Nonfibrillar diffuse amyloid deposition due to a γ ₄₂-secretase site mutation points to an essential role for N-truncated Aβ ₄₂ in Alzheimer's disease

Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid β-peptide (Aβ ₄₂) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid Aβ ₄₂ deposits have to mature in the presence of Aβ ₄₀ into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving γ-secretase cleavages of APP. The mutation had the most drastic effect on Aβ ₄₂/Aβ ₄₀ ration in vitro of ~ 11-fold, simultaneously increasing Aβ ₄₂ and decreasing Aβ ₄₀ secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated Aβ(42) in complete absence of Aβ ₄₀. These data indicate that N-truncated Aβ ₄₂ as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length Aβ ₄₂ by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated Aβ ₄₂.