Friday, September 29, 2023


Biotechnology News Magazine

Alzheimer’s Diagnostics: Innovative Alzheimer’s Disease Test Provides Answers for Patients & Families-Supports Payer Treatment Reimbursement Decisions

Current Diagnostic Techniques Are Inaccurate, Time-consuming, and Drain Financial Resources

Alzheimer’s Diagnostics

By Dr. Daniel Alkon, Chief Scientific Advisor SYNAPS Dx

Many people believe that dementia is a natural part of the aging process, but Alzheimer’s disease (AD), a type of dementia that affects memory, thinking and behavior, accounts for 60-80% of dementia cases and is not a normal aspect of aging. What’s more, current diagnostic techniques are inaccurate, time-consuming and drain financial resources. As new treatments for dementia emerge, the need for a simple, definitive way to distinguish AD from other neurodegenerative conditions has never been more important, especially in those recently diagnosed with dementia.

An estimated 5.8 million Americans aged 65 and older are living with AD. In 2020, AD and other dementias cost the nation $305 billion, including $206 billion in Medicare and Medicaid payments.

An early diagnosis of AD can help determine if a patient’s symptoms are truly due to AD or some other conditions that can be curable, such as infections, emotional distress or nutritional deficiencies, such as a vitamin B12 deficiency. But when it comes to diagnostic tests, considerable confusion exits in the marketplace, with many claims being made, even as demand among all stakeholders has emerged in response to attempts to develop drugs to treat AD.

The most promising breakthrough for diagnosing AD is an autopsy-confirmed, minimally invasive skin test to support clinicians’ definitive diagnosis of AD vs. other forms of dementia. This test is well positioned to help address a number of key issues that payers, providers and patients face when it comes to getting a diagnosis early in the patient journey—when it matters most.

Understanding AD

The brain has 100 billion nerve cells, with each cell connecting with other nerve cells through multiple communication networks (an average of ~1,000 trillion connections/brain). Different groups of nerve cells play a role in thinking, learning and remembering, while others involve seeing, hearing and smelling. Brain cells process, store information and communicate with each other through connections called synapses. Microscopic changes in these brain connections often begin concurrently with the first signs of memory loss.

AD is a complex neurodegenerative dementia and is believed to prevent parts of a brain cell from running properly. As damage spreads, synaptic connections are first reduced in number and then brain cells lose their ability to function and eventually die, causing irreversible changes in the brain and eventually dementia.

Symptoms of AD occur because nerve cells (neurons) and their connections (synapses) in parts of the brain involved in thinking, learning and memory (cognitive function) have been damaged or destroyed. Individuals typically live with AD symptoms for years. Over time, symptoms tend to increase and start interfering with individuals’ ability to perform everyday activities. At this point, the person is said to have dementia due to AD.

The majority of people with AD are 65 and older, with symptoms growing worse over a number of years. In the early stages of AD, memory loss is mild but gradually individuals lose the ability to respond to their environment. Typically, AD patients live four to eight years after diagnosis but can live as long as 20 years, depending on other factors. 

Plaques and Tangles

Two abnormal structures called plaques and tangles are the pathologic hallmarks that, together with dementia in the clinic, identify AD at autopsy. Plaques are deposits of a protein fragment called beta-amyloid that build up in the spaces between nerve cells. Tangles are twisted fibers of another protein called tau that build up inside cells.

While autopsy studies demonstrate that most people develop plaques and tangles as they age, individuals with AD may develop more of them in areas of memory before spreading to other regions. However, in studies of non-demented aged persons, varying plaques and tangles were found upon autopsy, suggesting that these findings are not associated with cognitive performance in the oldest-old (90 years old) without dementia.

Many experts hypothesize that plaques and tangles play a role in blocking communication among nerve cells and disrupting processes that cells require. However, there are other factors that may contribute to the onset of AD such as the loss of synaptic growth factors, inflammation, genetics and cellular dysfunction. While amyloid plaque is a hallmark of AD, it is not necessarily the root cause of disease.  A recent article demonstrated that centenarians with little or no cognitive decline were found to have high levels of plaque and tau at death, while another article suggested that more than one-third of people studied with mild to moderate AD had minimal levels of plaque accumulation in the cerebral cortex.

Challenges in Addressing AD

Some of the conditions that are often mistaken for AD can easily be addressed with inexpensive interventions. These conditions, other than AD, that can cause dementia include B12 deficiency, hypothyroidism, depression, Parkinson’s disease, and Pick’s disease.  Without a definitive diagnosis, however, it’s frustrating, expensive and overwhelming for patients and families, providers and payers to know how to proceed in the care journey.

The FDA recently approved Aduhelm™ (aducanumab-avwa), an amyloid beta-directed antibody indicated to treat early AD patients or mild cognitive impairment (MCI) that has not yet progressed to AD. Although Aduhelm reduces amyloid plaque, it’s cognitive benefits are not well-established, particularly in the absence of brain inflammation and/or swelling. Moreover, experts suggest that only 40 – 50% of individuals with MCI ever develop AD.

One-in-three patients with memory issues do not have AD and can benefit from treatment that’s more appropriate based on the cause of their dementia. For AD patients, it’s well understood that no drug, including the one recently approved by the FDA, can treat the underlying disease. Two acetylcholinesterase inhibitor drugs and one inhibitor of the synapse messenger, glutamate, have been approved and provide some temporary symptomatic relief.

An early diagnosis allows patients to start clinical interventions sooner, providing a cost savings for payers, as well as saving time, money and the despair of not knowing for those involved. Early diagnosis also gives patients the chance to have a say in their own care.

Value of Biopsy Validation

Clinicians face a number of challenges, including being unable to make the diagnosis in the first several years of the disease on their own. Secondly, they are unable to validate any biomarker that might assist in making the diagnosis with any degree of certainty. An AD diagnosis vs. other neurodegenerative dementias is only possible through autopsy validation. In 3-4 % of cases, the presence of an identified gene can be definitive since the known accompanying brain pathology includes amyloid plaques and neurofibrillary tangles.

Furthermore, many people with dementia have brain changes associated with more than one cause of dementia. This is called mixed dementia. Some studies report that the majority of people with the brain changes of AD also had the brain changes of a second cause of dementia on autopsy. Other degenerative causes of dementia include Parkinson’s disease, frontotemporal lobar degeneration (FTLD), Lewy body disease, cerebral vascular disease or a mix of these with or without AD. However, it is important that individuals receive an accurate diagnosis – even in the presence of mixed dementias – to ensure they receive treatment and follow-up care appropriate to their specific form of dementia.


AD is often misdiagnosed in patients with MCI because, until recently, no reliable diagnostic existed that could be utilized in the first four to five years of the dementia diagnosis. A meta-analysis of studies using the Mini-Mental State Examination (MMSE) to evaluate the conversion from MCI to AD dementia found that the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%, making them unreliable as a stand-alone metric.

Consistent with a study from Duke University where the mis-diagnosis rate of AD was 28.4% using the current battery of cognitive, blood and imaging tests (including MRI, FDG-PET and CSF puncture), a recent Cochrane analysis concluded that “MRI is not accurate enough to predict which patients with MCI will progress to Alzheimer disease because it will miss about 14% to 22% of cases and falsely predict approximately 48% to 60% of cases. Combining MMSE plus imaging, plus additional biomarkers have improved, but not solved for the need for accuracy of identifying AD in people with MCI.  Even after 10 years, most people with MCI will not develop dementia.

Unfortunately, most patients with AD are diagnosed in the late stages of the disease, with very few being diagnosed in the early stages when treatment can be the most effective. This has added significantly to the detrimental impacts on the patient and family, as well as adding to physician and payer burden.

According to FDA labeling, treatment of AD with Aduhelm™ should be initiated in patients with MCI or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease other than those in the clinical studies.

Accurate AD Test Available Today

For the benefit of patients, caregivers and healthcare providers, having a definitive diagnosis as early as possible in people diagnosed with dementia is essential for establishing care plans and planning for the future. The new test assesses the factors directly related to the formation of synaptic connections in the brain, impacting loss of memory and cognition in people living with AD, as well as regulators of amyloid plaque and tau formation, which are hallmarks of AD at autopsy.

The new DISCERN test’s assays have demonstrated >95% sensitivity and specificity. It also identifies the AD-specific degeneration biomarker for a definitive diagnosis, differentiates AD from other non-AD dementias and identifies those with AD in addition to other degenerative pathologies. Because this new AD test assesses factors that regulate synaptic loss and formations of amyloid plaque, it should be considered a tool to manage appropriate patient access to future approved therapies, in addition to the clinical and economic benefits of improved early, accurate diagnosis.

In this test, skin cells from a patient sample are grown in the lab and then assessed in three assays. The three assays are:

  • Morphometric Imaging — a method of evaluating the ability of neurons to form networks. Studies have shown that neural network formations in peripheral skin cells are well correlated to activity in the brain.
  • Protein Kinase C Epsilon (PKCƐ) — an enzyme that regulates synaptic and neural growth and death, as well as regulates the formation and degradation of amyloid beta toxic proteins and tangles. Tissue concentrations of PKCƐ have been shown to correlate with those concentrations in the brain.
  • AD Index – Extracellular-signal-regulated kinase 1 (ERK1) and ERK2 are two enzymes found in fibroblasts. When quantitatively imaged their ratio is highly correlated with AD and their values were also inversely correlated with duration of disease (time from onset of AD symptoms).

Key factors to look for in AD test include:

  • Accurate diagnosis of AD through a minimally invasive skin biopsy
  • Composed of three specific assays related to synaptic function
  • Developed by testing and following patients with dementia over several years prior to death, establishing plaque and tau at autopsy, which is validated against the NIH gold standard
  • Awarded reimbursement codes and a payment amount set by the Centers for Medicare & Medicaid
  • Demonstrates high specificity and sensitivity >95% in both early and late-stage AD

Giving providers, patients and their families a clear answer about AD helps them focus the patient journey, enables pharmaceutical companies to identify appropriate clinical trial participants and allow accredited sources of reimbursement to establish protocols and prior authorizations for prescribing and reimbursing treatment.

Editor’s Note: About Dr. Daniel Alkon, Chief Scientific Advisor at SYNAPS Dx.

Dr. Alkon is Chief Scientific Advisor at SYNAPS Dx. He joined the staff of the National Institutes of Health where during his 30-year career he became a medical director in the U.S. Public Health Service at the NINDS and chief of the Laboratory of Adaptive Systems.

In 1999, Dr. Alkon became the founding Scientific director of the Blanchette Rockefeller Neurosciences Institute and occupies the Toyota Chair in Neuroscience at the Institute. In this position, he and his team conducted multidisciplinary research on the molecular and biophysical mechanisms of memory and memory dysfunction in psychiatric and neurological disorders, particularly Alzheimer’s disease.



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