Skip to main content

Advertisement

SpringerLink
Log in

Selected LDLR and APOE Polymorphisms Affect Cognitive and Functional Response to Lipophilic Statins in Alzheimer’s Disease

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Effects of statins over clinical changes in Alzheimer’s disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576–A (14.5% heterozygotes), 0.346 for rs5930–A (42.5% heterozygotes), and 0.444 for rs5925–C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576–G had faster cognitive decline, while functional decline was slower for carriers of rs11669576–A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930–AA had improved caregiver burden, while carriers of haplotypes that included rs5930–AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925–TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Barbosa FAF, de Labio RW, Rigolin VOS, Minett T, Bertolucci PHF, Smith MAC, Payão SLM (2006) Apolipoprotein A-V gene polymorphism –1131T>C and Alzheimer’s disease. J Alzheimers Dis 10:365–369

    Article  CAS  PubMed  Google Scholar 

  • Bertolucci PHF, Brucki SMD, Campacci SR, Juliano Y (1994) The mini-mental state examination in an outpatient population: influence of literacy. Arq Neuropsiquiatr 52:1–7

    Article  CAS  PubMed  Google Scholar 

  • Cacabelos R, Torrellas C, Tejido O, Carril JC (2016) Pharmacogenetic considerations in the treatment of Alzheimer’s disease. Pharmacogenomics 17:1041–1074

    Article  CAS  PubMed  Google Scholar 

  • Chapman J, Wang N, Treves TA, Korczyn AD, Bornstein NM (1998) ACE, MTHFR, factor V Leiden, and APOE polymorphisms in patients with vascular and Alzheimer’s dementia. Stroke 29:1401–1404

    Article  CAS  PubMed  Google Scholar 

  • Chen DW, Yang JF, Tang Z, Dong XM, Feng XL, Yu S, Chan P (2008) Cholesteryl ester transfer protein polymorphism D442G associated with a potential decreased risk for Alzheimer's disease as a modifier for APOE ε4 in Chinese. Brain Res 1187:52–57

    Article  CAS  PubMed  Google Scholar 

  • Chen ES, Mazzotti DR, Furuya TK, Cendoroglo MS, Ramos LR, Araujo LQ, Burbano RR, Smith MAC (2010) Association of PPARα gene polymorphisms and lipid serum levels in a Brazilian elderly population. Exp Mol Pathol 88:197–201

    Article  CAS  PubMed  Google Scholar 

  • Crameri A, Biondi E, Kuehnle K, Lütjohann D, Thelen KM, Perga S, Dotti CG, Nitsch RM, Ledesma MD, Mohajeri MH (2006) The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Aβ generation in vivo. EMBO J 25:432–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Luca V, Orfei MD, Gaudenzi S, Caltagirone C, Spalletta G (2016) Inverse effect of the APOE epsilon4 allele in late- and early-onset Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 266:599–606

    Article  PubMed  Google Scholar 

  • De Oliveira FF, Bertolucci PHF, Chen ES, Smith MAC (2014a) Pharmacological modulation of cognitive and behavioral symptoms in patients with dementia due to Alzheimer’s disease. J Neurol Sci 336:103–108

    Article  PubMed  CAS  Google Scholar 

  • De Oliveira FF, Bertolucci PHF, Chen ES, Smith MC (2014b) Risk factors for age at onset of dementia due to Alzheimer’s disease in a sample of patients with low mean schooling from São Paulo, Brazil. Int J Geriatr Psychiatry 29:1033–1039

    Article  PubMed  Google Scholar 

  • De Oliveira FF, Wajman JR, Bertolucci PHF, Chen ES, Smith MC (2015a) Correlations among cognitive and behavioural assessments in patients with dementia due to Alzheimer’s disease. Clin Neurol Neurosurg 135:27–33

    Article  PubMed  Google Scholar 

  • De Oliveira FF, Pivi GAK, Chen ES, Smith MC, Bertolucci PHF (2015b) Risk factors for cognitive and functional change in one year in patients with Alzheimer's disease dementia from São Paulo, Brazil. J Neurol Sci 359:127–132

    Article  PubMed  Google Scholar 

  • De Oliveira FF, Chen ES, Smith MC, Bertolucci PHF (2017) Longitudinal lipid profile variations and clinical change in Alzheimer’s disease dementia. Neurosci Lett 646:36–42

    Article  PubMed  CAS  Google Scholar 

  • De Oliveira FF, Berretta JM, Almeida Junior GV, Almeida SS, Chen ES, Smith MC, Bertolucci PHF (2019) Pharmacogenetic analyses of variations of measures of cardiovascular risk in Alzheimer’s dementia. Indian J Med Res 150:261–271

    Article  PubMed  PubMed Central  Google Scholar 

  • Eckert GP, Wood WG, Müller WE (2005) Statins: drugs for Alzheimer’s disease? J Neural Transm 112:1057–1071

    Article  CAS  PubMed  Google Scholar 

  • Gopalraj RK, Zhu H, Kelly JF, Mendiondo M, Pulliam JF, Bennett DA, Estus S (2005) Genetic association of low density lipoprotein receptor and Alzheimer’s disease. Neurobiol Aging 26:1–7

    Article  CAS  PubMed  Google Scholar 

  • Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR Jr, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ (2004) Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 61:59–66

    Article  PubMed  Google Scholar 

  • Grundy SM, Cleeman JI, Merz CNB, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 110:227–239

    Article  PubMed  Google Scholar 

  • Jiang Q, Lee CYD, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE (2008) ApoE promotes the proteolytic degradation of Aβ. Neuron 58:681–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katz S, Akpom CA (1976) A measure of primary socio-biological functions. Int J Health Serv 6:493–508

    Article  CAS  PubMed  Google Scholar 

  • Larsson SC, Markus HS (2018) Does treating vascular risk factors prevent dementia and Alzheimer’s disease? A systematic review and meta-analysis. J Alzheimers Dis 64:657–668

    Article  PubMed  Google Scholar 

  • Lawton MP (1988) Instrumental Activities of Daily Living (IADL) Scale: self-reported version. Psychopharmacol Bull 24:789–791

    Google Scholar 

  • Leduc V, Théroux L, Dea D, Dufour R, Poirier J (2016) Effects of rs3846662 variants on HMGCR mRNA and protein levels and on markers of Alzheimer’s disease pathology. J Mol Neurosci 58:109–119

    Article  CAS  PubMed  Google Scholar 

  • Lee CYD, Landreth GE (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm 117:949–960

    Article  CAS  PubMed  Google Scholar 

  • Leon M, Sawmiller D, Giunta B, Tan J (2018) Therapeutic approach targeting apolipoprotein E binding region and low-density lipoprotein receptor for Alzheimer’s disease. Neuroimmunol Neuroinflammation 5:30

    Article  CAS  Google Scholar 

  • Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, Martins RN, Masters CL, Rowe C, Savage G, Szoeke C, Villemagne VL, Maruff P (2012) Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. Neurology 79:1645–1652

    Article  CAS  PubMed  Google Scholar 

  • Lima APV, Castilhos R, Chaves MLF (2017) The use of the clinical dementia rating scale sum of boxes scores in detecting and staging cognitive impairment/dementia in Brazilian patients with low educational attainment. Alzheimer Dis Assoc Disord 31:322–327

    Article  PubMed  Google Scholar 

  • Loera-Valencia R, Goikolea J, Parrado-Fernandez C, Merino-Serrais P, Maioli S (2019) Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: potential novel targets for treatment. J Steroid Biochem Mol Biol 190:104–114

    Article  CAS  PubMed  Google Scholar 

  • Maxwell WD, Ramsey LB, Johnson SG, Moore KG, Shtutman M, Schoonover JH, Kawaguchi-Suzuki M (2017) Impact of pharmacogenetics on efficacy and safety of statin therapy for dyslipidemia. Pharmacotherapy 37:1172–1190

    Article  PubMed  Google Scholar 

  • McGuiness B, Craig D, Bullock R, Malouf R, Passmore P (2014) Statins for the treatment of dementia (review). Cochrane Database Syst Rev 7:CD007514

    Google Scholar 

  • Morgen K, Frölich L, Tost H, Plichta MM, Kölsch H, Rakebrandt F, Rienhoff O, Jessen F, Peters O, Jahn H, Luckhaus C, Hüll M, Gertz HJ, Schröder J, Hampel H, Teipel SJ, Pantel J, Heuser I, Wiltfang J, Rüther E, Kornhuber J, Maier W, Meyer-Lindenberg A (2013) APOE-dependent phenotypes in subjects with mild cognitive impairment converting to Alzheimer’s disease. J Alzheimers Dis 37:389–401

    Article  CAS  PubMed  Google Scholar 

  • Oliveira FF, Chen ES, Smith MC, Bertolucci PH (2017) Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia. Rev Bras Psiquiatr 39:95–103

    Article  PubMed  PubMed Central  Google Scholar 

  • Ozudogru SN, Lippa CF (2012) Disease modifying drugs targeting β-amyloid. Am J Alzheimers Dis Other Dement 27:296–300

    Article  CAS  Google Scholar 

  • Park SK, Choi JY (2009) Risk assessment and pharmacogenetics in molecular and genomic epidemiology. J Prev Med Public Health 42:371–376

    Article  PubMed  Google Scholar 

  • Petek B, Villa-Lopez M, Loera-Valencia R, Gerenu G, Winblad B, Kramberger MG, Ismail MAM, Eriksdotter M, Garcia-Ptacek S (2018) Connecting the brain cholesterol and renin-angiotensin systems: potential role of statins and RAS-modifying medications in dementia. J Intern Med 284:620–642

    Article  CAS  PubMed  Google Scholar 

  • Poirier J (1999) Apolipoprotein E4, cholinergic integrity and the pharmacogenetics of Alzheimer’s disease. J Psychiatry Neurosci 24:147–153

    CAS  PubMed  PubMed Central  Google Scholar 

  • Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344

    Article  CAS  PubMed  Google Scholar 

  • Roses AD (2010) An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease. Arch Neurol 67:536–541

    Article  PubMed  PubMed Central  Google Scholar 

  • Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS (2011) A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 77:556–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith MAC (1999) Doença de Alzheimer. Rev Bras Psiquiatr 21:S03–S07

    Article  Google Scholar 

  • Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C (2005) Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 62:753–757

    Article  PubMed  Google Scholar 

  • Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman ER, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292

    Article  PubMed  PubMed Central  Google Scholar 

  • Taub A, Andreoli SB, Bertolucci PHF (2004) Dementia caregiver burden: reliability of the Brazilian version of the Zarit caregiver burden interview. Cad Saude Publica 20:372–376

    Article  PubMed  Google Scholar 

  • Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, Brooks AI, Kanagala S, Rubio A, Sagare A, Liu D, Li F, Armstrong D, Gasiewicz T, Zidovetzki R, Song X, Hofman F, Zlokovic BV (2005) Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med 11:959–965

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto N, Fujii Y, Kasahara R, Tanida M, Ohora K, Ono Y, Suzuki K, Sobue K (2016) Simvastatin and atorvastatin facilitates amyloid β-protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways. Glia 64:952–962

    PubMed  Google Scholar 

  • Yan HC, Wang W, Dou CW, Tian FM, Qi ST (2014) Relationships of LDLR genetic polymorphisms with cerebral infarction: a meta-analysis. Mol Biol Rep 41:4425–4434

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was sponsored by CAPES–Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (grant #1067/10) and FAPESP–The State of São Paulo Research Foundation (grant #2015/10109-5 and grant #2015/18125-0).

Author information

Authors and Affiliations

  1. Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), Sao Paulo, SP, Brazil

    Fabricio Ferreira de Oliveira & Paulo Henrique Ferreira Bertolucci

  2. Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), Sao Paulo, SP, Brazil

    Elizabeth Suchi Chen & Marilia Cardoso Smith

Authors
  1. Fabricio Ferreira de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth Suchi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marilia Cardoso Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paulo Henrique Ferreira Bertolucci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabricio Ferreira de Oliveira.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

All procedures were in accordance with the ethical standards of the Ethics Committee of Hospital São Paulo, Federal University of São Paulo–UNIFESP, according to the research project 1067/10 (CAAE 0540.0.174.000-10), and followed The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. All invited patients and their legal representatives agreed to participate on the research and signed the Informed Consent Form before the evaluation.

Additional information

Prior Presentation of Information from the Paper

Preliminary aspects of this study were previously presented (and published in the form of abstracts) at the following meetings:

1. AAIC>14 – Alzheimer’s Association International Conference 2014

(with an Alzheimer’s Association Travel Fellowship to the first author)

(Alzheimer’s Association, Copenhagen/DENMARK, July 2014):

https://doi.org/10.1016/j.jalz.2014.05.698

2. 29th CINP World Congress of Neuropsychopharmacology

(Collegium Internationale Neuro-Psychopharmacologicum, Vancouver/CANADA, June 2014)

https://doi.org/10.1017/S1461145714000741

3. 66th Annual Meeting of the American Academy of Neurology

(American Academy of Neurology, Philadelphia/USA, April 2014):

http://www.neurology.org/content/82/10_Supplement/P5.223.abstract?sid=adf1feeb-3dc6-43f6-9e1beea01faca6d1

4. AD/PD 2013 – The 11th International Conference on Alzheimer’s & Parkinson’s Diseases

(Kenes International, Florence/ITALY, March 2013)

Alzheimer’s and Parkinson’s Diseases: Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative Diseases. Basel: Karger, 2013, v.11, p. 700.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Oliveira, F.F., Chen, E.S., Smith, M.C. et al. Selected LDLR and APOE Polymorphisms Affect Cognitive and Functional Response to Lipophilic Statins in Alzheimer’s Disease. J Mol Neurosci 70, 1574–1588 (2020). https://doi.org/10.1007/s12031-020-01588-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-020-01588-7

Keywords

Search

Navigation