A rare variant in the amyloid precursor protein (APP) gene that has been shown to protect against Alzheimer’s disease (AD) is associated with decreased levels of plasma amyloid β (Aβ), a new study has shown.
This is the first human population-based randomly selected cohort study to show reduced plasma Aβ levels in APP A673T carriers, which “provides evidence that lower Aβ levels throughout the life may be protective against Alzheimer’s disease,” the researchers write.
Dr Mikko Hiltunen
The results support the amyloid cascade hypothesis, which suggests that an accumulation of brain Aβ plays a key role in AD, study author Mikko Hiltunen, PhD, professor of tissue and cell biology, Institute of Biomedicine, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland, told Medscape Medical News.
The new finding is a significant discovery, said Dr Hiltunen, because many ongoing AD drug trials focus on decreasing Aβ levels in the brain.
“From my point of view, this is a clear message for pharmaceutical companies that they are on the right track in their attempts to target β-amyloid as early as possible,” he said.
The study, published online May 26 in the Annals of Neurology, also showed that decreased Aβ levels are not associated with detrimental effects on metabolic or cardiovascular outcomes.
A neurodegenerative disease, AD is characterized by the accumulation of Aβ in brain tissue. Uncovering the genetic pathogenesis of AD has become an important target of research, with genome-wide mapping studies leading to significant advances in the field.
These studies have identified not only several new risk genes for AD but also gene variants that protect against the disease, including the APP variant A673T. It was thought that this variant might affect the risk for AD by modulating levels of Aβ.
Researchers used data from the METabolic Syndrome In Men (METSIM), a large population-based study carried out from 2005 to 2010. The study included over 10,000 men aged 45 to 70 years randomly selected from the population register of Kuopio, Eastern Finland (population 95,000). None of these men were diagnosed with AD.
Among 8629 genotyped individuals, 47 were heterozygous carriers of the A67T variant; 37 of 4916 genotyped individuals were heterozygous carriers of the ABCA7 rs200538373 gene variant.
Researchers compared plasma levels of Aβ40 and Aβ42 in carriers of both gene variants with levels in noncarrier controls from the cohort who were matched for age, body mass index, and similar apolipoprotein E (APOE) genotype distribution.
The analysis found that APP A673T carriers had on average 28% lower levels of Aβ compared with controls (P < 1.0 × 10–14).
“This very significant result shows how strong the effect is,” commented Dr Hiltunen.
A similar reduction was seen in both Aβ42 and Aβ40, while the Aβ42/40 ratio was similar in both the carriers and controls. This, said the authors, suggests “an overall reduction in the production of Aβ rather than the γ-secretase-related modulation of the different Aβ peptides.”
While researchers knew that individuals carrying the APP A673T gene variant were somehow protected from AD, there has been no clear explanation as to why.
“Now we are showing that this variant associates with, or is linked to, reduced plasma Aβ levels,” said Dr Hiltunen. “This new study provides a direct link between genetics and functional outcome.”
Aβ “is the most important player in AD,” he added.
Both altered β- and γ-cleavage have been suggested as possible mechanisms underlying decreased Aβ levels in the presence of the APP A673T variant. The APP protein produces Aβ, and the A673T variant is exactly in the location where the secretase initially responsible for clearing Aβ is located, said Dr Hiltunen.
Other Variant
The other rare variant researchers studied — ABCA7 rs200538373 — did not appear to affect amyloid levels, which was somewhat surprising to Dr Hiltunen.
“We were expecting to see some increase because that variant increases the risk of having AD based on genetic studies. So the idea was that if you have that variant, more Aβ is being produced, but that didn’t happen here,” he said. “What’s the reason for that? We don’t know.”
Researchers had access to data on laboratory measures, including total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglyceride levels, as well as plasma glucose, high-sensitivity C-reactive protein, and interleukin-1 receptor agonist levels. A total of 248 cardiovascular health- and metabolism-related parameters were available from the METSIM cohort.
In a comparison between the carrier and control groups, the analysis found no statistically significant differences in the most important parameters reflecting general health status.
“It seems like this kind of moderate reduction in Aβ doesn’t have any adverse effects on metabolic or cardiovascular outcome measures,” said Dr Hiltunen.
That’s good news for pharmaceutical companies because it means, he noted, that lowering Aβ in early stages of AD is safe. “There are no adverse effects on other functions.”
The analysis also found that Aβ40 — but not Aβ42 — had a positive correlation with age. This finding, said the authors, is consistent with a previous longitudinal study showing an increase in plasma Aβ40 levels in cognitively normal individuals over time.
CSF Levels
Dr Hiltunen and his colleagues did not have access to Aβ levels in cerebrospinal fluid (CSF) but, according to previous studies, “there is a clear correlation between blood levels and CSF levels,” said Dr Hiltunen. “So we assume that the same thing can be seen in the CSF and in brain tissue.”
However, the authors stressed that further studies are needed beyond plasma measurements to determine the levels and deposition of Aβ in the CSF and brain tissue of APP A673T variant carriers.
Although the gene variant is rare, the association with decreased plasma Aβ levels is important with respect to AD drug trials. Several ongoing trials focus on decreasing Aβ levels in brain tissue.
The key for clinical trials targeting amyloid is to start them early. Most of the drug trials that have failed to show a benefit of lowering amyloid, “very likely have been started too late,” said Dr Hiltunen.
“So patients are already in mid or late stages of the disease, and there is already tissue damage,” which can’t be repaired.
The new findings on the role of the APP A673T gene variant in AD may eventually help identify new drug targets and better predictive biomarkers, he said.
Commenting on the findings, Keith Fargo, PhD, Alzheimer’s Association director of scientific programs and outreach, said the findings suggest the gene variant known as APP A673T may offer protection from Alzheimer’s by reducing or preventing the accumulation of amyloid brain plaques.
“These plaques have long been a prime suspect in killing nerve cells in Alzheimer’s,” Dr Fargo told Medscape Medical News. “These new findings are important because they support this idea and provide further evidence that preventing amyloid plaque accumulation can be an effective Alzheimer’s therapy.”
Advances in brain imaging have allowed researchers to show that amyloid plaque accumulation and other brain changes associated with Alzheimer’s begin “years, perhaps even decades, before memory and thinking problems appear,” he said.
“As a result, the field is shifting toward approaches that target these changes early on to prevent dementia. For example, there are five ongoing large-scale Alzheimer’s prevention trials — including four the Alzheimer’s Association is helping to fund — that involve amyloid-targeting drug candidates. You may think of this approach as being similar to taking cholesterol-lowering medication to prevent heart attacks and strokes.”
Dr Hiltunen and Dr Fargo have disclosed no relevant financial relationships.
Ann Neurol. Published online May 26, 2017. Abstract
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