Clinical utility

a. Current clinical practice

• Currently the diagnosis of Alzheimer’s takes 6-12 months and includes neuropsychological tests. Also, various imaging procedures (CT or MR) may be used, primarily to rule out other diseases. In the Scandinavian countries, spinal fluid tests of beta-amyloid and tau have gained some use. In the ROW these tests are usually only used in clinical trials or special biomarker studies
• Blood based tests are currently used to rule out other diseases and among others includes thyroid hormones, Vitamin B12 and Folate/Homocysteine and lipid metabolism tests. Measurement of blood Beta-amyloid or Tau-proteins have no clinical diagnostic applicability.
• Population based statistics demonstrates that currently only 50% of the AD cases are properly diagnosed for treatment.
• Usually when patients reach the dementia stage, a few approved drugs are prescribed for treatment. However, they only have a moderate effect on symptoms and do not treat the underlying disease. In the US these drugs are also used in the predementia stage of AD (in the MCI stage), this use is not approved in Europe at present.
• Recent clinical studies have demonstrated a number of other interventions that may delay the disease progress. These include specific diets, brain stimulation and physical exercise. Studies also show that optimal treatment of co-morbidity (hypertension, diabetes, and stroke) is key to reduce the progression of dementia. Several nutritional supplements have also demonstrated positive effects on cognition and related measurements and a couple products have already been launched (like Nutricia/Danone Souvenaid) in Europe.

b. Near-term clinical utility

• Use of mid-domain beta-amyloid assay will ensure early identification of the underlying disease process in patients with some cognitive symptoms.
• A positive test result will, depending on the local clinical guidelines, lead to further testing (spinal fluid tests) or advanced imaging (PET).
• Depending on the result of the assay, the physician will also initiate other necessary measures. These would include diagnose and treat any co-morbidity, initiate treatment programs to delay disease progression and insure the patients and family have the help planning for the future. Currently the general practitioners do not utilize these measures in an optimum way.
• The assay result gives the physician a tool to identify an ongoing pathological process very early in the process, while treatment choices are still possible.

c. Clinical trial use

• Because of the failure of multiple new disease modifying Alzheimer drugs to demonstrate any clinical improvement in patients with mild to moderate dementia, the Pharma industry has begun to test the same drugs to patients who are still in the pre-dementia stage. These include subjective cognitive impairment (SCI) or mild cognitive impairment (MCI). Current clinical practice has low accuracy in identifying these early stage patients, resulting in costly invasive and imaging procedures to ensure clinical trial accuracy. Today, these clinical trials use both spinal fluid tests and PET-imaging, resulting in 15-20k USD costs per included patient. A review of AD clinical studies (ClinicalTrials.gov) predicts more than 40 ongoing phase 3 studies with more than 8k subjects included every year. This results in a potential of 70k tests per year of a FDA approved blood based test.
• Including a blood based mid-domain beta-amyloid assay in clinical trial screening, will improve patient recruitment as well as reduce the need for costly and invasive clinical procedures. This is especially important in the countries outside of Scandinavia since the use of invasive spinal fluid tests results in low patient recruitment numbers.
• The mid-domain beta-amyloid assay could be used as a Companion diagnostics. The use of a diagnostic test for patient selection to test a new drug is a rapidly growing market. Teaming up with leading pharma players in successful clinical trials will result in an immediate market access and a revenue stream based upon the pharma marketing muscle.

d. Future clinical use

• Upon arrival of new disease modifying drugs, the need for early non-invasive identification of patients will be key to successful intervention. Pharma companies will need patient selection tools. Performing a non-invasive blood based tests will receive widespread acceptance and increase the potential market size substantially.
• Current high cost imaging, like amyloid-PET, is approved by FDA but not by the reimbursement systems in the US and EU. Companies like GE Healthcare promotes the idea of initially using a lower cost blood based test to screen patients that would then be tested further with high cost procedures (PET). The blood test should have a high sensitivity and reasonable specificity. Any false positives would be resolved by high cost imaging procedure. A combined marketing strategy funded by the imaging company could build this market further.