Alzheimer’s Biomarkers in Diagnosis and Treatment

Researchers have successfully used biomarkers as tools for detection in diseases such as diabetes, atherosclerosis, and cancer. As our populations age, it is becoming increasingly necessary to find reliable Alzheimer’s biomarkers.¹

Alzheimer’s disease is a neurodegenerative disorder affecting the brain, which results in impaired cognition. It is characterized by brain atrophy, while abnormal tangles and plaques emerge and further diminish neuronal communication. Alzheimer’s is a degenerative dementia, primarily diagnosed in people over 65 years old. By 2050, researchers predict that 1 in 85 people will be affected by the disease.²

The often-used biofluid for studying Alzheimer’s disease is cerebral spinal fluid (CSF), due to its proximity and resemblance to the brain’s composition. Indicators within CSF offer diagnostic information. However, obtaining CSF involves invasive lumbar punctures.³ Using plasma samples, while less invasive, may not be as rich in information as CSF.⁴

Sato et al. (2012) recently published a paper identifying Alzheimer’s biomarkers in plasma samples.⁵ Sato et al. used lipidomics technologies focused on sterols that they had previously developed to find new biomarkers for Alzheimer’s disease. They used plasma and CSF samples of elderly controls and subjects diagnosed with Alzheimer’s disease, mild cognitive impairment, schizophrenia, and Parkinson’s Disease. Using LC-APCI-MS, they applied this method to the discovery of both plasma and CSF Alzheimer’s biomarkers.

In doing so, the investigators were able to identify a biomarker candidate, desmosterol, that changes in Alzheimer’s as compared to plasma from healthy controls. Additionally, they were able to show that the desmosterol plasma level and the desmosterol/cholesterol ratio in the same patient was significantly decreased in Alzheimer’s. They further went on to confirm this in CSF and found it to correlate with the CSF desmosterol/cholesterol ratio, suggesting that plasma desmosterol does reflect brain sterol synthesis and/or sterol metabolism. This correlation was unique to Alzheimer’s patients and those with mild cognitive impairment. With further confirmation, desmosterol could become an attractive plasma biomarker used both for diagnosis and monitoring disease progression.

Another, and perhaps more novel and certainly more accessible diagnostic for Alzheimer’s was found by Shi et al.⁶ Tau is a known player in Alzheimer’s. Using mass spectrometry, investigators quantitatively examined tau and phosphorylated tau and demonstrate that their ratio was significantly greater in Alzheimer’s patients. These results very strongly suggest that salivary tau could be an ideal Alzheimer’s biomarker.

Whilst physicians are able to diagnose dementia readily, Alzheimer’s on its own is not readily diagnosed. There currently exists no single test, but rather a combination of a number of physical, neurological, and imaging test results.

Plasma or saliva would be preferred candidates for an Alzheimer’s biomarker as opposed to CSF. Collection methods are less invasive. With diagnosis typically taking place well after Alzheimer’s has set in, there is little if any, opportunity for disease-modifying treatment. An Alzheimer’s biomarker, particularly one that is easily accessible and inexpensive, could be the difference between physicians intervening in the early stages of onset when there is mild cognitive impairment and progression to late stage dementia.

References

1. Mishur, R.J. and Rea, S.L. (2012) ‘Applications of mass spectrometry to metabolomics and metabonomics: Detection of biomarkers of ageing and of age-related diseases‘, Mass Spectrometry Reviews, 31 (1), (pp. 70-95)

2. Brookmeyer, R., et al. (2007) ‘Forecasting the global burden of Alzheimer’s disease‘, Alzheimer’s and Dementia, 3 (3), (pp. 186-191)

3. Myint, K.T., et al. (2009) ‘Quantitative profiling of polar cationic metabolites in human cerebrospinal fluid by reversed-phase nanoliquid chromatography/mass spectrometry‘, Analytical Chemistry, 81 (3), (pp. 1121-1129)

4. Greenberg, N., et al. (2009) ‘A proposed metabolic strategy for monitoring disease progression in Alzheimer’s disease‘, Electrophoresis, 30 (7), (pp. 1235-1239)

5. Sato, Y., et al. (2012) ‘Identification of a new plasma biomarker of Alzheimer’s Disease using metabolomics technology‘, Journal of Lipid Research, 53 (3), (pp. 567-576)

6. Shi, M., et al. (2011) ‘Salivary Tau Species are Potential Biomarkers of Alzheimer’s Disease‘, Journal of Alzheimer’s Disease, 27 (2), (pp. 299-305)