Abstract:
Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) are the most common causes of dementia and death in developed countries. AD is clinically characterized by a progressive decline in cognitive functions. In most AD patients, the first symptoms start after the age of 60 years (late-onset or senile AD); however, rarely, the disease onsets earlier (early-onset or presenile AD). The other degenerative brain disease FTD has overlapping features with AD and a variable onset. In the framework of this thesis, six patients with clinically diagnosed early-onset AD, were screened for mutations in Presenilin1 (PS1) and Presenilin 2 (PS2) genes, which cause AD when mutated. In addition, four FTD patients were analyzed for mutations in the exons 9-13 of the microtubule-associated protein Tau (MAPT) gene. Causative mutations in several patients remained unidentified, although the entire coding regions of PS1 and PS2 and the hotspot regions of MAPT were thoroughly investigated. This may have several reasons, including lack of family history and complicated differential diagnosis of early-onset familial AD (EOFAD) and FTD. As opposed to the above cases, a novel mutation was found in exon11 of a patient with autosomal dominant early onset AD. This is a GCC-ACC transition corresponding to an Ala396Thr substitution in the HL-VII domain of the PS1 protein. Its presence in the coding region of PS1 is thought to cause a change in the structure of the PS1 protein resulting in an alteration in amyloid precursor protein cleavage by constraining the structure of the protein. A better understanding of the complex etiology that underlies EOAD and FTD may be achieved through a multidisciplinary approach that combines clinical and neurophysiological characterization of these diseases with molecular investigations of genetic components.
