A Novel Missense Variant in SORBS2 Is Causative With Familial Alzheimer's Disease

Alzheimer's disease (AD) is a common neurodegenerative disorder with a substantial genetic component. Despite advances in elucidating the genetic underpinnings of AD, much of its heritability remains unexplained. Discovering novel genetic variants and understanding their pathogenic roles are crucial challenges in AD research.

This study aimed to identify pathogenic genes and elucidate their role in familial early-onset AD (EOAD).

Blood samples from an EOAD pedigree and Sorbin and SH3 Domain-Containing Protein 2 (SORBS2) T189M transgenic mice were analyzed. Cognitive function was assessed via the Morris water maze (MWM). Protein expression was evaluated by western blotting, while amyloid-β (Aβ) levels were quantified via immunohistochemistry and enzyme-linked immunosorbent assay. Inflammatory markers were measured using immunofluorescence and quantitative reverse transcription polymerase chain reaction (PCR). Neuronal morphology, including dendritic and spine alterations, was examined using Golgi staining.

We identified a novel SORBS2 variant (c. 566C>T, p. T189M) in a Han Chinese family, segregating with AD in a Mendelian fashion. SORBS2 T189M transgenic mice exhibited cognitive deficits, cortical Aβ accumulation, and an increased Aβ42/Aβ40 ratio. Additionally, elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglia, along with neuronal loss, were observed in the brains of T189M mice.

Our study suggest that the SORBS2 T189M variant is a novel candidate causal mutation associated with familial AD in a Chinese pedigree, contributing to AD pathogenesis by promoting neuroinflammation and neuronal injury. Notably, this study is the first to establish a link between SORBS2 mutations and AD.