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Testing Times for Alzheimer’s

LONDON – Alzheimer’s disease is by far the most common cause of dementia and one of the world’s most feared disorders. By 2050, there will be 135 million Alzheimer’s sufferers worldwide, a threefold increase from today, with three-quarters of cases occurring in low- and middle-income countries. Predicting the onset of Alzheimer’s, let alone preventing or curing it, remains an immense challenge.

Alzheimer’s disease was identified more than a century ago from autopsy results that showed characteristic brain lesions called “amyloid plaques.” The disease is more difficult to diagnose in the living. Doctors rely on observation of memory loss and other thinking deficits (such as reasoning or language comprehension) – signs that plaques are already present in the brain. But any cure would have to be administered before the plaques form, and years before symptoms of dementia appear.

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Alzheimer’s might be more predictable if scientists had the time and resources to conduct far-reaching longitudinal studies over many years. Such studies ideally would involve blood, imaging, memory, and medical tests, as well as detailed lifestyle questionnaires filled out by thousands of young and middle-aged people. Study participants would be followed over decades to see who developed the disease, and which tests proved positive before Alzheimer’s was diagnosed.

In fact, two famous longitudinal studies – the Framingham Heart Study in Massachusetts and the Kungsholmen Project in Sweden – have led to important progress in predicting the disease. These studies found that short-term memory may be impaired for up to ten years before an Alzheimer’s diagnosis. Major advances have since been made in brain imaging, biochemical analysis, and, perhaps most important, genetic testing.

Indeed, the risk of Alzheimer’s doubles if a parent or sibling has it, probably due in large part to the presence of the ApoE gene. The risk triples for Europeans who inherit a particular type of ApoE, called ε4; inheriting two copies of ε4 increases the risk roughly tenfold.

But genetic testing alone is unlikely to be an accurate predictor, because around half of Alzheimer’s sufferers do not carry ε4, and probably half of those with ε4 do not develop the disease. Moreover, though international studies of more than 70,000 people have found over 20 other genes linked to Alzheimer’s, their impact is minimal.

That said, a groundbreaking 2012 study published in the New England Journal of Medicine, analyzed a rare genetic mutation found in just 500 families around the world, which would lead to Alzheimer’s before the age of 50. The study showed which tests were able to predict the outcome most accurately decades ahead of onset.

The research found that amyloid-beta – the substance that clumps together and forms amyloid plaques – becomes depleted in the cerebrospinal fluid around the brain as long as 25 years before the onset of dementia. Fifteen years prior to onset, a positron emission tomography (PET) scan showed amyloid-beta being deposited in plaques in the brain itself. And detailed short-term memory tests were abnormal ten years before onset, as suggested in the Framingham and Kungsholmen studies.

These tests are now becoming part of clinical practice, and are available commercially. Memory and other cognitive tests can reveal whether one has minor problems with some aspects of thinking – a condition known as “mild cognitive impairment” that precedes Alzheimer’s disease. The problem is that the tests must be administered by a trained neuropsychologist and take more than an hour to complete; moreover, many people with mild cognitive impairment do not progress to dementia.

Sampling cerebrospinal fluid via a lumbar puncture (or “spinal tap”) can predict which people with mild cognitive impairment will progress to dementia with over 80% accuracy, but this still means a misdiagnosis for one in five patients. PET scans are slightly less accurate, while routine MRI brain scans can reveal with perhaps only 70% accuracy subtle abnormalities in people with mild cognitive impairment.

Scientists are therefore still searching for an accurate predictive test that is cheaper, quicker, and less invasive than PET scans or lumbar punctures. This year, two small studies of blood tests seemed to predict Alzheimer’s 1-3 years before it occurred, but the tests are complicated and require the measurement of ten or more substances.

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Whichever predictive methods doctors use over the next few years will probably enable them to inform those patients with mild cognitive impairment about their chances of developing Alzheimer’s in the short term. The trickier question is whether we will be able to predict Alzheimer’s disease accurately in those with normal cognition and memory, or to predict it more than five years in advance.

Even if accurate early prediction of Alzheimer’s eventually is achieved, there are currently no drugs available to prevent or cure it before the amyloid plaques start destroying the mind. That will be our next great challenge.