ARTICLE IN BRIEF
Investigators reported that more than half of cognitively normal people, ages 85 and older, at baseline who had evidence of amyloid-beta on neuroimaging did not become demented two years later.
Approximately 54 percent of cognitively normal individuals ages 85 and older have elevated levels of amyloid-beta (Abeta) deposition in the brain, according to new research from investigators at the University of Pittsburgh that developed the neuroimaging PET tracer agent, Pittsburgh Compound B (PiB).
In a presentation of new data at the AAN annual meeting in San Diego, lead author Oscar Lopez, MD, professor of neurology and director of the Alzheimer's Disease Research Center at the University of Pittsburgh, reported that more than half of those who were positive for amyloid on PET imaging — that is, they were PiB-positive — were still cognitively normal two years later.
A total of 191 subjects had brain MRI and PiB-PET scans in 2009, and were re-examined clinically in 2011. In 2009, 151 of the subjects were cognitively normal and 40 had mild cognitive impairment (MCI); 55 percent of the study subjects (N=105) were identified as PiB-positive.
By 2011, 20 percent of the normal patients had progressed to MCI and 7 percent to dementia, while 32.5 percent of the MCI patients had progressed to dementia. But although 46 percent of the PiB-positive participants had either MCI or dementia, the other 54 percent were still cognitively normal.
“This demonstrates that cognitively normal individuals aged 85 and older can have amyloid in the brain,” Dr. Lopez told Neurology Today. “We see with this study that, as we expected, people with higher levels of amyloid and lower hippocampal volumes frequently progress to dementia. But we also found that there are many people who are cognitively normal but nonetheless have the amyloid deposition and lower hippocampal volume similar to that seen in the participants who converted to dementia. The factors that protect these individuals from dementia are unknown.
“It is possible that cognitive reserve — greater education and mental acuity at baseline — is a factor that protects against dementia,” Dr. Lopez noted. “However, a high level of education and socioeconomic status are probably the most important determinants of longevity, so the cognitive reserve hypothesis is difficult to apply in this group.”
Conversely, individuals without abnormal levels of Abeta deposition sometimes converted to MCI or dementia. Of the 86 study subjects who were PiB-negative in 2009, 24 percent had developed MCI by 2011 and 7 percent had gone from cognitively normal to full dementia in just two years.
“We have people with the same hippocampal volume and the same degree of amyloid deposition, and some progressed to dementia at what we would say is the ‘normal’ pace — through the MCI stage — and others go straight from normal to dementia very fast, without passing through MCI,” Dr. Lopez said. “And again, the factors that are related to the speed of conversion are unknown.”
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That's an equally intriguing finding, said William Jagust, MD, a professor of neuroscience at the University of California, Berkeley, and it's consistent with other recent research from groups such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Mayo Clinic's Alzheimer's Disease Research Center, and his own laboratory. “We're seeing evidence of neurodegeneration in older people without brain amyloid, and I don't think this has received quite the attention it deserves,” he said. “Our current models sort of require amyloid to be present before these other neurodegenerative biomarkers appear.”
Other recent results from clinical trials suggest that as many as 15-20 percent of people clinically diagnosed with Alzheimer's disease do not have amyloid in their brain; the percentage is even higher among people who do not carry the APOE-4 allele polymorphism.
“You could say ‘wrongly diagnosed,’ but I hate to use that terminology,” said Michael Weiner, MD, professor of neurology at the University of California, San Francisco, and ADNI's principal investigator. “You can make a clinical diagnosis of Alzheimer's very well, but then there's the matching of that pathology to imaging. It's not clear what the diagnostic and prognostic significance of amyloid in the brain is. If you have it, you have Alzheimer's disease pathology, but if you don't have dementia, what does that mean?”
It's also important to have longitudinal, not just baseline, measures in order to make definitive conclusions, noted Anne Fagan, PhD, research professor of neurology at Washington University in St. Louis and the Biomarker Core Leader of the Knight Alzheimer's Disease Research Center. “The vast majority of studies that have led to the proposed trajectories of biomarker changes in AD are derived from cross-sectional analyses, comparing different people across different ages. Confirmation of the precise timing of these changes will require true longitudinal evaluation within individuals over time.”
The importance of that element is illustrated within the DIAN (Dominantly Inherited Alzheimer Network) cohort, for which Fagan is the Biomarker Core director. These individuals have a 50-50 chance of developing AD due to the presence of a disease-causing mutation in one of their parents, and if they have the mutation they will for certain get the disease.
“We know mutation carriers are going to get the disease, and it's going to be early — the average parental age of onset in our DIAN cohort is mid-40s,” she said. “We are recruiting family members as young as 18 years of age and are collecting fluid and imaging biomarkers in these individuals over time, and we can already see evidence of AD-like changes taking place 20 years prior to their estimated age of dementia onset (based on their parent's age of onset).”
That type of information is tough to obtain in sporadic cases, of course, because it's not known ahead of time if or when the average person is going to develop the disease. “But when we look at the DIAN cases, we have a good idea of when they are going to [become] demented so we can evaluate biomarker changes in the years prior to development of symptoms. It's possible that their Abeta levels have been changing for years, even potentially before they met the criteria for PiB-positive. That's why it's so important to have longitudinal biomarker evaluations,” Dr. Fagan said.
She suggested a combined measure of levels of cerebrospinal fluid Abeta and tau — a marker of neurodegeneration and/or neurofibrillary tangles — may provide a better predictor of dementia than Abeta alone.
“Biomarker literature tells us that it's actually tau — a marker of tangles and/or neuronal cell death — that is more related to cognitive decline than Abeta,” she said. “What if you combine those analytics? We recently submitted a manuscript showing that cognitively normal individuals who have evidence of both amyloid and tau in the brain go on to [become] demented faster than those with just one abnormal marker.”
The new Pittsburgh findings address one of the great questions in Alzheimer's research, said Dr. Weiner. “Why is it that some people who have amyloid in their brain progress to dementia and others do not? This paper is an important contribution to the field and allows us to better understand a very complicated story. It will require a lot of long-term follow up with large populations to really get to the bottom of these questions.”
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TUNE IN: What is the association between amyloid-beta deposition and incident dementia in the very old two years later? In a video interview, David Gill, MD, a cognitive behavioral neurologist at Unit Rehabilitation & Neurology in Rochester, NY, offers an analysis of the new data here, what further research is needed, and what it means for clinicians: http://bit.ly/aNQ4KB. Dr. Gill serves on the editorial advisory board of Neurology Today.
A ‘BEST PAPER’ PICK: Neurology Today editorial advisory board member David Gill, MD, a cognitive behavioral neurologist at Unit Rehabilitation & Neurology in Rochester, NY, selected this as one of the “best papers” on dementia from the AAN annual meeting.
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