Federico Licastro

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.

Increased plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?

Plasma concentrations of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), C reactive protein (CRP) and alpha-1-antichymotrypsin (ACT) in 145 patients with probable Alzheimers disease (AD) and 51 non-demented controls were measured. To investigate the cellular activation of peripheral immune system, plasma levels of neopterin were also investigated. Plasma levels of IL-1 were detectable in 17 patients with AD (13%) and only in one control (2%) and average levels of IL-1 were higher in AD patients than in controls (p < 0.001). IL-6 plasma levels were detectable in a higher proportion of AD and controls (53% and 27%, respectively), and were increased in patients with AD (p < 0.001). Plasma levels of ACT were increased in patients with AD (p < 0.001) and CRP levels were in the normal range. Plasma levels of neopterin were slightly lower in AD patients than in controls, but differences were not statistically significant. No significant correlation was observed between IL-1 and IL-6 levels or neopterin and cytokine levels in plasma from AD patients. Plasma levels of ACT negatively correlated with cognitive performances, as assessed by the mini mental state examination (MMSE; R = -0.26, p < 0.02) and positively correlated with the global deterioration state (GDS) of AD patients (R = 0.30, p < 0.007). Present findings suggested that detectable levels of circulating cytokines and increased ACT might not be derived by activation of peripheral immune system of AD patients. Detection of these molecules might be used for monitoring the progression of brain inflammation associated with 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.

Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains.

In this study, we investigated the presence and role of immunoproteasome and its LMP2 subunit polymorphism at codon 60 in Alzheimers disease (AD). Immunoproteasome was present in brain areas such as hippocampus and cerebellum and localized in neurons, astrocytes and endothelial cells. A higher expression of immunoproteasome was found in brain of AD patients than in brain of non-demented elderly, being its expression in young brain negligible or absent. Furthermore, AD affected regions showed a partial decrease in proteasome trypsin-like activity. The study of LMP2 polymorphism (R/H) showed that it does not influence LMP2 expression (neither the mRNA nor mature protein) in brain tissue. However, control brain areas of AD patients carrying the RR genotype showed an increased proteasome activity in comparison with RH carriers. To test whether this effect of the genotype might be related to AD onset we performed a genetic study, which allowed us to exclude an association of LMP2 codon 60 polymorphism with AD onset, despite its influence on the proteasome activity in human brain.

Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain

Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimers disease (AD) and non-demented controls. The -174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the -174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the -174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the -174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine.

Blood Levels of Alpha-1-Antichymotrypsin and Risk Factors for Alzheimer’s Disease: Effects of Gender and Apolipoprotein E Genotype

Concentrations of α1-antichymotrypsin (ACT) were measured in serum or plasma samples from 137 patients with late-onset probable Alzheimer’s disease (AD) and 89 controls. Levels of ACT from sera or plasma from both AD or controls were different, being highest in serum samples. Increased levels of serum or plasma ACT and normal levels of C-reactive protein (CRP) were found in AD. Differences in serum ACT levels between AD and controls were statistically significant, while those in plasma ACT were not. ACT serum levels were higher in women with AD that in female and male controls. Apolipoprotein E (APOE) genotypes did not independently affect blood ACT levels in both AD and controls; although, among AD patients, female AD patients with APOE 4,4 showed the highest level of serum ACT. The gender effect appeared to be prominent, since female AD patients with APOE 3,3 had similar ACT levels to those of female AD patients with APOE 4,4.

Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging.

Incidence studies of blood inflammatory markers as predictors of dementia in older age are few and did not take into account hyperhomocysteinemia, although this condition is associated with both inflammation and increased risk of dementia. We investigated the relationships of baseline serum C-reactive protein (CRP), serum interleukin 6 (IL6), plasma alpha-1-antichymotrypsin, and hyperhomocysteinemia (defined as plasma total homocysteine>15 micromol/L) with risk of incident Alzheimers disease (AD) and vascular dementia (VaD) in a dementia-free Italian population-based elderly cohort (n=804, 53.2% women, mean age 74 years) with 4 years of follow-up. No inflammatory marker, alone or in combination, predicted AD risk whereas the combination of high CRP and high IL6 was associated with risk of VaD (HR, 2.56; 95%CI, 1.21-5.50) independently of socio-demographic confounders, traditional risk factors and hyperhomocysteinemia. By contrast, in the same model, hyperhomocysteinemia was independently associated with AD (HR, 1.91; 95%CI, 1.02-3.56) but not VaD risk. Blood inflammatory markers are associated with increased VaD risk but do not predict AD, which seems selectively associated with hyperhomocysteinemia.

Gene polymorphism affecting α1‐antichymotrypsin and interleukin‐1 plasma levels increases Alzheimer's disease risk

Plasma levels of α1‐antichymotrypsin (ACT) and inter‐leukin‐1β (IL‐1β) were increased in patients with probable Alzheimers disease (AD). A common polymorphism within ACT and IL‐1β genes affected plasma levels of ACT or IL‐1β, and AD patients with the ACT T,T or IL‐1β T,T genotype showed the highest levels of plasma ACT or IL‐1β, respectively. The concomitant presence of the ACT T,T and IL‐1β T,T genotypes increased the risk of AD (odds ratio: 5.606, confidence interval: 1.654–18.996) and decreased the age at onset of the disease. Ann Neurol 2000;48:388–391

Microbes and Alzheimer's Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even thoug ...

Lectins and superantigens: Membrane interactions of these compounds with T lymphocytes affect immune responses

1. Lectins and superantigens belong to two different families of macromolecules which are able to interact with cells of the immune system. 2. The principal mechanisms by which they modulate immune responses are presented in this review. 3. Possible similarities shared by these proteins and their common mechanisms of action upon immunocytes will be presented along with a brief discussion regarding the role of these molecules in physiological immune responses and human diseases.