Brain amyloid Beta peptide (ABeta) is a requirement for the neuropathologic diagnosis of Alzheimer?s disease(AD). Previous research has shown that ABeta is also present in the peripheral blood. Although ABeta blood levelshave typically been found to be higher in AD patients, variability among subjects has confounded attempts touse this measure as an AD diagnostic. Studies by the applicant have demonstrated that some of the ABeta inblood is bound to erythrocytes as part of a mechanism for clearing ABeta to the liver for degradation. Twocharacteristics of this mechanism appear to be significantly altered in AD patients. Individual AD erythrocytesappear to be deficient in their ability to carry ABeta, suggesting that the amount of ABeta per erythrocyte might be asimple, inexpensive, relatively non-invasive way to diagnose AD. However, there are some 2-3 X 1013erythrocytes in the circulation?many more than enough to compensate for individual erythrocyte deficits.Thus, if one looks at the total amount of ABeta in the erythrocyte compartment, significantly increased values arefound in AD patients, suggesting a second diagnostic approach. In addition, the applicant?s preliminary studiesobserved a significant correlation of the two erythrocyte ABeta biodiagnostic measures with a common mentalstatus test, the MMSE. If true, then a longitudinal study might show these measures to be biological markersof disease progression, something that would greatly facilitate clinical trials of new drugs. Finally, patientsdiagnosed with mild cognitive impairment (MCI), a presumptive early stage of AD in many cases, haderythrocyte ABeta measures that substantially overlapped those of the AD group. It is possible, therefore , that themeasures may be picking out those MCI patients in whom the conversion to AD is most imminent.
Specific Aim. Test the hypothesis that erythrocyte Ais A) a sensitive and specific AD diagnostic,B) a measure that presages the transition of MCI patients to AD, and/or C) a useful biomarker ofdisease progression. A total of 125 AD, 125 MCI, 125 nondemented normal elderly (ND), and 125 patientswith a neurologic disorder other than AD (OND) will be recruited, evaluated, tested on six cognitive statusmeasures, and blood sampled for assays of erythrocyte ABeta levels. These procedures will be repeatedannually, yielding baseline, 1, 2, and 3 year data on diagnostic, prognostic, and biomarker potential of theerythrocyte measures. In addition, it is projected that some 96 of the subjects will come to autopsy, providing a?gold standard? for evaluating true sensitivity and specificity of the biodiagnostic approaches. NIA has provideda bridge grant to the PI to cover recruiting, baseline measures, and a pilot project to compare erythrocyte andCSF ABeta in Alzheimer?s Disease Neuroimaging Initiative subjects. However, without the present project?slongitudinal and neuropathology components, any such data will remain promising but preliminary.
This application seeks to develop a simple, inexpensive, safe blood test that can be used to diagnose Alzheimer?s disease (AD), measure its progression, and predict imminent conversion to the disorder. As new and more effective therapeutics come on line, the ability to accurately diagnose AD, especially early in the disease course, will have increasing importance and, conversely, a useful biomarker of disease progression will greatly abet the development of such therapeutics.
| Fonseca, Maria I; Chu, Shuhui; Pierce, Aimee L et al. (2016) Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function. PLoS One 11:e0149792 |
| Berchtold, Nicole C; Coleman, Paul D; Cribbs, David H et al. (2013) Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease. Neurobiol Aging 34:1653-61 |
| Wyss-Coray, Tony; Rogers, Joseph (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2:a006346 |
| Rogers, Joseph; Mastroeni, Diego; Grover, Andrew et al. (2011) The epigenetics of Alzheimer's disease--additional considerations. Neurobiol Aging 32:1196-7 |
| Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine et al. (2011) Epigenetic mechanisms in Alzheimer's disease. Neurobiol Aging 32:1161-80 |
| Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine et al. (2010) Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol Aging 31:2025-37 |
