Addressing Misdiagnoses, Ensuring Accurate Diagnosis to Inform Appropriate Prescribing and Treatment for Alzheimer Disease

Following years of waiting and hoping, the Alzheimer disease (AD) community is now hailing the FDA approval of a new class of drugs that bring hope to some patients in the fight to halt the progression of AD. Better, safer treatments are still needed, especially with the overall cost for administering these medications. Researchers report that the drugs work best for those demonstrating symptoms of cognitive decline, such as mild cognitive impairment (MCI) or early AD dementia, but how do you accurately diagnose these conditions? 

AD is a progressive disorder that starts with the loss of synapses and ultimately leads to damage and the destruction of nerve cells in the brain. Over time, the disease leads to a gradual loss of cognitive functions, including the ability to remember, reason, use language and recognize familiar places. It can also cause a range of behavioral changes. The growing number of aging adults led experts to predict there will be 13 million people with AD by 2050.

The opening chapter in FDA drug approvals heralds a new era of molecular therapies for AD and related neurodegenerative disorders. These first drugs attack plaques in the brain that are made of a protein called amyloid, disrupt cell function, and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of AD.

In reviewing the efficacy, benefits, safety issues, and costs of each, all decision-makers can better evaluate their value. Unfortunately, patients with more advanced disease showed little to no benefit from these drugs compared to those who received the placebo.

Across the board, there are prescribing restrictions for all these drugs. Given the safety and cost issues associated with treatment, the need for an accurate diagnosis is paramount to ensure that the right patients receive the drug at the right time.

Background

The drug development landscape for AD has been littered with failures, with less than 2% of successful drugs in 200 programs since 2003. Recently, 2 drugs have been approved by the FDA, aducanumab (Aduhelm) and lecanemab (Leqembi), with a third drug, donanemab, soon to complete FDA review. This new class of anti-amyloid monoclonal antibodies (anti-amyloid drugs), share common aspects of mechanism of action, safety considerations, route of administration, and efficacy.

This new class of drugs is indicated for the treatment of AD and their mechanism of action targets amyloid and tau, which are hallmarks of AD upon autopsy. This positions the evaluation of amyloid as a secondary consideration to the determination that AD is present.

Amyloid-related imaging abnormalities (ARIA) have been noted, with deaths reported in the clinical trials, some of which were attributable to the drug. The lecanemab label includes a black-box warning, requiring MRI monitoring for ARIA during the first months of treatment. The rates of ARIA vary among the therapies—from 20% to 40%—and appear to be impacted by APOE-4 genetic status.

There is also an unresolved question about the clinical significance of brain loss with these new drugs. In clinical trials, patients receiving lecanemab experienced higher rates of brain shrinkage on MRI than those receiving placebo, raising questions about their effect on long-term brain health and the adverse impacts of ARIA.

Challenges of Diagnosis and Misdiagnosis

Symptoms of dementia can be difficult to differentiate from typical age-related behavior changes and other common and potentially curable conditions. An early diagnosis of AD can help to alleviate worry for older Americans and families and get them on the optimal AD therapeutic journey earlier in the disease trajectory.

Unfortunately, physicians have found it difficult to diagnose AD, with 50% to 70% of symptomatic AD patients not correctly diagnosed in primary care and 25% to 30% misdiagnosed in specialized memory clinics. Additionally,one-third of older adults reported delaying care in 2021, whereas one-fifth of this population experienced negative impacts from delayed care. Without an accurate AD diagnosis, patients do not have access to the right treatment in a timely manner.

Efficacy and Benefits

The benchmarks for improvement associated with each drug vary. Two clinical trials tested aducanumab and together, they showed no change in remembering, learning, reasoning, or functioning compared with placebo, and changes are not likely to be noticeable for many patients or families. For lecanemab, researchers report that in a trial that involved 1795 participants with early-stage, symptomatic AD, the drug slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo. Donanemab has recorded even better results and studies found to slow disease progression by up to 60% for AD in the earliest, symptomatic stages.

Administration

All drugs are administered as an intravenous (IV) infusion, typically performed at hospitals and infusion therapy centers: aducanumab approximately 1 hour every 4 weeks and at least 21 days apart, lecanemab every 2 weeks, about 1 hour for each infusion. Donanemab is administered once every 4 weeks.

Coverage Restrictions and Cost

The Centers for Medicaid & Medicare Services (CMS) maintains a restrictive policy: aducanumab coverage is reserved to only those participating in a randomized, controlled clinical trial, whereas lecanemab coverage is tied to individual physician enrollment of the patient in a CMS-run registry.

Annual costs range from aducanumab, initially priced at $56,000 and subsequently reduced to $28,200 Biogen, whereas lecanemab is set at $26,500 and donanemab is projected to cost $28,000 at launch.

Questions Regarding Appropriate Intervention

AD is a complicated disease with several pathologies leading to cognitive decline. Although there is consensus that early intervention is important, the open question remains how to intervene.

MCI has a highly variable course of progression, with less than 50% of people living with MCI progressing to dementia in 10 years of onset. Further, many of the risk factors for cognitive decline are modifiable and it is estimated that up to 40% of dementia cases can be prevented. What physicians and health care decision-makers need to address is the challenge of evaluating the risk factors associated with these drugs, deciding who is a candidate and what is in the best interests of the patient.

Diagnostic Pathways

Researchers are continuing to study and develop biomarkers to improve diagnosis, keeping in mind the prevalence of misdiagnosis with AD due to the inaccuracies in current diagnostic tests, as well as the cost and access to certain tests. A recent study suggests that only about 5% of people with MCI would qualify for treatment with lecanemab, making appropriate patient selection even more critical, but also leaving these new treatments unavailable to patients who may otherwise benefit from them.

What is so encouraging is that studies show that about 40% of dementia cases can be prevented or delayed with lifestyle changes that address modifiable risk factors, including physical activity. Several studies show that physical activity can slow the development of MCI, the early stage of cognitive decline or memory loss.

For example, the EXERT study demonstrated that older adults who exercised regularly throughout an 18-month period had the same results on a cognitive assessment as they did in the beginning of the study, indicating physical activity stalled the progression of MCI. Moreover, the benefit was seen irrespective of the level of physical exertion. People performing simple seated exercises with stretching bands had similar benefits to those able to walk on a treadmill.

Similarly, the Systematic Multi-Domain Alzheimer's Risk Reduction Trial SMARRT study found that reducing risk factors such as physical inactivity, smoking, depression, mid-life hypertension, mid-life obesity and diabetes could also reduce the prevalence of AD in the United States.

Brain Imaging

Several types of brain scans, including CT, MRI, and PET, may help physicians diagnose AD or a related dementia. Typically, these tests are extremely expensive and may not be available in every community.

Furthermore, the available evidence supporting the clinical utility and cost-effectiveness of amyloid PET imaging in routine clinical practice remains unclear and inconclusive. While studies suggest the role of PET imaging in identifying amyloid plaques in the brain, there is a dearth of robust evidence demonstrating its impact on patient outcomes or treatment decision-making, which may lead to misdiagnosis.

For example, various studies have shown that between 20% and 40% middle-aged and elderly individuals are amyloid-positive without apparent signs of dementia. In individuals 80 years of age or older, 60% presented at autopsy with AD neuropathology but no cognitive impairment during life.

Cerebrospinal Fluid Biomarkers (CSF)

In clinical practice, CSF biomarkers are routinely used to help diagnose AD or other types of dementia. In addition to requiring that caregiver accompany the patient to and from the test, seniors face the risks of a CSF culture, including discomfort or pain during the procedure, bleeding into the spinal cord particularly in people who take blood thinners or have a low platelet count (thrombocytopenia), headache as a result of CSF leakage, infection, and nerve damage. Physicians perform a lumbar puncture, also called a spinal tap, to get CSF.

The most widely used CSF biomarkers for AD measure beta-amyloid 42 (the major component of amyloid plaques in the brain), tau, and phospho-tau (major components of tau tangles in the brain, which are another hallmark of AD).

Blood Biomarkers

Proteins that originate in the brain may be measured with sensitive blood tests. These blood biomarkers have historically been less accurate than CSF biomarkers for identifying AD and related dementias. Many blood biomarkers assess amyloid positivity, validated against amyloid findings from PET scans. While a hallmark of AD at death, blood tests assessing amyloid positivity do not identify AD itself.

As noted above, patients with normal cognition may have levels of amyloid plaque consistent with AD based on a PET scan. Given that MCI and dementia can be caused by a variety of risk factors, some of which are modifiable, assessing amyloid positivity before ruling out other causes may lead to excessive diagnostic workups and potential exposure to inappropriate treatments.

Skin Test

The link between the brain and skin is documented: looking at morphological changes that take place in the skin has shown to be a useful tool in the diagnosis of AD. The introduction of DISCERN, an autopsy-validated skin test has shown >95% sensitivity and specificity to identify AD in people recently diagnosed with dementia, even in those with mixed dementia.

The availability of an accurate autopsy-validated test has the potential to greatly improve the identification of appropriate candidates and improve referrals to physicians who will offer these new drugs. In a recent survey, clinicians indicated that they were 4-times more likely to prescribe these new drugs with a positive DISCERN test than a negative one.

DISCERN has received reimbursement PLA (CPT) codes (206U and 207U) and can be reimbursed by Medicare. The test is based on a 3 mm skin punch biopsy that is minimally-invasive and can easily be administered in the physician office setting, with the skin sample then processed in an approved laboratory.

This test is the only Autopsy-Validated Test(at98%) to identify AD and meets the NIH Gold Standard for confirming diagnostic accuracy, with patients followed for as long as 8 years prior to death. The test is comprised of 3 assays that assess the factors directly related to the formation of synaptic connections in the brain impacting loss of memory and cognition in people living with AD. The assays are also related to the formation of amyloid plaques and tau in neurofibrillary tangles, which are hallmarks of AD at autopsy.

Accurate Diagnosis is Critical

Because of the apparent safety issues associated with these risky AD drugs, and in the absence of meaningful benefits, an early and accurate AD diagnosis is critical. The emergence of an accurate test supports physician prescribing decisions and helps people avoid taking drugs such as lecanemab and donanemab, which have significant safety risks and expensive price tags.

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