Kuopion Yliopisto University of Kuopio

Alzheimer’s disease (AD) is the most common cause of progressive neurological disorder leading to dementia. It is neuropathologically characterized by extracellular and perivascular deposits of amyloid beta peptide and by the generation of intracellular neurofibrillary tangles. AD is subdivided into early and late onset forms and it has a genetic aetiology, which is most evident in the case of familial early onset AD (onset age before 65 years). At present, mutations in amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) genes are known to cause the autosomal dominant form of early onset AD while the apolipoprotein E (ApoE) ε4 allele has been associated with an increased risk of developing both early and late onset AD. The purpose of this study was to assess the genetic components involved in the early and late onset AD in Finland. Despite the well-established effects of the APP, PSEN-1, PSEN2 and ApoE genes in early and late onset AD, it is obvious that additional susceptibility genes are involved. In order to detect these novel chromosomal loci, a genome-wide linkage disequilibrium mapping was performed using late onset AD patients and age-matched control subjects from a geographically restricted area in Eastern Finland. In addition, the effects of different susceptibility and causative genes such as butyrylcholinesterase (BChE) K variant, ApoE promoter –491A/T polymorphism, and PSEN-1 were examined among Finnish early and late onset AD patients. The major findings of this study were as follows: 1) Identification of a novel 4.6-kb genomic deletion in PSEN-1 gene, which leads to the exclusion of exon 9 in an early onset AD family. This germline alteration was clearly a causative mutation for AD and the clinical and neuropathological phenotypes of patients were those of typical AD without indications of spastic paraparesis or ‘cotton wool’ plaques. The underlying recombination mechanism in this genomic deletion was considered to involve an Alu core sequence-stimulated non-homologous rearrangement. 2) Although the E318G substitution in the PSEN-1 gene was found to be a non-causative mutation in AD, the frequency of this substitution was increased both in the sporadic and familial AD patient groups suggesting that E318G could be a risk factor for AD. 3) BChE K variant and ApoE ε4 alleles do not act in synergy in Finnish late onset AD patients. Instead, reduced BChE K allele frequency among AD patient group under 75 years of age and carrying the ApoE ε4 allele points to a protective effect of the BChE K variant allele in this subgroup. 4) ApoE promoter –491A/T polymorphism did not reveal significant differences between late onset AD patients and age-matched controls. Consistent with previous studies, -491 A and ApoE ε4 alleles were found to be in linkage disequilibrium indicating that the ApoE ε4 status is still the strongest predictor of risk in Finnish late onset AD patients. 5) Initial genome-wide linkage disequilibrium mapping with 366 polymorphic microsatellite markers revealed 22 chromosomal regions which were associated with AD with P-values < 0.05. Comparison of single allele frequencies of the microsatellite markers in AD and control groups revealed the presence of both possible risk and protective alleles. Screening of the 22 LD regions with additional microsatellite markers revealed that eight chromosomal loci in 1p36.12, 2p22.2, 3q28, 4p13, 10p13, 13q12, 18q12.1 and 19p13.3 were associated with AD in more than one microsatellite marker. These chromosome regions found to be associated with AD in the present study will provide the primary targets for future genetic and functional studies into AD. National Library of Medicine Classification: WL 359, QZ 50 Medical Subject Headings: Alzheimer disease; apolipoproteins E; butyrylcholiesterase; chromosomes; human; linkage disequilibrium; polymorphism; promoter regions; risk factors.