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A lot of effort has been done to unravel the genetics underlying early-onset Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). However, many familial early-onset dementia (EOD) cases still show an unclear genetic background. The aim of this study was to evaluate the role of the known causative mutations and possible pathogenic variants associated with AD and FTLD in a Finnish EOD cohort. The cohort consisted of 39 patients (mean age at onset 54.8 years, range 39-65) with a positive family history of dementia or an atypical or rapidly progressive course of the disease. None of the patients carried the C9orf72 hexanucleotide repeat expansion. Mutations and variants in APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, FUS, TARDBP, TREM2, TMEM106B, UBQLN2, SOD1, PRNP, UBQLN1, and BIN1 were screened by using a targeted next generation sequencing panel. Two previously reported pathogenic mutations (PSEN1 p.His163Arg and MAPT p.Arg406Trp) were identified in the cohort. Both patients had familial dementia with an atypical early onset phenotype. In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD. In conclusion, targeted investigation of the known dementia-linked genes is worthwhile in patients with onset age under 55 and a positive family history, as well as in patients with atypical features.

The authors previously reported that genetic variation in the gene coding for nicastrin (NCSTN) modified risk for familial early-onset Alzheimer disease (AD) in a Dutch population-based sample. Risk was highest in patients without an APOE epsilon4 allele. Here, they evaluated if NCSTN polymorphisms increased risk of AD in the eastern Finnish population. A significant difference in one haplotype was observed in AD patients without the APOE epsilon4 allele.

Mutations in the presenilin-1 (PS-1) gene have been shown to cause early onset Alzheimer's disease (EOAD) in an autosomal dominant manner. We have identified a novel 4.6-kb genomic deletion in the PS-1 gene in a Finnish EOAD family, which leads to an inframe exclusion of exon9 (delta9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the delta9 splice-site mutations. In this present EOAD family, the clinical and neuropathological phenotype of patients are those of the typical AD without indications of spastic paraparesis or 'cotton wool' plaques, which are the hallmarks of the variant AD. A sequence analysis of the deletion crossover site of the mutant and corresponding wild type regions revealed complete homology with the recombigenic 26 bp Alu core sequence at intron 8. In addition, a segment at the intron 9 breakpoint displayed homology with the core sequence, but comparison of the 5' and 3' breakpoint sequences did not reveal significant identity favouring involvement of Alu core sequence-stimulated non-homologous recombination rather than Alu-mediated homologous pairing of the fragments. This study shows that large genomic rearrangements can affect the EOAD gene PS-1 through a mechanism, which may involve Alu core sequence-stimulated recombination.

Nearly all of the presenilin-1 (PSEN-1) mutations are missense mutations leading to Alzheimer's disease (AD). The role of the mutation E318G (a substitution of glutamic acid to glycine) in the PSEN-1 is controversial. It has been found both in AD patients and in non-demented control individuals. Using the polymerase chain reaction and the restriction fragment length polymorphism method, we screened for E318G mutation in a total of 16 familial (FAD) cases, in 64 sporadic neuropathologically confirmed AD cases and in 270 non-demented controls including 35 neuropathologically confirmed individuals. We detected the E318G mutation in four FAD cases, seven sporadic AD cases and 10 control individuals with highly varying onset-ages. Odds ratios for carrying the mutation were 7.6 and 3 in FAD and sporadic AD cases, respectively. Our results suggest that this mutation could be a risk factor in the Finnish FAD and sporadic AD population. It may be in linkage disequilibrium with a pathogenic change somewhere else in the PSEN-1 gene or in close proximity to the PSEN-1 gene.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.