The identification of mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes in families with autosomal dominant Alzheimer’s disease (AD) played a crucial part in developing our current understanding of the pathogenic mechanism that underlies AD. 1, 2 It therefore was of note that two PS-1 mutations recently were identified that are associated not with AD but with a clinical presentation of frontotemporal dementia (FTD). 3–5 However, interpretation of these findings was complicated by the absence of neuropathology studies in either family. Now in their report Dermaut and colleagues6 describe a novel PS-1 mutation in a family with clinical FTD and crucially autopsy findings that confirm the absence of characteristic AD-type neuropathology. These FTD-associated PS-1 mutations suggest that PS-1 dysfunction may lead to neurodegenerative disease by more than one mechanism and can result in an FTD-like clinical and neuropathological phenotype.

PS-1 and PS-2 are integral membrane proteins that are thought to be the catalytic subunits of the γ-secretase complex, required for the proteolytic processing of the amyloid precursor protein (APP) and the resulting production of Aβ. 7–10 Aβ is the major component of the amyloid plaques that are a characteristic feature of AD neuropathology. Aβ peptides have two major species, Aβ40 and Aβ42; the longer peptide Aβ42 aggregates more readily and is thought to initiate brain amyloid deposition. 11, 12 Significantly all AD-associated mutations in PS-1 and in PS-2 increase the relative production of Aβ42, although the exact mechanism is uncertain. 13, 26 This observation provided strong support for the hypothesis that the pathogenic cascade that results in AD is initiated by the progressive accumulation of neurotoxic Aβ polymers. 14, 15 It is important to recognize, however, that γ-secretase, a multiprotein aspartyl protease, 16 acts on multiple type 1 transmembrane proteins including Notch1-4 and the Erb-4 receptor tyrosine kinase, as well as APP. 17, 18 For many of these substrates, γ-secretase cleavage results in release of a soluble intracellular domain that mediates signaling events. 19 PS-1 gene knock-out results in embryonic lethality in mice, 20 presumably reflecting the multifunctional role of γ-secretase, and conditional ablation of PS-1 and PS-2 expression in the brains of adult mice recently was shown to cause neurodegeneration and cognitive