Advertisement

Molecular biology of APO E alleles in Alzheimer’s and non-Alzheimer’s dementias

  • C. M. Morris
  • H. M. Massey
  • R. Benjamin
  • A. Leake
  • C. Broadbent
  • M. Griffiths
  • H. Lamb
  • A. Brown
  • P. G. Ince
  • S. Tyrer
  • P. Thompson
  • I. G. McKeith
  • J. A. Edwardson
  • R. H. Perry
  • E. K. Perry
Part of the Journal of Neural Transmission Supplement book series (NEURAL SUPPL, volume 47)

Summary

Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the ε4 allele has been shown to be a risk factor for late onset Alzheimer’s disease (AD) where there is an increased frequency of the ε4 allele. The ε4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependant manner, with the ε2 allele having an opposing effect.

We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein ε4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased ε4 frequency is also found though a normal ε2 frequency exists, unlike in AD where the ε2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinson’s disease with or without dementia, or in Down’s syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype.

Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the ε2 allele frequency may indicate a genetic difference between AD and LBD. The ε4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.

Keywords

Neurofibrillary Tangle Senile Plaque Lewy Body Dementia Choline Acetyl Transferase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Benjamin R, Leake A, Edwardson JA, McKeith IG, Ince PG, Perry RH, Morris CM (1994) Apolipoprotein E genes in Lewy body and Parkinson’s disease. Lancet 343: 1565PubMedCrossRefGoogle Scholar
  2. Berr C, Hauw J-J, Delaère P, Duyckaerts C, Amouyel P (1994) Apolipoprotein E allele 84 is linked to increased deposition of the amyloid (3-peptide (A-(3) in cases with or without Alzheimer’s disease. Neurosci Lett 178: 221–224Google Scholar
  3. Bètard C, Robitaille Y, Gee M, Tiberghien D, Larrivée D, Roy P, Mortimer JA, Gauvreau D (1994) Apo E allele frequencies in Alzheimer’s disease and vascular dementia. NeuroReport 5: 1893–1896Google Scholar
  4. Castano EM, Prelli F, Wisniewski T, Golabek A, Kumar RA, Soto C, Frangione B (1995) Fibrillogenesis in Alzheimer’s disease of the amyloid [3 peptides and apolipoprotein E. Biochem J 306: 599–604Google Scholar
  5. Corder E, Basun H, Lannfelt L, Viitanen M, Winblad B (1995) Apolipoprotein E-E4 gene dose. Lancet 346: 967–968PubMedCrossRefGoogle Scholar
  6. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921–923Google Scholar
  7. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Rinnuler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, PericakVance MA (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer’s disease. Nature Genet 7: 180–184Google Scholar
  8. Dai XY, Nanko S, Hattori M, Fukuda R, Nagata K, Isse K, Ueki A, Kazamatsuri H (1994) Association of apolipoprotein E4 with sporadic Alzheimer’s disease is more pronounced in early onset type. Neurosci Lett 175: 74–76PubMedCrossRefGoogle Scholar
  9. Evans KC, Berger EP, Cho C-G, Weisgraber KH, Lansbury PT Jr (1995) Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. Proc Natl Acad Sci USA 92: 763–767Google Scholar
  10. Feskens EJM, Havekes LM, Kalmijn S, de Knijff P, Launer LJ, Kromhout D (1994) Apolipoprotein E4 allele and cognitive decline in elderly men. Br Med J 309: 1202–1206CrossRefGoogle Scholar
  11. Fonnum F (1975) A rapid radiochemical method for the determination of choline acetyltransferase. J Neurochem 24: 407–409PubMedCrossRefGoogle Scholar
  12. Galasko D, Saitoh T, Xia Y, Thal LJ, Katzman R, Hill LR, Hansen L (1994) The apolipoprotein E allele E4 is over represented in patients with the Lewy body variant of Alzheimer’s disease. Neurology 44: 1950–1951Google Scholar
  13. Ganguli M, Cauley JA, De Kosky ST, Kamboh MI (1995) Dementia among elderly apolipoprotein E type 4/4 homozygotes: a prospective study. Genet Epidemiol 12: 309–311Google Scholar
  14. Goate AM, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance MA, Roses AD, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704–706PubMedCrossRefGoogle Scholar
  15. Han S-H, Hulette C, Saunders AM, Einstein G, Pericak-Vance M, Strittmatter WJ, Roses AD, Schmechel DE (1994) Apolipoprotein E is present in hippocampal neurones without neurofibrillary tangles in Alzheimer’s disease and in age-matched controls. Exp Neurol 128: 13–26Google Scholar
  16. Hansen LA, Galasko D, Samuel W, Xia Y, Chen X, Saitoh T (1994) Apolipoprotein-E E4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimer’s disease. Neurosci Lett 182: 63–65PubMedCrossRefGoogle Scholar
  17. Harrington CR, Louwagie J, Rossau R, Vanmechelen E, Perry RH, Perry EK, Xuereb JH, Roth M, Wischik CM (1994) Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer’s disease. Am J Pathol 145: 1472–1484Google Scholar
  18. Helkala E-L, Koivisto K, Hänninen T, Vanhanen M, Kervinen K, Kuusisto J, Mykkänen L, Kesäniemi YA, Laakso M, Riekkinen P Sr (1995) The association of apolipoprotein E polymorphism with memory: a population based study. Neurosci Lett 191: 141–144Google Scholar
  19. Hixon JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31: 545–548Google Scholar
  20. Huang DY, Goedert M, Jakes R, Weisgraber KH, Garner CC, Saunders AM, PericakVance MA, Schmechel DE, Roses AD, Strittmatter WJ (1994) Isoform-specific interactions of apolipoprotein E with the microtubule-associated protein MAP 2c: implications for Alzheimer’s disease. Neurosci Lett 182: 55–58Google Scholar
  21. Kamboh MI, Sanghera DK, Ferrell RE, DeKosky ST (1995) APO E 4-associated Alzheimer’s disease risk is modified by al-antichymotrypsin polymorphism. Nature Genet 10: 486–488Google Scholar
  22. Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J (1994) Apolipoprotein E polymorphism in Japanese patients with Alzheimer’s disease or vascular dementia. J Neurol Neurosurg Psychiatry 57: 1414–1416PubMedGoogle Scholar
  23. Kida E, Choi-Miura N-H, Wisniewski KE (1995) Deposition of apolipoproteins E and J in senile plaques is topographically determined in both Alzheimer’s disease and Down’s syndrome. Brain Res 685: 211–216Google Scholar
  24. Koller WC, Glatt SL, Hubble JP, Paolo A, Tröster AI, Handler MS, Horvat RT, Martin C, Schmidt K, Karst A, Wijsman EM, Yu C-E, Schellenberg GD (1995) Apolipoprotein E genotypes in Parkinson’s disease with and without dementia. Ann Neurol 37: 242–245Google Scholar
  25. Lannfelt L, Lilius L, Nastase M, Viitanen M, Fratiglioni L, Eggertsen G, Berglund L, Angelin B, Linder J, Winblad B, Basun H (1994) Lack of association between apolipoprotein E allele E4 and sporadic Alzheimer’s disease. Neurosci Lett 169: 175–178Google Scholar
  26. La Du MJ, Falduto MT, Manelli AM, Reardon CA, Getz GS, Frail DE (1994) Isoform- specific binding of apolipoprotein E to (3-amyloid. J Biol Chem 269: 23403–23406Google Scholar
  27. Lehtovirta M, Laakso MP, Soininen H, Helisalmi S, Mannermaa A, Helkala E-L, Partanen K, Ryynänen M, Vainio P, Hartikainen P, Riekkinen PJ Sr (1995) Volumes of hippocampus amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes. Neuroscience 67: 65–72CrossRefGoogle Scholar
  28. Lippa CF, Smith TW, Saunders AM, Crook R, Pulaski-Salo D, Davies P, Hardy J, Roses AD, Dickson D (1995) Apolipoprotein E genotype and Lewy body disease. Neurology 45: 97–103Google Scholar
  29. Locke PA, Conneally PM, Tanzi RE, Gusella JF, Haines JL (1995) Apolipoprotein E4 allele and Alzheimer disease: examination of allelic association and effect on age at onset in both early-and late-onset cases. Genet Epidemiol 12: 83–92PubMedCrossRefGoogle Scholar
  30. Lucotte G, Visvikis B, Leininger-Miller B, Berriche DS, Réveilleau S, Couderc R, Babron MC, Aguillon D, Siest G (1994) Association of apolipoprotein E allele E4 with late onset sporadic Alzheimer’s disease. Am J Med Genet 54: 286–288Google Scholar
  31. Ma J, Yee A, Brewer B, Jr, Das S, Potter H (1994) Amyloid-associated proteins a-1 antichymotrypsin and apolipoprotein E promote assembly of Alzheimer (3-protein into filaments. Nature 372: 92–94Google Scholar
  32. MacKenzie IRA (1994) Senile plaques do not progressively accumulate with age. Acta Neuropathol 87: 520–525PubMedCrossRefGoogle Scholar
  33. Mahley RW, Rall SC Jr (1989) Type III hyperlipoproteinaemia (dysbetalipoproteinaemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1195–1213Google Scholar
  34. Mann DMA, Marcyniuk B, Yates PO, Neary D, Snowden JS (1988) The progression of the pathological changes of Alzheimer’s disease in frontal and temporal neocortex examined both at biopsy and at autopsy. Neuropathol Appl Neurobiol 14: 177–195PubMedCrossRefGoogle Scholar
  35. Marder K, Maestre G, Cote L, Mejia H, Alfaro B, Halim A, Tang M, Tycko B, Mayeux R (1994) The apolipoprotein E4 allele in Parkinson’s disease with and without dementia. Neurology 44: 1330–1331PubMedGoogle Scholar
  36. Martins RN, Clarnette R, Fisher C, Broe GA, Brooks WS, Montgomery P, Gandy SE (1995) Apo E genotypes in Australia: roles in early and late onset Alzheimer’s disease and Down’s syndrome. NeuroReport 6: 1513–1516Google Scholar
  37. Mayeux R, Ottman R, Maestre G, Ngai C, Tang M-X, Ginsberg H, Chun M, Tycko B, Shelanski M (1995) Synergistic effects of traumatic head injury and apolipoprotein-e4 in patients with Alzheimer’s disease. Neurology 45: 555–557PubMedGoogle Scholar
  38. McKeith IG, Perry RH, Fairbairn AF, Jabeen S, Perry EK (1992) Operational criteria for senile dementia of the Lewy body type (SDLT). Psychol Med 22: 911–922PubMedCrossRefGoogle Scholar
  39. Muramatsu T, Higuchi S, Arai H, Sasaki H, Yamada K, Hayashida M, Trojanowski JO (1994) Apolipoprotein E e4 allele distribution in alcoholic dementia and in Alzheimer’s disease in Japan. Ann Neurol 36: 797–799Google Scholar
  40. Murrel J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with heriditary Alzheimer’s disease. Science 254: 97–99CrossRefGoogle Scholar
  41. Nalbantoglu J, Gilfix BM, Bertrand P, Robitaille Y, Gauthier S, Rosenblatt DS, Poirer JS (1994) Predictive value of apolipoprotein E genotyping in Alzheimer’s disease: results of an autopsy series and an analysis of several combined studies. Ann Neurol 36: 889–895Google Scholar
  42. Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541: 163–166Google Scholar
  43. Nicoll JAR, Roberts GW, Graham DI (1995) Apolipoprotein E E4 allele is associated with deposition of amyloid (3-protein following head injury. Nature Med 1: 135–137Google Scholar
  44. Nitsch RM, Rebeck GW, Deng M, Richardson I, Tennis M, Schenk DB, Vigo-Pelfrey C, Lieberburg I, Wurtman RJ, Hyman BT, Growdon JH (1995) Cerebrospinal fluid levels of amyloid 13-protein in Alzheimer’s disease: inverse correlation with severity of dementia and effect of apolipoprotein E genotype. Ann Neurol 37: 512–518CrossRefGoogle Scholar
  45. Ohm TG, Kirca M, Bohl J, Scharnagl H, Groß W, März W (1995) Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation. Neuroscience 66: 583–587PubMedGoogle Scholar
  46. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2: 1457–1459PubMedCrossRefGoogle Scholar
  47. Perry EK, Johnson M, Kerwin JM, Piggott MA, Court JA, Shaw PJ, Ince PG, Brown A, Perry RH (1992) Convergent cholinergic activities in ageing and Alzheimer’s disease. Neurobiol Aging 13: 393–400PubMedCrossRefGoogle Scholar
  48. Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK (1990) Senile dementia of the Lewy body type: a clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci 95: 119–139PubMedCrossRefGoogle Scholar
  49. Pickering-Brown SM, Mann DMA, Bourke JP, Roberts DA, Balderson D, Burns A, Byrne J, Owen F (1994) Apolipoprotein E4 and Alzheimer’s disease pathology in Lewy body disease and in other (3-amyloid-forming diseases. Lancet 343: 1155PubMedCrossRefGoogle Scholar
  50. Poirer J, Davignon J, Bouthillier D, Kogan S, Bertrand D, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342: 697–699Google Scholar
  51. Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11: 575–580Google Scholar
  52. Roses AD (1994a) Apolipoprotein E affects the rate of Alzheimer’s disease expression: (3-amyloid burden is a secondary consequence dependant on Apo E genotype and duration of disease. J Neuropathol Exp Neurol 53: 429–437Google Scholar
  53. Roses AD, (1994b) Apolipoprotein E is a relevant susceptibility gene that affects rate of expression of Alzheimer’s disease. Neurobiol Aging 15: S165–S167CrossRefGoogle Scholar
  54. Roses AD (1995) Apolipoprotein E genotyping in the differential diagnoses not prediction, of Alzheimer’s disease. Ann Neurol 38: 6–14PubMedGoogle Scholar
  55. Royston MC, Mann D, Pickering-Brown S, Owen F, Perry R, Raghavan R, Khin-Nu C, Tyrer S, Day K, Crook R, Hardy J, Roberts GW (1994) Apolipoprotein E E2 allele promotes longevity and protects patients with Down’s syndrome from dementia. NeuroReport 5: 2583–2585Google Scholar
  56. Sanan DA, Weisgraber KH, Russel SJ, Mahley RW, Huang D, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD, Strittmatter WJ (1994) Apolipoprotein E associates with (3-amyloid peptide of Alzheimer’s disease to form novel monofibris. Isoform Apo E4 associates more efficiently than Apo E3. J Clin Invest 94: 860–869Google Scholar
  57. Saunders AM, Strittmatter WJ, Schmechel D, St George Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472Google Scholar
  58. Schmechel DE, Saunders AM, Strittmatter WJ, Crain B, Hulette CM, Joo SH, PericakVance MA, Goldgaber D, Roses AD (1993) Increased amyloid 13-peptide deposition as a consequence of apolipoprotein E genotype in late onset Alzheimer’s disease. Proc Natl Acad Sci USA 90: 9649–9653CrossRefGoogle Scholar
  59. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin G, Holman K, Tsuda T, Mar L, Foncin J-F, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early onset familial Alzheimer’s disease. Nature 375: 754–760PubMedCrossRefGoogle Scholar
  60. Soininen H, Kosunen O, Helisalmi S, Mannermaa A, Paljärvi L, Talasniemi S, Ryynänen M, Riekkinen P Sr (1995) A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein E4 allele. Neurosci Lett 187: 79–82PubMedCrossRefGoogle Scholar
  61. Sorbi S, Nacmias B, Forleo P, Latorraca S, Gobbini I, Bracco L, Piacentini S, Amaducci L (1994) Apo E allele frequencies in Italian sporadic and familial Alzheimer’s disease. Neurosci Lett 177: 100–102Google Scholar
  62. St Clair D, Norrman J, Perry R, Yates C, Wilcock G, Brookes A (1994) Apolipoprotein E E4 allele frequency in patients with Lewy body dementia, Alzheimer’s disease and age-matched controls. Neurosci Lett 176: 45–46Google Scholar
  63. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance AM, Enghild J, Salvesen GS, Roses AD (1993a) Apolipoprotein E: high avidity binding to 13-amyloid and increased frequency of type E4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci USA 90: 1977–1981CrossRefGoogle Scholar
  64. Strittmatter WJ, Weisgraber KM, Huang DY, Dong L-M, Salvesen GS, Pericak-Vance AM, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993b) Binding of human apolipoprotein E to synthetic amyloid 13 peptide: isoform specific effects and implications for late onset Alzheimer’s disease. Proc Natl Acad Sci USA 90: 8098–8102Google Scholar
  65. Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KM, Dong L-M, Jakes R, Huang DY, Pericak-Vance AM, Schmechel D, Roses AD (1994a) Isoform specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer’s disease. Proc Natl Acad Sci USA 91: 11183–11186Google Scholar
  66. Strittmatter W, Weisgraber KH, Goedert M, Saunders AM, Huang D, Corder EH, Dong LM, Jakes R, Alberts MJ, Gilbert JR, Han SH, Hulette C, Einstein G, Schmechel DE, Pericak-Vance MA, Roses A (1994) Hypothesis: microtubule instability and paired helical filament formation in Alzheimer’s disease brain are related to apolipoprotein E genotype. Exp Neurol 125: 163–171CrossRefGoogle Scholar
  67. van Broeckhoven C, Backhovens H, Cruts M, Martin JJ, Crook R, Houlden H, Hardy J (1994) APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer’s disease. Neurosci Lett 169: 179–180PubMedCrossRefGoogle Scholar
  68. van Duijn CM, de Knijff P, Cruts M, Wehnert A, Havekes LM, Hofman A, Van Broeckhoven C (1994) Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease. Nature Genet 7: 74–78PubMedCrossRefGoogle Scholar
  69. van Duijn CM, de Knijff P, Wehnert A, De Voecht J, Bronzova JB, Havekes LM, Hofman A, Van Broeckhoven C (1995) The apolipoprotein E E2 allele is associated with an increased risk of early-onset Alzheimer’s disease and a reduced survival. Ann Neurol 37: 605–610Google Scholar
  70. Wenham PR, Price WH, Blundell G (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337: 1158–1159Google Scholar
  71. Wisniewski T, Castano EM, Golabek A, Vogel T, Frangione B (1994) Acceleration of Alzheimer’s fibril formation by apolipoprotein E in vitro. Am J Pathol 145: 1030–1035Google Scholar
  72. Yoshizawa T, Yamakawa-Kobayashi K, Komatsuzaki Y, Arinami T, Oguni E, Mizusawa H, Shoji S, Hamaguchi H (1994) Dose-dependant association of Apolipoprotein E allele E4 with late onset sporadic Alzheimer’s disease. Ann Neurol 36: 656–659Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • C. M. Morris
    • 1
  • H. M. Massey
    • 1
  • R. Benjamin
    • 1
  • A. Leake
    • 1
  • C. Broadbent
    • 1
  • M. Griffiths
    • 1
  • H. Lamb
    • 1
  • A. Brown
    • 1
  • P. G. Ince
    • 1
  • S. Tyrer
    • 1
  • P. Thompson
    • 1
  • I. G. McKeith
    • 1
  • J. A. Edwardson
    • 1
  • R. H. Perry
    • 1
  • E. K. Perry
    • 1
  1. 1.MRC Neurochemical Pathology Unit and Department of NeuropathologyNewcastle General HospitalNewcastle upon Tyne, Tyne and WearUK

Personalised recommendations