title: Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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<5×10-8 and trait specific scores using SNPs associated exclusively with each trait at p<5 × 10-8 were 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.
  
  
  CONCLUSIONS
  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. Please see later in the article for the Editors' Summary.
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom; Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.affiliation: Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.affiliation: Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, United Kingdom.
authors.forename: Latha
authors.initials: L
authors.lastname: Velayudhan
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Newhouse
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: Isabella
authors.initials: I
authors.lastname: Fogh
authors.affiliation: Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, United Kingdom.
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, United Kingdom.
authors.forename: Makrina
authors.initials: M
authors.lastname: Daniilidou
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: Megan
authors.initials: M
authors.lastname: Pritchard
authors.affiliation: Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Kloszewska
authors.affiliation: Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.affiliation: Department of Internal and Geriatrics Medicine, INSERM U 1027, Gerontopole, Hôpitaux de Toulouse, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Stewart
authors.affiliation: Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Pak
authors.initials: P
authors.lastname: Sham
authors.affiliation: University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D002784:Cholesterol / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood / Q000235:genetics*
chemical_list: D014280:Triglycerides; D002784:Cholesterol