Becky McCall

March 16, 2012

March 16, 2012 (London, United Kingdom) — Beta-amyloid burden present in the brains of healthy controls before the appearance of symptoms indicates potential for future cognitive impairment and Alzheimer's disease (AD), according to research presented here at the Alzheimer's Disease International (ADI) 27th International Conference.

David Ames, MD, professor of ageing and health, and director, National Ageing Research Institute at the University of Melbourne, Australia, leads the Australian Imaging Biomarkers and Lifestyle (AIBL) flagship study of aging, which looks at amyloid protein brain imaging, blood biomarkers, and lifestyle factors in the detection and prevention of early AD.

According to Dr. Ames, the 3-year follow-up data are particularly exciting because they support the association between amyloid protein build-up in the brain and future cognitive impairment. "We need to follow people up for longer, but we do see a correlation between 3-year decline on memory tests and the amount of amyloid in the brain at baseline in apparently healthy older people," he said.

The study shows that if an individual meets clinical criteria for mild cognitive impairment (MCI) and has amyloid protein in the brain, within 3 years there is a greater than 50% risk that person will have AD, whereas that risk is less than 10% for those with MCI who are free of amyloid at baseline.

Of the 58 patients positive for Pittsburgh compound B (PiB) on positron emission tomography (PET) at baseline, 56% converted to AD and 44% did not convert to any type of dementia. "We would predict that if we scan again at 54 months we will have around 70% [conversion to AD] and more again at 72 months. What is so fascinating in this group not one person progressed to another form of dementia," remarked Dr. Ames.

"If you have more amyloid at baseline you are more likely to show decline even though you are still functioning OK and you haven't yet met the criteria for dementia, there is something that is happening to your cognitive function that means you appear to be on a track towards that," he told Medscape Medical News.

Ambitious Study

AIBL is ambitious but is delivering on its promise, with more than 50 publications to date. It aims to improve the understanding of the pathogenesis and diagnosis of AD using neuropsychological, neuroimaging, and biomarker techniques, with a focus on the early diagnosis of AD. It also has a preventive strand, by examining factors related to lifestyle and diet that may be involved in the pathogenesis of AD and might affect future lifestyle intervention.

Study cohorts were assessed according to clinical and cognitive features, biomarkers, imaging, and lifestyle factors, and patients underwent follow-up every 18 months. A total of 278 participants (one quarter of the 1112 studied) underwent PiB imaging, and all 278 had magnetic resonance imaging as well to eliminate those with brain tumors or strokes. The researchers wanted to note biological, imaging, and biomarker differences in patients with AD, those with MCI, and healthy controls at baseline.

"Over time, we wanted to look at these different cohorts and see what predicts the decline and eventual diagnosis of AD, but equally we wanted to discover what predicted a healthy cognitive aging experience," Dr. Ames explained.

The researchers found that baseline burden of amyloid protein correlates with memory decline over 3 years in healthy persons. According to Dr. Ames, memory impairment is usually the first symptom seen in people with AD. The correlation is 0.38 (P = .0005).

Prediction that a healthy person would progress to MCI or AD over 3 years shows that of 129 PiB-negative (without amyloid protein) patients at baseline, 7% progressed to MCI/AD at 3 years, whereas of 66 PiB-positive persons at baseline, 19% progressed to MCI/AD.

Regarding progression from MCI at baseline to dementia, of 34 PiB-negative persons at baseline, 10% converted to AD, 17% converted to another form of dementia, and 73% did not progress to any dementia.

"What this study shows is that if you are amyloid negative with MCI, then over 3 years there is a 1 in 10 chance of getting AD. These people might progress to frontal dementia or dementia with Lewy bodies so MCI signified there was something cognitively wrong but because it was PiB negative meant it was not usually AD. So 90% of this group did not progress to AD," reported Dr. Ames.

Dr. Ames also highlighted the finding derived from various studies that the prevalence of AD increases exponentially with age. By 100 years of age, there is a greater than 50% chance of having AD. Autopsies also reveal that the presence of amyloid also increases exponentially with age, but this curve is 15 years ahead of the epidemiologic dementia prevalence curve.

"What is so interesting and relevant to our study," said Dr. Ames, "is that if we project our imaging data from healthy controls onto this graph it almost perfectly parallels the autopsy data. Our data are therefore consistent with the autopsy data suggesting that maybe 15 years before AD develops, an individual shows a positive signal on a brain scan."

Looking into the future, Dr. Ames suggests that these findings might mean that people with a strong family history or genetic predisposition to AD might be imaged and diagnosed so they could be treated, "if we had a therapy that worked," commented Dr. Ames.

Finally, among the many findings from AIBL to date, Dr. Ames highlighted the association between a healthy individual's level of exercise and cognitive impairment. "There's a tendency that the more intense physical activity they do, the better their memory," he said.

AIBL has also found that the hippocampus, the part of the brain responsible for memory, is smaller in people who exercise less and is larger in those who exercise more. He added that they need prospective data to confirm this as a causal relationship.

A further study, AIBL-2, has been refunded by the Australian Science and Industry Endowment Fund for 2011-2014. That study will involve repeat assessments at 36 and 54 months.

No Guarantees

Bruno Dubois, MD, professor of neurology, Dementia Research Centre, Salpêtrière Hospital, Paris, France, moderated the session. When asked for his opinion of Dr. Ames' work, he told Medscape Medical News that the study had yielded some interesting results, not least that amyloid protein shown on PiB PET does not guarantee the presence of AD.

"Only 50% of MCI patients and less than 20% of healthy controls, PIB positive, will convert to AD within 3 years," Dr. Dubois noted. "Of course, a longer duration of follow up is needed for knowing the exact proportion of conversions. However, these features indicate that amyloidosis in the brain is only a state marker of Alzheimer pathology and does not signify something else."

"We do not know the algorithm of conversion to a clinical disease. Therefore, in the absence of knowledge about the factors, which determine the occurrence of a clinical disease, we should be prudent and we should avoid considering these individuals as having a preclinical AD," he concluded.

The study received support from Pfizer, CSIRO (AUS), National Health and Medical Research Council (NHMRC) (AUS), Alzheimer's Association (USA), Alzheimer's Drug Discovery Foundation (USA), an anonymous foundation (USA), GE Healthcare, Astra Zeneca, and the Science and Industry Endowment Fund. Dr. Ames has been a consultant to Pfizer in the past. Dr. Dubois has disclosed no relevant financial relationships.

Alzheimer's Disease International (ADI) 27th International Conference Abstract OC037 and OC035. Presented March 8, 2012.

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