Research Papers: Gerotarget (Focus on Aging):

APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study

Diego Iacono _, Peter Zandi, Myron Gross, William R. Markesbery, Olga Pletnikova, Gay Rudow and Juan C. Troncoso

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Oncotarget. 2015; 6:14082-14091. https://doi.org/10.18632/oncotarget.4118

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Diego Iacono1,2,3,4, Peter Zandi5, Myron Gross6, William R. Markesbery7,8,9, Olga Pletnikova1, Gay Rudow1 and Juan C. Troncoso1,10

1 Neuropathology Division, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

2 Neuropathology Research, Biomedical Research Institute of New Jersey, Cedar Knolls, NJ, USA

3 Atlantic Neuroscience Institute, Overlook Medical Center, Summit, NJ, USA

4 Department of Neurology, Icahn School of Medicine at Mount Sinai, Newyork, NY, USA

5 Department of Mental Health, Johns Hopkins University, Baltimore, MD, USA

6 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

7 Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

8 Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

9 Alzheimer’s Disease Center, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

10 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

Correspondence to:

Diego Iacono, email:

Keywords: Gerotarget, AD pathology, APOε2, higher education and language skills, neuronal hypertrophy, preserved cognition

Received: March 11, 2015 Accepted: April 30, 2015 Published: May 12, 2015


Asymptomatic Alzheimer’s disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology.

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