Diagnostics Development

When it begins, Alzheimer's disease (AD) is often difficult to distinguish from other dementias as well as other causes of mild cognitive impairment (MCI).  Potential treatments of AD, however are likely to have their greatest efficacy before the devastating and widespread impairment of brain function that inevitably develops with longstanding AD.

BRNI has recently validated a new, internally controlled peripheral biomarker for skin fibroblasts (with potential for blood cells as well) that shows its greatest sensitivity during the first 1-2 years of AD onset. The inflammatory signal, bradykinin, which occurs naturally in brain, skin, and blood cells, stimulates a change in the enzyme target called MAP kinase Erk1/2.  The Erk 1/2 response was abnormal for AD vs. age matched controls and vs. non-AD dementias such as Parkinson's disease, multiple infarct dementia and Huntington's Chorea.  The BRNI biomarker showed high accuracy for tissue bank samples as well as for samples obtained in a previous study from patients with autopsy-confirmed diagnoses.

With this painless skin test the accuracy of clinical diagnosis was significantly enhanced, particularly for early AD when treatment could be most beneficial.  The molecular pathway measured by the BRNI biomarker (and related biomarkers under development at BRNI) includes the same enzyme, PKC, that is targeted by the AD drug, bryostatin, to treat both the symptoms and neurodegeneration of AD.  The fact that AD shows an early abnormality of this PKC-regulated target provides additional support that therapeutics directed toward the PKC pathway are affecting changes close to the underlying cause of the disease itself.

Such a causal role for PKC isozymes in AD receives further support from the recently established close and reciprocal relationship of PKC epsilon and soluble A Beta.  When A Beta becomes elevated it lowers PKC epsilon as shown first in BRNI research and subsequently in other laboratories.  Conversely, when PKC epsilon is elevated, for example in response to the BRNI therapeutic PKC activators, it lowers A Beta.  In fact, PKC epsilon elevation lowers A Beta by increasing its degradation and by reducing its synthesis.  The former effect is achieved by activating the A Beta degradation enzyme called ECE.  The latter effect (decreased synthesis) is achieved by inhibiting the enzyme BACE that is important for A Beta synthesis and by activating the competing enzyme, alpha secretase responsible for synthesizing the non-toxic soluble amyloid alpha protein.

Alzheimer ’s Disease Systemic Expression

These results with skin fibroblasts demonstrate that AD not only affects the brain.  It also affects many tissues throughout the body.  Now, data from many laboratories around the world have validated this view.  We know now that many of the enzymes critical for metabolizing the proteins that are the precursors to A Beta are ubiquitous in body tissues.  It is, therefore, not surprising that enzyme abnormalities in A Beta metabolism may provide an accurate, non-invasive method of confirming the clinical diagnosis of AD.  Ultimately, this peripheral AD biomarker approach will have to be conclusively validated with a large number of autopsies that confirm the accuracy, sensitivity, and specificity of this diagnostic method.

Clinical and Autopsy Validation of the BRNI Biomarker for Alzheimer’s Disease

Autopsy validation of the BRNI Biomarker has already been achieved for more than 70 patients.  In collaboration with our private sector partner, Inverness Medical Innovations, Inc., BRNI is now preparing to expand this autopsy-confirmed patient population to a much larger number, so ultimately it can be made available around the world to help patients and their families diagnose the disease, and diagnose the disease earlier enough so that AD therapeutics can prevent or significantly ameliorate the disease.