Fig. 1 |. The probabilistic model of Alzheimer disease.

We propose three Alzheimer disease (AD) variants — autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD — on the basis of genetic backgrounds and featuring differences in lifetime risk of dementia, the influence of stochastic factors, topography and the burden of amyloid pathology (A), tau pathology (T), neurodegeneration (N) and cognitive symptoms (C). A, T and N burdens in various brain regions are represented by the intensity of red, green and blue, respectively, with darker colours indicating greater burden. The topography of pathology and its global burden are reported in TABLE 1. The relative burden within and between variants for A is based on REFS^113,117, for T on REFS^{124,126–128} and for N on REFS^{125–127,129}. The proportions of dark and light grey people (affected and unaffected individuals, respectively) are approximate representations for the lifetime prevalence of A⁺, T⁺, N⁺ and cognitive impairment in the three AD variants. Autosomal dominant AD individuals almost invariably develop A, T, N and C. In sporadic AD, the interplay of APOE genotype with stochastic factors leads to a weaker cascade from A to T, N and C, resulting in fewer affected cases. The lifetime risk of dementia is very high (nearly 100%¹²) in autosomal dominant AD, intermediate (22–95%^133,134) in APOE ε4-related AD and low (7–35%^133,134) in APOE ε4-unrelated AD. The vertical bars graphically denote the weight of genetic and stochastic factors (white and grey, respectively).