Dementia diagnostics: preparing for a pending healthcare epidemic

July 18, 2013

As the Baby Boomer generation eases into its retirement years, the prevalence and costs of dementia are significantly increasing. By 2020 there will be more than 50 million Americans over the age of 65, and there are expected to be nearly 500,000 new diagnoses of Alzheimer’s disease (AD).1,2 A recent study estimated the cost of caring for people with dementia in the United States at between $159 billion and $215 billion in 2010,3 and noted that the price tag will skyrocket in the coming years. Judging by these staggering statistics on prevalence and cost, dementia is reaching epidemic proportions. It has the potential to paralyze the U.S. healthcare system.

Clinical diagnostics are at the center of addressing both case management and the costs of dementia. Advances in neurological diagnostics are yielding insights into the neurobiological basis of AD. While still in their infancy, discoveries of the molecular and genetic factors in AD will, over time, create a body of clinical evidence that will lead to better disease management, systemic cost efficiencies, and eventually preventive therapies.

New diagnostic-based guidelines

Diagnostics were a key driver in the development of the new criteria and clinical guidelines to identify and manage Alzheimer’s disease developed by workgroups of the Alzheimer’s Association and the National Institute on Aging (NIA), an agency of the U.S. National Institutes of Health (NIH). The updated criteria, published in 2011, supplant widely used guidelines from the past 30 years.

Three of the new guidelines focus on three stages of Alzheimer’s disease: preclinical (pre-symptomatic) Alzheimer’s; mild cognitive impairment (MCI) due to Alzheimer’s; and dementia due to Alzheimer’s. (A fourth guideline updates post-mortem criteria for documenting and reporting Alzheimer’s-related changes).

According to the Alzheimer’s Association, these new classifications reflect current thinking that Alzheimer’s “begins creating distinct and measurable changes in the brains of affected people years, perhaps decades, before memory and thinking symptoms are noticeable.” The general consensus of the new guidelines is that the best way to address and potentially treat the disease is at the earliest possible stage—ideally, when it is pre-symptomatic. Of course, identifying a disease when it is pre-symptomatic requires clinical diagnostics to aid in identifying the disease or its risk factors before symptoms and other signs manifest.

The implication of the new guidelines is to elevate the importance of biomarker-based staging and diagnosis. In the preclinical stage of AD, the guidelines do not establish diagnostic criteria, but rather support the pursuit of additional biomarker evidence, including longitudinal studies that indicate whether the presence of beta amyloid is a predictor of cognitive decline; biomarker comparison studies and clinical trials; and biomarker standardization.

Advances in diagnostics

Although diagnosing and treating AD and other dementias remains a challenge, numerous advances in diagnostics for dementia during the past decade have improved the ability of clinicians to identify different forms of dementia.

These tests begin at the most fundamental level, when patients first present with symptoms of cognitive impairment. Not all causes of cognitive impairment are due to dementia but rather may be caused by treatable conditions such as B12 deficiency, hypothyroidism, anemia, and diabetes. In recent years, the American Academy of Neurology, the American Geriatrics Association, a National Institutes of Health Consensus Panel, and the European Federation of Neurological Societies have issued guidelines for clinical tests that examine these and other conditions to determine if a patient’s impairment is due to dementia or secondary, treatable causes.

There has also been a significant increase in the use of neuroimaging technologies that show evidence for beta amyloid (Aß) protein plaques in the brain. The presence of these plaques, along with dementia symptoms, is a key feature of Alzheimer’s disease. Physicians sometimes order these scans as part of a diagnostic work-up to confirm or allay fears of an AD diagnosis in patients.

However, neurological diagnostics that provide information on genetic dementias prior to symptom onset are broadly acknowledged as key to better disease management. The most prevalent known genetic risk factor for Alzheimer’s disease is Apolipoprotein E (ApoE) genotype, which contributes to the risk of developing AD after age 65 in demented individuals. There are three alleles of ApoE: ε2, ε3, and ε4. A demented patient harboring two ApoE ε4 alleles has a 91% chance of developing AD by age 80, whereas a demented patient harboring one ε4 allele presents a 47% chance of developing the disease by age 80.4. ApoE is neither fully sensitive or specific and has no diagnostic role in predictive testing of asymptomatic individuals. The American College of Medical Genetics and the National Society of Genetic Counselors do not recommend genetic testing for AD susceptibility loci due to limited clinical utility and poor predictive value.

However, ApoE genotyping may have an adjunctive role in the diagnosis of AD in symptomatic individuals. Recent studies show that the combination of ApoE genotyping with the measurement of Aß and tau proteins in the cerebrospinal fluid (CSF) may have a sensitivity for AD detection of 96.4%.4 Aß and tau proteins have been shown to be biomarkers of Alzheimer’s disease. Aß42 is a free-floating protein in the CSF. Abnormally phosphorylated tau protein is the main component of neurofibrillary tangles. Based on a number of studies, elevated levels of tau protein and low levels of Aß42 protein in the CSF are correlated with a diagnosis of AD. New evidence suggests that APOEε4 carriers with MCI have lower Aß1-42 than noncarriers with MCI, indicating an increased probability of conversion to AD compared with other ApoE genotypes.5

Insights from genetic information

Because experts agree that early medical therapies may be the most effective tool to combat the personal impact and enormous costs of the dementia epidemic, pre-symptomatic genetic information is a critical component of disease management.

Research funded by the National Institutes of Aging has established strong clinical evidence that CSF beta amyloid protein measurements show abnormalities more than two decades before the overt symptoms of dementia appear in genetic forms of AD.

In addition to the ApoE gene, identification of early onset AD can also be furthered by isolation of the three autosomal dominant genes—presenilin-1, presenilin-2, and amyloid precursor protein gene—which account for many of the early onset cases of the disease, defined as symptomatic before age 60. Exciting research is being conducted through the Alzheimer’s Prevention Initiative (API) in Colombia with a 5,000-member family with identified autosomal dominant Alzheimer’s disease (ADAD).6 Based on diagnostic identification of the ADAD-causing gene, API is conducting clinical studies testing therapies targeting beta amyloid. Delaying or even preventing the appearance of Alzheimer’s in these family members could offer compelling evidence for the promise of beta amyloid as a therapeutic target.

Diagnosis is, of course, only the first step on the long pathway of AD management. The potential partnership between diagnostic companies and the pharmaceutical industry in assisting physicians with guidelines-based dementia diagnosis and therapeutic management offers great promise.

Existing therapies such as cholinesterase inhibitors, which boost levels of chemical messengers involved in memory, and memantine, which regulates the activity of glutamate, work to slow progression or minimize symptoms of dementia. However, these therapies are prescribed only after the onset of symptoms, when dementias are generally already well-established.

Additionally, the effectiveness of current pharmaceutical therapies has been limited by the lack of availability of reliable diagnostic information that can confirm AD diagnosis. The industries must work closely together to develop diagnostics and therapies that show promise in both pre- and post-symptomatic stages of Alzheimer’s.

A growing body of evidence

Traditionally, care and management of dementia patients has been hindered by two factors. First, the varied symptoms, response, and progression of the disease impede the ability to manage it and build a conclusive body of clinical evidence to support care guidelines. Second, prior to the usage of diagnostic tools that helped identify amyloid beta and tau protein in living patients (as opposed to post-mortem), a diagnosis could not be considered definitive, limiting the utility of the test and thereby hindering the management of the disease.

The insights yielded through diagnostics will contribute to the development of decision trees, an element sorely lacking in AD management. These decision trees, based on clinical information gleaned from randomized controlled trials and other sources, will allow medical professionals to use evidence-based medical information while evaluating individual patient factors, considering multiple options, and proceeding with a program of care that supports cost efficiencies and improved patient care. The combination of guidelines-based medical care and medical decision trees will promote appropriate utilization of diagnostic tests and potential therapies, helping to manage medical costs.

Clinical diagnostics in dementia will increasingly drive innovations in personalized disease identification, management, pharmacogenomics therapies, and more. As with many of the diseases that continue to defy those working in modern medicine, the most meaningful measurement of diagnostic success will be its contribution to empowering patient health and outcomes.

Joseph J. Higgins, MD, FAAN, serves as medical director for Quest Diagnostics Neurology and its subsidiary Athena Diagnostics. Quest Diagnostics recently announced the availability of a clinical test panel for aiding the diagnosis of suspected dementia due to treatable forms of cognitive impairment.


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