NEW YORK(GenomeWeb) – Researchers at Washington University in St. Louishave identified a relationship between aging and the kinetics of Alzheimer's disease biomarker β-amyloid-42.
Specifically, they found a strong correlation between increasing age and slowing turnover of Aβ42. Detailed in a paper published last month in the Annals of Neurology, the findings provide insight into the increased risk of Alzheimer's in older populations and could offer a tool for Alzheimer's early detection and risk assessment, Wash U researcher Randall Bateman, senior author on the paper, told GenomeWeb.
For the study, the researchers used data from 100 sporadic Alzheimer's patients enrolled in ongoing, longitudinal studies at the university. They looked at 56 men aged 60 to 88 and 44 women aged 64 to 85. Additionally, they included data on 12 younger amyloid-negative subjects ranging in age from 33 to 63.
The researchers collected the data using the SILK approach developed by Bateman and study co-author David Holtzman, which combines in vivo stable isotope labeling with mass spectrometry. To measure the kinetics of Aβ molecules including Aβ38, Aβ40, and Aβ42 they gave the subjects a nine-hour infusion of isotopically labeled leucine, which was then incorporated into newly synthesized proteins. They then sampled patient cerebrospinal fluid and plasma for 36 hours, allowing them to measure the kinetics of these Aβ isoforms.
The study found that Aβ turnover was highly correlated with age, with a Pearson correlation of .77. The discovery of a correlation was not in and of itself unexpected, Bateman noted, but the strength of the correlation was somewhat surprising.
"The magnitude of the effect was what was surprising," he said, noting that the correlations were strong enough that the researchers could tell the rough age of a patient simply by glancing at the shape of the curve of their Aβ kinetics.
Bateman also noted that, while age is known to be one of the greatest risk factors for Alzheimer's, it was not obvious that age would translate into changes in Aβ kinetics.
"We had hypothesized that there would potentially be a change [in Aβ kinetics] with age, but there was also some evidence that suggested there might not be," he said. That evidence was the fact that there is not actually a strong correlation between age and Aβ concentration in CSF or plasma.
Given that, investigating changes in kinetics with age "was a lower priority for us," Bateman said.
Aβ42 concentration is an established biomarker for diagnosis of Alzheimer's disease and is also being extensively explored as a marker for early detection and predicting patients who will progress from mild cognitive impairment to the disease. Changes in Aβ kinetics might provide an even earlier look at the disease and patient risk, Bateman suggested.
"Aβ42 is a fantastic marker," he said. "It works very well for identifying who has amyloidosis and who has Alzheimer's, but it doesn't change in and of itself with age. And so we think the change in Aβ42 concentration is actually a result of the disease, and the change that occurs with aging may be the cause of the disease — the reason that it starts in the first place."
"The way we are putting this together is that we think the kinetics could potentially be [linked to] the relative risk of getting Alzheimer's, and then the [Aβ42] concentration changes once you have it," Bateman added. "So a change in kinetics leads to an increased risk of amyloidosis, and then that leads to a change in the Aβ42 concentration."
A key question, Bateman said, is whether people with Aβ half-lives older than their chronological age are at increased risk of developing Alzheimer's.
"A person who has the of a 70 year old but is only 62 — does that person have a much higher risk of getting amyloidosis?" he asked.
Additional longitudinal studies are needed to answer this question, Bateman said, noting that such work is ongoing.
Better understanding of the mechanisms behind the slowing Aβ turnover might also provide basic insights into the workings of Alzheimer's, possibly providing new targets for a disease that has thus far by and large stymied pharma companies despite significant investments in drug development.
Bateman and his colleagues are also interested in investigating whether any of the drugs in development to target the amyloid plaques thought to cause Alzheimer's affect Aβ turnover rates.
"If a slowing Aβ half life is a risk for accumulating amyloid, do the drugs currently being developed change that?" he asked. "If they do, then, how do they do it? How much do they do it? And then what are the implications of [measuring Aβ kinetics] as a biomarker for drug therapy?"
C2N Diagnostics, a company Bateman and Holtzman co-founded in 2007 to commercialize the SILK technology, has for several years been developing Alzheimer's markers based on Aβ kinetics.
As company CEO Joel Braunstein told GenomeWeb in a 2013 interview, measuring Aβ kinetics as opposed to absolute concentration of the molecule offers a potentially more sensitive and less variable look at patient Aβ levels.
An issue with tracking absolute Aβ levels, Braunstein said, "is that the hour-to-hour variability [of this measure] is incredibly high."
"Within a single individual, if you were to measure hourly [Aβ] levels over 24 hours, you can actually have variability ranging from 50 percent to 400 percent," he said.
Aβ production, on the other hand, "is very tightly regulated," Braunstein said, so that "by tagging the newly produced protein, you can follow its progression over time in the presence of all sorts of amyloid processing or metabolism, and you can pick up all sorts of subtle differences between individuals."
Last year the company announced it was expanding its partnership with Wash U to support commercialization of a blood-based Alzheimer's test using the SILK technology to measure Aβ kinetics.