Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals

Abstract

Dementia is a major cause of disability in later life with no currently available curative treatment [ 1 x [1] Dementia: a Public Health Priority. WHO Press, World Health Organization and Alzheimer's Disease International, Geneva; 2012: 1–102 Google Scholar See all References , 2 x [2] Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 385: 117–171 Abstract | Full Text | Full Text PDF | PubMed | Scopus (2482) | Google Scholar See all References ]. The global prevalence is increasing, especially in low- and middle-income countries [ 1 x [1] Dementia: a Public Health Priority. WHO Press, World Health Organization and Alzheimer's Disease International, Geneva; 2012: 1–102 Google Scholar See all References , 3 x [3] Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W., and Ferri, C.P. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013; 9: 63–75 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1367) | Google Scholar See all References , 4 x [4] Querfurth, H.W. and LaFerla, F.M. Alzheimer's disease. N Engl J Med. 2010; 362: 329–344 Crossref | PubMed | Scopus (2296) | Google Scholar See all References ]. For high income countries declining incidences and prevalences have recently been observed and may be attributed to improved cardiovascular risk factor control [ 5 x [5] Langa, K.M., Larson, E.B., Crimmins, E.M., Faul, J.D., Levine, D.A., Kabeto, M.U. et al. A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Intern Med. 2017; 177: 51–58 Crossref | PubMed | Scopus (110) | Google Scholar See all References , 6 x [6] Satizabal, C.L., Beiser, A.S., Chouraki, V., Chene, G., Dufouil, C., and Seshadri, S. Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med. 2016; 374: 523–532 Crossref | PubMed | Scopus (219) | Google Scholar See all References ]. Apolipoprotein E (apoE) is pivotal for peripheral and cerebral cholesterol metabolism as well as for cerebral clearance of β-amyloid—a toxic peptide that aggregates into amyloid plaques in Alzheimer's disease (AD) [ 7 x [7] Verghese, P.B., Castellano, J.M., and Holtzman, D.M. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 2011; 10: 241–252 Abstract | Full Text | Full Text PDF | PubMed | Scopus (354) | Google Scholar See all References , 8 x [8] Cramer, P.E., Cirrito, J.R., Wesson, D.W., Lee, C.Y., Karlo, J.C., Zinn, A.E. et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science. 2012; 335: 1503–1506 Crossref | PubMed | Scopus (590) | Google Scholar See all References ]. The APOE ε4 allele is a well-established genetic risk factor for dementia, and recently observational prospective studies established that low plasma levels of apoE are associated with increased risk of dementia [ 9 x [9] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993; 261: 921–923 Crossref | PubMed | Scopus (5779) | Google Scholar See all References , 10 x [10] Rasmussen, K.L., Tybjaerg-Hansen, A., Nordestgaard, B.G., and Frikke-Schmidt, R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015; 77: 301–311 Crossref | PubMed | Scopus (44) | Google Scholar See all References , 11 x [11] Wolters, F.J., Koudstaal, P.J., Hofman, A., Duijn, C.M., and Ikram, M.A. Serum apolipoprotein E is associated with long-term risk of Alzheimer's disease: the Rotterdam Study. Neurosci Lett. 2016; 617: 139–142 Crossref | PubMed | Scopus (9) | Google Scholar See all References ]. Whether this observational association reflects a causal effect remains to be clarified.