PIN1 gene variants in Alzheimer's disease.

BACKGROUND: Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. METHODS: We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls. RESULTS: Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. CONCLUSION: Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort.

Mutations in the presenilin 1 (PSEN1) gene are known to cause nearly 50% of early-onset, familial Alzheimer's disease (AD) cases. To determine whether E318G mutation is related causally to AD in the Polish population E318G mutation frequency was assessed using PCR-RFLP method in a total of 659 subjects: 256 AD patients, 210 healthy, age-matched control subjects, 100 Parkinson's disease patients and 93 centenarians. When the mutation frequencies were compared to healthy controls, no significant differences between the groups were found. It could be concluded that E318G mutation is not related causally to AD in the Polish population, either as a risk factor or a disease causing mutation.

Cognitive patterns of normal elderly subjects are consistent with frontal cortico-subcortical and fronto-parietal neuropsychological models of brain aging.

Three neuropsychological theories have been developed according to a possible existence of a similar pattern of cognitive decline in elderly individuals and patients with brain damage. The respective neuropsychological theories attribute age-related deficits to: (a) dysfunction of the frontal lobes, (b) temporo-parietal dysfunction, or (c) decline of right-hemisphere functions. In the present study, we examined which of these theories best explains the cognitive patterns of normal elderly subjects older than 80 years of age (old elderly). Thirty normal old elderly subjects, 14 patients with subcortical vascular dementia, 14 with mild Alzheimer's disease, 15 with damage of the right hemisphere of the brain, and 20 young elderly controls participated. A test battery covering the main cognitive domains was administered to all participants. A hierarchical cluster analysis revealed five groups of individuals with different cognitive patterns across the whole sample. Old elderly subjects were assigned to four groups according to: (a) preserved overall cognitive performance, (b) processing speed decline, (c) attention decline, or (d) executive impairment. The results of the study are most congruent with models emphasizing frontal-lobe cortical-subcortical and fronto-parietal changes in old age. The results also indicate considerable heterogeneity in the cognitive patterns of normal old elderly adults.

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland.

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimer's disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.