Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease

Inheritance of the apolipoprotein E (apoE) ε4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE ε4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty‐one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and Aβ deposits were assessed in a high‐order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the ε4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. Aβ deposition, by contrast, was not related to clinical features but was elevated in association with apoE ε4. These results indicate that apoE ε4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE ε4 on amyloid deposition.

[1]  D. Galasko,et al.  Apolipoprotein-E ε-4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimer's disease , 1994, Neuroscience Letters.

[2]  Giovanni B. Frisoni,et al.  Gene dose of the ε4 allele of apolipoprotein E and disease progression in sporadic late‐onset alzheimer's disease , 1995 .

[3]  G. Schellenberg,et al.  Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans , 1995, Annals of neurology.

[4]  B. Hyman,et al.  Multiple, diverse senile plaque–associated proteins are ligands of an apolipoprotein e receptor, the α2‐macroglobulin receptor/low‐density‐lipoprotein receptor—related protein , 1995, Annals of neurology.

[5]  A D Roses,et al.  Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[6]  S. Younkin,et al.  Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. , 1993, Science.

[7]  M. Pericak-Vance,et al.  Apolipoprotein E ∈4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases , 1993, The Lancet.

[8]  B. Tycko,et al.  The apolipoprotein ε4 allele in patients with Alzheimer's disease , 1993, Annals of neurology.

[9]  B. Hyman,et al.  Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. , 1995, Archives of neurology.

[10]  R. Mantegna,et al.  Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome). , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[12]  B. Hyman,et al.  Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy , 1995 .

[13]  B. Hyman.  Studying the Alzheimer's disease brain: Insights, puzzles, and opportunities , 1994, Neurobiology of Aging.

[14]  Mark J. West,et al.  New stereological methods for counting neurons , 1993, Neurobiology of Aging.

[15]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[16]  S. Weintraub.  The record of independent living , 1986 .

[17]  Margaret A. Pericak-Vance,et al.  Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype , 1994, Experimental Neurology.

[18]  M. Pericak-Vance,et al.  Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Roses,et al.  Apolipoprotein E Is Localized to the Cytoplasm of Human Cortical Neurons: A Light and Electron Microscopic Study , 1994, Journal of neuropathology and experimental neurology.

[20]  D. Schaid,et al.  Apolipoprotein E: risk factor for Alzheimer disease. , 1994, American journal of human genetics.

[21]  P. Wilson,et al.  Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. , 1987, Journal of lipid research.

[22]  C. Duyckaerts,et al.  Apolipoprotein E allele ε4 is linked to increased deposition of the amyloid β-peptide (A-β) in cases with or without Alzheimer's disease , 1994, Neuroscience Letters.

[23]  J. Miller,et al.  Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older. , 1993, Archives of neurology.

[24]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E. Perry,et al.  Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease. , 1994, The American journal of pathology.

[26]  M. Rossor,et al.  Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. , 1994, Human molecular genetics.

[27]  H. Brewer,et al.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments , 1994, Nature.

[28]  B T Hyman,et al.  Kunitz Protease Inhibitor‐Containing Amyloid β Protein Precursor Immunoreactivity in Alzheimer's Disease , 1992, Journal of neuropathology and experimental neurology.

[29]  G. V. Van Hoesen,et al.  The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. , 1991, Cerebral cortex.

[30]  K. Welch,et al.  Cerebral microvessel 2‐deoxy‐D‐glucose uptake during ischemia‐induced seizures , 1980, Annals of neurology.

[31]  J. Haines,et al.  Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease , 1995, Neurology.

[32]  M. Roth,et al.  The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Grey Matter of Elderly Subjects , 1968, British Journal of Psychiatry.

[33]  W. März,et al.  Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation , 1995, Neuroscience.

[34]  G. Schellenberg,et al.  Apolipoprotein E genotypes in Parkinson's disease with and without dementia , 1995, Annals of neurology.

[35]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[36]  S. Younkin,et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. , 1994, Science.

[37]  B. Hyman,et al.  Alzheimer's disease with and without coexisting Parkinson's disease changes , 1995, Neurology.

[38]  B. Hyman,et al.  Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions , 1993, Neuron.

[39]  Thomas Wisniewski,et al.  Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid , 1992, Neuroscience Letters.

[40]  G. Getz,et al.  Isoform-specific binding of apolipoprotein E to beta-amyloid. , 1994, The Journal of biological chemistry.

[41]  J. Morrison,et al.  Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. , 1994, Cerebral cortex.

[42]  R. Mahley,et al.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. , 1988, Science.

[43]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[44]  P. Landais,et al.  Apolipoprotein E‐ε4 allele doses in late‐onset Alzheimer's disease , 1994 .

[45]  A. Roses.  Apolipoprotein E Affects the Rate of Alzheimer Disease Expression: (β-Amyloid Burden Is a Secondary Consequence Dependent on APOE Genotype and Duration of Disease , 1994, Journal of neuropathology and experimental neurology.

[46]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[47]  S. DeKosky,et al.  Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity , 1990, Annals of neurology.

[48]  T. Wisniewski,et al.  Apolipoprotein E : binding to soluble Alzheimer's β-amyloid , 1993 .

[49]  S. Gauthier,et al.  Apolipoprotein E polymorphism and Alzheimer's disease , 1993, The Lancet.

[50]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[51]  Robert H. Brown,et al.  Apolipoprotein E ϵ4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis , 1995 .

[52]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[53]  B. Hyman,et al.  The Lack of Accumulation of Senile Plaques or Amyloid Burden in Alzheimer's Disease Suggests a Dynamic Balance Between Amyloid Deposition and Resolution , 1993, Journal of neuropathology and experimental neurology.

[54]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[55]  Ellen M. Wijsman,et al.  The Apolipoprotein E E4 Allele and Sex-Specific Risk of Alzheimer's Disease , 1995 .

[56]  A. M. Saunders,et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease , 1994, Nature Genetics.

[57]  P. Davies,et al.  A protein kinase associated with paired helical filaments in Alzheimer disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Z. Khachaturian.  Diagnosis of Alzheimer's disease. , 1985, Archives of neurology.