Do biomarkers for Alzheimer’s disease have utility in everyday practice?

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
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Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.