Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to Repeat Expansions.

Roberta Ghidoni, Silvia Fostinelli, Claudia Saraceno, Giuliano Binetti, Antonio Longobardi, Ilenia Libri, Sonia Bellini, Barbara Borroni, Alessandro Padovani, Andrea Pilotto, Chiara Tolassi, Roland Nicsanu, Andrea Geviti, Alessandro Facconi

Journal: International journal of molecular sciences 2024;25(13):

PMID: 39000564

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Abstract

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and / mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin () gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 () gene, which was significantly associated with age at onset in the group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism () and in the modulation of the calcium signalling/axonal anterograde transport of vesicles () as genetic modulators in AD and FTLD due to expansions.

Address: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.; Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.; Neurology Unit, Department of Continuity of Care and Frailty, ASST Spedali Civili Hospital, 25123 Brescia, Italy.; Neurobiorepository and Laboratory of Advanced Biological Markers, University of Brescia and ASST Spedali Civili Hospital, 25123 Brescia, Italy.; Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.; Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.; MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.; Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.; Cognitive and Behavioural Neurology, ASST Spedali Civili Hospital, 25123 Brescia, Italy.; Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy.; Neurology Unit, Department of Continuity of Care and Frailty, ASST Spedali Civili Hospital, 25123 Brescia, Italy.; Neurobiorepository and Laboratory of Advanced Biological Markers, University of Brescia and ASST Spedali Civili Hospital, 25123 Brescia, Italy.; Brain Health Center, University of Brescia, 25123 Brescia, Italy.

DOI: 10.3390/ijms25137457

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MeSH Terms: Humans, Alzheimer Disease, C9orf72 Protein, Frontotemporal Lobar Degeneration, Age of Onset, Female, Male, Aged, Middle Aged, DNA Repeat Expansion, Aged, 80 and over, Polymorphism, Single Nucleotide, Transferrin, Genetic Predisposition to Disease, Genetic Variation