Alzheimer's disease: a blood diagnostic and biomarker of disease progression

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Abstract

Brain amyloid βpeptide (Aβ) is a requirement for the neuropathologic diagnosis of Alzheimer[unreadable]s disease (AD). Previous research has shown that Aβis also present in the peripheral blood. Although Aβblood levels have typically been found to be higher in AD patients, variability among subjects has confounded attempts to use this measure as an AD diagnostic. Studies by the applicant have demonstrated that some of the Aβin blood is bound to erythrocytes (red blood cells) as part of a mechanism for transporting Aβto the liver for removal from the body. Two characteristics of this mechanism appear to be significantly altered in AD patients. Estimates of the ability of individual erythrocytes to carry Aβindicate that AD erythrocytes may have significant deficiencies, suggesting that the amount of Aβper erythrocyte might be a simple, inexpensive, relatively non-invasive way to distinguish or diagnose AD. However, there are some 2-3 X 1013 erythrocytes in the circulation[unreadable]many more than enough to compensate for individual erythrocyte deficits. In essence, the system is non-saturable. Thus, if one looks at the total amount of Aβin the erythrocyte compartment, significantly increased values are found in AD patients, suggesting a second diagnostic approach. In addition, the applicant[unreadable]s preliminary studies also observed a significant correlation of the two erythrocyte Aβbiodiagnostic measures with a common mental status test, the MMSE. If true, then a longitudinal study over several year[unreadable]s time should show that these measures may be biological markers of disease progression, something that would greatly facilitate clinical trials of new drugs. Finally, patients diagnosed with mild cognitive impairment (MCI), a presumptive early stage of AD in many cases, had erythrocyte Aβmeasures that substantially overlapped those of the AD group. It is possible, therefore, that the measures may be picking out those MCI patients in whom the conversion to AD is most imminent. The specific aim of the present application is to determine whether or not erythrocyte Aβ is A) a sensitive and specific AD diagnostic, B) a measure that presages the transition of MCI patients to AD, or C) a useful biomarker of disease progression. A total of 125 AD, 125 MCI, 125 nondemented normal elderly (ND), and 125 patients with a neurologic disorder other than AD (OND), including non-AD dementia, will be recruited, evaluated, tested on 6 cognitive status measures, and blood sampled for assays of erythrocyte Aβ levels. These procedures will be repeated annually for four years. Over the study, it is projected that some 96 of the subjects will come to autopsy, providing a [unreadable]gold standard[unreadable] for evaluating true sensitivity and specificity of the biodiagnostic approaches. It is also projected that approximately 30 of the MCI patients will convert to AD during the study, so that the ability of the approaches to predict such conversion can be tested. Finally, changes in the subjects[unreadable] erythrocyte Aβlevels can be compared to changes in their cognitive status over time in order to determine the utility of the measures as biomarkers of disease progression.