What Biomarkers in Dementia Mean for Geriatric Clinical Care

We have now entered the age of biomarkers in dementia. This is a major change in an area where scientific advancement has been slow. It is a step forward in diagnostic accuracy that provides momentum toward finding effective disease-specific and disease-modifying treatments. But how do biomarkers currently impact clinical practice? 

The clinical usefulness of these advances beyond the research setting have been questioned, since, at present, there is only symptomatic treatment for dementias. Thus, many providers may ask, “so what?” or “what’s the point?” when there are still no disease-specific or disease-modifying treatments. This is true, but I believe one day—hopefully sooner rather than later—there will be such treatments, and then it will be important not just for the patient but for families to know what specific dementia subtype their parent, grandparent, or sibling had. 

Biomarkers are by definition objective, quantifiable characteristics of biological processes. A biomarker provides “objective indications of medical state…which can be measured accurately and reproducibly.”¹ The ideal biomarker must be reproducible, stable over time, widely available, and directly reflect relevant disease process.² Biomarkers are currently being used as inclusion criteria and outcome measures for research, specifically clinical trials. For clinical dementia practice, biomarkers offer the potential to improve diagnostic accuracy by providing evidence of the specific underlying pathophysiologic changes responsible for different clinical subtypes of dementia. 

The use of biomarkers in laboratory testing has become so commonplace that it is accepted almost without question. An estimated 70% of clinical decisions are directly or indirectly influenced by a laboratory test result.³ But for dementia diagnosis, this is a “brave new world.” Currently available biomarkers in dementia include imaging modalities, specifically computerized tomography or magnetic resonance imaging (already widely used in clinical practice), positron emission tomography (PET) scans, and cerebrospinal fluid (CSF) measures that have only recently been developed and are in the process of moving from exclusive use in research into the clinical setting. At present, there are no blood- or urine-based biomarkers available for clinical use in dementia, and, given current knowledge about the underlying pathophysiology, a diagnostic blood test for one or more of the dementias seems unlikely.

The role of structural imaging in dementia evaluation is well established and accepted as basic medical evaluation whether done in a primary care setting or specialty memory disorders practice. Functional imaging’s role is increasing with the use of fluorodeoxyglucose-PET scans primarily to differentiate patterns of hypometabolism between Alzheimer disease (AD) and frontotemporal dementias. The role of more disease-specific amyloid PET imaging in clinical practice is not yet established and is currently the focus of the IDEAS (Imaging Dementia-Evidence for Amyloid Scanning) study being conducted nationally by Medicare. CSF analysis through lumbar puncture (LP) is a well-established procedure in medical practice, however, its use in the clinical evaluation of dementia is not routine but done primarily in suspected cases of infection or inflammation (eg, encephalitis, vasculitis). Proficiency in performing LPs among providers is predominantly among those working in neurology, anesthesiology, and emergency medicine. If CSF analysis is to become a routine part of the clinical evaluation of dementia, one can foresee the development of LP clinics (already occurring in some dementia centers), and more primary care providers will need to gain proficiency in this procedure in order to incorporate this into the diagnostic evaluation process. 

Biomarkers have been incorporated into the newest diagnostic criteria for AD.⁴ Disease-related biomarkers that are part of the current diagnostic arsenal in dementia, specifically AD, include specific changes in structural imaging, CSF analysis, and PET imaging. The CSF pattern of decreased amyloid β 42, increased phosphorylated tau, total tau, and neurofilament light protein have been shown to be highly consistent with AD.⁵ In the clinical setting, such biomarkers have to be interpreted along with the data from a patient’s medical assessment.  However, it is important to recognize that there is overlap in pathology between AD and other neurodegenerative disorders; for example, amyloid is also found in Lewy body dementia. Additionally, the high proportion of cognitively normal older adults with pathological changes on autopsy of plaques, tangles, and neurodegeneration limits the specificity of CSF biomarkers. These findings also raise questions regarding normal aging vs disease that continue to confound clinicians caring for patients with dementia, as well as other age-associated disorders. 

The progress in biomarker development for dementia means that one no longer has to wait until a patient dies to make a diagnosis of AD with certainty. The ability to clinically differentiate the various subtypes of dementia can now be validated with objective tests. This is the result of research that has helped us better understand the biochemical pathology of the “tangles and plaques” that Dr Alzheimer first described in 1906 and that have become the neuropathological markers for AD. Being able to better diagnose AD with certainty, to tell patients and families whether someone does or does not have AD, and if not, which other type of dementing illness they may have, is an initial step toward clinical clarity. 

The value of the use of a diagnostic test in practice should relate to its benefit for the patient in terms of outcomes which includes qualify of life. If biomarkers are proved to be highly accurate in diagnosing AD, the patient benefit needs to be considered. What value is gained by the individual with mild cognitive impairment (MCI) to know that it is actually early AD? The Cochrane reviews have concluded that there is not sufficient evidence to support the routine use of CSF, amyloid β, or PET in the diagnosis of MCI due to AD.⁶ 

At present, there is an uncertain balance between benefits and harms of a diagnosis when no disease-modifiable treatment is available. In the case of specific biomarkers that have been well characterized and repeatedly shown to correctly predict relevant clinical outcomes across a variety of treatments and populations, this use is entirely justified and appropriate. But we in the field of dementia are not yet at this point when it comes to clinical diagnosis. Therefore, the utility of such testing in the clinical setting should be addressed with each patient and family in open and frank discussions that take into consideration the patients’ (and families’) values and acknowledges the limitations of the applicability of these tests. 

References

1. Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010;5(6):463-466.

2. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmcol Ther. 2001;69(3):89-95.

3. Beastall GH, Watson ID. Clinical chemistry and laboratory medicine: an appreciation. Clin Lab Med. 2013;51(1):3-4.

4. McKann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimers disease. Alzheimers Dement. 2011;7(3):263-269.

5 Olson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimers disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15(7):673-684.

6. Ritchie C, Smailagic N, Noel-Storr Anna H, et al. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer’s disease and other dementias in people with  mild cognitive impairment (MCI). Cochrane Databae Syst Rev. 2014;10(6):CD008782. doi:10.1002/14651858.CD008782.pub4