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A recent study has shown that a genetic variation in the Cathepsin D (catD) gene is a major risk factor for the development of Alzheimer's disease (AD). CatD is an intracellular aspartyl protease involved in neurodegeneration. A C-->T (Ala-->Val) transition at position 224 has been associated with altered intracellular maturation. Recently, a significant overrepresentation of the T allele of the catD gene in AD patients compared with controls was reported. However, this finding has not yet been confirmed. We analyzed the distribution of catD and apolipoprotein E polymorphisms in Italian patients with sporadic and familial AD (FAD). Our studies revealed that the distribution of catD polymorphism did not differ in AD and FAD patients and controls. Thus, our data do not support a role for the catD gene as a genetic risk factor in the development of AD.

We investigated the prognostic significance of microsatellite instability (MI) in 50 consecutive patients with sporadic mucinous colorectal cancer who had undergone only surgery. We evaluated MI and the pathological features with a possible prognostic value for each tumor, and the effect of the examined parameters on patients' outcome was statistically analyzed (univariate and multivariate analysis). All patients were followed-up for a minimum of 72 months or until death; in evaluating survival, only deaths of colorectal cancer were considered. DNA extracted from tumor sections and the corresponding normal tissue was analyzed by polymerase chain reaction at six microsatellite loci: D2S123, D3S1611, D3S49, D5S107, BAT26, BAT40. Alterations at two or more loci were detected in 36% of cases (MI+ tumors). MI+ and MI- cancers differed significantly in the pattern of growth, and most MI+ tumors showed an expanding type of growth (72.2%, P = .005). At univariate analysis, improved survival rate was significantly associated with MI, as well as with the following parameters: expanding cancer growth, Dukes stage, and absence of venous invasion. Nevertheless, at multivariate analysis, only the pattern of cancer growth and Dukes stage were independent prognostic factors, whereas the effect on survival of MI and venous invasion was found to be negligible. In our study, MI+ and MI- cancers differ only on the pattern of growth; therefore, our data suggest that the better survival rate in mucinous cancers with genomic instability is strictly related to their less aggressive type of growth.

Background Mutations in the presenilin 1 ( PS1 ) and presenilin 2 ( PS2 ) genes, and more rarely in β-amyloid precursor protein (βAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD). Objective To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the βAPP to find pathogenetic mutations in FAD. Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy. Design and Methods Polymerase chain reaction–single-strand conformation polymorphism and DNA se-quencing were used to investigate the affected members of families with FAD. Results We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the βAPP Val717Ile mutation. Conclusions One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and βAPP genes was beneficial in characterizing gene function in FAD.