ABSTRACT
Lipoprotein(a) [Lp(a)] level is a newly established vascular risk factor which has been suggested to play a role in dementia. However, the majority of Lp(a) cell-to-cell interactions are mediated by its specific apolipoprotein(a) [apo(a)] moiety. This suggests that the size polymorphism of apo(a) may be of importance in conveying the Lp(a)-related risk. Specifically, we postulated that variation in apo(a) isoform size may lead to increased risk of vascular dementia (VaD), Alzheimer's disease (AD), stroke, or all three of them. Under a case-control design we compared Lp(a) plasma levels and the distribution of apo(a) phenotypes in groups of subjects consisting of 50 VaD patients, 162 sporadic AD patients, 95 non-demented stroke patients (NDS), and 105 normal controls. The prevalence of small-sized apo(a) isoforms in the VaD group was significantly higher than that in the stroke and normal control groups, with an odds ratio of 5.29 (95% CI 2.24-12.49, p = 0.0001) for the development of VaD for individuals with at least one apo(a) isoform of low molecular weight (LMW). Furthermore, the possession of at least one small-sized apo(a) isoform significantly increased the risk of AD to 1.92 (95% CI 1.02-3.61, p = 0.0434). Our results demonstrate that possession of at least one LMW apo(a) isoform is significantly associated with dementia and specifically offer new evidence of a strong association between the lipoprotein system and post-stroke dementia.
Subject(s)
Alzheimer Disease/diagnosis , Dementia, Vascular/diagnosis , Lipoprotein(a)/blood , Aged , Aged, 80 and over , Alzheimer Disease/blood , Alzheimer Disease/genetics , Apolipoproteins A/blood , Apolipoproteins A/genetics , Cerebral Infarction/blood , Cerebral Infarction/complications , Cerebral Infarction/genetics , Dementia, Vascular/blood , Dementia, Vascular/genetics , Female , Gene Frequency/genetics , Humans , Intracranial Embolism/blood , Intracranial Embolism/complications , Intracranial Embolism/genetics , Italy , Lipoprotein(a)/genetics , Male , Molecular Weight , Phenotype , Polymorphism, Genetic/genetics , Protein Isoforms/blood , Protein Isoforms/genetics , Reference Values , Risk FactorsABSTRACT
Apolipoprotein(a) [apo(a)] is a highly polymorphic glycoprotein which has been suggested to play a role in Alzheimer's disease (AD). Plasma lipoprotein(a) [Lp(a)] levels and the differential expression of apo(a) isoforms were analyzed in 73 sporadic AD patients compared with 73 age- and gender-matched healthy controls. The distribution of apo(a) isoforms and Lp(a) concentrations were similar in the two groups. However, we observed that AD patients with no apo(a) isoform from immunoblots (subjects with the 'null phenotype') had a mean age at onset of 76.8+/-8.8 versus 66.9+/-9.6 years of those who expressed at least one apo(a) band (P = 0.010). Multivariate analysis showed that this effect was independent of apolipoproteinE epsilon4 allele. We conclude that the expression of at least one apo(a) isoform may interact with other pathogenic mechanisms involved in controlling the age at onset of AD.
Subject(s)
Alzheimer Disease/genetics , Apolipoproteins/deficiency , Genetic Predisposition to Disease/genetics , Lipoprotein(a)/deficiency , Age of Onset , Aged , Alzheimer Disease/blood , Alzheimer Disease/epidemiology , Apolipoprotein E4 , Apolipoproteins/blood , Apolipoproteins/genetics , Apolipoproteins E/blood , Apolipoproteins E/genetics , Apoprotein(a) , DNA Mutational Analysis , Female , Genetic Testing , Humans , Lipoprotein(a)/blood , Lipoprotein(a)/genetics , Male , Phenotype , Protein Isoforms/blood , Protein Isoforms/geneticsABSTRACT
We describe an Italian pedigree with hereditary dementia associated with a novel T122R mutation in the presenilin-2 gene (PSEN2). The clinical history, symptom presentation, and structural neuroimaging were consistent with an atypical form of dementia. Disease expression varied within family members. One in a pair of mutated monozygotic twins had evident signs of disease, whereas the other did not, even if her functional neuroimaging investigations, cerebrospinal fluid levels of Abeta1-42, and Tau protein were able to provide markers for future disease development. These observations suggest the importance of still unknown biological and perhaps environmental factors in the disease determination.
Subject(s)
Dementia/genetics , Membrane Proteins/genetics , Mutation , Aged , Brain/pathology , Dementia/cerebrospinal fluid , Dementia/pathology , Dementia/psychology , Female , Humans , Male , Middle Aged , Pedigree , Presenilin-2ABSTRACT
Apolipoprotein(a) [apo(a)] is a genetically polymorphic glycoprotein that has several similarities to apolipoprotein E. However, its role as a risk factor for frontotemporal dementia (FTD) remains to be elucidated. We therefore investigated the effect of an apo(a) polymorphism on the incidence of FTD in a sample of Caucasian Italian patients. From the entire group of FTD patients (n=54), 55.6% of the subjects had at least one apo(a) low molecular weight (MW) isoform, compared to 29.9% of non-demented controls (n=77). The difference between the two groups was statistically significant (odds ratio 2.93, 95% confidence interval 1.42-6.06, P=0.003). The FTD group was further divided into sporadic (n=26) and familial (n=28) cases. Even after such dichotomization, both sporadic and familial FTD patients showed a significantly higher prevalence of low MW apo(a) isoforms than the cognitively healthy controls (P=0.011 and P=0.025, respectively). Our data suggest a role of apo(a) phenotypes of low MW in mediating susceptibility to FTD.
Subject(s)
Apolipoproteins A/blood , Dementia/blood , Protein Isoforms/blood , Aged , Aged, 80 and over , Apolipoproteins A/metabolism , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoblotting , Italy/epidemiology , Lipoprotein(a)/blood , Male , Middle Aged , Phenotype , Polymorphism, Genetic , Protein Isoforms/metabolism , Random Allocation , Regression Analysis , Statistics, NonparametricABSTRACT
CST3 is the coding gene for cystatin C (CysC). CST3 B/B homozygosity is associated with an increased risk of developing Alzheimer disease. We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3. Pulse-chase experiments demonstrated that the release of the B variant of CysC has a different temporal pattern compared to that of the A one. Fibroblasts B/B homozygous displayed a reduced secretion of CysC due to a less efficient cleavage of the signal peptide, as suggested by high-resolution Western blot analysis and by in vitro assay. In the brain, the reduced level of CysC may represent the molecular factor responsible for the increased risk of Alzheimer disease.
Subject(s)
Alzheimer Disease/genetics , Cystatins/genetics , Cystatins/metabolism , Aged , Blotting, Western , Cells, Cultured , Cystatin C , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Genetic Predisposition to Disease , Haplotypes , Homozygote , Humans , Male , Middle Aged , Protein Sorting Signals/physiology , Skin/cytologyABSTRACT
Frontotemporal dementia (FTD) is a clinical entity grouping different diagnostic conditions. FTD can occur in a sporadic form; however in 30-50% of cases a familial form of FTD has been observed. Mutations in the TAU gene were associated to familial FTD linked to chromosome 17. Our aim was to investigated the proportion of FTD cases attributable to TAU gene mutations in an Italian clinical series. We analyzed 38 patients with FTD; of these, 13 had a positive family history of FTD. All TAU gene exons and flanking intronic regions were sequenced. In our familial FTD sample the estimation of TAU gene mutations accounted for a relative low prevalence (7.6%); based on our results we could argue the existence of other mutations in regulatory regions in the TAU gene or, on the other hand, other genes might be responsible for the most cases of familial FTD.
