The single cell origin of sporadic Alzheimer's disease: A developmental biallelic somatic mutation model

Alzheimer's disease (AD) is a neurodegenerative disorder beginning decades prior to diagnosis and characterized by aggregates of amyloid-β (Aβ) 42 and of hyperphosphorylated tau (ptau) proteins. The etiology of sporadic AD (sAD) is unclear and there are problems in our understanding of dominantly inherited familial AD (fAD). In carriers the dominant mutation is expressed throughout the brain in every neuron in utero ; why then is the appearance of Aβ 42 plaques focal? To explain this, a single cell origin model for sAD is proposed based on Knudson's biallelic mutation model for neoplasia. Familial neoplasia (fN) syndromes have an autosomal dominant pattern of inheritance. However, if the fN mutations are dominant at the cellular level then every cell expressing the mutation would become a tumor and that is not the case. Tumors originate from single cells and somatic loss of heterozygosity (LOH) in a fN carrier cell is necessary for tumorigenesis and defines fN mutations as recessive. Analogously somatic LOH is necessary in a fAD carrier neuron for it to produce Aβ 42 monomers in sufficient concentration (Aβ 42 neuron) to potentiate Aβ 42 nucleation and to generate prion-like Aβ 42 oligomers. In sAD the biallelic mutations in the founder Aβ 42 neuron are somatic. Endogenous neuronal somatic mutations peak in incidence during development. The number of founder Aβ 42 neurons, the variant of the fAD mutation, and the location and neural connectivity of the Aβ 42 neuron to the locus coeruleus will impact the age of onset and clinical heterogeneity. Knudson's biallelic somatic mutation model in development is applicable to all prion-like neurodegenerative disorders.