Short arm of chromosome 11 and sporadic Alzheimer's disease: catalase and cathepsin D gene polymorphisms.

Catalase (CAT) -262 C/T promoter (rs1001179), cathepsin D (CTSD) exon 2 (rs17571), and apolipoprotein E (APOE) gene polymorphisms were studied in 242 patients with sporadic Alzheimer's disease (AD) and 421 unrelated age-, sex-, and ethnically matched control subjects from Apulia (Southern Italy). No statistically significant differences in CAT rs1001179 and CTSD rs17571 genotype and allele distribution between AD cases and healthy controls were observed for the whole AD sample, and when AD group was categorized by age at onset in early- and late-onset AD subsets. Furthermore, we did not find any statistically significant differences in rates between CAT rs1001179 and CTSD rs17571 genotypes and AD controlling for APOE e4 allele status. Our data, at present, do not support a role of two gene polymorphisms of the short arm of the chromosome 11, the CAT rs1001179 and CTSD rs17571, as a possible susceptibility factors for sporadic AD.

Macronutrients, aluminium from drinking water and foods, and other metals in cognitive decline and dementia.

A possible role of the macronutrients and the basic elements of carbohydrates (glucose administration or depletion), proteins (amino acids such as tryptophan and tyrosine), and fat (unsaturated fatty acids) was recently proposed for age-related changes of cognitive function, and the cognitive decline of degenerative (AD) or vascular origin. The availability and utilization of glucose has been implicated in cognitive function not only as a result of nutritional and systemic metabolic conditions, but also, although speculatively, as a crucial phase of the mechanism of action of molecules used as cognitive-enhancers. Furthermore, many lines of evidence have focused on the importance of oxidative stress mechanisms and free radical damage in AD pathogenesis. In addition, epidemiological studies have recently reported an association between alcohol and the incidence of AD and predementia syndromes. Foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD, aluminium more likely acting as a cofactor somewhere in the cascade of events leading to the demented brain. A role for other metals in dementia have been speculated, given the encouraging results reported from studies on peripheral zinc concentrations, zinc supplementation, serum copper, either bound with ceruloplasmin or not, and iron metabolism in AD. Nonetheless, more data are needed to support a possible role of these metals in dementing diseases. Healthy diets, antioxidant supplements, and the prevention of nutritional deficiencies or exposure to foods and water with high content of metals could be considered the first line of defence against the development and progression of cognitive decline.

Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine.

A 77-year-old patient with initial behavioral and psychological symptoms of dementia was treated with clozapine (50 mg/daily). Since no clinical benefit was apparent, clozapine was discontinued after six weeks and the patient started on paroxetine (20 mg/daily). After three weeks on paroxetine, he was given another trial of clozapine at a starting dosage of 25 mg/daily. While clozapine had previously been well tolerated, this time he rapidly developed fever, mental confusion, lethargy, muscle spasms and rigidity. The diagnosis of neuroleptic malignant syndrome was delayed, because there was no leukocytosis and serum creatine phosphokinase was initially not elevated. Subcutaneous apomorphine was then given but, after an initial improvement, the patient developed a multiple organ failure syndrome and died.

Dietary fatty acids intakes and rate of mild cognitive impairment. The Italian Longitudinal Study on Aging.

The possible impact of diet, particularly the intake of fatty acids, on cognitive decline and dementia was addressed recently by several studies. We investigated the role of dietary fatty acids on the rate of mild cognitive impairment (MCI) in a population-based, prospective study carried out on 278 and 186 nondemented elderly subjects (65-84 years) at the 1st (1992-1993) and 2nd (1995-1996) survey from the cohort of Casamassima, Bari, Italy (n=704), one of the eight centers of the Italian Longitudinal Study on Aging. During the median follow-up of 2.6 years, 18 new events of MCI were diagnosed, and high polyunsaturated fatty acids (PUFA) intake appeared to be a protective factor against the development of MCI [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.43-0.98, trend-test, df=1, p<0.04]. However, when we controlled for the possible confounders (age, sex, education, Charlson comorbidity index, and total energy intake), the HR slightly changed, and the highly skewed 95% CI, while not statistically significant, may be important (HR: 0.62, 95% CI: 0.34-1.13, p=0.12). In our population, dietary fatty acids intakes were not associated with incident MCI in older age, only high PUFA intake evidenced a borderline nonsignificant trend for a protective effect against the development of MCI.

Cerebrovascular disease in the elderly: lipoprotein metabolism and cognitive decline.

Data concerning the treatment of lipoprotein disturbances in patients with cerebrovascular disease (CVD) are less robust than those for coronary heart disease (CHD), raising clinical questions as to which is the appropriate therapeutic approach to stroke patients. Although observational cohort studies have failed to demonstrate an association between lipoprotein disorders and stroke incidence, recently completed trials of subjects at risk for CHD have shown that statins reduce not only the risk of myocardial infarction and death, but also that of brain infarction and transient ischemic attacks. At present, it seems reasonable to conclude that stroke patients with undesirable lipid profiles who have a history of CHD should receive specific treatment for the lipid disorder. Recommendations are more problematic for stroke patients with lipid disorder but no history of CHD. Furthermore, many of the risk factors for CVD and vascular dementia (VaD), including serum total cholesterol (TC), lipoprotein(a), diabetes, atrial fibrillation, hypertension, apolipoprotein E levels, and atherosclerosis, have also been shown to increase the risk of Alzheimer's disease (AD). In a recent study, we estimated the prevalence, incidence and rate of progression of Mild Cognitive Impairment (MCI) to dementia, and correlated vascular risk factors with incident MCI and its progression to dementia. We evaluated 2963 individuals from the population-based sample of 5632 subjects 65-84 years old of the Italian Longitudinal Study on Aging, with a 3.5-year follow-up. We found a progression rate to dementia (all causes) of 3.8/100 person-years. Furthermore, age was a risk factor for incident MCI, while education was protective, and serum TC evidenced a non-significant borderline trend for a protective effect. There was a non-significant trend for stroke as a risk factor of progression of MCI to dementia. In conclusion, in our population, among MCI patients who progressed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factors and CVD may influence the development of MCI and the rate of progression to dementia.

Lipid metabolism in cognitive decline and dementia.

This review will focus on the current knowledge on circulating serum and plasma risk factors of cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD) linked to cholesterol homeostasis and lipoprotein disturbances, i.e. total cholesterol (TC), 24S-hydroxy-cholesterol, lipoprotein(a) (Lp(a)), or apolipoprotein E (APOE). These measures linked to lipoprotein metabolism appear to be altered in AD, VaD, or predementia syndrome relative to controls, but with contrasting results. At present, several studies have demonstrated the dependence of APOE serum levels upon the APOE genotype, nonetheless serum APOE levels seems not to be a credible risk factor or a biochemical marker for AD instead of APOE genotyping. In fact, there was no consistent association of serum or plasma apoE protein levels with the disease when controlled for APOE genotype. In addition, there are some evidence that higher Lp(a) levels could be linked with AD, although there are studies suggesting an increased presence of low molecular weight apo(a) in AD, VaD, and frontotemporal dementia, that are associated with elevated Lp(a) levels. In fact, the apo(a) gene is highly polymorphic in length due to variation in the numbers of a sequence encoding the apo(a) kringle 4 domain, and plasma levels of Lp(a) are inversely correlated with apo(a) size. Furthermore, although serum/plasma levels of TC and 24S-hydroxycholesterol are not credible diagnostic markers for AD and cognitive decline, the current evidence suggests that they may be modifiable risk/protective factors. The prevailing wisdom is that high TC is a risk factor for dementia. However, the relationship between TC and dementia may vary considerably depending on when cholesterol is measured over the life course or, alternatively, in relation to the underlying course of the disease. Several observational studies have suggested that statins, which are effective in lowering cholesterol, may reduce the risk of dementia, but the results of these reports are inconclusive. Thus, more studies with long-term follow-up and serial assessments of TC are needed to further clarify the causal relationship between cholesterol and dementia.

Efficacy and tolerability of combined treatment with L-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus.

Lipoprotein(a) [Lp(a)] concentration is generally related to coronary artery disease (CAD) and cerebrovascular disease. However, at present, few interventions are available to lower Lp(a) concentrations. We investigated the effects of l-carnitine, co-administered with simvastatin, on hyper-Lp(a) in patients with type 2 diabetes mellitus. We conducted an open, randomised, parallel-group study, in one investigational center (University hospital). Fifty-two patients with type 2 diabetes mellitus, a triglyceride serum levels <400mg/dL (<4.5 mmol/L), and Lp(a) serum levels >20mg/dL (0.71 mmol/L) were randomised to receive simvastatin alone (n=26) or simvastatin plus l-carnitine (n=26) for 60 days. Simvastatin was administered, in both groups, at a dosage of 20 mg/day, while l-carnitine was administered at a dosage of 2g/day once daily. Both treatments were given orally. Serum levels of triglycerides, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol (total cholesterol minus HDL cholesterol), apolipoprotein B, and Lp(a) were measured at baseline and 60 days after starting treatment. No difference in time by groups (simvastatin and simvastatin plus l-carnitine) were observed in the reduction of LDL cholesterol, non-HDL cholesterol, and apoB serum levels. On the other hand, Lp(a) serum levels increase from baseline to 60 days in the simvastatin group alone versus a significant decrease in the combination group. Our findings provide support for a possible role of combined treatment with l-carnitine and simvastatin in lowering Lp(a) serum levels in patients with type 2 diabetes mellitus than with simvastatin alone. Our results strongly suggest that l-carnitine may have a role among lipid-lowering strategies.

Circulating biomarkers of cognitive decline and dementia.

Plasma and serum biochemical markers proposed for cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin and predementia syndromes (mild cognitive impairment and other related entities) are based on pathophysiologic processes such as lipoprotein metabolism (total cholesterol, apolipoprotein E, 24S-hydroxy-cholesterol), and vascular disease (homocysteine, lipoprotein(a)); SP formation (amyloid beta(Abeta)-protein, Abeta autoantibodies, platelet APP isoforms), oxidative stress (isoprostanes, vitamin E), and inflammation (cytokines). This review will focus on the current knowledge on circulating serum and plasma biomarkers of cognitive decline and dementia that are linked to cholesterol homeostasis and lipoprotein abnormalities, senile plaque formation and amyloid precursor protein (APP) metabolism, oxidative stress, and inflammatory reactions. Special emphasis will, however, be placed on biomarkers related to lipoprotein metabolism and vascular disease. Analytically, most plasma and serum proteins or metabolites lack reproducibility, sensitivity, or specificity for the diagnosis, risk and progression assessment, or therapeutic monitoring of AD and other dementing disorders. Measures linked to lipoprotein metabolism and vascular disease, APP metabolism, oxidative stress, or inflammation appear altered in AD relative to controls, but lack sufficient discriminatory power. Measures combining several biomarkers or incorporating a range of proteins in plasma and small molecule metabolites are promising approaches for the development of plasma or serum-based diagnostic tests for AD and other dementing disorders, as well as for predementia syndromes.

Cognitive frailty: Predementia syndrome and vascular risk factors.

With increasing emphasis on early diagnosis of Alzheimer disease (AD), clinical research has focused on the identification of risk factors that may be modified at a preclinical and early clinical stage of dementing disorders. Prevalence and incidence of different predementia syndromes vary as a result of different diagnostic criteria, as well as different sampling and assessment procedures. Particular interest in mild cognitive impairment (MCI) arises from the fact that MCI is thought to be a prodromal phase and therefore highly predictive of subsequent AD. Furthermore, many of the risk factors for cerebrovascular disease (CVD) and vascular dementia (VaD), including serum total cholesterol, hypertension, atherosclerosis, and apolipoprotein E (APOE) genotype have also been shown to increase the risk of AD. Both vascular factors and APOE epsilon4 allele have been associated with higher risk of AD. Some recent studies suggested further that CVD or vascular factors increased the risk of conversion of MCI to dementia. This review will focus on the possible role of vascular risk factors in modulating the risk of age-related cognitive decline, and the progression of predementia syndrome such as MCI to dementia.

Candidate genes for late-onset Alzheimer's disease: focus on chromosome 12.

In recent years, there was an increasing interest on candidate genes may play an important role in the development of Alzheimer's disease (AD). Several genome wide screens have undertaken so far or expanded recently, and suggested a number of genomic areas that may contain novel susceptibility genes for AD, in particular most compelling have been the findings on chromosome 12. Polymorphisms in different susceptibility genes on chromosome 12 (A2M, LRP1, CP2 and OLR1) are now being suggested as possible genetic markers for increased risk of developing AD. However, many of these studies are controversial and have shown conflicting results. Thus far, the search for the chromosome 12 Alzheimer's gene must continue and there are several other genes in this region that we are looking at. In this article, we focused on the current knowledge of the genetics of familial late-onset and sporadic AD linked to the chromosome 12, and the future search for other candidate genes.

The cathepsin D gene exon 2 (C224T) polymorphism and sporadic Alzheimer's disease in European populations.

The cathepsin D gene (CTSD) exon 2 (C224T) polymorphism has been associated with an increased risk for sporadic Alzheimer's disease (AD), but with controversial findings. We studied CTSD exon 2 (C224T) and apolipoprotein E (APOE) genotype frequencies in 168 AD patients and 218 age-matched healthy controls from Southern Italy. No statistically significant differences were found in CTSD allele or genotype frequencies between AD patients and controls, and there were no interactions with sex or APOE genotype. Furthermore, comparing our results with the findings from other European populations, the CTSD*T allele frequency showed a statistically significant increasing trend from Northern to Southern regions of Europe in AD patients and controls (z=2.51, p<.01; z=4.02, p<.001, respectively), with a concomitant inverse trend for CTSD*C allele frequency. The regional differences in CTSD allele frequencies could be related to the different patterns of association between this polymorphism and AD in various European studies.

Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and risk of Alzheimer's disease.

The +1073 C/T polymorphism of the oxidized low-density lipoprotein receptor-1 (OLR1) gene has been reported to be associated with late-onset Alzheimer's disease, whereas for the +1071 T/A polymorphism no association was found. We genotyped 169 sporadic Alzheimer's disease patients and 264 sex- and age-matched nondemented controls from Southern Italy for OLR1 +1073 C/T and +1071 T/A polymorphisms and for apolipoprotein E and LBP-1c/CP2/LSF. We also performed haplotype analysis. For the +1073 C/T polymorphism, the C allele and the CC genotype have been associated with a higher risk for Alzheimer's disease without apolipoprotein E or CP2 interaction. The two polymorphisms were in linkage disequilibrium, with the haplotype T-C at significant increased risk of developing Alzheimer's disease in the whole sample and in elderly persons 70 years or older. In our population, the +1073 C/T OLR1 polymorphism exhibited a significant association with Alzheimer's disease, further supporting the role of OLR1 as a candidate risk gene for sporadic Alzheimer's disease.

Dietary fatty acids intake: possible role in cognitive decline and dementia.

There is a recent increase in the level of interest in the possible role of dietary fatty acids in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimer's disease, AD) or vascular origin. At present, several studies suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions. Furthermore, a clear reduction of risk of cognitive decline has been found in a population sample with a high intake of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). These findings were confirmed by studies in which high intakes of n-6 PUFA, n-3 PUFA, MUFA, and weekly fish consumption, providing large amount of n-3 PUFA, appear to be protective against the risk of AD. In our elderly population from Southern Italy, elevated unsaturated fatty acids intake (MUFA and PUFA), high levels of antioxidant compounds, and very low SFA intake could act synergistically in improving cognitive performance. Epidemiological studies on the association between diet and cognitive decline suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia, both of degenerative or vascular origin. Appropriate dietary measures or supplementation with specific micro- and macronutrients might open new ways for the prevention and management of cognitive decline and dementia.

Unsaturated fatty acids intake and all-causes mortality: a 8.5-year follow-up of the Italian Longitudinal Study on Aging.

Recent evidence suggested a protective role of dietary monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) intakes against several chronic diseases and, therefore, an increased human longevity. After a median follow-up of 8.5 years, we investigated the possible role of MUFA, PUFA, and other selected food groups in protecting against all-causes mortality in a population-based, prospective study, conducted in one of the eight centers of the Italian Longitudinal Study on Aging (ILSA), Casamassima, Bari, Italy. Out of 704 elderly subjects (65-84 years), 278 nondemented persons agreed to participate at the first survey (1992-1993). During the follow-up, there were 91 deaths. A semi-quantitative food frequency questionnaire evaluating macronutrient daily intakes were performed at the first survey. Higher MUFA intake was associated with an increase of survival (hazard ratio 0.81, 95% CI 0.66-0.99), a higher unsaturated fatty acids (UFA) to SFA ratio (hazard ratio 1.20, 95% CI 0.99-1.45) increased total mortality only marginally, while no effect about other selected food groups were found. In conclusion, in this prospective study on older nondemented subjects with a typical Mediterranean diet, a higher MUFA intake increased survival, while a higher UFA/SFA ratio increased total mortality, but only marginally.

Interleukin 6-174 G/C promoter gene polymorphism and sporadic Alzheimer's disease: geographic allele and genotype variations in Europe.

The interleukin 6 (IL-6) gene in humans is located in the short arm of chromosome 7 and has a-174 G/C polymorphism in its promoter region. The C allele at position-174 in the promoter of the interleukin 6 (IL-6) gene has been associated with reduced gene expression and reduced plasma levels of IL-6. Given the supposed role of several inflammatory mediators in neurodegeneration and Alzheimer's disease (AD), the IL-6-174 G/C promoter polymorphism has been associated with AD with contrasting findings. First aim of the present study was to investigate whether there was evidence in Southern Italy of an association between the IL-6-174 G/C promoter polymorphism and AD. Secondly, we also tested a possible effect of geographic genetic variations on existing reported associations comparing our results with the findings from published studies on other European populations. We examined apolipoprotein E (APOE) and IL-6-174 G/C promoter polymorphisms in a cohort of 168 sporadic AD patients and 220 sex- and age-matched nondemented controls from Southern Italy. No differences have been found in the IL-6-174 G/C promoter allele and genotype frequencies between AD patients and controls nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between IL-6-174 G/C promoter alleles and AD among APOE allele strata were found. Finally, comparing our results with the findings from other European populations, the IL-6*G/*G genotype frequency showed a statistically significant increasing trend from Northern to Southern regions of Europe in AD patients and controls, with a concomitant increase in IL-6*C/*G genotype frequency. Furthermore, an increasing geographical trend from North to South was found for the IL-6*G allele, with a concomitant inverse trend for IL-6*C allele. We suggest that regional European differences in genotype and allele frequencies of the IL-6-174 G/C promoter polymorphism may explain in part controversial findings on this polymorphism in AD in various European studies.

Interleukin 6-174 G/C promoter gene polymorphism in centenarians: no evidence of association with human longevity or interaction with apolipoprotein E alleles.

The C allele at position -174 in the promoter of the interleukin 6 (IL-6) gene has been associated with reduced gene expression and reduced plasma levels of IL-6. Given that IL-6 tracks with functional disability and age-related diseases, there may be attrition or reduction in the frequency of the homozygous subjects, who produce higher IL-6 serum levels, in older survivors in a population. In fact, a marked reduction of the IL-6*G/*G genotype was recently demonstrated in male though not female Italian centenarians compared with younger age groups. First aim of the present study was to investigate whether there was evidence of an association among IL-6 -174 G/C promoter polymorphism and extreme longevity in a population of 81 centenarians compared with a control group of 122 middle-aged healthy subjects (mean age: 51+/-18 SD; range: 19-73 years), from Apulia (Southern Italy). Secondly, we also tested possible interaction of apolipoprotein E (APOE) alleles with the IL-6 -174 G/C promoter polymorphism in view of our recent findings for reduced APOE epsilon4 allele in centenarians. No differences have been found in the IL-6 -174 G/C promoter allele and genotype frequencies between centenarians and controls nor was there any observed interaction with APOE alleles that are also reputed to be linked to longevity. Regional genetic differences in conjunction with differing environmental factors may explain in part previous results suggesting a role of this polymorphism in longevity.

Vascular genetic factors and human longevity.

Complex inter-relationships between age-associated illnesses, such as vascular disease and Alzheimer's disease (AD), suggest that biological and genetic pathways may be worthy of examination in centenarian populations to provide insights into human longevity. This is also borne out by the involvement of lipoprotein metabolism and a number of vascular genetic risk factors. Repeated findings of a higher frequency of the apolipoprotein E (APOE) epsilon4 allele in middle-aged subjects compared with centenarians were reported. Furthermore, we have also shown how in different populations there is a significant trend in reduction of serum APOE levels from APOE epsilon2- to epsilon4-carrier as well as significant differences in serum APOE levels respect to age in epsilon4-carriers but only after adjustment for HDL cholesterol. In contrast, findings of increased prevalence of the angiotensin I converting enzyme 1 (ACE1) D allele in French centenarians have not been replicated, suggesting the possibility that regional differences may occur in ACE1(*)D frequency within Europe in centenarians, as has been recently reported for APOE epsilon2 and epsilon4 alleles. A number of studies have examined the potential role in longevity of other genes involved in vascular risk, haemostasis, and blood pressure regulation [methyltetrahydrofolatereductase (MTHFR), apolipoprotein A1 (APOA-I), apolipoprotein C3 (APOC-III), apolipoprotein A4 (APOA-IV), paraoxonase 1 (PON1), plasminogen activator inhibitor type I (PAI-1)], with contrasting results. While further studies are needed to confirm the possible role of APOE concentration as putative longevity factor, this paper provides an overview of genetic vascular factors potentially involved in human longevity.

Regional European differences in allele and genotype frequencies of low density lipoprotein receptor-related protein 1 polymorphism in Alzheimer's disease.

The low density lipoprotein receptor-related protein 1 (LRP1 gene) is a candidate gene for Alzheimer's disease (AD), because it is a ligand for proteins involved in AD pathogenesis, such as apolipoprotein E (APOE), alpha2-macroglobulin (A2M), amyloid precursor protein (APP), and is located on chromosome 12, within a region linked with AD. An association between a silent polymorphism (C/T) in exon 3 and late onset AD has been reported, with an increased frequency of the C allele, although with conflicting results. We examined this polymorphism in a cohort of 166 sporadic AD patients and 225 sex- and age-matched nondemented controls from Southern Italy. No statistically significant differences were found in LRP1 genotype and allele frequencies between the whole AD sample and controls, nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between LRP1 alleles and AD among APOE allele, age, or gender strata were found. Finally, comparing our results with the findings from other European populations, the LRP1 C allele frequency showed a statistically significant decreasing trend from Northern to Southern regions of Europe, with a concomitant increase in LRP1 T allele frequency, but in AD patients only. Finally, in the AD sample, a decreasing geographical trend from North to South of Europe was found for LRP1 CC genotype, and an inverse trend for LRP1 CT genotype frequency. We suggest that these regional variations in LRP1 genotype and allele frequencies in AD could be related to the different patterns of association between this polymorphism and the disease in various European studies.