Abstract
With the recent interest in Alzheimer's disease course modification and earlier, even preclinical, intervention, questions have arisen regarding the potentially confounding impact of apolipoprotein E (APOE) genotype on study design, therapeutic outcomes, and even clinical practice. APOE e4 carriers have a faster rate of cognitive decline both preclinically and during the mild cognitive impairment (MCI) stage, and a higher burden of cerebrovascular amyloid that may be the basis for the observed gene-dose-related increased frequency of immunomodulatory therapy-induced meningoencephalitis and cerebral microhemorrhages. To date, this has impacted study design in some research trials but not clinical practice.
Highlights
The discovery in 1993 that apolipoprotein E (APOE) genotype influenced the relative risk and age of onset of Alzheimer’s disease (AD) represented a paradigm shift that continues to advance our understanding of AD pathogenesis
It has been thought that e4 has a greater effect on amyloid than tau-based pathology, supported by the relative under-representation of e4 among patients with neurofibrillary tanglepredominant AD, a subgroup that tends to be in the older age range, but a more recent study of the oldest subjects showed that e2 carrier status was associated with greater amyloid as well as tau pathology, and the effect on amyloid was greater than that on tau [6]
Returning to our first question, there is strong evidence that APOE genotype influences the accuracy of diagnosis, age of symptomatic onset, and rate of disease progression both preclinically and during the mild cognitive impairment (MCI) stage
Summary
The discovery in 1993 that apolipoprotein E (APOE) genotype influenced the relative risk and age of onset of Alzheimer’s disease (AD) represented a paradigm shift that continues to advance our understanding of AD pathogenesis. Clinical differences between APOE subgroups Clinically, the effect of APOE genotype on age of onset has been reconfirmed many times since the original report from Roses’ group [1]. Neuropathological differences between APOE subgroups Neuropathologically, there is over a 97% chance that an e4 carrier dying with dementia will have AD at autopsy [5].
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