By Eleanor McDermid, Senior medwireNews Reporter
A longitudinal study of people with autosomal dominant Alzheimer’s disease (AD) shows that β-amyloid (Aβ) deposition begins well before neurodegeneration and cognitive decline.
And the findings “also suggest that Aβ accumulation is largely complete before the initiation of progressive neurodegeneration and cognitive decline”, write William Klunk (University of Pittsburgh, Pennsylvania, USA) and study co-authors in The Lancet Neurology.
The first sign of change in the patients relative to controls was increased amyloidosis, detected on 11C-Pittsburgh Compound-B positron emission tomography (PET), which occurred an average of 7.5 years before the expected age of AD symptom onset based on their parent’s age at first reported cognitive decline.
Amyloid deposition plateaued at around the age of expected onset. At this point, posterior cortical metabolism, measured with 18F-fluorodeoxyglucose PET, began to decline but hippocampal volume and verbal memory did not decline until 7.5 years after expected onset, contrasting with the overlap in Aβ deposition and neurodegeneration predicted by the AD biomarker model.
Cognitive impairment on the Mini-Mental State Examination did not occur until an average of 10 years after expected onset.
The 16 study participants underwent between two and eight assessments over 2 to 11 years of follow-up. They were aged between 28 and 53 years at baseline, so the researchers were able to study biomarkers from around 13 years before to 12 years after the expected age of symptom onset.
Among seven patients with the longest follow-up (6 to 11 years), three patients showed progressive amyloid deposition, but had no changes in the other biomarkers. Four patients had amyloidosis that had plateaued, but while two patients had progressively reduced metabolism and cognitive decline, with one also having hippocampal volume reductions, the other two had no biomarker changes.
The researchers found that the timing of neurodegeneration onset ranged from immediately at the point of amyloidosis plateau to more than 7 years later. “[This] suggests that additional vulnerability or protective factors can modify the disease course”, they say. “To uncover and understand these factors might inform the development of novel neuroprotective therapies.”
Writing in an accompanying commentary, Giovanni Frisoni (University Hospitals and University of Geneva, Switzerland) and Pieter Jelle Visser (VU University Medical Centre, Amsterdam, Netherlands) say: “This small study provides strong evidence that abnormal amyloid markers in cognitively normal individuals are really an early marker of Alzheimer’s disease, with obvious diagnostic implications”.
They add: “Although most cases of Alzheimer’s disease are not of known genetic origin but sporadic, these results concord well with findings in sporadic Alzheimer’s disease, suggesting similar pathophysiology and, possibly, similar therapeutic strategies.”
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