Measuring Longitudinal Change of Biomarkers in Cognitive Decline

Researchers have known that using biomarkers to facilitate early detection of Alzheimer disease (AD) is crucial for developing potential treatment. Studies have shown that Aβ42 and tau protein levels in cerebrospinal fluid (CSF), region-specific fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging (MRI) all are markers associated with AD.

Because these biomarkers and the APOE4 gene are all associated with AD or cognitive impairment, researchers recently conducted a study to examine the dynamic change of >1 biomarker simultaneously and assess the relative importance and pathologic significance of each biomarker. In this study, ADNI (Alzheimer’s Disease Neuroimaging Initiative) [Arch Neurol. 2011;68(10):1257-1266], the investigators sought to delineate the trajectories of the Aβ42 level in CSF, FDG uptake, and hippocampal volume as well as the influence of the APOE4 gene, and then evaluated their relative associations with cognitive function in participants with normal cognition (NC), mild cognitive impairment (MCI), or AD. A total of 819 research participants (229 with NC, 397 with MCI, and 193 with AD) were enrolled in ADNI from 59 centers in the United States and Canada during 2005-2007. Screening criteria for entry included the Mini-Mental State Examination score, the Clinical Dementia Rating scale, and an education-adjusted cutoff score on delayed recall of 1 paragraph from the Logical Memory subtest of the Wechsler Memory Scale–Revised. All participants were between 55 and 90 years of age and had at ≥6 years of education.

Main outcome measures were rates of change in level of Aβ42 in CSF, FDG uptake, hippocampal volume, and the Alzheimer Disease’s Assessment Scale–cognitive (ADAS-cog) subscale score during up to 36 months of follow-up by diagnostic group as well as prediction of cognitive change by each biomarker. Aβ42 level in CSF appeared to decrease faster in participants with NC (−0.46 picograms per milliliter per month) than in participants with MCI (−0.26 pg/mL/mo) or AD (−0.29 pg/mL/mo), but intergroup differences were not significant; changes in total tau and phosphorylated tau levels in CSF for the most part were not significantly different from zero. Brain regional glucose metabolic decline (measured in units of normalized intensity per month) was significantly slower in participants with NC (−7.4 × 10−4 normalized intensity per month) than in participants with MCI (−1.9 × 10−3 normalized intensity per month) or AD (−4.2 × 10−3 normalized intensity per month) and slower in participants with MCI than in participants with AD. The rate of MRI hippocampal atrophy (measured in units of cubic millimeters per month) was also significantly slower in participants with NC (−2.95 mm3/mo) than in participants with MCI (−5.52 mm3/mo) or AD (−8.01 mm3/mo) and slower in participants with MCI than in participants with AD. Cognitive function assessed by the ADAS-cog declined (increased in ADAS-cog score) in participants with MCI and declined even faster in participants with AD, but it improved (decreased in ADAS-cog score) slightly in participants with NC. Associations between APOE4 status and the baseline value of biomarkers were significant in the NC group for level in CSF and FDG uptake and in the MCI group for all 3 biomarkers. Positive APOE4 status did not appear to modify the rate of change in the level in CSF or glucose metabolism in all 3 groups, but it accelerated hippocampal atrophy in the MCI and AD groups. For participants with NC, although changes in cognitive function were not captured by any of these time-varying biomarkers, Aβ42 level in CSF (R2=0.12) appeared to better explain the total variance of ADAS-cog scores over time than did FDG uptake (R2=0.07) or MRI hippocampal volume (R2=0.03).