Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study

Article type: Research Article

Authors: McGrath, Emer R.^{a; b; *} | Himali, Jayandra J.^{b; c; d; e} | Levy, Daniel^{b; f} | Yang, Qiong^{b; c} | DeCarli, Charles S.^g | Courchesne, Paul^b | Satizabal, Claudia L.^{b; e} | Finney, Rebecca^{b; d} | Vasan, Ramachandran S.^{b; d} | Beiser, Alexa S.^{b; c; d} | Seshadri, Sudha^{b; d; e}

Affiliations: [a] HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland | [b] The Framingham Heart Study, Framingham, MA, USA | [c] Boston University School of Public Health, Boston, MA, USA | [d] Boston University School of Medicine, Boston, MA, USA | [e] Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA | [f] Population Sciences Branch of the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, USA | [g] Department of Neurology, University of California, Davis, CA, USA

Correspondence: [*] Correspondence to: Emer McGrath, HRB Clinical Research Facility, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland. Tel.: +353 91 524411; E-mail: emer.mcgrath@nuigalway.ie.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. Objective:To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer’s disease (AD) dementia. Methods:We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998–2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance. Results:During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18–2.64) and AD dementia (HR 1.76, 95% CI 1.11–2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, –0.28±0.11, p = 0.01) and hippocampal volumes (–0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, –0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1). Conclusion:Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

Keywords: Alzheimer disease, biomarkers, dementia, vascular brain injury

DOI: 10.3233/JAD-215053

Journal: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1657-1666, 2022