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Published on: November 8, 2012
by Kristina Fiori for MedPage Today:
Patients at genetic risk for Alzheimer’s disease developed changes in the brain, as well as blood and cerebrospinal biomarkers, in their 20s — long before clinical symptoms would have been expected to appear, two imaging studies showed.
In a family of SPEN1 E280A mutation carriers, those ages 18 to 26 had elevated levels of beta amyloid in both cerebrospinal fluid (CSF) and blood (P=0.008 and P=0.01, respectively), reported Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, and colleagues online in The Lancet Neurology.
In a second study in the same population, fibrillar amyloid beta began to accumulate at around age 28 and plateaued around age 37, long before the expected onset of symptomatic disease, the researchers said.
Given the disappointing results of drug therapy aimed at amyloid beta deposition thus far, researchers are now looking for ways to recognize Alzheimer’s in its earlier stages, theorizing that medications given to symptomatic patients may be too little, too late. So to identify characteristics of the disease in asymptomatic patients who are genetically susceptible to developing Alzheimer’s, Reiman and colleagues assessed a family in Antioquia, Colombia, that carries the PSEN1 E280A mutation.
Patients in this family have a median age of onset of 44 for mild cognitive impairment and 49 for onset of dementia.
In one study, the researchers compared mutation carriers, ages 18 to 26, with non-carriers between January and August 2010. All 44 patients (20 carriers, 24 non-carriers) had structural MRI, functional MRI, and cognitive assessments.
Among these patients, 10 carriers and 10 non-carriers also had CSF and plasma samples taken as well.
The researchers found that carriers had significantly higher levels of amyloid beta in both CSF and plasma (P=0.008 and P=0.01, respectively).
These raised levels “seem to precede the reduced CSF [amyloid beta] concentrations that have been reported in the subsequent pre-clinical and clinical stages of both late-onset and familial Alzheimer’s disease and that are thought to be a result of deposition of diffuse and neuritic plaques in the subsequent pre-clinical stages,” the researchers wrote.
They also found that carriers had greater right hippocampal and parahippocampal activation (P=0.001 and P<0.014, respectively), as well as less precuneus and posterior cingulate deactivation (P<0.01).
“These findings suggest that brain changes begin many years before the clinical onset of Alzheimer’s disease, and even before the onset of amyloid plaque deposition,” Reiman said in a statement. “They raise new questions about the earliest brain changes involved in the predisposition to Alzheimer’s and the extent to which they could be targeted by future prevention therapies.”
The study was limited by its small sample size and by the absence of longitudinal data. It’s also unclear if the findings are generalizable to other forms of Alzheimer’s disease.
In an accompanying editorial, Nick Fox, MD, of University College London, also highlighted these limitations, noting that the cross-sectional data can’t determine exactly when such changes began or how they’ve advanced over time.
Still, the findings suggest that Alzheimer’s patients may go through a long pre-symptomatic period that can be tracked and targeted for therapeutic intervention.
“Pragmatically, we might need to balance potential benefits of very early treatment against greater feasibility of trials in presymptomatic individuals nearer to clinical onset,” he wrote. “These are difficult choices but ones with substantial implications for future trials in Alzheimer’s disease.”
In the second study in the same group of patients, Adam Fleisher, MD, also of Banner Alzheimer’s Institute in Phoenix, along with Reiman and colleagues, assessed 11 symptomatic patients, 19 pre-symptomatic mutation carriers, and 20 asymptomatic non-carriers, ages 20 to 56.
All patients had florbetapir amyloid PET scans to determine early brain changes.
The researchers found that fibrillar amyloid beta began to accumulate in mutation carriers at a mean age of 28.2 years, about 16 years before the predicted median age at onset of mild cognitive impairment, and 21 years before anticipated dementia onset.
Deposition then rose steeply over the next 9.4 years, the researchers reported, plateauing at a mean age of 37.6 years, or about 6 years before MCI onset and 11 years before dementia onset, they wrote.
Florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia, they added.
In an accompanying editorial, William Jagust, MD, of the University of California at Berkeley, wrote that these results are similar to those of the DIAN (Dominantly Inherited Alzheimer Network) study, which found that amyloid beta accumulation was seen 15 years, on average, before the onset of progressive cognitive decline.
Jagust also highlighted the limitations of this study, including the lack of longitudinal data and the fact that the findings may not apply to other forms of Alzheimer’s.
“Autosomal-dominant disease, for example, is probably related to overproduction of amyloid beta, whereas Alzheimer’s disease related to the APOE e4 genotype is more closely associated with reduced clearance of amyloid beta,” Jagust wrote.
Still, the two studies taken together suggest that CSF amyloid beta levels “could be an early indicator of disease, and that neural alterations can precede or accompany evidence of brain amyloid beta deposition,” he concluded.
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