Novel CSF biomarkers being investigated in AD


Preliminary studies suggest that visinin-like protein 1 (VILIP-1) may be useful as a biomarker of neuronal injury in patients with Alzheimer’s disease. VILIP-1 is one of a class of neuronal calcium sensor proteins regulating calcium ion homeostasis. It has been shown to affect intracellular neuronal signalling involved in synaptic plasticity, and may be associated with calcium-mediated neuronal injury. Thus, VILIP-1 provides a link between calcium-mediated neurotoxicity and pathological changes in AD (Groblewska et al. J Alzheimers Dis 2015;47:17-32).

The usefulness of VILIP-1 in cerebrospinal fluid as a biomarker of brain atrophy was investigated in a longitudinal observational study of early AD and healthy controls (Tarawneh et al. JAMA Neurol 2015;72:656-665; free full text at Results were compared to those for tau, p-tau181 and beta-amyloid42 in CSF. CSF and MRI were obtained over a 2-3 year follow-up. Mean age was 72.6 years.

VILIP-1, tau and p-tau181 at baseline were comparably predictive of subsequent whole-brain and regional atrophy. Beta-amyloid42 was not useful as an atrophy biomarker. VILIP-1 was predictive of whole-brain, hippocampal and entorhinal atrophy rates in early AD patients.  In addition, healthy controls without cognitive dysfunction but with VILIP-1 levels in the upper tercile demonstrated higher rates of whole-brain, hippocampal and entorhinal atrophy compared to controls in the lower terciles. This may indicate that VILIP-1 could be useful in identifying individuals with preclinical AD at risk of cognitive decline.

Indeed, this issue was examined in a six-year longitudinal analysis of CSF samples obtained from cognitively normal middle-aged subjects (ages 45-74 years) in the Adult Children Study (Sutphen et al. JAMA Neurol 2015;72:1029-1042). Amyloid PET imaging with Pittsburgh compound was also obtained.

Beta-amyloid42 showed an inconsistent pattern over time, although some subjects showed reductions in beta-amyloid42; low levels were associated with the development of cortical amyloid plaques.

VILIP-1 and other markers of neuronal injury (total tau, p-tau181) showed marked increases in some individuals in mid-to-late middle-age, whereas the neuroinflammatory marker YKL-40 gradually increased over time. These patterns were more apparent in APOE4 carriers and appeared to be associated with future cognitive dysfunction.

The study concluded that VILIP-1 and other CSF biomarkers may be able to identify preclinical AD in early middle age before there is evidence of cognitive decline.

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