A long-term study with 20-year follow-up has found that the presence of 15 plasma proteins was associated with cognitive decline and dementia.
An international team of researchers analyzed 4,953 plasma proteins in two patient cohorts, the British Whitehall II and US Atherosclerosis Risk in Communities (ARIC) study, which together included 13,657 participants. Their goal was to determine the role of proteins in the early stages of neurodegeneration when dementia may still be preventable.
“Our study design thus explicitly takes into consideration the long preclinical phase of dementia,” they write in their paper published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Amyloid beta and tau proteins have dominated pathophysiological research on dementia etiology, but to date prevention and treatment trials targeting these biomarkers have been unsuccessful. This has motivated researches to search also other potential mechanisms that could predispose to dementia.
“Recent development of scalable platforms has made it possible to analyze a wide range of circulating proteins, which may reveal novel biological processes linked to dementias,” the authors write. In this study, plasma levels were first measured beginning in late middle age using the SOMAscan assay. The assay uses a mix of thousands of slow off-rate modified aptamers (SOMAmers). The aptamers bind to proteins in participants’ plasma samples and the specificity is validated with a two-step process analogous to a conventional immunoassay.
The researchers then tested cognitive performance five times over 20 years noting subsequent cognitive decline and dementia.
At completion of the study, 15 non-amyloid/non-tau–related proteins were associated with cognitive decline and dementia. They were found consistently in both the British and US patient cohorts and not explained by known dementia risk factors. Of the 15 identified and replicated proteins, 14 (N-terminal pro-BNP, CDCP1, MIC-1, CRDL1, RNAS6, SAP3, HE4, TIMP-4, IGFBP-7, OPG, SVEP1, TREM2, NPS-PLA2, MARCKSL1) were secreted and one (SIGLEC-7) was a cell membrane protein. They were mostly expressed in tissues other than the brain.
“This study did not systematically examine processes underlying the associations between proteins and dementia,” the authors write. “However, the observed associations are biologically plausible as there are several mechanisms that could link the 15 proteins to dementia pathologies, including immune dysfunction, blood-brain-barrier dysfunction, vascular damage, and central insulin resistance. More specifically, hyper-activation of the innate and adaptive immune system can cause endothelium damage, neuroinflammation, and amyloid and tau accumulation in the brain.”
Notably, levels of six of the proteins—NPS-PLA2, CDCP1, MIC-1, IGFBP-7, N-terminal pro-BNP, and OPG—are modifiable by currently approved medications for other conditions.
“This new study is the first step in our 5-year Wellcome Trust funded research programme,” says co-author Mika Kivimäki, Director of the Whitehall II study at University College London. “We will next examine whether the identified proteins have a causal association with dementia, and whether they are likely to be modifiable, and druggable.” The ultimate aim of the research program is to identify novel drug targets for dementia prevention.