Elisa Porcellini

Homocysteine and folate as risk factors for dementia and Alzheimer disease

BACKGROUND In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results. OBJECTIVE We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. DESIGN A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12. RESULTS Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 micromol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (< or = 11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12. CONCLUSIONS Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimers disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.

Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation

BACKGROUND A number of studies associate Alzheimers disease with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute phase proteins. We integrated this information to better define risk and determine the relative importance of APOE and immunological mediators. METHODS We investigated functional gene variants for APOE, IL-10 (3 loci), ACT (2 loci), HMGCR, IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma, and IL-6 found for 260 AD patients and 190 controls enrolled in Northern Italy. A fuzzy latent classification approach, namely grade-of-membership analysis (GoM), was taken to identify extreme pure type risk sets, or profiles. This approach automatically relates individuals to each profile via graded membership scores. FINDINGS Four extreme pure type risk sets were identified. Set I defined low intrinsic risk and had a low probability of carrying pro-inflammatory alleles or APOE epsilon4. Three sufficient risk sets were identified: early onset AD (set II) was characterized by a high density of pro-inflammatory alleles, a rapid cognitive decline and independent of APOE epsilon4. Late onset AD had a lower density (ages 65-74, set III), or a subset homozygous (ages 75+, set IV), for these alleles and a high probability of one or two APOE epsilon4 alleles. A total of 97% of the subjects who were cases strongly resembled, i.e. had at least 50% membership in, the sufficient risk sets, as did 25% of middle aged control subjects. IL-10, HMGCR, ACT, and IL-1beta gene variants were each more informative in identifying the risk sets than was APOE. INTERPRETATION AD likely has many determinants including APOE polymorphism and gene variants that modulate innate immunity. Identification of these factors, risk prediction for individuals, and successful prevention and treatment trials require integration of relevant information.

Interleukin-6 gene polymorphism is an age-dependent risk factor for myocardial infarction in men.

Several studies show that inflammatory components may contribute to atherosclerosis and increase the risk for myocardial infarction (MI). Interleukin‐6 (IL‐6) is a key pro‐inflammatory and immune‐modulatory cytokine of relevance for cardiovascular diseases. In this case‐control study, 200 patients with MI and 257 healthy controls were genotyped for the polymorphism present in −174 promoter region of the IL‐6 gene. Plasma concentrations of IL‐6 and C‐reactive protein (CRP) in a group of patients and controls were measured. The −174 C allele was associated with an increased risk of developing MI (OR = 2.886, c.i. = 1.801–4.624, P = 0.0001) in older patients, while no association was found in younger ones. The IL‐6 plasma levels were higher in patients with MI carrying the CC genotype than in GG patients (CC carriers, IL‐6 = 2.97 pg mL−1 vs. GG carriers = 1.81 pg mL−1, P = 0.016). A positive correlation of IL‐6 levels with those of CRP in serum from patients with MI was also found. Data from this study suggest that the C allele of the promoter polymorphism in the IL‐6 gene is a risk factor for MI in the elderly, and the production of the IL‐6 is differentially affected by different genotypes of the IL‐6 −174 promoter polymorphism.

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

The only established genetic determinant of non-Mendelian forms of Alzheimers disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.

Herpes virus in Alzheimer's disease: relation to progression of the disease

Studies regarding different viruses of the herpes family, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or human herpes virus 6 (HHV-6) in Alzheimers disease (AD) are scarce. DNA from peripheral blood leukocytes (PBL) and brain samples were analyzed for the presence of CMV, EBV, or HHV-6. All samples were negative for CMV. EBV positivity was 6% in AD brains, whereas 45% of PBL samples from AD patients and 31% from controls were positive for EBV (p = 0.05). HHV-6 showed a 23% positivity in PBL samples from AD and 4% from controls (p = 0.002). 17% of AD brains were HHV-6 positive. Within a group of elderly individuals, followed up for 5 years, EBV-positive or HHV-6-positive PBL increased in those who developed clinical AD. Virus serological positivity was also investigated, and IgG levels for CMV and EBV antigens were also increased in those subjects who developed AD during the follow-up. Our findings suggest that EBV and HHV-6 may be environmental risk factors for cognitive deterioration and progression to AD in elderly persons.

Alzheimer's disease gene signature says: beware of brain viral infections

BackgroundRecent findings from a genome wide association investigation in a large cohort of patients with Alzheimers disease (AD) and non demented controls (CTR) showed that a limited set of genes was in a strong association (p > l0-5) with the disease.Presentation of the hypothesisIn this report we suggest that the polymorphism association in 8 of these genes is consistent with a non conventional interpretation of AD etiology.Nectin-2 (NC-2), apolipoprotein E (APOE), glycoprotein carcinoembryonic antigen related cell adhesion molecule- 16 (CEACAM-16), B-cell lymphoma-3 (Bcl-3), translocase of outer mitochondrial membrane 40 homolog (T0MM-40), complement receptor-1 (CR-l), APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A) result in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging, leading to neuronal loss, inflammation and amyloid deposition.Implications of the hypothesisWe hypothesized that such genetic trait may predispose to AD via complex and diverse mechanisms each contributing to an increase of individual susceptibility to brain viral infections

A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer’s disease

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimers disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.

Gene Signature in Alzheimer's Disease and Environmental Factors: The Virus Chronicle

Genome wide association investigations from large cohorts of patients with Alzheimers disease (AD) and non demented controls (CTR) showed that a limited set of genes were associated (p > 10-5) with the disease. A very recent study from our group showed that an additional limited group of SNP in selected genes were associated with AD. In this report we argue that the association of these genes with AD is suggestive of a pivotal role of environmental factors in the pathogenesis of the disease and one of these factors is virus infection. In other words, the genetic signature revealed by genome wide association (GWA) studies discloses a network of genes that might influence the ability of the central nervous system to cope with and fight against the invasion by virus of the herpes family. In fact, Nectin-2 (NC-2); apolipoprotein E (APOE); glycoprotein carcinoembryonic antigen related cell adhesion molecule-16 (CEACAM-16); B-cell lymphoma-3 (Bcl-3); translocase of outer mitochondrial membrane 40 homolog (T0MM-40); complement receptor-1 (CR-l); APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A); Phosphatidyl inositol- binding clathrin assembly protein gene (PICALM); ATP-bonding cassette, sub family A, member 7 (ABCA7); membrane spanning A4 (MSA4); CD2 associated protein (CD2AP); cluster of differentiation 33 (CD33); and ephrin receptor A1 (EPHA1) result in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and amyloid deposition.