Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis

Petroula Proitsi, Michelle K Lupton, Latha Velayudhan, Stephen Newhouse, Isabella Fogh, Magda Tsolaki, Makrina Daniilidou, Megan Pritchard, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Vellas, Julie Williams, Denise Harold, Rebecca Sims, Amy Gerrish, Jade Chapman, Valentina Escott-Price, Richard Abraham, Paul HollingworthMarian Hamshere, Jaspreet Singh Pahwa, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R Morgan, Kate Williams, Simon Lovestone, John F Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S Brown, Peter Passmore, David Craig, Bernadette Mcguinness, Janet A. Johnston, Stephen Todd, Clive Holmes, David Mann, A David Smith, Seth Love, Patrick G Kehoe, John Hardy, Rita Guerreiro, Andrew B Singleton, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Reiner Heun, Britta Schürmann, Alfredo Ramirez, Tim Becker, Christine Herold, André Lacour, Dmitriy Drichel, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Markus M Nöthen, Peter A Holmans, Michael C O'Donovan, Michael J Owen, Julie Williams, Robert C Stewart, Pak Sham

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Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.

We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10−8and trait specific scores using SNPs associated exclusively with each trait at p<5×10−8were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.

Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.

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Original languageEnglish
JournalPLoS Medicine
Issue number9
Publication statusPublished - 16 Sep 2014

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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