Frank Amato: “According to experts, 1 in 5 Alzheimer’s or 35,000 cases a year in the US may be misdiagnosed based on a study of nearly 1,000 people listed in the National Alzheimer’s Coordinating Center database. In one recently reported instance, a patient was incorrectly diagnosed and treated for Alzheimer’s disease (AD) for seven years, which he said destroyed his life.” Read on.
Current AD diagnostic approaches have inadequate accuracy, especially in early stages of the disease and with mixed dementia. By placing their focus on surrogate markers that are related to AD but not the disease itself, the distinction of AD can be difficult. An earlier diagnosis, prior to dementia, into mild cognitive impairment (MCI) can be even more challenging because most patients never progress to AD or dementia. This is especially an issue as new drugs become available targeting people with MCI or early dementia due to AD.
New methods of diagnosis are needed now more than ever. The most promising breakthrough for identifying AD is an autopsy-confirmed, minimally invasive skin test to support clinicians’ definitive diagnosis of AD vs. other forms of dementia. This test has the potential to help patients and families get the right support or treatment path for improved quality of life.
For example, DISCERN™ is a diagnostic test that 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—hallmarks of AD at autopsy. This test, which has 95% sensitivity and 95% specificity in the diagnosis and management of AD, combines three biomarkers: 1) Morphometric Imaging to measure fibroblasts’ ability to form networks, 2) Protein Kinase C ε to measure synaptic growth and 3) AD-Index to measure phosphorylation of Erk1 and Erk2 in response to bradykinin.
Closer Look at AD
The brain has 100 billion nerve cells, with each cell connecting with multiple communication networks. Different groups of nerve cells play a role in thinking, learning and remembering, while others involve seeing, hearing and smelling. Brain cells process and store information and communicate with other cells. Microscopic changes in the brain begin long before the first signs of memory loss.
AD accounts for 60-80% of dementia cases and is not a normal aspect of aging. Scientists believe AD prevents parts of a neuron or brain cell from running properly. As damage spreads, neurons lose their ability to function and eventually die, causing irreversible and devastating changes in the brain.
The majority of people with AD are 65 and older, with cognitive deficits that worsen over a relatively short period of time. 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.
Causes
AD is a complex disease and its causes are not yet fully understood, but many believe it is most likely due to a combination of age-related changes in the brain, along with genetic, environmental, and lifestyle factors. The importance of these factors can increase or decrease the risk of AD and vary from person to person.
This progressive brain disease is characterized by changes in the brain—including the accumulation of amyloid plaques and neurofibrillary, or tau tangles—that result in loss of neurons and their connections. These changes to the brain contribute to a person’s ability to remember and think and, eventually, to live independently.
Plaques and Tangles
Plaques and tangles are abnormal structures that may contribute to damaging and killing nerve cells. 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 builds up inside cells. While these are often seen in people with AD, they are not closely associated with the loss of memory or cognitive decline seen in people with AD.
While autopsy studies demonstrate that most people develop plaques and tangles as they age, individuals with AD typically develop far more of them in areas of memory before spreading to other regions.
While most experts believe plaques and tangles play a critical role in blocking communication among nerve cells and disrupting processes that cells require, there are other factors that affect the ability of neurons to communicate effectively. This destruction and death of nerve cells causes memory failure, personality changes, problems carrying out daily activities, and other symptoms of AD.
A recent study of 330 centenarians found varying levels of plaque and tau at autopsy, with no correlation to a reduction in cognitive functioning during life. This reinforces that while tau and plaque may be present in brain tissue, they may not be the primary cause of AD. Mounting evidence suggests that memory failure, personality changes, problems carrying out daily activities and other symptoms of AD are caused by loss of activity of synapses and neurons.
Scientists now believe that age-related changes in the brain may harm neurons and affect other types of brain cells to contribute to AD. These changes include atrophy of certain parts of the brain, inflammation, vascular damage, production of unstable molecules called free radicals and breakdown of energy production within cells. But age is only one risk factor, and many people live into their 90s and beyond without ever developing dementia.
Genetics
Genetic risk factors are changes or differences in genes that can influence the chance of getting a disease. Early-onset AD has a genetic component, which can cause anxiety for those with a family member who has AD. While having a family history of AD can affect the likelihood of developing the disease, it’s not guaranteed.
Closer Look at Misdiagnosis
Experts predict that the number of Americans living with AD could rise from 5 million to 16 million by 2050. Given the complexity of this disease, with a complicated diagnostic process, avoiding misdiagnosis is critical for ensuring that people get the right treatment as soon as possible.
Studies show that 54% of people living with AD also have dementia attributable to other conditions. Often, people who experience subtle short-term memory changes and are easily confused don’t have AD. Many treatable conditions have symptoms similar to AD or another form of dementia, and without the right diagnostic tools or training, some doctors are challenged to make a clear distinction.
Leading and often treatable conditions that can be mistaken for AD include:
Other neurocognitive disorders – While AD accounts for the majority of neurocognitive disorder cases, other types of dementia and medical conditions can similarly affect mental functions, such as vascular dementia and Parkinson’s disease. For example, if a senior has a small stroke or a benign brain growth, they might show signs of cognitive impairment. For example, one patient turned out to have a benign tumor. After surgery, he lived another 10 years.
MCI — Although someone with MCI might experience problems with memory, the changes don’t typically disrupt daily life or inhibit independence. Over time, 28.7% of MCI can progress to dementia.
Mood disorders — Major depression or bipolar disorder can make it difficult to focus, think clearly or make decisions. Depending on someone’s emotional and mental state, memory loss can worsen. When properly treated, these symptoms can improve.
Delirium – This can be caused by chronic illness, certain medications, infection or surgery, with symptoms including confusion, disorientation, and memory impairment. Typically, it comes on quickly and can be reversed with proper treatment, such as stopping a particular medication or treating an infection.
Alcohol and other substances — Drinking too much alcohol over a long period of time can lead to memory loss. Heavy drinking destroys brain cells and worsens memory problems. Also, prescription and over-the-counter medications can interfere with cognition and mimic dementia.
Other common causes of memory loss include urinary tract infections, thyroid disease, diabetes, vitamin B12 deficiency, normal pressure hydrocephalus, and vision and hearing problems.
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.
Importance of Early AD Diagnosis
Until now, only autopsy studies have been definitive to identify mixed dementia as current tests don’t adequately measure most dementia-related brain changes in living people. Having an accurate diagnosis of AD in people living with mixed dementia can improve care plans and therapeutic interventions.
Furthermore, an early diagnosis enables patients to begin 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 and/or their families the chance to have a say in their own care.
How AD Test Works
The new AD test assesses factors directly related to the formation of synaptic connections in the brain, impacting loss of memory and cognition in people living with AD. Synaptic connections allow the brain’s nerve cells to communicate with each other. It also identifies the AD-specific degeneration for a definitive diagnosis even in the presence of other co-existing degenerative disorders.
This new AD test 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.
Key factors to look for in an AD test include:
- Accurate diagnosis of AD through a minimally invasive procedure in the clinician’s office
- Accurately assess several critical factors directly related to AD and that regulate memory, the presence of functional synaptic connections among neurons, the level of amyloid plaques and the level of neurofibrillary tangles in the brain
- Accuracy identifying AD earlier in people diagnosed with dementia. 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 and distinguishing AD in people living with mixed dementia.
The goal of using such a test is to give providers, patients, and their families a definitive answer about AD to provide a more focused patient journey, enable 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: Frank Amato is CEO and president of SYNAPS Dx. Previously, after two decades in the pharmaceutical and biotech industries, he was president, CEO, and director of electroCore, a NASDAQ-traded bioelectronic medicine company focused on treating neurological conditions. Frank is an accomplished leader with a track record for consistently delivering strong results.
Prior to his tenure at electroCore, Frank was vice president of the Specialty Commercial Operations Group at Merck, which comprised nine specialty therapeutic divisions. After Merck’s acquisition of Schering-Plough, he led the integration of approximately 3,000 employees into the new company. In addition to his day-to-day business responsibilities, Amato was accountable for various aspects of due diligence, negotiation, integration and launching products in neuroscience, virology and ophthalmology.
After serving as an infantry field medic in the 82nd Airborne Division, U.S. Army, Frank began his career as a sales professional in New York City with the Upjohn Company. Throughout his career, Frank has worked on key initiatives in the U.S., Europe, and Japan, managing teams of senior executives in sales, marketing, operations, finance, legal, medical, regulatory and research and development.
