The Thr354Ile substitution in <i>PSEN1:</i>

Abstract

Alterations in the gene ( PSEN1 ) encoding for the presenilin-1 protein (PS1) are thought to cause early-onset familial Alzheimer disease (FAD) through altered γ-secretase cleavage of amyloid precursor protein, leading to a relative increase in the amount of β-amyloid protein-42 (Aβ42)1 produced. That this form of the protein aggregates more readily than the more abundant Aβ40 species and its early presence in the amyloid plaques characteristic of the illness have provided support for the “amyloid hypothesis” of AD pathogenesis. A few alterations in the PSEN1 gene associated with AD occur in the portion of the gene coding for the cytoplasmic loop domain.2 The function of this portion of the protein remains unclear as deletion of the hydrophilic cytoplasmic domain from residues 304 to 371 has no effect on Aβ42 production.3 We report a case that raises the question as to whether alterations in this portion of PS1 consistently cause early-onset FAD. A 46-year-old man presented with cognitive decline over 5 …