions. She was in the habit of dragging sheets about her house and would scream for hours during the night. Her doctor, Alois Alzheimer, asked her to write her name, and she would start, then seemingly forget, and say: "I have lost myself."
When she died in 1906, Alzheimer studied her brain and published a paper outlining his findings of plaques and fibrules and their connection with the condition. He made no attempt to suggest this was his own discovery, or indeed anything new in the investigation of dementia. It was his co-worker, Emil Kraepelin - now widely considered the father of modern scientific psychiatry - who, in his 1910 book, Psychiatrie, identified Alzheimer's disease. He cited it as proof, in his battle against the Freudians, that mental illness could be caused by physical changes.
Few nowadays dispute that Alzheimer's is an organic disease. In the past 30 years the battle for a cure has switched from Freud versus Kraepelin to tau versus amyloid ß , the "tauists" versus the "ßaptists". In his dogged adherence to tau, Wischik was pushing against the scientific grain that amyloid was the key. But he was sure of his evidence. Working at Cambridge University in the 1980s, he measured not just the levels of the tau tangles and proteins, but also those of the amyloid in sufferers.
"We discovered that you can have high levels of amyloid in your brain and play bridge," he said, "but if you have high levels of aggregate of tau in your brain, you can't find your way to the toilet." The discovery encouraged Wischik to continue, even when he and his team were feeling that: "There's too much opposition. Let's just walk from this." Again and again, he would think it through and come to this conclusion: "Who else is going to be stupid enough to do this? Nobody. We're it."
As so often in scientific discoveries, accident played a role. In 1987, while conducting some analysis of tau tangles, Wischik came across a substance that made them disappear. This, he immediately thought, was significant. It signalled the possibility of finding a drug that could break down the filaments within the nerve cells. Yet he did not publish his findings until 1996. "I couldn't, after all, just present a chance discovery. I needed to understand what the mechanism was."
After further research, Wischik published his findings in 1996. Then - partly because he loved Scotland - he moved his research team to Aberdeen. Now, he was ready to go about developing a drug.
The Phase II trial of remberTM was the largest there has been in a disease-modifying Alzheimer's treatment so far. It involved 300 people, mostly from around Aberdeen and Birmingham, some with mild Alzheimer's, some with moderate. Following standard procedure, half the participants were put on the drug, half on a placebo.
One of those who received the drug itself was Helen Carle. Today, there are no obvious signs that she has Alzheimer's. Bright and chatty, she talks in an Aberdonian machine-gun rattle. Her sisters often tell her they think she has been misdiagnosed. But the symptoms of the disease are subtly present in her life, to the extent that her husband, George, is required to act as her carer. She leaves food cooking on the stove, then sits down to read a book and forgets about it. "One or two things have been burned. But it's still eatable," she says. She has left the bath running twice. On the day that we meet she is distressed because, although she recently took some plant cuttings, she can't now find them.
For Carle, the disease first arrived in the form of depression, which she had never experienced before. There were dizzy spells and forgetfulness, but mostly she just felt down. She went for long walks in an effort to lift her mood. And although the doctors prescribed anti-depressants, her sisters couldn't believe she was depressed. "No, Helen, not you," they said. In Ibiza she had her first big flash of memory loss. After coming out of a shop, she hadn't a clue where she was. Other episodes of forgetfulness followed. At the shop where she worked, she let someone leave without paying. Finally she went to the doctor again. When the diagnosis came, her response was: "But I'm only 62. That's an old person's disease."
Carle was immediately asked if she would like to go on the trial. For her that meant taking large blue pills three times a day. It meant having brain scans and doing regular monthly cognitive tests. The pills turned her urine blue. They also seemed to help. "I think I'm probably more alert," she says. "It's hard to tell. If you've got a busy day you're not going to remember everything. I don't think I've got any worse." In her latest test, she boasts, she got 30 out of 30, having used a new storytelling memory technique.
One of the surprises about remberTM is that it looks as though it may work at almost all stages of the disease. Given this, it could function, like statins, as a preventative. It could halt the development of the tau tangles long before there are any symptoms.
Does Wischik foresee a future in which everyone over 60 will begin popping these pills with their muesli? No. Rather, he hopes that, using diagnostic tests he is developing, those who need the drug will be identified and targeted. The potential market is huge. Wischik's research suggests that more people than were previously realised currently have undetected Alzheimer-type patterns in their brains. He recognises six stages of deterioration. By stage two there is a small amount of memory loss. A person gets demented "somewhere between stage two and stage four". Of the 10m over-65s in Britain, he notes, 6m are at stage two or beyond. "That," he says, "funnels down to about a million who have full-blown Alzheimer's, and even that, I think, is an underestimate."
Is remberTM the miracle pill? Sceptics remain. There are reasons, after all, why others dismissed tau. Professor Rudy Castellani of the University of Maryland, for instance, believes tau may be "an effect, rather than a cause, of the disease". This, he says, does not necessarily mean that remberTM will not work, but rather that its mechanism may be yet to be understood.
And what matters, surely, is whether the drug is effective. "Scientists can attempt to uncover the mechanism in retrospect," says Castellani, "but the empirical results are much more meaningful ... The hope is that effective therapy for Alzheimer's disease will be stumbled upon by accident. This may or may not be the case with remberTM. Time will tell."
Neither Helen nor George Carle chooses to think too much about their future with the disease. "We just get on with it. That's it," says George. They are managing fine just now. Nevertheless, if the drug fails, there is the possibility Helen will deteriorate to a state where she can no longer recognise her husband. How would they then cope? "As Helen says herself," says George, "if she ever got really bad, she would do away with herself."
That feeling is a common one. We fear this disease, not so much because of what the sufferer experiences, but because of its burden on carers and loved ones. Such is our hunger for a cure that Wischiks announcement was pounced upon by the world's media. As a result, the University of Aberdeen received 800 phone calls, mostly from sufferers' relatives, asking if there was any way they could be put on the Phase III trial. Does remberTM merit that frenzy of hope?
Wischik quotes a former colleague who said: "The difference between science and reading a detective novel is that in science when you turn the page, it's blank, whereas with a detective novel you can go to the back and see who did it." Are we close to the final page of this particular book? More likely than not we are merely half-way through. It is possible, however, that Wischik has struck on the big plot twist. If the drug works, it will be an important turning point.
Too late, perhaps, for some. Too late, probably, for Jean Rankin, who is unlikely to be hauled back from her diminishing pasts into the present. Too late for my partner's mother, an Alzheimer's sufferer who died before I even got to meet her.
But perhaps not too late for future generations of Rankin's family, or even my own. One of the features of Alzheimer's is that it has been shown to have a genetic element. Sometimes, when she is looking after her mother, Marjorie Allan is haunted by the possibility that she is confronting a vision of her own future. "I often say to my friends," she says, "don't let me get like this'."