"These are by far the best-studied [biomarkers], and show the greatest differences with regard to Alzheimer’s disease, and also they have the most direct link to the neuropathology of Alzheimer’s disease," said Dr. Zetterberg, professor and group leader of the research team on neurochemical pathogenesis and diagnostics at the University of Gothenburg (Sweden).
Although more biomarkers will most likely be identified in the future, these CSF proteins have shown the most consistent results across studies thus far, and they have high sensitivity and specificity for Alzheimer’s disease.
"The basic question we were trying to address is actually, ‘When do these biomarkers turn positive? When can we detect Alzheimer’s disease by measuring these proteins?’ " he said.
In his study of 137 patients with mild cognitive impairment, the levels of amyloid beta 42 were already fully decreased to levels that indicate a high risk of developing Alzheimer’s dementia in 5-10 years.
During nearly 10 years of follow-up, 54% of subjects developed Alzheimer’s disease and 16% developed other forms of dementia. Baseline amyloid beta 42 levels in those who developed Alzheimer’s disease were significantly reduced, compared with nonconverters, and total and p-tau levels were elevated, Dr. Zetterberg said.
Furthermore, the amyloid beta 42 levels were equally reduced at baseline in early and later converters (those who converted within 0-5 years, and those who converted between 5 and 10 years, respectively), while CSF levels of total and p-tau were significantly higher in the early converters, compared with the later converters.
A ratio of baseline levels of amyloid beta 42 to p-tau predicted development of Alzheimer’s disease within the study period with a sensitivity of 88% and a specificity of 90%, he said.
"So the conclusion might be that Alzheimer’s disease can actually be accurately diagnosed 5-10 years before onset of dementia," he said.
The findings support the hypothesis that altered amyloid beta metabolism precedes tau-related pathology and neuronal degeneration. These CSF biomarkers may be useful for selecting patients for early intervention in clinical trials, as well as for monitoring treatment effects, Dr. Zetterberg concluded.
Dr. Burnham and Dr. Zetterberg said they had no relevant financial disclosures.