Correspondence

Apolipoprotein E and the Neuropathology of Dementia

N Engl J Med 1996; 334:599-600February 29, 1996

Article

To the Editor:

Polvikoski et al. (Nov. 9 issue)1 have convincingly demonstrated that there is a greater accumulation of β-amyloid protein in the brain and more neurofibrillary tangles in elderly Finnish subjects with the ε4 allele of apolipoprotein E than in those without it.

We recently investigated the relation between the apolipoprotein E genotype and the density of senile plaques and number of neurofibrillary tangles in 69 elderly Japanese patients. Among these subjects, 49 did not have dementia (age at death, 86.2±7.8 years) and 20 had Alzheimer's disease (age at death, 83.8±8.3 years). Two subjects had the ε2/ε3 genotype, 52 the ε3/ε3 genotype, and 15 the ε3/ε4 genotype. The frequency of the ε4 allele was significantly higher in the subjects with Alzheimer's disease than in those without dementia (20.0 percent vs. 7.1 percent, P<0.05). However, the densities of total senile plaques (including diffuse plaques) and neuritic plaques and numbers of neurofibrillary tangles in the cerebral cortex and hippocampus were not significantly different between subjects with the ε3/ε3 genotype and those with the ε3/ε4 genotype, regardless of whether Alzheimer's disease was present (Figure 1Figure 1Relation between Apolipoprotein E Genotype and the Density of Senile Plaques.). These results should not be ascribed to the smallness of the sample, because we found that a considerable number of subjects with the ε3/ε3 genotype had marked Alzheimer-type pathological changes, whereas some with the ε3/ε4 genotype had only slight changes. Similarly, no significant difference was found in the severity of cerebral amyloid angiopathy between those with the ε3/ε3 genotype and those with the ε3/ε4 genotype.2

The correlation between the ε4 allele and Alzheimer's disease varies among races. In an elderly Nigerian population, for example, the frequency of the ε4 allele did not differ significantly between patients with Alzheimer's disease and control subjects (16.7 percent vs. 20.5 percent).3 The ε4 allele was associated with the severity of cerebral amyloid angiopathy in an American study,4 but not in our study of a Japanese population.2 Hence, racial differences affect the linkage between the ε4 allele and the density of senile plaques and number of neurofibrillary tangles.

How the ε4 allele influences the development of Alzheimer's disease remains to be elucidated. The isoform specificity of apolipoprotein E in binding to β-amyloid protein is still controversial.5 Further study is needed to clarify whether the accelerated formation of Alzheimer-type pathological changes is a direct effect of the ε4 allele or a consequence of the development of Alzheimer's disease.

Yoshinori Itoh, M.D.
Yokufukai Geriatric Hospital, Tokyo 168, Japan

Masahito Yamada, M.D.
Tokyo Medical and Dental University, Tokyo 113, Japan

5 References

1. 1

   Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein. N Engl J Med 1995;333:1242-1247
   Full Text | Web of Science | Medline

2. 2

   Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E. Influence of apolipoprotein E genotype on cerebral amyloid angiopathy. Stroke (in press).
   

3. 3

   Osuntokun BO, Sahota A, Ogunniyi AO, et al. Lack of an association between apolipoprotein E ε4 and Alzheimer's disease in elderly Nigerians. Ann Neurol 1995;38:463-465
   CrossRef | Web of Science | Medline

4. 4

   Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT. Apolipoprotein E ε4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol 1995;38:254-259
   CrossRef | Web of Science | Medline

5. 5

   LaDu MJ, Pederson TM, Frail DE, Reardon CA, Getz GS, Falduto MT. Purification of apolipoprotein E attenuates isoform-specific binding to β-amyloid. J Biol Chem 1995;270:9039-9042
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Itoh and Yamada discuss possible racial differences in the relation between the apolipoprotein E genotype and Alzheimer-type neuropathological changes, based on a comparison of their observations in Japanese subjects with our findings. However, their results cannot be directly compared with ours. First, our study was a prospective population-based autopsy study, whereas they do not specify the source of their subjects. The average age of the Japanese subjects was somewhat younger than in our study, and the age range in the various apolipoprotein E–genotype groups is not given. There are also differences in sampling and morphometric methodology. Drs. Itoh and Yamada measured plaque density in the cerebral cortex and hippocampus, whereas we quantified the fractions of neocortical specimens covered by methenamine silver–stained plaques. Counting the individual plaques on methenamine silver–stained sections is problematic and may give misleading results, owing to the huge variations in the form and size of the plaques, particularly the diffuse ones.

We have not postulated that patients with Alzheimer's disease who have the apolipoprotein E ε4 allele would have more extensive deposition of β-amyloid protein than patients with Alzheimer's disease without the ε4 allele. Indeed, it may be difficult to establish such a difference, because the neuropathological diagnosis of Alzheimer's disease itself depends on the presence of a sufficient minimal density of neocortical neuritic plaques.1,2

The apolipoprotein E ε4 allele also seems to be a risky allele in the Japanese population. According to the results of Itoh and Yamada and others,3 the frequency of this allele is increased even in Japanese patients with Alzheimer's disease as compared with the frequency in control subjects without dementia.

The reported number of elderly people with dementia in Ibadan, Nigeria, is surprisingly low: only 28 of 2494 subjects who were 65 years of age or older.4 Unfortunately, apolipoprotein E genotyping was possible in only 17 subjects. Much larger population-based studies are needed to confirm the possible effect of racial differences on the association between the apolipoprotein E genotype and Alzheimer's disease.

We agree that the mechanism linking the apolipoprotein E ε4 allele to Alzheimer-type pathological changes awaits further clarification.

Tuomo Polvikoski, M.D.
University of Helsinki, FIN-00014 Helsinki, Finland

Raimo Sulkava, M.D.
University of Kuopio, Fin-70211 Kuopio, Finland

Matti Haltia, M.D.
University of Helsinki, FIN-00014 Helsinki, Finland

4 References

1. 1

   Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105
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2. 2

   Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991;41:479-486
   Web of Science | Medline

3. 3

   Noguchi S, Murakami K, Yamada N. Apolipoprotein E genotype and Alzheimer's disease. Lancet 1993;342:737-737
   CrossRef | Web of Science | Medline

4. 4

   Osuntokun BO, Sahota A, Ogunniyi AO, et al. Lack of association between apolipoprotein E ε4 and Alzheimer's disease in elderly Nigerians. Ann Neurol 1995;38:463-465
   CrossRef | Web of Science | Medline

Citing Articles (11)

Citing Articles

1. 1

   Jungsu Kim, Jacob M. Basak, David M. Holtzman. (2009) The Role of Apolipoprotein E in Alzheimer's Disease. Neuron 63:3, 287-303
   CrossRef

2. 2

   Simon M. Laws, Eugene Hone, Sam Gandy, Ralph N. Martins. (2003) Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. Journal of Neurochemistry 84:6, 1215-1236
   CrossRef

3. 3

   U. Thaker, A. M. McDonagh, T. Iwatsubo, C. L. Lendon, S. M. Pickering-Brown, D. M. A. Mann. (2003) Tau load is associated with apolipoprotein E genotype and the amount of amyloid beta protein, Abeta40, in sporadic and familial Alzheimer's disease. Neuropathology and Applied Neurobiology 29:1, 35-44
   CrossRef

4. 4

   G. Leguizamón, H. Krupitzki, D. Glujovsky, M. Olivera Ravasi, E. A. Reece. (2002) Blood glucose monitoring in gestational diabetes mellitus: 1- versus 2-h blood glucose determinations. Journal of Maternal-Fetal and Neonatal Medicine 12:6, 384-388
   CrossRef

5. 5

   Maarit Lehtovirta, Mikko P Laakso, Giovanni B Frisoni, Hilkka Soininen. (2000) How does the apolipoprotein E genotype modulate the brain in aging and in Alzheimer’s disease? A review of neuroimaging studies. Neurobiology of Aging 21:2, 293-300
   CrossRef

6. 6

   Lan Chen, Larry Baum, Ho-Keung Ng, Lisa Y.S Chan, Chi-Pui Pang. (1999) Apolipoprotein E genotype and its pathological correlation in Chinese Alzheimer's disease with late onset. Human Pathology 30:10, 1172-1177
   CrossRef

7. 7

   E.J. Mufson, E-Y. Chen, E.J. Cochran, L.A. Beckett, D.A. Bennett, J.H. Kordower. (1999) Entorhinal Cortex β-Amyloid Load in Individuals with Mild Cognitive Impairment. Experimental Neurology 158:2, 469-490
   CrossRef

8. 8

   Masahito Yamada, Yoshinori Itoh, Nobuyuki Sodeyama, Naomi Suematsu, Eiichi Otomo, Masaaki Matsushita, Hidehiro Mizusawa. (1998) Aging of the human limbic system: Observations of centenarian brains and analyses of genetic risk factors for senile changes. Neuropathology 18:2, 228-234
   CrossRef

9. 9

   Rainer Bachus, Sebastian Bader, Reinhard Gener, Albert C. Ludolph. (1997) Lack of association of apolipoprotein E ?4 allele with bulbar-onset motor neuron disease. Annals of Neurology 41:3, 417-417
   CrossRef

10. 10

    D.M.A Mann, T Iwatsubo, S.M Pickering-Brown, F Owen, T.C Saido, R.H Perry. (1997) Preferential deposition of amyloid β protein (Aβ) in the form Aβ40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele. Neuroscience Letters 221:2-3, 81-84
    CrossRef

11. 11

    Younga J. Kwon, Julia Tsai, Norman R. Relkin. (1996) Bibliography NIA/AlzA Conference on Apolipoprotein E Genotyping in Alzheimer's Disease. Annals of the New York Academy of Sciences 802:1 Apolipoprotei, 177-224
    CrossRef