Molecular Neurobiology

, Volume 55, Issue 5, pp 4333–4344 | Cite as

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer’s Disease

  • Davide Seripa
  • Francesco Panza
  • Giulia Paroni
  • Grazia D’Onofrio
  • Paola Bisceglia
  • Carolina Gravina
  • Maria Urbano
  • Madia Lozupone
  • Vincenzo Solfrizzi
  • Alessandra Bizzarro
  • Virginia Boccardi
  • Chiara Piccininni
  • Antonio Daniele
  • Giancarlo Logroscino
  • Patrizia Mecocci
  • Carlo Masullo
  • Antonio Greco


Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50–65 years (group 1), 66–80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer’s disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.


Biogerontology Brain aging Cognition Dementia Genetics Alzheimer’s disease 



This study was completely supported by “Ministero della Salute,” I.R.C.C.S. Research Program, Ricerca Corrente 2015-2017, Linea n. 2 “Malattie complesse e terapie innovative” and by the “5 × 1000” voluntary contribution. We wish to thank Dr. Michele Lauriola for help us for the management of electronic databases.

Authorʼs Contributions

Davide Seripa, Francesco Panza, and Antonio Greco conceived and designed the study, interpreted the data, wrote the manuscript, and are the guarantors for the study. Giulia Paroni, Grazia D’Onofrio, Madia Lozupone, and Antonio Daniele assisted in literature search, interpretation of data and manuscript preparation. Davide Seripa and Vincenzo Solfrizzi assisted in study design and in the data interpretation, performed the statistical analysis, and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Paola Bisceglia, Carolina Gravina, Maria Urbano, Alessandra Bizzarro, Virginia Boccardi, and Chiara Piccininni performed genetic analyses in the three study sites and assisted in interpretation of data and manuscript preparation. Giancarlo Logroscino, Patrizia Mecocci, and Carlo Masullo participated to the interpretation of the data and performed the internal review process.

Compliance with Ethical Standards

This was a multicenter case-control association study fulfilling the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The approval of the study for experiments using human subjects was obtained from the local Ethics Committees on human experimentation. Written informed consent for research was obtained from each patient or from relatives/legal caregiver in case of critically disabled demented patients. Statements related to ethics/ethical standards must be presented in the back matter. Thus, the relevant text was copied and captured under "Compliance with....”This query is not clear. Statements related to ethics/ethical standards are presented in the back matter, i.e. after the acknowledgements.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_547_MOESM1_ESM.doc (48 kb)
Supplementary Table 1 (DOC 48 kb)
12035_2017_547_MOESM2_ESM.doc (49 kb)
Supplementary Table 2 (DOC 49 kb)
12035_2017_547_Fig1_ESM.jpg (31 kb)
Supplementary Figure 1

Apolipoprotein E (APOE) estimated allele frequency distribution in older subjects without cognitive impairment (NoCI) according to different age groups (JPEG 30 kb)

12035_2017_547_Fig2_ESM.jpg (30 kb)
Supplementary Figure 2

Apolipoprotein E (APOE) estimated allele frequency distribution in patients with Alzheimer’s disease (AD) according to different age groups (JPEG 30 kb)

12035_2017_547_Fig3_ESM.jpg (33 kb)
Supplementary Figure 3

Comparison of the apolipoprotein E (APOE) allele frequencies observed in older subjects without cognitive impairment (NoCI) and patients with Alzheimer’s disease (AD) according to different age groups (JPEG 33 kb)


  1. 1.
    Schächter F, Faure-Delanef L, Guénot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D (1994) Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6(1):29–32PubMedCrossRefGoogle Scholar
  2. 2.
    Panza F, Solfrizzi V, D’Introno A, Colacicco AM, Capurso C, Kehoe PG, Capurso A (2003) Angiotensin I converting enzyme (ACE) gene polymorphism in centenarians: Different allele frequencies between the north and south of Europe. Exp Gerontol 38(9):1015–1020PubMedCrossRefGoogle Scholar
  3. 3.
    Seripa D, Franceschi M, Matera MG, Panza F, Kehoe PG, Gravina C, Orsitto G, Solfrizzi V et al (2006) Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: A population-based study from southern Italy. J Gerontol A Biol Sci Med Sci 61(9):918–923PubMedCrossRefGoogle Scholar
  4. 4.
    Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV et al, CHARGE Consortium, GERAD1 Consortium, EADI1 Consortium (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303(19):1832–1840PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43(5):436–441PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099PubMedCrossRefGoogle Scholar
  7. 7.
    Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N et al (2010) Meta-analysis confirms CR1, CLU, and PICALMas alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67(12):1473–1484PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S et al (2011) Alzheimer’s disease neuroimaging initiative. Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer’s disease. PLoS One 6(2):e16616PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS et al (2010) Replication of CLU, CR1, and PICALM associations with Alzheimer disease. Arch Neurol 67(8):961–964PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lambert JC, Zelenika D, Hiltunen M, Chouraki V, Combarros O, Bullido MJ, Tognoni G, Fievet N et al (2011) Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations. Neurobiol Aging 32(4):8CrossRefGoogle Scholar
  12. 12.
    Grupe A, Abraham R, Li Y, Hollingworth P, Morgan A, Jehu L, Segurado R, Stone D et al (2007) Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet 16(8):865–873PubMedCrossRefGoogle Scholar
  13. 13.
    Yu JT, Tan L (2012) The role of clusterin in Alzheimer’s disease: Pathways, pathogenesis, and therapy. Mol Neurobiol 45(2):314–326PubMedCrossRefGoogle Scholar
  14. 14.
    Thambisetty M, Simmons A, Velayudhan L, Hye A, Campbell J, Zhang Y, Wahlund LO, Westman E et al (2010) Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry 67(7):739–748PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Thambisetty M, An Y, Kinsey A, Koka D, Saleem M, Güntert A, Kraut M, Ferrucci L et al (2012) Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment. NeuroImage 59(1):212–217PubMedCrossRefGoogle Scholar
  16. 16.
    Lancaster TM, Brindley LM, Tansey KE, Sims RC, Mantripragada K, Owen MJ, Williams J, Linden DE (2015) Alzheimer’s disease risk variant in CLU is associated with neural inefficiency in healthy individuals. Alzheimers Dement 11(10):1144–1152PubMedCrossRefGoogle Scholar
  17. 17.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database. Nat Genet 39(1):17–23PubMedCrossRefGoogle Scholar
  18. 18.
    Wilson MR, Zoubeidi A (2017) Clusterin as a therapeutic target. Expert Opin Ther Targets 21(2):201–213PubMedCrossRefGoogle Scholar
  19. 19.
    Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C et al (2013) ApoE influences amyloid- β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A 110(19):E1807–E1E16PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Alvira-Botero X, Carro EM (2010) Clearance of amyloid-β peptide across the choroid plexus in alzheimer’s disease. Curr Aging Sci 3(3):219–229PubMedCrossRefGoogle Scholar
  21. 21.
    Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330(6012):1774PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12(7):856–861PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Dreyling MH, Martinez-Climent JA, Zheng M, Mao J, Rowley JD, Bohlander SK (1996) The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family. Proc Natl Acad Sci U S A 93(10):4804–4809PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tebar F, Bohlander SK, Sorkin A (1999) Clathrin assembly lymphoid myeloid leukemia (CALM) protein: Localization in endocyticcoated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol Biol Cell 10(8):2687–2702PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Zhang B, Koh YH, Beckstead RB, Budnik V, Ganetzky B, Bellen HJ (1998) Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron 21(6):1465–1475PubMedCrossRefGoogle Scholar
  26. 26.
    Wendland B, Emr SD (1998) Pan1p, yeast eps15, functions as a multivalent adaptor that coordinates protein-protein interactions essential for endocytosis. J Cell Biol 141(1):71–84PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, Bento CF, Puri C et al (2014) PICALM modulates autophagy activity and tau accumulation. Nat Commun 5:4998PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ando K, Brion JP, Stygelbout V, Suain V, Authelet M, Dedecker R, Chanut A, Lacor P et al (2013) Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains. Acta Neuropathol 125(6):861–878PubMedCrossRefGoogle Scholar
  29. 29.
    Harel A, Mattson MP, Yao PJ (2011) CALM, a clathrin assembly protein, influences cell surface GluR2 abundance. NeuroMolecular Med 13(1):88–90PubMedCrossRefGoogle Scholar
  30. 30.
    Xu W, Tan L, Yu JT (2014) The role of PICALM in Alzheimer’s disease. Mol Neurobiol 52(1):399–413PubMedCrossRefGoogle Scholar
  31. 31.
    Schjeide BM, Schnack C, Lambert JC, Lill CM, Kirchheiner J, Tumani H, Otto M, Tanzi RE et al (2011) The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. Arch Gen Psychiatry 68(2):207–213PubMedCrossRefGoogle Scholar
  32. 32.
    Hoehn GT, Stokland T, Amin S, Ramírez M, Hawkins AL, Griffin CA, Small D, Civin CI (1996) Tnk1: A novel intracellular tyrosine kinase gene isolated from human umbilical cord blood CD34+/Lin−/CD38- stem/progenitor cells. Oncogene 12(4):903–913PubMedGoogle Scholar
  33. 33.
    Azoitei N, Brey A, Busch T, Fulda S, Adler G, Seufferlein T (2007) Thirty-eight-negative kinasi 1 (TNK 1) facilitates TNF a-induced apoptosis by blocking NF-kb activation. Oncogene 4 26(45):6536–6545CrossRefGoogle Scholar
  34. 34.
    Henderson MC, Gonzales IM, Arora S, Choudhary A, Trent JM, Von Hoff DD, Mousses S, Azorsa DO (2011) High-throughput RNAi screening identifies a role for TNK1 in growth and survival of pancreatic cancer cells. Mol Cancer Res 9(6):724–732PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Pilotto A, Cella A, Pilotto A, Daragjati J, Veronese N, Musacchio C, Mello AM, Logroscino G et al (2017) Three decades of comprehensive geriatric assessment: Evidence coming from different healthcare settings and specific clinical conditions. J Am Med Dir Assoc 18(2):192.e1–192.e11CrossRefGoogle Scholar
  36. 36.
    Pfeiffer E (1975) A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 23(10):433–441PubMedCrossRefGoogle Scholar
  37. 37.
    Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW (1963) Studies of illness in the aged: The index of ADL - a standardized measure of biological and psychological function. JAMA 185:914–919PubMedCrossRefGoogle Scholar
  38. 38.
    Lawton MP, Brody EM (1969) Assessment of older people: Self-maintaining and instrumental activities of daily living. Gerontologist 9(3):179–186PubMedCrossRefGoogle Scholar
  39. 39.
    D’Ath P, Katona P, Mullan E, Evans S, Katona C (1994) Screening, detection and management of depression in elderly primary care attenders. I: The acceptability and performance of the 15 item geriatric depression scale (GDS15) and the development of short versions. Fam Pract 11(3):260–266PubMedCrossRefGoogle Scholar
  40. 40.
    Folstein M, Folstein S, McHugh PR (1975) “mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198PubMedCrossRefGoogle Scholar
  41. 41.
    Morris JC (1993) The clinical dementia rating (CDR): Current version and scoring rules. Neurology 43(11):2412–2414PubMedCrossRefGoogle Scholar
  42. 42.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, ArlingtonCrossRefGoogle Scholar
  43. 43.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 56(3):303–308PubMedCrossRefGoogle Scholar
  44. 44.
    Busse A, Bischkopf J, Riedel-Heller SG, Angermeyer MC (2003) Subclassifications for mild cognitive impairment: Prevalence and predictive validity. Psychol Med 33(6):1029–1038PubMedCrossRefGoogle Scholar
  45. 45.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ et al (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):263–269PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM et al (1993) Vascular dementia: Diagnostic criteria for research studies: Report of the NINDS-AIREN international workshop. Neurology 43(2):250–260PubMedCrossRefGoogle Scholar
  47. 47.
    Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, Russell RW, Symon L (1975) Cerebral blood flow in dementia. Arch Neurol 32(9):632–637PubMedCrossRefGoogle Scholar
  48. 48.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE et al, Consortium on DLB (2005) Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology 65(12):1863–1872PubMedCrossRefGoogle Scholar
  49. 49.
    Piguet O, Hornberger M, Mioshi E, Hodges JR (2011) Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol 10(2):162–167PubMedCrossRefGoogle Scholar
  50. 50.
    Mesulam MM (2003) Primary progressive aphasia: A language-based dementia. N Engl J Med 349(16):1535–1542PubMedCrossRefGoogle Scholar
  51. 51.
    Miller SA, Dykes DD, Polesky HF (1993) A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215CrossRefGoogle Scholar
  52. 52.
    Seripa D, Signori E, Gravina C, Matera MG, Rinaldi M, Fazio VM (2006) Simple and effective determination of apolipoprotein E genotypes by positive/negative polymerase chain reaction products. Diagn Mol Pathol 15:180–185PubMedCrossRefGoogle Scholar
  53. 53.
    Gerdes LU, Klausen IC, Sihm I, Faergeman O (1992) Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol 9(3):155–167PubMedCrossRefGoogle Scholar
  54. 54.
    R Development Core Team (2008) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna URL http://www.R-project.orgGoogle Scholar
  55. 55.
    Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A et al, World Federation of Neurology, Dementia Research Group (2008) Alzheimer’s disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol 7(9):812–826PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Gerdes LU (2003) The common polymorphism of apolipoprotein E: Geographical aspects and new pathophysiological relations. Clin Chem Lab Med 41(5):628–631PubMedCrossRefGoogle Scholar
  57. 57.
    Panza F, Solfrizzi V, Torres F, Mastroianni F, Del Parigi A, Colacicco AM, Basile AM, Capurso C et al (1999) Decreased frequency of apolipoprotein E epsilon4 allele from northern to southern Europe in Alzheimer’s disease patients and centenarians. Neurosci Lett 277(1):53–56PubMedCrossRefGoogle Scholar
  58. 58.
    Pallaud C, Stranieri C, Sass C, Siest G, Pignatti F, Visvikis S (2001) Candidate gene polymorphisms in cardiovascular disease: A comparative study of frequencies between a French and an Italian population. Clin Chem Lab Med 39(2):146–154PubMedCrossRefGoogle Scholar
  59. 59.
    Guéant-Rodriguez RM, Guéant JL, Debard R, Thirion S, Hong LX, Bronowicki JP, Namour F, Chabi NW et al (2006) Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: A comparative study in Mexican, west African, and European populations. Am J Clin Nutr 83(3):701–707PubMedCrossRefGoogle Scholar
  60. 60.
    Ooi EL, Chan ST, Cho NE, Wilkins C, Woodward J, Li M, Kikkawa U, Tellinghuisen T et al (2014) Novel antiviral host factor, TNK1, regulates IFN signaling through serine phosphorylation of STAT1. Proc Natl Acad Sci U S A 111(5):1909–1914PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Osella AR, Misciagna G, Leone A, Di Leo A, Fiore G (1997) Epidemiology of hepatitis C virus infection in an area of southern Italy. J Hepatol 27(1):30–35PubMedCrossRefGoogle Scholar
  62. 62.
    Liu Z, Dai X, Zhang J, Li X, Chen Y, Ma C, Chen K, Peng D et al (2017) The interactive effects of age and PICALM rs541458 polymorphism on cognitive performance, brain structure, and function in non-demented elderly. Mol Neurobiol doi: 10.1007/s12035–016–0358-5
  63. 63.
    Lin YL, Chen SY, Lai LC, Chen JH, Yang SY, Huang YL, Chen TF, Sun Y et al (2012) Genetic polymorphisms of clusterin gene are associated with a decreased risk of Alzheimer’s disease. Eur J EpidemiolGoogle Scholar
  64. 64.
    Tycko B, Feng L, Nguyen L, Francis A, Hays A, Chung WY, Tang MX, Stern Y et al (1996) Polymorphisms in the human apolipoprotein-J/clusterin gene: Ethnic variation and distribution in Alzheimer’s disease. Hum Genet 98(4):430–436PubMedCrossRefGoogle Scholar
  65. 65.
    Guerreiro RJ, Beck J, Gibbs JR, Santana I, Rossor MN, Schott JM, Nalls MA, Ribeiro H et al (2010) Genetic variability in CLU and its association with Alzheimer’s disease. PLoS One 5(3):e9510PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Comings DE, MacMurray JP (2000) Molecular heterosis: A review. Mol Genet Metab 71(1–2):19–31PubMedCrossRefGoogle Scholar
  67. 67.
    Hessner MJ, Dinauer DM, Kwiatkowski R, Neri B, Raife TJ (2001) Age-dependent prevalence of vascular disease-associated polymorphisms among 2689 volunteer blood donors. Clin Chem 47(10):1879–1884PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Davide Seripa
    • 1
  • Francesco Panza
    • 1
    • 2
    • 3
    • 4
  • Giulia Paroni
    • 1
  • Grazia D’Onofrio
    • 1
  • Paola Bisceglia
    • 1
  • Carolina Gravina
    • 1
  • Maria Urbano
    • 1
  • Madia Lozupone
    • 2
  • Vincenzo Solfrizzi
    • 5
  • Alessandra Bizzarro
    • 6
  • Virginia Boccardi
    • 7
  • Chiara Piccininni
    • 6
  • Antonio Daniele
    • 6
  • Giancarlo Logroscino
    • 2
    • 3
  • Patrizia Mecocci
    • 7
  • Carlo Masullo
    • 6
  • Antonio Greco
    • 1
  1. 1.Complex Structure of Geriatrics, Research Laboratory, Department of Medical SciencesI.R.C.C.S. Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
  2. 2.Unit of Neurodegenerative Disease, Department of Basic Medicine Sciences, Neuroscience, and Sense OrgansUniversity of “BariAldo Moro”BariItaly
  3. 3.Unit of Neurodegenerative Disease, Department of Clinical Research in NeurologyUniversity of Bari “Aldo Moro” at “Pia Fondazione Card. G. Panico”TricaseItaly
  4. 4.Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense OrgansUniversity of Bari Aldo MoroBariItaly
  5. 5.Geriatric Medicine-Memory Unit and Rare Disease CentreUniversity of Bari Aldo MoroBariItaly
  6. 6.Institute of NeurologyCatholic University of Sacred HeartRomeItaly
  7. 7.Institute of Gerontology and Geriatrics, Department of MedicineUniversity of PerugiaPerugiaItaly

Personalised recommendations