In clinically normal older people, the cognitive decline associated with high levels of amyloid-beta in the cerebrospinal fluid only takes place if elevated phospho-tau levels also are present, according to a report published online April 23 in Archives of Neurology.
This indicates that amyloid-beta deposition by itself is not associated with the cognitive decline that is characteristic of Alzheimer’s disease (AD) but becomes so when accompanied by high levels of phospho-tau (p-tau). "In the absence of p-tau, the effect of amyloid-beta on longitudinal clinical decline is not significantly different from zero," said Dr. Rahul S. Desikan of the department of radiology, University of California in San Diego, and his associates.
The study findings suggest that p-tau may be an important marker of Alzheimer’s-associated degeneration, more so than total tau (t-tau). "Elevations of CSF t-tau are seen in a number of neurologic disorders characterized by neuronal and axonal death, whereas increased CSF p-tau correlates with increased neurofibrillary pathology and can distinguish AD from other neurodegenerative disorders," they said.
The investigators examined the relationships among CSF markers of AD at the preclinical stage of the disease using data on 107 healthy control subjects from 50 sites across the United States and Canada who participated in the Alzheimer Disease Neuroimaging Initiative, a collaborative effort begun in 2003 and funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Food and Drug Administration, several pharmaceutical companies, and nonprofit organizations. The initiative examined whether serial MRI and PET images, together with biological markers, clinical assessments, and neuropsychological testing, could measure the progression of mild cognitive impairment and early AD.
For their study, Dr. Desikan and his colleagues classified the 107 normal subjects as having either high or low levels of p-tau and high or low levels of amyloid-beta in CSF samples. The subjects were followed for a mean of 3 years, undergoing periodic assessments of cognitive status using the global Clinical Dementia Rating scale, the CDR–Sum of Boxes (CDR-SB) subscale, and the Alzheimer Disease Assessment Scale–cognitive (ADAS-cog) subscale.
Study subjects who had high CSF levels of amyloid-beta showed declines on the cognitive assessments only if they also had elevated CSF levels of p-tau. "These data suggest that the combination of p-tau and amyloid-beta likely reflects underlying pathobiology of the preclinical stage of AD," the researchers said (Arch. Neurol. 2012 April 23 [doi:10.1001/archneurol.2011.3354]).
Specifically, in older patients, positive CSF amyloid-beta1-42 status significantly correlated with change in global CDR (beta1 = 0.03; standard error = 0.01; P = .04), CDR-SB (beta1 = 0.09; SE = 0.05; P less than .05), and ADAS-cog (beta1 = 0.59; SE = 0.23; P = .01). To ensure that our results were not owing to a categorical treatment of variables, we examined CSF amyloid-beta1-42 as a continuous variable and found significant associations between decreased CSF amyloid-beta1-42 levels and change in global CDR (beta-coefficient = -0.0002; SE = 0.0001; P = .03), CDR-SB (beta-coefficient = -0.0009; SE = 0.0004; P = .04), and ADAS-cog (beta-coefficient = -0.005; SE = 0.002; P = .02)," according to the investigators.
"From a clinical perspective, these results are consonant with the three-stage preclinical AD framework recently proposed by the National Institute on Aging–Alzheimer Association workgroup, and indicate that a biomarker profile consisting of both CSF amyloid-beta and CSF p-tau levels may better identify those older individuals who are at an elevated risk for progressing to eventual AD dementia than either biomarker by itself," they added.
Their results also highlight the need for therapies that specifically target tau. It is reasonable to hypothesize that amyloid-beta "initiates the degenerative cascade" in AD, but that elevated tau levels signal a second phase of the pathologic process in which neurodegenerative declines occur independently of amyloid-beta. "Targeting downstream events, such as tau phosphorylation and aggregation, in older individuals ... may be an additionally beneficial treatment strategy," the researchers said.
The study findings must be validated in future research, preferably that involving cohorts of older people in the general population, since the subjects of this study were highly selected, healthy older adults motivated to participate in a clinical study of AD, Dr. Desikan and his associates noted.
This study was supported by the National Institutes of Health and the Alzheimer’s Association of San Diego. Dr. Desikan’s associates reported ties to numerous industry sources.