Prevention of Alzheimer's disease through drug intervention: Design of quantitative biomarker monitoring protocol

Background: Alzheimer's Disease, the commonest form of dementia poses a large burden to caregivers, public health systems and physicians. This Abstract concerns the design and implementation of a clinical drug trial to be guided by novel, non-invasive biomarkers of the disease. Approach and Methodology: A Repurposed drug, minocycline, a second generation tetracycline is used to reverse neuronal loss and inhibit neuroinflammation. Number of patients = 80; Drug 50mg by mouth for 6 months. Safety blood urea and liver function tests. Open label trial for N=12 Measures: neuropsychological exam (RBANS); MMSE; quantitative MRI (hippocampal volume) magnetic resonance spectroscopy of brain (N-acetyl aspartate; myoinositolNAA/mI) repeat measures monthly. Results: Preliminary results from 12 subjects (AD = 4; amnestic mild cognitive impairment (aMCI) =1; Normal elderly =7. MMSE and RBANS readily distinguished while hippocampal volume (normal range 6.6 – 8.8cm3) defined AD + aMCI vs Normal. Most striking was the novel MRS biomarker pair NAA/mI (Normal range =2.1 – 2.6) which not only confirmed clinical, neuropsychology and QMRI but allowed detection of a drug response within 1 month in 3/12 subjects. Conclusions: Problems and Solutions: Promising diagnostic tools permit study of novel Alzheimer drug therapies using smaller numbers of patients. Promising preliminary ‘open label' without placebo must be discounted. A Clinical Trial Consultant advises 3:1 drug-placebo blind study. Pharmacist will compound Minocycline placebo. ‘Power” calculation indicates that N=12 patients may suffice in the planned double blind trial. Future: Novel FDA approved anti neuroinflammatory drugs evaluated using the present Protocols.