Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2004 Mar;75(3):370–376. doi: 10.1136/jnnp.2003.014993

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease

L Mosconi 1, B Nacmias 1, S Sorbi 1, M T R De Cristofaro 1, M Fayazz 1, A Tedde 1, L Bracco 1, K Herholz 1, A Pupi 1
PMCID: PMC1738980  PMID: 14966149

Abstract

Objectives: Declines in brain glucose metabolism have been described early in Alzheimer's disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods.

Methods: Eighty six consecutive mild to moderate AD patients included in the Network for Efficiency and Standardisation of Dementia Diagnosis database underwent FDG-PET scans at rest. PCR was used to determine the ApoE genotype. Patients were grouped as e4 non-carriers (n = 46), e3/e4 (n = 27) and e4/e4 (n = 13) carriers. A voxel-based mapping program was used to compare each AD subgroup with a database of 35 sex and age matched controls (p<0.001, corrected for cluster extent) and also to compare between the subgroups (p<0.001, uncorrected).

Results: No difference was found as to age at examination, age at onset, sex, disease duration, educational level, or severity of dementia between AD subgroups. Compared with controls, all AD subgroups had equivalent METglc reductions in the precuneus, posterior cingulate, parietotemporal, and frontal regions. Direct comparisons between AD subgroups indicated that patients with at least one e4 allele had METglc reductions within additional associative and limbic areas compared with e4 non-carriers.

Conclusions: The present FDG-PET study showed different metabolic phenotypes related to the ApoE genotype in clinical AD patients, as revealed with voxel based statistical methods. The results suggest a generalised disorder in e4 carriers impairing metabolism globally, in addition to the more localised changes typical of AD patients.

Full Text

The Full Text of this article is available as a PDF (599.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Caselli R. J., Graff-Radford N. R., Reiman E. M., Weaver A., Osborne D., Lucas J., Uecker A., Thibodeau S. N. Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes. Neurology. 1999 Jul 13;53(1):201–207. doi: 10.1212/wnl.53.1.201. [DOI] [PubMed] [Google Scholar]
  2. Chetelat Gaël, Baron Jean-Claude. Early diagnosis of Alzheimer's disease: contribution of structural neuroimaging. Neuroimage. 2003 Feb;18(2):525–541. doi: 10.1016/s1053-8119(02)00026-5. [DOI] [PubMed] [Google Scholar]
  3. Corbetta M., Miezin F. M., Dobmeyer S., Shulman G. L., Petersen S. E. Selective and divided attention during visual discriminations of shape, color, and speed: functional anatomy by positron emission tomography. J Neurosci. 1991 Aug;11(8):2383–2402. doi: 10.1523/JNEUROSCI.11-08-02383.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Corder E. H., Jelic V., Basun H., Lannfelt L., Valind S., Winblad B., Nordberg A. No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes. Arch Neurol. 1997 Mar;54(3):273–277. doi: 10.1001/archneur.1997.00550150035013. [DOI] [PubMed] [Google Scholar]
  5. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  6. Craft S., Teri L., Edland S. D., Kukull W. A., Schellenberg G., McCormick W. C., Bowen J. D., Larson E. B. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology. 1998 Jul;51(1):149–153. doi: 10.1212/wnl.51.1.149. [DOI] [PubMed] [Google Scholar]
  7. Farrer L. A., Cupples L. A., Haines J. L., Hyman B., Kukull W. A., Mayeux R., Myers R. H., Pericak-Vance M. A., Risch N., van Duijn C. M. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22;278(16):1349–1356. [PubMed] [Google Scholar]
  8. Friston K. J., Frith C. D., Liddle P. F., Frackowiak R. S. Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991 Jul;11(4):690–699. doi: 10.1038/jcbfm.1991.122. [DOI] [PubMed] [Google Scholar]
  9. Helkala E. L., Koivisto K., Hanninen T., Vanhanen M., Kervinen K., Kuusisto J., Mykkanen L., Kesaniemi Y. A., Laakso M., Riekkinen P., Sr Memory functions in human subjects with different apolipoprotein E phenotypes during a 3-year population-based follow-up study. Neurosci Lett. 1996 Feb 9;204(3):177–180. doi: 10.1016/0304-3940(96)12348-x. [DOI] [PubMed] [Google Scholar]
  10. Herholz K., Salmon E., Perani D., Baron J. C., Holthoff V., Frölich L., Schönknecht P., Ito K., Mielke R., Kalbe E. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage. 2002 Sep;17(1):302–316. doi: 10.1006/nimg.2002.1208. [DOI] [PubMed] [Google Scholar]
  11. Hirono N., Hashimoto M., Yasuda M., Ishii K., Sakamoto S., Kazui H., Mori E. The effect of APOE epsilon4 allele on cerebral glucose metabolism in AD is a function of age at onset. Neurology. 2002 Mar 12;58(5):743–750. doi: 10.1212/wnl.58.5.743. [DOI] [PubMed] [Google Scholar]
  12. Hirono N., Mori E., Yasuda M., Ishii K., Ikejiri Y., Imamura T., Shimomura T., Hashimoto M., Yamashita H., Sasaki M. Lack of association of apolipoprotein E epsilon4 allele dose with cerebral glucose metabolism in Alzheimer disease. Alzheimer Dis Assoc Disord. 1998 Dec;12(4):362–367. doi: 10.1097/00002093-199812000-00018. [DOI] [PubMed] [Google Scholar]
  13. Ibáez V., Pietrini P., Alexander G. E., Furey M. L., Teichberg D., Rajapakse J. C., Rapoport S. I., Schapiro M. B., Horwitz B. Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease. Neurology. 1998 Jun;50(6):1585–1593. doi: 10.1212/wnl.50.6.1585. [DOI] [PubMed] [Google Scholar]
  14. Johnson K. A., Jones K., Holman B. L., Becker J. A., Spiers P. A., Satlin A., Albert M. S. Preclinical prediction of Alzheimer's disease using SPECT. Neurology. 1998 Jun;50(6):1563–1571. doi: 10.1212/wnl.50.6.1563. [DOI] [PubMed] [Google Scholar]
  15. Lancaster J. L., Woldorff M. G., Parsons L. M., Liotti M., Freitas C. S., Rainey L., Kochunov P. V., Nickerson D., Mikiten S. A., Fox P. T. Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp. 2000 Jul;10(3):120–131. doi: 10.1002/1097-0193(200007)10:3&#x0003c;120::AID-HBM30&#x0003e;3.0.CO;2-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lehtovirta M., Kuikka J., Helisalmi S., Hartikainen P., Mannermaa A., Ryynänen M., Riekkinen PSr, Soininen H. Longitudinal SPECT study in Alzheimer's disease: relation to apolipoprotein E polymorphism. J Neurol Neurosurg Psychiatry. 1998 Jun;64(6):742–746. doi: 10.1136/jnnp.64.6.742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lehtovirta M., Soininen H., Laakso M. P., Partanen K., Helisalmi S., Mannermaa A., Ryynänen M., Kuikka J., Hartikainen P., Riekkinen P. J., Sr SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele. J Neurol Neurosurg Psychiatry. 1996 Jun;60(6):644–649. doi: 10.1136/jnnp.60.6.644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Levine B., Cabeza R., McIntosh A. R., Black S. E., Grady C. L., Stuss D. T. Functional reorganisation of memory after traumatic brain injury: a study with H(2)(15)0 positron emission tomography. J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):173–181. doi: 10.1136/jnnp.73.2.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Matsuda Hiroshi, Kitayama Noriyuki, Ohnishi Takashi, Asada Takashi, Nakano Seigo, Sakamoto Shigeki, Imabayashi Etsuko, Katoh Asako. Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer's disease. J Nucl Med. 2002 Mar;43(3):304–311. [PubMed] [Google Scholar]
  20. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
  21. Minoshima S., Koeppe R. A., Frey K. A., Kuhl D. E. Anatomic standardization: linear scaling and nonlinear warping of functional brain images. J Nucl Med. 1994 Sep;35(9):1528–1537. [PubMed] [Google Scholar]
  22. Mirra S. S., Heyman A., McKeel D., Sumi S. M., Crain B. J., Brownlee L. M., Vogel F. S., Hughes J. P., van Belle G., Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479–486. doi: 10.1212/wnl.41.4.479. [DOI] [PubMed] [Google Scholar]
  23. Nobili Flavio, Koulibaly Malick, Vitali Paolo, Migneco Octave, Mariani Giuliano, Ebmeier Klaus, Pupi Alberto, Robert Philippe H., Rodriguez Guido, Darcourt Jacques. Brain perfusion follow-up in Alzheimer's patients during treatment with acetylcholinesterase inhibitors. J Nucl Med. 2002 Aug;43(8):983–990. [PubMed] [Google Scholar]
  24. Poirier J., Davignon J., Bouthillier D., Kogan S., Bertrand P., Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):697–699. doi: 10.1016/0140-6736(93)91705-q. [DOI] [PubMed] [Google Scholar]
  25. Poirier J., Delisle M. C., Quirion R., Aubert I., Farlow M., Lahiri D., Hui S., Bertrand P., Nalbantoglu J., Gilfix B. M. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12260–12264. doi: 10.1073/pnas.92.26.12260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reiman E. M., Caselli R. J., Chen K., Alexander G. E., Bandy D., Frost J. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3334–3339. doi: 10.1073/pnas.061509598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Reiman E. M., Caselli R. J., Yun L. S., Chen K., Bandy D., Minoshima S., Thibodeau S. N., Osborne D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996 Mar 21;334(12):752–758. doi: 10.1056/NEJM199603213341202. [DOI] [PubMed] [Google Scholar]
  28. Roses A. D. Apolipoprotein E and Alzheimer's disease. The tip of the susceptibility iceberg. Ann N Y Acad Sci. 1998 Nov 30;855:738–743. doi: 10.1111/j.1749-6632.1998.tb10653.x. [DOI] [PubMed] [Google Scholar]
  29. Small G. W., Ercoli L. M., Silverman D. H., Huang S. C., Komo S., Bookheimer S. Y., Lavretsky H., Miller K., Siddarth P., Rasgon N. L. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6037–6042. doi: 10.1073/pnas.090106797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Small G. W., Mazziotta J. C., Collins M. T., Baxter L. R., Phelps M. E., Mandelkern M. A., Kaplan A., La Rue A., Adamson C. F., Chang L. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA. 1995 Mar 22;273(12):942–947. [PubMed] [Google Scholar]
  31. Sorbi S., Nacmias B., Forleo P., Piacentini S., Amaducci L. Alzheimer's disease and apolipoprotein E in Italy. Ann N Y Acad Sci. 1996 Jan 17;777:260–265. doi: 10.1111/j.1749-6632.1996.tb34429.x. [DOI] [PubMed] [Google Scholar]
  32. St George-Hyslop P. H. Molecular genetics of Alzheimer's disease. Biol Psychiatry. 2000 Feb 1;47(3):183–199. doi: 10.1016/s0006-3223(99)00301-7. [DOI] [PubMed] [Google Scholar]
  33. de Leon M. J., Convit A., Wolf O. T., Tarshish C. Y., DeSanti S., Rusinek H., Tsui W., Kandil E., Scherer A. J., Roche A. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001 Aug 28;98(19):10966–10971. doi: 10.1073/pnas.191044198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. van Dyck C. H., Gelernter J., MacAvoy M. G., Avery R. A., Criden M., Okereke O., Varma P., Seibyl J. P., Hoffer P. B. Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease. Arch Neurol. 1998 Nov;55(11):1460–1466. doi: 10.1001/archneur.55.11.1460. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES