Influence of APOE genotype in primary age-related tauopathy
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RESEARCH
Influence of APOE genotype in primary age‑related tauopathy Andrew C. Robinson1,2* , Yvonne S. Davidson1, Federico Roncaroli1,2, James Minshull1, Phillip Tinkler1, Michael A. Horan1, Antony Payton3, Neil Pendleton1† and David M. A. Mann1†
Abstract The term “Primary age-related tauopathy” (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer’s disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis. Keywords: Primary age-related tauopathy, Alzheimer’s disease, APOE, Cognition Introduction For many years, neuropathologists have observed neurofibrillary tangles (NFTs) without associated beta-amyloid (Aβ) pathology in the brains of aged individuals both with and without cognitive impairment. NFTs are almost ubiquitous in the brains of older people [22]. Significant tau burden (Braak tau stage III-IV) but few Aβ plaques have been observed in 2–10% of individuals in community-based settings [15, 21, 29]. The inability to assign *Correspondence: [email protected] † Neil Pendleton and David M. A. Mann have contributed equally to this work 1 Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, The University of Manchester, Salford M6 8HD, UK Full list of author information is available at the end of the article
a diagnosis of Alzheimer’s disease (AD) to cognitively impaired individuals with these findings led to terms such as “senile dementia with tangles” or “tangle-only dementia” [11]. In those cognitively intact, “age-related
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