Young Onset Alzheimer’s Disease Associated with C9ORF72 Hexanucleotide Expansion: Further Evidence for a Still Unsolved Association

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are recognized as part of a disease continuum (FTD-ALS spectrum), in which the most common genetic cause is chromosome 9 open reading frame 72 (C9ORF72) gene hexanucleotide repeat expansion. The clinical phenotype of patients carrying this expansion varies widely and includes diseases beyond the FTD-ALS spectrum. Although a few cases of patients with C9ORF72 expansion and a clinical or biomarker-supported diagnosis of Alzheimer’s disease (AD) have been described, they have been considered too sparse to establish a definite association between the C9ORF72 expansion and AD pathology. Here, we describe a C9ORF72 family with pleomorphic phenotypical expressions: a 54-year-old woman showing cognitive impairment and behavioral disturbances with both neuroimaging and cerebrospinal fluid (CSF) biomarkers consistent with AD pathology, her 49-year-old brother with typical FTD-ALS, and their 63-year-old mother with the behavioral variant of FTD and CSF biomarkers suggestive of AD pathology. The young onset of disease in all three family members and their different phenotypes and biomarker profiles make the simple co-occurrence of different diseases an extremely unlikely explanation. Our report adds to previous findings and may contribute to further expanding the spectrum of diseases associated with C9ORF72 expansion.

A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?

“…But interestingly, Nookala et al (2012) did reveal that the crystal structure for the C-terminal fragment of FLCN, contained a DENN (differentially expressed in normal and neoplastic cells) domain that was highly similar to the DENN domain of the C9orf72 protein (Nookala et al, 2012), whose dominant expansion of a noncoding GGGGCC hexanucleotide repeat has been proven to be causative of both ALS and FTD (DeJesus-Hernandez et al, 2011). Moreover, C9orf72 repeat expansion may play a role in the neurodegeneration associated to AD (Lall et al, 2021;Vinceti et al, 2023).…”

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation

“…In line with this, the German Neurological Society has officially recognized C9orf72 expansion alleles as a primary HD phenocopy in their guidelines for the differential diagnosis of chorea ( 11 ). Furthermore, the phenotypes associated with C9orf72 can vary significantly, even within the same family lineage, manifesting in diverse neurodegenerative presentations ( 12 ).…”