Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ɛ4 allele

Summary

Some patients with early-onset Alzheimer's disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. These presentations are associated with specific patterns of atrophy and frequently with a young age at onset. Age is not, however, the only determinant of phenotype; underlying factors, especially genetic factors, seem also to affect phenotype and predispose patients to younger or older age at onset. Importantly, patients with atypical early-onset disease seldom carry the APOE ɛ4 allele, which is the most important risk factor for lowering the age of onset in patients with AD. Additionally, theAPOE ɛ4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE ɛ4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown.

Introduction

In 1907, Alois Alzheimer¹ wrote a case description of Auguste D, who presented at his clinic with signs and symptoms including profound language difficulties and behavioural disturbances, such as paranoid delusions and anxiety. Although episodic memory loss was present, it was not the most prominent sign. This patient would now be deemed as having an atypical form of Alzheimer's disease (AD). Additionally, Auguste D was 51 years old when she developed the disease, and thus had a form of early-onset AD.

For decades AD was thought to be rare, to occur at an early age (younger than 65 years), and to involve focal symptoms. In the 1970s, histopathological studies showed that the neuropathological features of senile dementia, which was clinically characterised by progressive memory impairment, were the same as those described by Alzheimer at the beginning of the century.2, 3 This finding caused a major paradigm shift, with senile dementia no longer being viewed as an inevitable, age-related disorder and AD becoming increasingly recognised as a prevalent disease in ageing populations. The publication of clinical criteria for diagnosis of AD in 1984 led to a new era in which AD was classified as one disease with a typical age at onset of 40–90 years.⁴ Since the 1980s, however, heterogeneity has been recognised in the forms of disease, which can involve mixed disease (vascular or Lewy body pathology), cortical versus subcortical presentation, and genetic versus sporadic disease.⁵

Age at onset remains clinically important in determining phenotype. Here, we argue that age at onset underpins the existence of distinct AD phenotypes, albeit in synergy with other factors. First, we provide an overview of similarities and differences in AD according to age at onset. We then attempt to provide a theoretical framework to explain selective vulnerability in early-onset and late-onset AD, and put forward the hypothesis that APOE ɛ4 allele status is a driving factor for differences in the manifestations of the disease.