Abstract
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.
Highlights
Many decades of clinicopathologic investigations on sporadic Alzheimer’s disease (AD) have enormously contributed to the definition of the main pathologic lesions associated with AD, i.e. β-amyloid neuritic plaques (AβNP) and tau-neurofibrillary tangles, and to a better understanding of the possible relationships between cognitive deficits and AD lesions [1, 2]
APOε2 and education on later cognition even in presence of AD pathology burdens that are equivalent to those found in the mild cognitive impairment (MCI) and some definite AD cases
Previous epidemiological studies have reported a protective role of APOε2 [46] and higher education [60] against AD, but only few have been confirmed by autopsy findings [61]
Summary
Many decades of clinicopathologic investigations on sporadic Alzheimer’s disease (AD) have enormously contributed to the definition of the main pathologic lesions associated with AD, i.e. β-amyloid neuritic plaques (AβNP) and tau-neurofibrillary tangles (tau-NFT), and to a better understanding of the possible relationships between cognitive deficits and AD lesions [1, 2]. Other investigators referred to ASYMAD under different appellations, such as “high pathology controls” [16] or “preclinical AD” [17]. Those investigators essentially referred to the same concept: there are older individuals cognitively silent for AD even with consistent levels of AD pathology at autopsy. This clinicopathologic dissociation has been described employing “in vivo” functional neuroimaging studies [18,19,20,21,22]
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