Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset Alzheimer Disease and Frontotemporal Lobar Degeneration

Abstract

Mutations in 3 genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as causing a proportion of early-onset Alzheimer disease (eoAD) cases. A few PSEN mutations have also been previously detected in patients with frontotemporal lobar degeneration (FTLD). In order to evaluate the role of these genes in a clinical series of Finnish eoAD and FTLD patients, we sequenced exons 16 and 17 of the APP gene and the coding regions of the PSEN1 and PSEN2 genes in 140 eoAD and 66 FTLD patients. No pathogenic mutations were identified in the cohort. The E318G variant was detected with similar frequencies in the cases with eoAD and FTLD and the healthy controls, therefore, showing no association between E318G and eoAD. Furthermore, the PSEN2 R71W variant seems to be nonpathogenic, because it was present in our healthy controls. Mutations in the PSEN1, PSEN2, and APP genes seem to be rare in this population, as these genes exhibited no pathogenic mutations in our cohort of eoAD and FTLD patients even though about 40% of the cases were familial ones. This suggests the involvement of other, still unknown genetic factors in the pathogenesis of these diseases.

Mutation Analysis of the Genes Linked to Early Onset Alzheimer’s Disease and Frontotemporal Lobar Degeneration

“…However, the facts that it did not appear to segregate with AD in the families of the carriers, nor did it affect the Aβ42/Aβ40 ratio in an in vitro assay, and it was also found in healthy controls suggest that it is likely a benign mutation [10,20,28]. Interestingly though, the brain biopsy of the patient in our study revealed AD-type neuropathology.…”

“…The C9orf72 hexanucleotide repeat expansion or MAPT and GRN mutations underlie the majority of the familial FTLD [5,6]. In Finland, the prevalence of the C9orf72 repeat expansion is exceptionally high [7], whereas MAPT and GRN mutations associated with FTLD or PSEN1, PSEN2 and APP mutations associated with AD have been found to be very rare [8][9][10].…”

Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Patients with Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis with the <b><i>C9ORF72 </i></b>Repeat Expansion

“…microtubule-associated protein tau, MAPT) may explain the mixed type of neuropathology, but a combination of 2 pathogenic mutations in 1 person is rare [26]. The influence of other pathogenic mutations is unlikely in the present study, because our previous studies have shown that mutations in MAPT or progranulin are rare or absent in the Finnish population [27,28,29,30]. The disease process and neurodegeneration itself can also be reflected on AD biomarker values [31].…”

Genetics of dementia in a Finnish cohort

“…Only a few PSEN1 variants have been reported in Finnish AD families: two families carry the 'Cotton-wool' variant, Δ9Finn (c.869_955del) [45], p.(Met146Val) has been reported in a Swedish family of Finnish descent [46,47] and p. (Pro264Leu) in one family [48]. Screening of APP, PSEN1 and PSEN2 in a cohort of 140 EOAD patients revealed no variants that might affect function [49]. In addition, duplication of APP was not detected in a cohort of 64 Finnish EOAD patients [50].…”