Novel Biomarker for Incipient Alzheimer's Promising

Megan Brooks

June 22, 2011

June 22, 2011 — In patients with mild cognitive impairment (MCI), the concentration of soluble amyloid precursor protein β (sAPP-β) in cerebrospinal fluid (CSF) may provide an early and specific indicator of incipient Alzheimer's disease (AD), according to research published online June 22 in Neurology.

"This novel biomarker was able to quite accurately identify persons who were about to develop AD in the next few years in a group of individuals with memory deficits," study author Robert Perneczky, MD, of Technical University Munich in Germany, noted in an email to Medscape Medical News.

Dr. Robert Perneczky

"Most importantly, the new biomarker was superior to the established marker amyloid-β 42," he wrote.

Soluble APP-β "probably provides diagnostic information that is more proximate to the core pathological processes of AD than amyloid-β 42, which only mirrors pathological events at the end of the disease cascade," Dr. Perneczky explained.

Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, who was not involved in the study, agrees. "Because this biomarker measures events that happen 'upstream,' it could be a more reliable indicator of what the future may hold for an individual," he noted in an interview with Medscape Medical News.

More Reliable Indicator of Future Cognition

Dr. Gustavo C. Román

Dr. Perneczky and colleagues studied 58 patients with MCI and 16 patients with frontotemporal dementia (FTD). At baseline, CSF concentrations of sAPP-α, sAPP-β, tau, and amyloid-β 42 were measured.

After nearly 3 years of follow-up, 21 of the 58 patients with MCI had progressed to probable AD, 27 still had MCI, 8 reverted to normal, and 2 had developed FTD and were excluded.

The investigators found that baseline CSF sAPP-β concentrations were significantly higher (P < .05) in patients who evolved to AD, relative to those whose cognition remained stable or improved and those who had FTD.

Table. Baseline Cerebrospinal Fluid Concentrations of Soluble APP-β by Group

Measure MCI to AD (n = 21) MCI or Normal (n = 35) FTD (n = 16)
sAPP-β, ng/mL 1200 932 630

AD = Alzheimer disease; FTD = frontotemporal dementia; MCI = mild cognitive impairment; sAPP = soluble amyloid precursor protein β

The combination of sAPP-β, tau, and age differentiated subjects who did and did not progress to AD with 80% sensitivity and 81% specificity. The best model for the differentiation of MCI to AD and FTD groups included sAPP-β and tau, with 95% sensitivity and 81% specificity.

In this study, amyloid-β 42 did not significantly contribute to the predictive models, the investigators report.

These results, they say, suggest that sAPP-β "may be clinically useful and superior" to amyloid-β 42 in the early identification of patients with MCI who will go on to develop AD and in the differentiation of AD from FTD.

'Elegant' Study

"This is an elegant study," Dr. Román said, and the observations are "worth studying further."

"Having so much of this precursor in the spinal fluid suggests that that's where a key mechanism [for AD] is going to be found," Dr. Román commented. "We know so little about what controls the overproduction of this protein. This overproduction could be calling our attention to a different pathogenic mechanism.

"An equally interesting observation," Dr. Román said, is that, in 35 patients (60%), cognitive function remained stable or improved. "This tells us that we are not too good clinically at predicting what is going to happen to patients, especially patients who will revert back to normal cognitive function."

The study was supported by the League of Friends of the Technical University Munich and the Commission for Clinical Research of the Rechts der Isar Munich Hospital. Dr. Perneczky serves on the editorial board of the Journal of Alzheimer's Disease, Open Journal of Nuclear Medicine, and Open Longevity Science and has received speaker fees from Janssen Pharmaceuticals. A complete list of author disclosures can be found with the original article. Dr. Román has disclosed no relevant financial relationships.

Neurology. 2011;77:35-38.


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