Elisabetta Broggio

Different pattern of association of paraoxonase Gln192-->Arg polymorphism with sporadic late-onset Alzheimer's disease and coronary artery disease.

The paraoxonase (PON1) Gln192-->Arg polymorphism was examined in a group of sporadic late-onset Alzheimers disease (AD) patients, in a group of coronary artery disease (CAD) patients, and in normal subjects. The AD sample showed a PON1*R allele frequency significantly lower than the control group (0.225 vs. 0.281, P=0.049). In the CAD patients the *R allele was more frequent than in the controls (0.230 vs. 0.213), though not significantly (P=0.28). The odds ratios (OR) adjusted for age, gender, and APOE polymorphism by logistic regression analysis highlighted that in AD the PON1 RR genotype was significantly protective (OR=0.41, 95% CI=0.19-0.90; P=0.025), whereas in CAD it appeared to be a significant risk factor (OR=5.11, 95% CI=1.09-23.9; P=0.038) limited to younger patients.

Combined Effect of Apolipoprotein E Genotype and Past Fertility on Age at Onset of Alzheimer’s Disease in Women

Background: Various risk factors influence the development of Alzheimer’s disease (AD). Apolipoprotein E (APOE) e*4 allele has a major role in AD susceptibility and its presence reduces age at AD onset. APOE is also thought to influence human reproduction, and common APOE genotypes seem to be associated with differential fertility. With this study, we investigated possible relationships between APOE genotype, past fertility, and AD onset age. Methods:APOE genotypes were determined in a sample of 176 women with sporadic AD. The number of children each woman had delivered was recorded. Results: A comparison of APOE genotype distribution in parous and nulliparous AD women confirmed that the e*3/e*3 genotype is associated with higher fertility and the e*4-carrying genotypes with lower fertility. When the combined effects of fertility and APOE genotypes on AD onset age were analyzed, parity was found to be associated with a significantly lower AD onset age (73.8 ± 6.2 years) than nulliparity (80.7 ± 5.0 years; p = 0.0007) among subjects carrying e*3/e*3 and e*3/e*2 genotypes. A similar effect was absent among e*4 carriers. Considering the high frequency of e*3/e*3 plus e*3/e*2 genotypes in Europe (range: 63–87%), past fertility may influence AD onset age in many women. Conclusion: Past fertility may have a relevant effect on AD onset age and this effect is influenced by APOE genotype.

Influence of variation in the follicle-stimulating hormone receptor gene (FSHR) and age at menopause on the development of Alzheimer's disease in women.

Background: The higher prevalence of sporadic Alzheimer’s disease (AD) in women may be explained by their longer life expectancy, but also by biological gender-specific factors such as a woman’s past fertility. Methods: We investigated the relationship between fertility and susceptibility to AD in women by studying two polymorphisms at codons 307 and 680 of the follicle-stimulating hormone receptor gene (FSHR) involved in determining human fertility. The role of age at menopause (AM) as a gender-specific AD susceptibility determinant was also examined. The study population comprised 291 AD patients (70.1% women) and 134 controls (63.4% women). Results: Logistic regression analysis showed that only among the women the FSHR AS/AS genotype was associated with a significantly lower risk of AD (OR = 0.36, 95% CI: 0.15–0.85), suggesting a gender-specific protective role of the FSHR genotype against AD susceptibility. A lower age at natural menopause was observed in the AD patients (49.7 ± 2.53) than in the controls (50.7 ± 2.53, p = 0.02) and on linear regression analysis an association emerged between an earlier AM and an earlier AD onset (p = 0.004). Conclusions: Genetic and non-genetic gender-specific factors may contribute to the AD pathogenesis in women, although further investigations are required to clarify their actual role.

The H+ allele of the lipoprotein lipase (LPL) HindIII intronic polymorphism and the risk for sporadic late-onset Alzheimer's disease.

A sample of 243 Italian patients affected by the sporadic late-onset form of Alzheimers disease (AD) was studied for the HindIII intronic polymorphism of the lipoprotein lipase (LPL) gene and compared with a sample of 148 healthy subjects. Since this polymorphism has been reported to be associated with CAD and because the two pathologies share common aspects, we decided to study it in AD too. We found a difference in the allele distribution, in that the H+ allele was more frequent in patients (0.782) than in controls (0.720); this difference was not quite significant (P = 0.059). The odds ratio from the logistic regression analysis for the H+ carrying genotypes was 2.7 (95% CI = 1.01-7.21; P = 0.048). When the separate genotypes H+H+ and H+H- were entered into the analysis, only H+H+ was found to significantly increase the risk with respect to H-H- (P = 0.029). This means that carrying this allele significantly increases the risk of developing AD, and the risk is mostly associated with the H+H+ genotype.

Cognitive stimulation of executive functions in mild cognitive impairment: specific efficacy and impact in memory.

Executive functions play an important role in the maintenance of autonomy in day-to-day activities. Nevertheless, there is little research into specific cognitive training for Mild Cognitive Impairment (MCI). We present the results of a program which aims to teach specific strategies and metacognitive abilities in order for patients to be able to carry out attentional and executive tasks. Two groups (A and B) were compared in a cross-over design. After the first evaluation, Group A (but not B) participated in a six month cognitive stimulation program. After a second assessment, only Group B received treatment and then a final evaluation was carried out on both groups. The results show that: i) both groups improved their performance as an effect of training; ii) improvements generalized to memory and general cognitive tasks; iii) in the interval without training, Group Bs performance worsened and iv) Group A partially maintained their results over time.

Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease

Family history of dementia (FH) is a recognized risk factor for developing late‐onset Alzheimers disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH−). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH− AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH− AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44–5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53–4.44; P = 0.0004). Having a first‐degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3–6.4; P = 0.009 and OR 2.7, 95%CI 1.1–6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not.

Apolipoprotein E genotypes and plasma levels in mild cognitive impairment conversion to Alzheimer's disease: A follow‐up study

Mild cognitive impairment (MCI) is the transition stage between the normal aging process and dementia itself. The most common clinical phenotype is amnestic MCI (aMCI) [subtypes: single domain (sMCI) and multiple domains (mMCI)], which is considered prodromal to Alzheimers disease (AD). The APOE (apolipoprotein E) e4 allele is the most important genetic risk factor for AD, but its association with MCI onset and conversion to AD is controversial. In this follow‐up study of 88 aMCI patients (68% sMCI and 32% mMCI at baseline), we examined APOE genotypes and plasma levels in relation to MCI development and progression based on their clinical/cognitive data obtained at baseline and follow‐up assessment (mean follow‐up time = 6.6 ± 3.4 years). A control sample (n = 164) was collected in previous investigations. The overall conversion rate to mMCI or AD was 52.2%. The APOE e4 allele was associated with a higher risk of developing MCI (OR: 2.23; 95%CI: 1.22–4.08). The conversion rate in the e4 allele carriers (32% of the sample) was 71%, and the e4 allele was associated with a higher risk of conversion to mMCI/AD (OR: 4.1; 95%CI: 1.2–13.6). APOE e2 allele carriers were 7% (all sMCI) and none progressed to mMCI/AD. Among MCI subjects, e4 carriers had the lowest plasma apoE levels (37.8 ± 12.5 mg/L), and e2 carriers had the highest (78.6 ± 38.1 mg/L). APOE e4 is a risk allele for the development and progression of aMCI, the APOE e2 allele seems to be protective, and apoE levels associated to them are an integral part of their action.

Association study of two steroid biosynthesis genes (COMT and CYP17) with Alzheimer's disease in the Italian population

The greater predisposition of women to Alzheimers disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case-control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity.

C-338A polymorphism of the endothelin-converting enzyme (ECE-1) gene and the susceptibility to sporadic late-onset Alzheimer's disease and coronary artery disease

The human endothelin-converting enzyme (ECE) is involved in β-amyloid synthesis and regulation of the endothelin-1 (ET-1) vasoconstricting peptide. We investigated the distribution of the C-338A polymorphism of the ECE-1b gene in sporadic late-onset Alzheimer’s disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C-338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively). The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.

Transient epileptic amnesia mistaken for mild cognitive impairment? A high-density EEG study

Mild cognitive impairment (MCI) converts to Alzheimers disease within a few years of diagnosis in up to 80% of patients. The identification among such a population of a rare form of epilepsy (transient epileptic amnesia [TEA]), characterized by mixed anterograde and retrograde amnesia with apparent preservation of other cognitive functions, excessively rapid decay of newly acquired memories, and loss of memories for salient personal events of the remote past, strongly affects prognosis and medical treatment. Our aim was to define the clinical utility of routine high-density electroencephalography (EEG) in patients with MCI for the detection of epilepsy, especially TEA. Using high-density EEG (256 channels), we were able to single out 3 cases of TEA previously misdiagnosed as MCI in this cohort of 76 consecutive patients with MCI diagnosed at our center. Antiepileptic treatment effectively stopped the acute episodes of memory loss. To our knowledge, this is the first report of an incidence of 4% of TEA recorded in such a cohort.