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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., (Copyright 2003 Wiley-Liss, Inc.)

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.

Variants of the angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE1) gene and the apolipoprotein E gene (APOE) have been suggested to be associated with human longevity. We tested the association between the ACE1 insertion (I allele)/deletion (D allele) polymorphism and longevity in a population from Southern Italy and examined the impact of geographical variation on ACE1 allele frequencies on reported associations from other European countries. ACE1 and APOE genotypes were obtained on 82 centenarians and 252 middle-aged, unrelated subjects or volunteers. No statistically significant differences were found in ACE1 genotype or allele frequencies between centenarians and controls in this Southern Italian population nor was there any observed interaction with APOE alleles that are also reputed to be linked to longevity. However, decreasing gradients in ACE1*I allele frequencies, both in centenarians and controls, with concomitant increases in ACE1*D allele frequencies (particularly the ACE1*D/*D genotype) were observed to be statistically significant from Northern to Southern regions of Europe. These findings did not support the previously reported association between ACE1 polymorphism and longevity. However, there were interesting and significant differences, as one moves from Northern to Southern Europe, with regard to the distribution of ACE1 alleles. Such genetic differences in conjunction with differing environmental factors may explain in part previous results suggesting a role of this polymorphism in longevity.

Vascular factors may play a role in the etiology of Alzheimer's disease (AD) and increased serum apolipoprotein E (APOE) levels in AD could be of interest, as APOE concentration is associated with vascular disease. Aims of this study were to evaluate the influence of APOE genotype on serum APOE levels, and, secondly, to study serum APOE concentrations in relation to age and AD. APOE genotypes, serum total cholesterol, LDL cholesterol, HDL cholesterol, total cholesterol/HDL cholesterol ratio, triglycerides, and serum APOE were performed on 52 healthy centenarians, 49 AD patients, 45 age-matched controls, and 72 young healthy adults. In all study population a significant trend in reduction of serum APOE levels from APOE epsilon2- to epsilon4 carriers was observed. The difference in serum APOE levels among age groups significantly decreased in epsilon4 carriers only, including HDL cholesterol; no significant differences between AD patients and age-matched controls were found. In these highly selected populations, APOE genotype distribution strongly influences serum APOE concentration, not suggesting, at present, a possible role as a biochemical marker for AD, but only as a putative longevity factor.

Recent findings suggest a possible role of diet in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimer's disease, AD) or vascular origin. In particular, in an older population of Southern Italy with a typical Mediterranean diet, high monounsaturated fatty acids energy intake appeared to be associated with a high protection against cognitive decline. In addition, dietary fat and energy in older people seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in the European and North American countries. Moreover, foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD. Vitamin deficiencies, especially vitamin B6, B12 and folates, and antioxidant deficiencies (vitamins E and C) could also influence the memory capabilities and have an effect on cognitive decline. Dietary anti-oxidants and supplements and specific macronutrients of the diet may act synergistically with other protective factors opening new possibilities of intervention for cognitive decline.

Progress in clinical and basic research of Alzheimer's disease (AD) suggested theoretical models of possible pathogenetic mechanisms, with a primary role of the genetic factors that have been implicated in AD. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial AD (presenilins 1 and 2, and amyloid beta protein precursor [APP]): well characterized but that account for only a small proportion of AD cases. Secondly, late onset, sporadic AD is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease: particularly, apolipoprotein E (apo E) polymorphism and many others suggested by linkage studies [alpha-macroglobulin, low density receptor protein (LRP1), bleomycin hydrolase], with a precise role in beta-amyloid metabolism and deposition. Many of these are controversial and studies have shown conflicting results, but apoE polymorphism seems to be only one of the possible genetic factors suggested to play a role in the multifactoral pathogenesis of AD. Regional and ethnic differences may affect the strength of association between apoE epsilon 4 allele and the disease, and we reported evidences of the decreasing frequency of epsilon 4 allele in AD patients and centenarians from Northern to Southern European regions. Finally, several genetic risk factors of vascular origin (angiotensin converting enzyme, methyltetrahydropholate-reductase, and NOS3 gene polymorphisms) have been implicated in the development of both vascular dementia and AD with conflicting results.

We determined the reliability and validity of a cancellation test of symbols (Symbol Cancellation Test [SCT]), designed to assess visual selective attention deficits in the elderly, on 34 Alzheimer's disease (AD) patients from Bari University Hospital Center, Bari, Italy, and 232 nondemented elderly subjects, aged 68 to 87 years, from the second prevalence survey (1995 through 1996) of the Italian Longitudinal Study on Aging (Casamassima, Bari, Italy). To assess convergent and discriminant validity, the Digit Cancellation Test (DCT), Mini-Mental State Examination (MMSE), and Babcock Story Recall Test (BSRT) were administered. Finally, discriminant accuracy of SCT between AD patients and nondemented elderly subjects was assessed. Inter-rater and test-retest reliability for P1 and P2 was excellent for both AD patients and the normal population, with a high degree of internal consistency. The SCT was significantly correlated with the DCT (0.67), MMSE (0.60), and BSRT (0.33). The classification accuracies of overall performance on the SCT for subjects with and without AD were 0.62 and 0.91, respectively. The SCT is a valid and reliable test to assess selective attention in elderly subjects, in whom dementing illness must be diagnosed and clinically distinct from age-related cognitive decline.

Objectives: To explore the possible role of serum lipoprotein(a) (Lp(a)), apolipoprotein E polymorphism, and total cholesterol (TC) serum concentrations in Alzheimer's disease (AD)., Methods: Lp(a) serum concentrations, apolipoprotein E genotypes, and TC serum concentrations were determined in 61 patients with a diagnosis of probable AD and in 63 healthy unrelated age matched controls. Genomic DNA was obtained and amplified by polymerase chain reaction and apolipoprotein E genotypes were defined following a previously described procedure., Results: Lp(a) serum concentrations were significantly associated in a non-linear relation with an increased risk for AD, independently of apolipoprotein E genotypes and sex and dependent on age (truth association) and TC serum concentrations (spurious association). The effect of age adjusted for TC on the odds of having AD increased non-linearly with increasing Lp(a) serum concentrations, with a plateau between 70 and 355 mg/l (odds ratio 11.33). For Lp(a) serum concentrations > or = 360 mg/l, the effect of age (> or = 72 years) was associated with a reduction in odds of having AD (odds ratio 0.15)., Conclusion: It is suggested that increased Lp(a) serum concentrations, by increasing the risk for cerebrovascular disease, may have a role in determining clinical AD.

High levels of serum lipoprotein(a) [Lp(a)] have been associated with increased risk of coronary artery disease (CAD), but this association apparently is not confirmed in elderly people. We evaluated the interactions of Lp(a) with lipid and nonlipid CAD risk factors in a sample of subjects enrolled in the prevalence survey (1992 to 1993) of the Italian Longitudinal Study on Aging (ILSA). The entire population consisted of 5,632 elderly people, aged 65 to 84 years, randomly selected in 8 Italian municipalities. The present cross-sectional study included 400 free-living elderly subjects (74 +/- 6 years) from the randomized cohort of Casamassima (Bari, Southern Italy) (n = 704). The results showed that in the elderly population, high serum Lp(a) is a CAD risk factor dependent on type 2 diabetes mellitus and elevated low-density lipoprotein (LDL) cholesterol levels. In particular, the combined effect of high Lp(a) (> or =20 mg/dl) and high LDL cholesterol (> or =3.63 mmol/L [> or =140 mg/dl]), increases coronary risk by 2.75 (95% confidence interval 7.70 to 0.99); finally, the effect of Lp(a) > or =20 mg/dl and LDL cholesterol > or =3.63 mmol/L (> or =140 mg/dl), combined with type 2 diabetes mellitus, increases risk of CAD by 6.65 (95% confidence interval 35.40 to 1.25). In the elderly, elevated Lp(a) levels appear not to be an independent predictor of CAD, but this lipoprotein is a risk factor only in subjects with type 2 diabetes mellitus and elevated LDL cholesterol.

Apolipoprotein E (apoE) polymorphism was evaluated in 81 sporadic late onset Alzheimer's disease (LOAD) patients, 28 sporadic early-onset Alzheimer's disease (EOAD) and 92 sex- and age-matched healthy controls from Apulia, Southern Italy. ApoE genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. The frequency of apoE epsilon 4 allele was significantly higher in EOAD patients than in the control group, but not in LOAD patients. Furthermore, EOAD patients carrying epsilon 4 allele had lower age at onset of AD symptoms (about 4. 5 years). In the whole sample, epsilon 4 was associated to AD by an odds ratio of 2.14, while it increased up to 6.55 in < 65 years old subjects. Finally, in both < 65 and > or = 65 subgroups of subjects, epsilon 2 played a protective role against the development of AD. It is concluded that the geographic decreasing trend of epsilon 4 allele and the age at onset may influence the association of apoE polymorphism with sporadic AD in a Southern Italian sample.

Apolipoprotein E (apoE) polymorphism was studied in 79 sporadic late onset Alzheimer's disease (LOAD) patients, 125 unrelated caregivers or volunteers (19-80 years), and 67 centenarians from Apulia, Southern Italy. The frequency of apoE epsilon2 allele was higher in centenarians than in LOAD patients, while epsilon4 was lower. In middle-aged adults, the epsilon4 allele frequency was higher than in centenarians. The epsilon4 allele frequency was lower in healthy adults than in LOAD patients, while epsilon2 was higher. Compared with the allele frequencies of Northern and Central European countries, a geographic trend for epsilon3 and epsilon4 alleles in LOAD and middle-aged adults was observed. The frequency of epsilon3 increased from Northern to Southern Europe, while epsilon4 decreased significantly. In centenarians, epsilon2 showed a North-South increasing pattern, while epsilon4 was in opposite trend.

The effect of a spring mineral water from Montecatini (Italy) on bile acid excretion, and lipid and apolipoprotein serum levels was evaluated. The study was conducted in subjects with serum total cholesterol (TC) level > 240 mg/dL and LDL cholesterol (LDL-C) > 170 mg/dL, over a 9-week period, with 3 weeks of dietary stabilization, 3 weeks of active treatment, and 3 weeks of tap-water treatment as a control period. Serum lipids and apolipoproteins, total and fractionated bile acid excretion, gallbladder motility, and safety parameters were evaluated. Active treatment with mineral water significantly reduced serum TC by 7.5%, LDL-C by 12.5%, TC/HDL-cholesterol ratio by 6.3%, and apolipoprotein B by 6.3%; total fecal bile acid excretion was increased by 98.9%, and gallbladder volume was reduced by 40%. The reduction in serum and LDL-cholesterol levels observed during the active treatment period ran parallel to the increased excretion of bile acids in the stools. We suggest that salt-rich spring water treatment reduces serum and LDL-cholesterol levels in subjects with mild hypercholesterolemia through a mechanism of increased excretion of fecal bile acid sterols.