Development of Novel Biomarkers for Alzheimer's Disease

Moe, James

Abstract

There is a critical unmet need for novel biomarkers for differential diagnosis of Alzheimer's disease (AD) at early onset and to stage disease progression. Presently, definitive diagnosis of AD requires tissue biopsy or autopsy of the brain, which can occur only after the patient dies. Currently, there are no validated biomarkers identified in patient samples such as cerebrospinal fluid (CSF), blood, and urine that can be used to definitely monitor the progression or regression of AD. Most approaches focus on quantitative changes of individual proteins such as tau and A2 in patient samples as biomarkers. These studies have led to a consensus that an increase in total and p-tau and a concomitant decrease in A21-42 in CSF may be indicative of neurodegeneration. However, these changes are not specific indicators of AD and may also occur in some other forms of dementia. Therefore, these biomarkers cannot be used for differential diagnosis of AD at early onset and to stage disease progression. The development of novel biomarkers based on the paradigm of protein-protein interactions, rather than on specific protein levels, may create opportunity for earlier and more specific diagnosis and disease monitoring for better patient management. Using the approach of measuring pathological interactions between proteins may provide urgently needed novel AD biomarkers. These biomarkers can also serve as drug targets for the identification of new medication therapies to treat AD and to monitor different therapeutic effects when used to treat AD. OLIGOMERIX is evaluating novel AD biomarkers based on soluble complexes containing tau oligomers and complexes containing both tau and A21-42. Preliminary feasibility studies with a limited number of CSF samples have indicated that tau oligomers and tau- A21-42 complexes are enhanced in CSF from AD compared to non-AD controls. ELISAs of different formats were developed to measure these parameters in CSF. The objective of this project is to expand the preliminary studies using a statistically significant number of clinical lumbar CSF samples that include severe, mild and age-matched non-AD controls to assess the potential of tau oligomers tau A2, and tau-apoE complexes as specific biomarkers for early detection and progression of AD. This work will be performed in collaboration with Drs. Richard Mayeux and Lawrence Honig at the Taub Institute for Research on Alzheimer's disease and the Aging Brain at Columbia University Medical Center.
The specific aims of the proposed program are as follows: """""""" Develop biomarker assays for AD measuring tau oligomers and complexes of tau with A2 or apoE in CSF """""""" Conduct feasibility study of developed biomarker assays using clinical CSF samples Towards this end Dr. Honig will provide about 250 CSF samples for a statistically significant study of the biomarkers. OLIGOMERIX will perform ELISAs on de-identified blinded samples, and Dr. Honig will analyze the data. The biomarkers may be out-licensed to the pharmaceutical industry for clinical evaluation of compounds targeting tau oligomers, tau-A2, or tau-apoEcomplexes. Key Words Alzheimer's disease, biomarker, tau, A2, apoE, oligomer.

Public Health Relevance

The proposed program is focused on the identification and development of novel biomarkers for Alzheimer's disease (AD), based on the paradigm of protein-protein interactions. Presently, AD biomarker studies are primarily focused on the quantitative changes in the levels of protein involved in AD etiology. In addition to AD, these changes may also occur in some other forms of dementia, therefore, are not specific indicators of AD. Here we propose to evaluate novel AD biomarkers based on soluble complexes containing key protein players in AD: tau, A21-42 and apoE. Our goal is to 1) develop biomarker assays to measure the interactions of tau protein with itself (tau oligomers), A2 or apoE in human CSF samples, 2) evaluate the feasibility of using tau oligomers, or tau complexes with A2 or apoE as biomarkers for AD using a significantly large number of CSF samples.