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Dissociation of Neuropathologic Findings and Cognition:  Case Report of an Apolipoprotein E ε2/ε2 Genotype FREE

Daniel J. Berlau, PhD; Kristin Kahle-Wrobleski, PhD; Elizabeth Head, PhD; Matthew Goodus, BA; Ronald Kim, MD; Claudia Kawas, MD
[+] Author Affiliations

Author Affiliations: Institute of Brain Aging and Dementia (Drs Berlau, Kahle-Wrobleski, Head, and Kawas and Mr Goodus) and Departments of Neurology and Neurobiology and Behavior (Dr Kawas) and Pathology (Dr Kim), University of California, Irvine.


Arch Neurol. 2007;64(8):1193-1196. doi:10.1001/archneur.64.8.1193.
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Published online

ABSTRACT

Background  The apolipoprotein E (APOE) ε2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease.

Objective  To describe a dissociation between neuropathologic findings with normal cognition in a woman with severe Alzheimer disease with the APOE ε2/ε2 genotype.

Design  Case report from a community-based prospective study of persons 90 years or older (The 90+ Study).

Participant  A 92-year-old woman without dementia with the APOE ε2/ε2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed.

Intervention  Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles.

Results  Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits.

Conclusions  The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE ε2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.

Figures in this Article

In the last decade, many studies (for a review, see Laws et al1) have examined the role of the apolipoprotein E (APOE) genotype in the development of Alzheimer disease (AD) and neuropathologic findings in AD. There are 3 APOE alleles: ε2, ε3, and ε4. The ε3 allele is the most common, representing approximately 78% of all alleles; the ε2 and ε4 alleles are much less common, representing 7% and 15%, respectively, of all alleles.2 Of the 6 possible genotypes, ε2/ε2 is the rarest, occurring in less than 1.4% of most populations3 and severely limiting research opportunities.

The ε2 allele (APOE2) has been suggested as having a protective effect and delaying the age of onset of AD.4 In addition, APOE2 appears with reduced frequency in sporadic cases of AD5 and patients with AD with APOE2 have less β-amyloid (Aβ) density in the frontal and parietal cortices compared with patients with AD with the ε3/ε3 genotype.6

We report the case of a woman with the rare ε2/ε2 genotype, who died at age 92 years. At brain autopsy, substantial AD-like neuropathologic features were noted, but the participant had not demonstrated any cognitive deficits indicative of AD. Many studies have found evidence of a weak association between neuropathologic features of AD and cognition in the elderly,7,8 a finding that is more common in studies that included oldest old subjects.911 However, these studies rarely reported dissociation of the magnitude observed in our participant, and most do not examine the contribution of the APOE genotype. It is suggested that the unusual APOE status in our participant may have had a protective effect, delaying or possibly preventing the onset of cognitive symptoms but not AD-like neuropathologic features.

REPORT OF A CASE

The subject was a 92-year-old right-handed woman with hypertension but no diabetes mellitus who was a participant in The 90+ Study, a prospective population-based study of cognition and longevity in the oldest old. She reported mild short-term memory loss in 2004 but was still living independently despite blindness in the left eye as a result of shingles.

As part of the Leisure World Cohort Study,12 the participant had completed a health questionnaire in 1984 and follow-up surveys in 1992 and 1998. These surveys indicated a history of vitamins A and E and ascorbic acid usage for 25 years and estrogen supplementation (1.25 mg) for more than 15 years. The participant indicated that she exercised, on average, 7 hours per week.

Her medical history included hypertension and hypercholesterolemia diagnosed in 1980, a transient ischemic attack in 1990, and atrial fibrillation diagnosed in 1999. Her medications were atenolol, levothyroxine sodium, hydrochlorothiazide, acyclovir, calcium, and potassium chloride. There was a family history of stroke (her brother had a stroke at an unknown age), but no family history of dementia was reported. The participant completed high school and some college. She smoked one-fourth pack of cigarettes a day for 17 years, but stopped at age 37 years. No alcohol consumption was reported.

On November 14, 2003, the participant was examined using the Cognitive Abilities Screening Instrument via telephone and scored 33 of a possible 33, indicating intact global cognitive functioning. In 2004, she was examined twice. During these visits, she completed a neuropsychology battery including the Mini-Mental Status Examination (MMSE); California Verbal Learning Test (9 items); Digit Span (forward and backward) subtest of the Wechsler Adult Intelligence Scale, Third Edition; Boston Naming Test (15 items); animal and letter /F/ fluency; Constructional Praxis subtest of the Consortium to Establish a Registry for Alzheimer Disease Psychological Battery; and Trail Making Test, parts A through C. The results are given in Table. Her performance at the first visit was within normal limits for her age group13 on all measured domains including attention, language, visuoconstruction, verbal memory, and executive function. Between visits, in September 2004, the participant had a stroke that resulted in dysarthria, dysphagia, and right-sided weakness for 10 to 14 days. Her performance on the neuropsychological tests administered after the stroke remained within normal limits across domains, with 2 exceptions. Phonemic fluency declined, and she demonstrated mild executive dysfunction as reflected by inability to complete the Trail Making Test, part B. These deficits are best characterized as mild and, on the basis of family reports, did not result in functional loss. The participant died after a second stroke in December 2004.

Table Graphic Jump LocationTable. Neuropsychological Test Scores 6 Months and 1 Month Before Death

At autopsy, the brain weighed 1140 g. Senile plaque formation, which was moderately intense, was predominantly diffuse, although neuritic plaques were readily observed. Neurofibrillary tangle formation, in addition to being present within the hippocampus, subiculum, entorhinal-transentorhinal region, and amygdala, was also seen in moderately severe to severe degree within the frontal, temporal, parietal, and occipital layers of the neocortex (Figure 1). Overall, the pathological changes were judged to be of stage VI-C severity by Braak and Braak staging criteria (the stage that represents the highest frequency of senile plaques and neurofibrillary tangles). These neuropathologic changes are considered highly likely to be associated with dementia according to criteria of the National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer Disease,14 although our participant did not experience significant cognitive dysfunction. Additional immunostaining (Figure 2) for Aβ and tau proteins was performed to compare findings in our participant with those in a subject without dementia with a similar MMSE score but with few pathologic features of AD (age, 99 years; female sex; MMSE score 28; and Braak and Braak classification III-0) and a subject with dementia with similar neuropathologic features of AD but a much lower MMSE score (age, 94 years; female sex; MMSE score 0; and Braak and Braak classification VI-C). The results showed that senile plaques in our participant's brain were both diffuse and neuritic, compared with only neuritic as observed in the comparison subject with dementia.

Place holder to copy figure label and caption
Figure 1.

The case subject demonstrated neocortical neuropathologic features of Alzheimer disease. At histopathologic analysis, a section of inferior parietal cortex immunostained with polyclonal rabbit anti-human tau (DAKO, Carpenteria, California) showed neuritic plaque formation and neurofibrillary degeneration (arrows).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Neuropathologic features in the case subject compared with matched control subjects. Note pathologic features in area CA1/subiculum of the hippocampus in the case subject. β-Amyloid deposition is absent in area CA1/subiculum in a 99-year-old woman without dementia (A), primarily diffuse in the case subject (B), and associated with extracellular neurofibrillary tangles and compact neuritic plaques in a 94-year-old woman with dementia (C). Neurofibrillary tangle accumulation was sparse in the control subject without dementia (D) but was comparable in the case subject (E) and the control subject with dementia (F). AD indicates Alzheimer disease; bar, 100 μm.

Graphic Jump Location

COMMENT

This case shows a prominent dissociation between severe neuropathologic features of AD and preserved cognitive function. Although many potential mechanisms may be responsible, the rare APOE genotype (ε2/ε2) in our participant may have contributed to this dissociation. Current research suggests that APOE2 may delay the onset of clinical AD by increasing Aβ clearance15 and protecting against the formation of neurofibrillary tangles.16 Also, APOE2 is typically associated with reduced neuropathologic features of AD,17 and APOE2 injected in PDAPP mouse brains, a model of AD, reduces Aβ and facilitates degradation and turnover.18 Despite the extensive plaque deposition observed in our participant, many plaques appeared as diffuse β-amyloid deposits, suggesting that the presence of APOE2 may mediate a more rapid turnover of Aβ deposits and lead to less neuronal injury.

Although our participant demonstrated diffuse plaque formation, extensive neuritic plaque and neurofibrillary tangles were also observed in the presence of intact cognition. Therefore, APOE2 may contribute to this dissociation independently of the formation of senile plaques and neurofibrillary tangles, exerting its protective effect through alternative mechanisms such as the reduction of oxidative stress damage19,20 and the preservation of synaptic viability.21

This case provides insight into a possible mechanism for preserved cognition with severe neuropathologic features of AD. In addition to providing evidence of a possible protective mechanism of APOE2, this case report also underscores the importance of clinical confirmation to support a neuropathologic diagnosis of AD, especially in the oldest old.

ARTICLE INFORMATION

Correspondence: Daniel J. Berlau, PhD, Institute of Brain Aging and Dementia, University of California, Irvine, 1515 Hewitt Hall, Irvine, CA 92697-1400 (danb@uci.edu).

Accepted for Publication: November 23, 2006.

Author Contributions:Study concept and design: Berlau. Acquisition of data: Kahle-Wrobleski, Head, Goodus, Kim, and Kawas. Analysis and interpretation of data: Berlau, Kahle-Wrobleski, and Head. Drafting of the manuscript: Berlau, Kahle-Wrobleski, and Head. Critical revision of the manuscript for important intellectual content: Berlau, Kahle-Wrobleski, Goodus, Kim, and Kawas. Statistical analysis: Kahle-Wrobleski. Obtained funding: Kawas. Administrative, technical, and material support: Berlau, Head, and Goodus. Study supervision: Berlau and Kim.

Funding/Support: This study was supported by grant RO1-AG 21055 from the National Institute on Aging (Dr Kawas).

Financial Disclosure: None reported.

REFERENCES

Laws  SMHone  EGandy  SMartins  RN 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. J Neurochem 2003;84 (6) 1215- 1236
PubMed Link to Article
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240 (4852) 622- 630
PubMed Link to Article
Eichner  JEDunn  STPerveen  GThompson  DMStewart  KEStroehla  BC Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002;155 (6) 487- 495
PubMed Link to Article
Corder  EHSaunders  AMRisch  NJ  et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7 (2) 180- 184
PubMed Link to Article
West  HLRebeck  GWHyman  BT Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett 1994;175 (1-2) 46- 48
PubMed Link to Article
Lippa  CFSmith  TWSaunders  AMHulette  CPulaski-Salo  DRoses  AD Apolipoprotein E-epsilon 2 and Alzheimer's disease: genotype influences pathologic phenotype. Neurology 1997;48 (2) 515- 519
PubMed Link to Article
Crystal  HDickson  DFuld  P  et al.  Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 1988;38 (11) 1682- 1687
PubMed Link to Article
Galvin  JEPowlishta  KKWilkins  K  et al.  Predictors of preclinical Alzheimer's disease and dementia: a clinicopathologic study. Arch Neurol 2005;62 (5) 758- 765
PubMed Link to Article
Katzman  RTerry  RDeTeresa  R  et al.  Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 1988;23 (2) 138- 144
PubMed Link to Article
Bennett  DASchneider  JAArvanitakis  Z  et al.  Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66 (12) 1837- 1844
PubMed Link to Article
Prohovnik  IPerl  DPDavis  KLLibow  LLesser  GHaroutunian  V Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 2006;66 (1) 49- 55
PubMed Link to Article
Paganini-Hill  ARoss  RKHenderson  BE Prevalence of chronic disease and health practices in a retirement community. J Chronic Dis 1986;39 (9) 699- 707
PubMed Link to Article
Whittle  CCorrada  MMDick  M  et al.  Neuropsychological data in nondemented oldest old: The 90+ Study. J Clin Exp Neuropsychol 2007;29 (3) 290- 299
PubMed Link to Article
National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 1997;18 (4) (suppl)S1- S2
PubMed Link to Article
Yang  DSSmith  JDZhou  ZGandy  SEMartins  RN Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem 1997;68 (2) 721- 725
PubMed Link to Article
Strittmatter  WJRoses  AD Apolipoprotein E and Alzheimer's disease. Proc Natl Acad Sci U S A 1995;92 (11) 4725- 4727
PubMed Link to Article
Tiraboschi  PHansen  LAMasliah  EAlford  MThal  LJCorey-Bloom  J Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 2004;62 (11) 1977- 1983
PubMed Link to Article
Dodart  JCMarr  RAKoistinaho  M  et al.  Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2005;102 (4) 1211- 1216
PubMed Link to Article
Lee  YAono  MLaskowitz  DWarner  DSPearlstein  RD Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity. Neurochem Int 2004;44 (2) 107- 118
PubMed Link to Article
Miyata  MSmith  JD Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet 1996;14 (1) 55- 61
PubMed Link to Article
Love  SSiew  LKDawbarn  DWilcock  GKBen-Shlomo  YAllen  SJ Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging 2006;27 (6) 797- 803
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The case subject demonstrated neocortical neuropathologic features of Alzheimer disease. At histopathologic analysis, a section of inferior parietal cortex immunostained with polyclonal rabbit anti-human tau (DAKO, Carpenteria, California) showed neuritic plaque formation and neurofibrillary degeneration (arrows).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Neuropathologic features in the case subject compared with matched control subjects. Note pathologic features in area CA1/subiculum of the hippocampus in the case subject. β-Amyloid deposition is absent in area CA1/subiculum in a 99-year-old woman without dementia (A), primarily diffuse in the case subject (B), and associated with extracellular neurofibrillary tangles and compact neuritic plaques in a 94-year-old woman with dementia (C). Neurofibrillary tangle accumulation was sparse in the control subject without dementia (D) but was comparable in the case subject (E) and the control subject with dementia (F). AD indicates Alzheimer disease; bar, 100 μm.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Neuropsychological Test Scores 6 Months and 1 Month Before Death

References

Laws  SMHone  EGandy  SMartins  RN 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. J Neurochem 2003;84 (6) 1215- 1236
PubMed Link to Article
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240 (4852) 622- 630
PubMed Link to Article
Eichner  JEDunn  STPerveen  GThompson  DMStewart  KEStroehla  BC Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002;155 (6) 487- 495
PubMed Link to Article
Corder  EHSaunders  AMRisch  NJ  et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7 (2) 180- 184
PubMed Link to Article
West  HLRebeck  GWHyman  BT Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. Neurosci Lett 1994;175 (1-2) 46- 48
PubMed Link to Article
Lippa  CFSmith  TWSaunders  AMHulette  CPulaski-Salo  DRoses  AD Apolipoprotein E-epsilon 2 and Alzheimer's disease: genotype influences pathologic phenotype. Neurology 1997;48 (2) 515- 519
PubMed Link to Article
Crystal  HDickson  DFuld  P  et al.  Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 1988;38 (11) 1682- 1687
PubMed Link to Article
Galvin  JEPowlishta  KKWilkins  K  et al.  Predictors of preclinical Alzheimer's disease and dementia: a clinicopathologic study. Arch Neurol 2005;62 (5) 758- 765
PubMed Link to Article
Katzman  RTerry  RDeTeresa  R  et al.  Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 1988;23 (2) 138- 144
PubMed Link to Article
Bennett  DASchneider  JAArvanitakis  Z  et al.  Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66 (12) 1837- 1844
PubMed Link to Article
Prohovnik  IPerl  DPDavis  KLLibow  LLesser  GHaroutunian  V Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 2006;66 (1) 49- 55
PubMed Link to Article
Paganini-Hill  ARoss  RKHenderson  BE Prevalence of chronic disease and health practices in a retirement community. J Chronic Dis 1986;39 (9) 699- 707
PubMed Link to Article
Whittle  CCorrada  MMDick  M  et al.  Neuropsychological data in nondemented oldest old: The 90+ Study. J Clin Exp Neuropsychol 2007;29 (3) 290- 299
PubMed Link to Article
National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 1997;18 (4) (suppl)S1- S2
PubMed Link to Article
Yang  DSSmith  JDZhou  ZGandy  SEMartins  RN Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem 1997;68 (2) 721- 725
PubMed Link to Article
Strittmatter  WJRoses  AD Apolipoprotein E and Alzheimer's disease. Proc Natl Acad Sci U S A 1995;92 (11) 4725- 4727
PubMed Link to Article
Tiraboschi  PHansen  LAMasliah  EAlford  MThal  LJCorey-Bloom  J Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 2004;62 (11) 1977- 1983
PubMed Link to Article
Dodart  JCMarr  RAKoistinaho  M  et al.  Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2005;102 (4) 1211- 1216
PubMed Link to Article
Lee  YAono  MLaskowitz  DWarner  DSPearlstein  RD Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity. Neurochem Int 2004;44 (2) 107- 118
PubMed Link to Article
Miyata  MSmith  JD Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet 1996;14 (1) 55- 61
PubMed Link to Article
Love  SSiew  LKDawbarn  DWilcock  GKBen-Shlomo  YAllen  SJ Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging 2006;27 (6) 797- 803
PubMed Link to Article

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