Study of Alzheimer's disease- and frontotemporal dementia-associated genes in the Cretan Aging Cohort

In addition to age, a major risk factor for Alzheimer's disease (AD; the commonest form of dementia in the elderly) is positive family history for dementia (Lautenschlager et al., 1996). This genetic predisposition is most pronounced for the rare, young-onset, familial form of AD, where causative variants in 3 genes (PSEN1, PSEN2 and APP) have been reported (Bird, 2005; Loy, 2014; Nussbaum and Ellis, 2003). On the other hand, for the frequent sporadic, late-onset, form of AD, intensive research toward the identification of risk factors has brought to light the ε4 allele of the APOE gene, a genotype that significantly increases the risk for the disease and reduces the age of disease onset (Corder et al., 1993; Liu et al., 2013). Furthermore, numerous variants in many different genes have been reported to be associated with AD (such as TREM2, ADAM10, CR1, CLU, EPHA1, PICALM, UNC5C, SORL1, PLD3, etc.), conferring though lower risk compared to the risk attributed to the APOE ε4 genotype (Baker et al., 2019; Bird, 2005; Cruchaga et al., 2014; Del-Aguila et al., 2015; Jansen et al., 2019; Kunkle et al., 2019; Lacour et al., 2017; Lambert et al., 2013; Ridge et al., 2016; Van Cauwenberghe et al., 2016). In addition, genes implicated in glutamate metabolism, including the GLUD1 and GLUD2 genes (encoding for human glutamate dehydrogenase 1 and 2; hGDH1 and hGDH2, respectively), appear to play a major role in neurodegenerative processes (Bao et al., 2009; Lawingco et al., 2020; Plaitakis et al., 2010). The isoenzymes hGDH1 and hGDH2 are involved in brain glutamate metabolism and glutamatergic signaling, an area of increasing interest for the pathophysiology of AD (Ghosh et al., 2020, Sanabria-Castro et al., 2017). These isoenzymes have been a long-time focus of our and other research groups working on the pathophysiology of neurodegeneration (Bao et al., 2009; Burbaeva et al., 2005; Dimovasili et al., 2021; Kim and Baik, 2019; Mathioudakis et al., 2019; Plaitakis et al., 2010; Plaitakis and Zaganas, 2001; Zaganas et al., 2009; Zaganas et al., 2014).

Despite intense efforts to decipher the genetic mechanisms related to AD, including well-conducted GWAS studies that explain a sizeable proportion of the disease risk (Kunkle et al., 2019; Lawingco et al., 2020; Shen and Jia, 2016), research so far seems to have only scratched the surface of such complex and multifactorial processes. However, new hope was kindled by the development of Next Generation Sequencing (NGS) technologies employed in Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS) (Foo et al., 2012; Goodwin et al., 2016; Kumar et al., 2013). Using an NGS approach several rare variants of interest for AD have surfaced, such as rare variants in the TREM2 gene (Bellenguez et al., 2017; Cukier et al., 2017; Del-Aguila et al., 2015; Ming et al., 2021; Sims et al., 2017). These studies have enabled better understanding of the AD-associated pathophysiological processes involving the TREM2 protein, which acts as a receptor and enhances the uptake of lipoprotein (e.g., LDL, HDL) and apolipoprotein (e.g., APOA1/2, APOE 2/3/4, CLU) particles in microglia (Ulland and Colonna, 2018; Ulrich et al., 2017).

Hampering these genetic studies is the less-than-optimal accuracy of the clinical criteria for the diagnosis of AD and the overlapping phenotypes with other diseases, such as frontotemporal dementia (FTD) (Arvanitakis et al., 2019). As a matter of fact, the sensitivity and specificity of clinical diagnosis of AD can be as low as 70% and 40%, respectively (Beach et al., 2012). Thus, it is not uncommon to revise the antemortem diagnosis of AD to a different dementia disorder after performing autopsy (Grandal Leiros et al., 2018; Mok et al., 2004). To overcome this clinical uncertainty, imaging and biological markers are increasingly used in the differential diagnosis of dementia (Bourbouli et al., 2017; Niemantsverdriet et al., 2018; Paraskevas et al., 2017; Vemuri et al., 2011). Among these biological markers, genetic testing is offering a promising approach for accurate diagnosis, and especially for differentiating AD from FTD (Blauwendraat et al., 2018; Cruchaga et al., 2012a; Goldman and Van Deerlin, 2018; Lautenschlager et al., 1996; Loy et al., 2014; Perrone et al., 2018).

The most common genetic change causing FTD is the C9orf72 hexanucleotide repeat expansion. This expansion is also the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS), which forms part of the same pathophysiological spectrum with FTD (Blauwendraat et al., 2018; Hinz and Geschwind, 2017). Other frequent genetic causes of FTD are pathogenic variants in the progranulin (GRN), the Microtubule Associated Protein Tau (MAPT) and the Transactive Response DNA Binding Protein (TARDBP) genes (Ahmed et al., 2007; Baker et al., 2006; Borroni et al., 2009; Cruts et al., 2006; Hutton et al., 1998; Kabashi et al., 2008; Kwiatkowski et al., 2009; Mackenzie et al., 2006; Neumann et al., 2006; Synofzik et al., 2012; Vance et al., 2009). Interestingly, rare patients diagnosed with FTD have been found to harbor pathogenic variants in the PSEN1 and PSEN2 genes that, as described above, are a cause of AD (Blauwendraat et al., 2018; Lohmann et al., 2012; Mendez and McMurtray, 2006). Inversely, even though variants in MAPT, GRN and C9orf72 are typically related with FTD phenotypes, recent studies have demonstrated that these genetic alterations are also associated with other forms of dementia (Guven et al., 2016; Jin et al., 2012; Pastor et al., 2016).

In the present report, based on a multidisciplinary study (Thalis-Multidisciplinary Network for the Study of Alzheimer's Disease; Thalis-MNSAD), we aimed to investigate the genetic factors that contribute to cognitive impairment in the Cretan Aging Cohort (CAC) (Zaganas et al., 2019), a culturally homogeneous population of well-studied older adults residing in the prefecture of Heraklion, Crete, Greece. WES data were obtained from a representative subgroup of AD and Mild Cognitive Impairment (MCI) patients, as well as cognitively intact controls, who had been thoroughly characterized by neuropsychiatric evaluations and assessment of numerous clinical, epidemiological and biological factors. Here we report the results of an initial genetic characterization of the CAC in respect to APOE ε4 genotype and variants in the PSEN1, PSEN2, APP, GLUD1, GLUD2 and 16 FTD-associated genes.

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