Dissociation of Neuropathologic Findings and Cognition: Title and subTitle BreakCase Report of an Apolipoprotein E ε2/ε2 Genotype FREE

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.^{9 - 11} 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.

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.

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.

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 damage^{19 - 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.

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.