By Michael T. Lin, MD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Lin reports no financial relationships relevant to this field of study.

SYNOPSIS: At the present time, no blood-based biomarkers have been identified as reliable indicators of A-beta amyloid deposition in the brain.

SOURCE: Khan AT, Dobson RJB, Sattlecker M, et al. Alzheimer's disease: Are blood and brain markers related? A systematic review. Ann Clin Transl Neurol 2016;3:455-462.

Lack of an easy biological test for Alzheimer’s disease
(AD) is a barrier to early diagnosis, entry into trials, and initiation of treatment. Currently available biological tests (amyloid PET or CSF A-beta and tau measurement) are expensive and/or invasive, so there is considerable interest in developing a blood test. Unfortunately, as reviewed recently by Khan and colleagues, there is still a long way to go.

The authors began by searching PubMed for studies of protein markers in AD brains, looking for discovery-based (as opposed to candidate-based) proteomic studies not focused on post-translational modifications. They found only 11 such studies, and of the 371 proteins identified across these studies, only three proteins (heat shock cognate 71 kDa protein, ubiquitin C-terminal hydrolase L1, and 2',3'-cyclic nucleotide 3'-phosphodiesterase) were found in multiple studies, with a consistent direction of change in all studies that identified them.

Next, the authors compared 176 blood proteins that they had found in a previous review1 to the 371 brain proteins identified, and found 18 overlaps between blood and brain. However, only one overlap, complement C4a, occurred multiple times in both blood and brain studies.


As noted within the article, these results are extremely preliminary, at best. There is no clear relationship between any of the proteins mentioned above (HSC71, UCHL1, CNP, C4a) and A-beta and tau; moreover, none of the brain studies reviewed identified A-beta or tau. It is encouraging that this review found some overlap (C4a) between blood and brain studies. The specific finding of a complement protein agrees with recent studies showing an AD blood profile dominated by complement proteins.2 Moreover, a recent laboratory study suggests that complement plays a role in loss of synapses in AD.3 However, it is very unlikely that any complement protein will be a marker specific for AD. Finally, because of the blood-brain barrier, it is not clear that there will necessarily be any relationship between brain pathology and blood markers. Perhaps any overlap between brain and blood is simply by chance. A recent paper suggests breakdown of the blood-brain barrier in aging human hippocampus,4 so it might be possible to find a blood signature for AD brain pathology, but such a signature remains to be found and validated.


  1. Westwood S, Leoni E, Hye A, et al. Blood-based biomarker candidates of cerebral amyloid using PiB PET in non-demented elderly. J Alzheimers Dis 2016;52:561-572.
  2. Chiam JT, Dobson RJ, Kiddle SJ, et al. Are blood-based protein biomarkers for Alzheimer's disease also involved in other brain disorders? A systematic review. J Alzheimers Dis 2015;43:303-314.
  3. Hong S, Beja-Glasser VF, Nfonoyim BM, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016;352:712-716.
  4. Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 2015;85:296-302.