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Origins of Alzheimer's disease across the life-course

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Broader study shows role of lifestyle choices in Alzheimer’s

The onset of Alzheimer’s disease is usually subtle, making early diagnosis difficult. By studying the brain’s ‘reserve’ capacity across the entire lifespan, ORACLE sought to extend the window of opportunity for prevention.

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Approximately 55 million people worldwide are thought to have Alzheimer’s disease (AD), the cause of 60–70 % of dementia cases. An early indicator is short-term memory loss, followed by problems with planning, language, behaviour and bodily functions. “Unlike other conditions such as stroke, the onset is insidious, with symptoms overlapping with those of normal ageing. All we know is that the onset was likely to have been at least 5 years pre-diagnosis,” notes Arfan Ikram, coordinator of the EU-funded ORACLE project. ORACLE’s approach was to search for AD signals going back to birth. As well as investigating genetic variation and using brain scans, the project studied function, alongside cognition. “Separating cognition from motor function is artificial, they both rely on the same neural networks,” adds Ikram from Erasmus University Medical Centre, the project host. ORACLE also explored the hypothesis that ‘reserve brain capacity’ developed early in life, protects against AD.

Going further back

The agreed signals of AD are: sticky proteins called amyloid which accumulate in the brain; brain atrophy or shrinkage; and vascular brain damage, such as microbleeds or white matter lesions. “But there isn’t a clear correlation between what you see in the brain and in an individual. Some people with lots of amyloid don’t experience memory loss,” explains Ikram. To investigate as much of the lifespan as possible, ORACLE worked with three cohorts totalling 40 829 individuals: children in the Generation R Study (in utero–18 years); parents of the children in the Generation R Study (18–45 years); and the Rotterdam Study (45 years and over). “We conducted the usual mix of brain imaging and cognitive tests but our innovation was to test motor function,” says Ikram. The team adapted a 6-metre electronic walkway containing thousands of sensors to test the gait of subjects. For the first time they found a correlation between tiny variations in the gait of younger people (as young as 36) with cognitive degeneration, evidenced by brain imaging. The team also replicated AD associations in older people with younger subjects. High blood pressure, for example, correlates with reduced cognition and a correlation was indeed found between elevated blood pressure and reduced cognition in children. “It doesn’t mean they will develop AD but demonstrates the vital role blood vessels play early in life,” remarks Ikram.

Reserve capacity

To explore the influence of genetics, ORACLE used the ‘brain reserve’ theory which suggests that larger brains, with more neurons, inherently cope better with damage. But while genes are likely to constrain an individual’s brain reserve, this is not straightforward biological determinism. “People with the same amount of neurons and brain damage as AD sufferers, are sometimes free of AD. Protection is conferred not from simply having bigger brains but from using their brains differently, creating ‘cognitive reserve’,” explains Ikram. This could explain why AD treatments concentrated on clearing amyloid have been largely disappointing, with Ikram more hopeful for cardiovascular and cognitive reserve health advice. “Up to a third of AD could be prevented through lifestyle choices. ‘What’s good for the heart is good for the brain’ and also if you challenge your brain, by learning new languages for instance, you increase cognitive reserve,” says Ikram. ORACLE’s insights could help identify those at high AD risk, for targeted prevention strategies. “We shouldn’t be thinking of AD as an old-age disease; early life choices impact what happens later,” concludes Ikram.

Keywords

ORACLE, Alzheimer’s disease, dementia, brain, cognitive, gait, amyloid, vascular, neural, genetic, lifespan

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