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Alzheimer's disease (AD) represents the most prevalent manifestation of the cognitive disorders in the elderly. The dramatic nature and the economic burden of the disease make AD a worl-wide problem. This paper reviews the genetic factors which explain the pathogenesis of AD, i.e., mutations of the genes encoding the amyloid precursor protein (APP), presenilin 1 (PS-1) and 2 (PS-2). Moreover, the polymorphism of the ApoE gene and the mutations of the hemochromatosis gene (HFE) are discussed. HFE mutations may anticipate the clinical manifestation of AD. The epigenetic factors related to AD are also discussed

To evaluate the stability and reproducibility of selected peripheral oxidative stress markers and their possible relation to cognitive performance, three different blood samples were taken at 7- to 10-day intervals from 11 patients with probable Alzheimer disease (AD) and 11 nondemented controls. Blood samples were also collected once from 6 patients with vascular dementia (VT). alpha -1-Antichymotrypsin (ACT), C-reactive protein (CRP), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), lactoferrin (LTF), and total lipid peroxidation (LPO) were then measured. Blood levels of ACT and GSH-Px were increased in AD patients but not in patients with VD. Levels of LTF, CRP, and LPO were comparable between AD patients and controls. Erythrocyte SOD activity was increased in AD patients. Blood levels of ACT negatively correlated with LPO levels and positively correlated with scores of the Global Deterioration Scale of AD patients. ACT might be implicated in controlling oxidative damage of blood lipids and their turnover during the progression of AD.

Apolipoprotein E genotypes were determined in 30 healthy elderly controls, 42 patients with Alzheimer's disease, 13 subjects with vascular dementia and 31 individuals with Down's syndrome. The frequency of epsilon4 allele carriers was significantly increased in the Alzheimer's disease group (chi(2)=4.918, P0.05) but also in the vascular dementia subjects (P0.01, Fisher's exact test). The established relationship between genotype and age at onset of Alzheimer's disease was not statistically significant in these data. Frequencies of the genotypes in the Down's syndrome group did not differ from those of controls. The results obtained in this sample of the Italian population suggest that the apolipoprotein E genotype may be of limited use in the differential diagnosis of dementia.

In the present study we analysed the genotype of HFE, the gene involved in hemochromatosis, in 107 patients with sporadic late-onset AD and in 99 age-matched non-demented controls. We observed that patients carrying the mutant HFE-H63D allele had a mean age at onset of 71.7 +/- 6.0 years versus 76.6 +/- 5.8 years of those who were homozygous for the wild-type allele (p = 0.001). The frequency of the HFE-H63D mutation was highest (0.22) in the patients aged < 70 years at the time of disease onset, whereas it was 0.12 in those with disease onset at an age of 70-80 years, and 0.04 in those aged more than 80 years, The APOE genotype did not significantly modify the effect of HFE on age at onset. We conclude that mild disturbances of iron homeostasis associated with a common genetic determinant may interact with other pathogenic mechanisms involved in AD. HFE mutations may anticipate AD clinical presentation in susceptible individuals. (C) 2001 Elsevier Science Inc. All rights reserved.

The objective of our study was to evaluate the effects of the apolipoprotein E (ApoE) phenotype and gender on the response to tacrine treatment in Alzheimer's disease (AD). ApoE phenotyping was performed on 76 patients treated with tacrine for AD. This group comprised 33 ApoE epsilon4 allele carriers (epsilon4+) and 43 non-epsilon4 carriers (epsilon4-). Patients were treated blindly in relation to the ApoE phenotype, with incremental tacrine dosages ranging from 40 mg/day up to the highest dosage (160 mg) tolerated without side-effects. At least 6 weeks elapsed between each increase. Changes in the scores for the Alzheimer Disease Assessment Scale-Cognitive Component (ADAS-Cog) between baseline and each increment in dosage were assessed in the epsilon4- and epsilon4+ groups. The cut-off point for being considered as responsive to tacrine treatment was a 4-point decrease in the ADAS-Cog score. There was no tendency for the epsilon4- carriers to respond better than the epsilon4+ carriers. When patients were stratified by gender, no differences were found between the effects of the treatment on men and women. Consequently, these results do not support the hypothesis that the ApoE phenotype and gender are predictors of the response to tacrine in AD patients.

Plasma concentrations of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), C reactive protein (CRP) and alpha-1-antichymotrypsin (ACT) in 145 patients with probable Alzheimer's 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

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).

A rapid and specific diagnostic test for Alzheimer’s disease (AD), the prevalent cause of dementia in the elderly, is currently unavailable. The aim of this study was to verify the validity of the recently proposed ‘Eye Test’ in the identification of AD patients, based on their supposed greater mydriatic response to cholinergic antagonists. We tested the pupillary response to the instillation of 0.01% tropicamide in 48 subjects: 15 patients with probable or possible Alzheimer’s disease, five patients with vascular dementia (VD), 16 elderly controls (EC) and 12 young controls (YC). Mean pupil dilation in the treated eye at 30 and 40 min after drops instillation was not significantly different among the four groups. The mean change in anisocoria at 30 min was significantly greater in the AD group (0.90 mm, S.D. 0.83) than in the YC group (0.21 mm, S.D. 0.46), but no significant difference was found among the AD group, the EC group and the VD group. Our results, therefore, do not support the potential usefulness of the pupillary response to dilute tropicamide for identifying individuals with AD.

The e4 allele of apolipoprotein E (ApoE) has been associated with Alzheimer’s disease (AD): the frequency of the e4 allele is elevated in samples of AD patients1,2 and individuals with a single or double dose of the s4 allele have earlier onset of AD symptoms1. Furthermore, subjects with one or two e4 alleles have been shown to have increased amounts of the neurofibrillary tangles and amyloid plaques associated with AD3.

The analysis of variance for repeated measures was utilized, using the change of pupil diameter from baseline in the eye treated with tropicamide as a dependent variable. In a second analysis, we considered the change in anisocoria (difference between the change of pupil diameter in the treated eye and that in the contralateral eye) as a dependent variable, using the