Vascular risk factors, alcohol intake, and cognitive decline.

Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin. At present, cumulative evidence suggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk of cognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could be employed together to delay the onset of dementia syndromes.

Dietary fatty acids, age-related cognitive decline, and mild cognitive impairment.

Currently available epidemiological evidence suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions, while increased polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) may be protective against cognitive decline. In a Southern Italian elderly population from the Italian Longitudinal Study on Aging (ILSA), a clear reduction of risk of age-related cognitive decline (ARCD) has been found with elevated intake of PUFA and MUFA. Furthermore, in the ILSA, while dietary fatty acids intakes were not associated with incident mild cognitive impairment (MCI), high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. These epidemiological findings on predementia syndromes, i.e. MCI or ARCD, together with a recent randomised controlled trial on a possible effect on cognitive and depressive symptoms of omega-3 PUFA supplementation in patients with very mild AD, suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia.

In search of a biological pattern for human longevity: impact of apo A-IV genetic polymorphisms on lipoproteins and the hyper-Lp(a) in centenarians.

We studied centenarians to investigate the biological basis of human longevity focusing on the apolipoprotein A-IV and lipoprotein(a), potentially involved in the susceptibility to atherogenic mechanisms. We analyzed two restriction polymorphisms, HinfI347 (alleles +, -) and Fnu4HI360 (alleles 1, 2), and a VNTR (alleles 3, 4) at the 3' region of the apo A-IV gene. The allele frequencies, the lipoprotein concentrations and their association in centenarians and adults have been compared. In centenarians, the HinfI genotype distribution is different (P < 0.05) and the (+13) haplotype is prevalent (0.54 vs. 0.39), with a greater association of (+3), indicating the selection of a favourable allele. The lipoprotein modulation by the apo A-IV polymorphisms is suggested by significant associations in adults ((+/+) homozygotes have lower LDL-cholesterol and apo B than heterozygotes; (1/1) homozygotes have higher TG and apo B than heterozygotes), that in centenarians still exists as a trend. Centenarians show peculiar lipoprotein features: lower LDL-cholesterol (mean 103 vs. 115 mg/dl; P < 0.02), and higher lipoprotein(a) (median 17.5 vs. 4.5; P < 0.002). Large part of them (47%), especially the Hinf(+/+) and the (+13) homozygotes, have a lipoprotein(a) > 20 mg/dl, value considered as the threshold for atherogenic risk, surprisingly compatible with healthy longevity.

Apolipoprotein E in Southern Italy: protective effect of epsilon 2 allele in early- and late-onset sporadic Alzheimer's disease.

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.

Decreased frequency of apolipoprotein E epsilon4 allele from Northern to Southern Europe in Alzheimer's disease patients and centenarians.

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.

Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid.

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of beta-amyloid (Abeta) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Abeta have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Abeta clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Abeta monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, beta-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of gamma-secretase, the protease that regulates the last metabolic step generating Abeta, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Abeta aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Abeta approaches in clinical testing, we will know in few years if the Abeta hypothesis of AD is correct.

Interleukin 6 variable number of tandem repeats (VNTR) gene polymorphism in centenarians.

Recent population-based studies identified the magnitude of interleukin 6 (IL6) serum levels as a marker for functional disability, and a predictor of disability and mortality among the elderly. We investigated whether there was evidence in Southern Italy of an association between the IL6 gene variable number of tandem repeats (VNTR) polymorphism and extreme longevity, and tested for the possible interaction of apolipoprotein E (APOE) alleles with the IL6 VNTR alleles. Four alleles coding for variants of four different lengths have been identified: allele A [760 base pairs (bp)], allele B (680 bp), allele C (640 bp), and allele D (610 bp). IL6 VNTR and APOE allele and genotype frequencies were studied in a total of 61 centenarians and 94 middle-aged subjects from Southern Italy. The IL6 VNTR allele B was overrepresented in the younger control group compared with centenarians (odds ratio: 0.56, 95% confidence interval: 0.35-0.88, Bonferroni p-value < 0.05). No interactions between IL6 VNTR alleles and APOE alleles on the odds ratios to reach extreme longevity were evaluated for the smallest number of subjects in centenarians and younger controls. Our findings suggested that the presence of the IL6 VNTR allele B could be detrimental for reaching extreme longevity.

Alcohol consumption, mild cognitive impairment, and progression to dementia.

OBJECTIVE: To estimate the impact of alcohol consumption on the incidence of mild cognitive impairment and its progression to dementia. METHODS: We evaluated the incidence of mild cognitive impairment in 1,445 non-cognitively impaired individuals and its progression to dementia in 121 patients with mild cognitive impairment, aged 65 to 84 years, participating in the Italian Longitudinal Study on Aging, with a 3.5-year follow-up. The level of alcohol consumption was ascertained in the year before the survey. Dementia and mild cognitive impairment were classified using current clinical criteria. RESULTS: Patients with mild cognitive impairment who were moderate drinkers, i.e., those who consumed less than 1 drink/day (approximately 15 g of alcohol), had a lower rate of progression to dementia than abstainers (hazard ratio [HR] 0.15; 95% CI 0.03 to 0.78). Furthermore, moderate drinkers with mild cognitive impairment who consumed less than 1 drink/day of wine showed a significantly lower rate of progression to dementia than abstainers (HR 0.15; 95% CI 0.03 to 0.77). Finally, there was no significant association between higher levels of drinking (> or =1 drink/day) and rate of progression to dementia in patients with mild cognitive impairment vs abstainers. No significant associations were found between any levels of drinking and the incidence of mild cognitive impairment in non-cognitively impaired individuals vs abstainers. CONCLUSIONS: In patients with mild cognitive impairment, up to 1 drink/day of alcohol or wine may decrease the rate of progression to dementia.

Apo C-II deficiency type Bari.

We formerly studied an Italian family with apo C-II deficiency. Two probands were homozygous for the defect (unmeasurable circulating apolipoprotein C-II and absence of C-II bands on immunoelectrophoresis). We documented the synthesis of the protein at the intestinal level in the probands with immunohistological techniques. With the purpose of investigating the molecular basis of the defect, Southern analysis, polymerase chain reaction (PCR) amplification and sequence analysis were carried out on one of the two cases. We identified a point mutation C to G transversion in the third exon of the gene causing a premature stop codon. Our hypothesis is that the truncated protein of 36 aa., instead of 79 aa., lacks its functional domain. This causes inefficiency in the activation of lipoprotein lipase (LPL) and the instability of the circulating molecule, which could have an higher catabolic rate compared to a normal protein. The faster disappearance from the circulating compartment make it unmeasurable. The mutation destroys a Rsa I site, present in the normal gene sequence. We suggest the use of this site for a rapid Restriction Fragment Length Polymorphism (RFLP) on PCR amplification products to screen this defect in the Italian population.

Lipoprotein(a), apolipoprotein E genotype, and risk of Alzheimer's disease.

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.

A new Italian case of lipoprotein lipase deficiency: a Leu365- > Val change resulting in loss of enzyme activity.

We describe a second Italian family with primary Lipoprotein Lipase deficiency. A new mutation in exon 8 causes a Leu365- > Val change resulting in severe mass reduction and loss of enzyme activity. We suggest that this change interferes with the correct folding and stability of the protein and impairs the assembly of the active homodimer. The procedures applied are useful to screen a large sample of population for genetic variants and allow the clear identification of asymptomatic heterozygous subjects at risk from atherosclerosis disease.

F175S change and a novel polymorphism in presenilin-1 gene in late-onset familial Alzheimer's disease.

We analyzed at the molecular level with presenilin-1 (PS-1) and apolipoprotein E (apoE) genotyping the affected subjects and asymptomatic relatives of an Italian family with several members affected by late-onset familial Alzheimer's disease (AD). The screen for PS-1 gene mutations revealed a novel missense substitution phenylalanine 175 to serine in 1 of the affected individuals and 2 asymptomatic sons of the patient. This change was not found in other relatives of this family, as well as in 60 individuals with sporadic late-onset AD and 40 normal controls. Furthermore, a GG/TT substitution in the 3' end of intron 6 at the boundary with exon 7 was found in all relatives of the second and third generations of this family. All the affected relatives were female homo- or heterozygotes for apoE epsilon4 allele. This study provides evidence that a PS-1 gene missense change does not necessarily associate with early-onset disease, and can occur in single cases affected by late-onset disease.

Vascular risk and genetics of sporadic late-onset Alzheimer's disease.

In recent years, it is becoming apparent that genes may play an important role in the development of late-onset Alzheimer's disease (LOAD), and genetic studies could unravel new clues. Based on a growing vascular hypothesis for the pathogenesis of LOAD and other dementias, there is increasing interest for environmental and genetic vascular factors. Polymorphisms in different susceptibility genes already implicated in vascular disease risk are now also being suggested as possible genetic markers for increased risk of developing LOAD; however, many of these studies have shown conflicting results. Thus far, the apolipoprotein E (APOE) gene seems to be the only vascular susceptibility factor that is agreed to play a role in the multifactorial pathogenesis of AD although emerging genetic and biological evidence is now strengthening the case for additional inclusion of angiotensin I-converting enzyme 1 (ACE1) into this category. This review will focus on the current knowledge on genetic and nongenetic vascular factors likely to be involved in LOAD, with special emphasis placed on the APOE and ACE1 genes.

Mediterranean diet and cognitive decline.

OBJECTIVE: To investigate the possible role of diet in age-related cognitive decline (ARCD) and cognitive impairment of both degenerative (Alzheimer's disease, AD) and vascular (vascular dementia, VaD) origin. DESIGN: Literature review. RESULTS: In an elderly population of southern Italy with a typical Mediterranean diet, high energy intake of monounsaturated fatty acids (MUFA) appeared to be associated with a high level of protection against ARCD. In addition, dietary fat and energy in the elderly seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in European and North American countries. Finally, the relative risk of dementia (AD and VaD) was lower in the subjects of a French cohort who drank three or four glasses of red wine each day compared with total abstainers. CONCLUSION: Essential components of the Mediterranean diet--MUFA, cereals and wine--seem to be protective against cognitive decline. As such, dietary antioxidants and supplements, specific macronutrients of the Mediterranean diet, oestrogens and anti-inflammatory drugs may act synergistically with other protective factors, opening up new therapeutic interventions for cognitive decline.

Vascular risk factors, incidence of MCI, and rates of progression to dementia.

OBJECTIVE: To estimate 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. METHODS: The authors evaluated 2,963 individuals from the population-based sample of 5,632 subjects 65 to 84 years old, at the first (1992 to 1993) and second survey (1995 to 1996) of the Italian Longitudinal Study on Aging (ILSA), with a 3.5-year follow-up. Dementia, Alzheimer disease (AD), vascular dementia (VaD), other types of dementia, and MCI were classified using current clinical criteria. RESULTS: Among the 2,963 participants, 139 MCI patients were diagnosed at the first ILSA survey. During the 3.5-year follow-up, 113 new events of MCI were diagnosed with an estimated incidence rate of 21.5 per 1,000 person-years. We found a progression rate to dementia (all causes) of 3.8/100 person-years. Specific progression rates for AD, VaD, and other types of dementia were 2.3, 1.3, and 0.3/100 person-years. Furthermore, age was a risk factor for incident MCI (RR: 5.93, 95% CI: 3.17 to 11.10), while education was protective (RR: 0.06, 95% CI: 0.03 to 0.10), and serum total cholesterol evidenced a borderline nonsignificant trend for a protective effect. There was a nonsignificant trend for stroke as a risk factor of progression of MCI to dementia. CONCLUSIONS: In this population, among those who progressed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factors influence incident mild cognitive impairment and the rate of progression to dementia.

Increased bile acid excretion and reduction of serum cholesterol after crenotherapy with salt-rich mineral water.

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.