Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Changes in severity of depressive symptoms and mortality: the Italian Longitudinal Study on Aging.

BACKGROUND: Depression is recognized as being associated with increased mortality. However, there has been little previous research on the impact of longitudinal changes in late-life depressive symptoms on mortality, and of their remission in particular. METHOD: As part of a prospective, population-based study on a random sample of 5632 subjects aged 65-84 years, with a 10-year follow-up of vital status, depressive symptoms were assessed by the 30-item Italian version of the Geriatric Depression Scale (GDS). The number of participants in the GDS measurements was 3214 at baseline and 2070 at the second survey, 3 years later. Longitudinal changes in depressive symptoms (stable, remitted, worsened) were examined in participants in both evaluations (n=1941). Mortality hazard ratios (MHRs) according to severity of symptoms and their changes over time were obtained by means of Cox proportional hazards regression models, adjusting for age and other potentially confounding factors. RESULTS: Severity is significantly associated with excess mortality in both genders. Compared to the stability of depressive symptoms, a worsened condition shows a higher 7-year mortality risk [MHR 1.46, 95% confidence interval (CI) 1.15-1.84], whereas remission reduces by about 40% the risk of mortality in both genders (women MHR 0.55, 95% CI 0.32-0.95; men MHR 0.59, 95% CI 0.37-0.93). Neither sociodemographic nor medical confounders significantly modified these associations. CONCLUSIONS: Consistent with previous reports, the severity and persistence of depression are associated with higher mortality risks. Our findings extend the magnitude of the association demonstrating that remission of symptoms is related to a significant reduction in mortality, highlighting the need to enhance case-finding and successful treatment of late-life depression.

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.

Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008.

Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimer's disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).

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.

Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review.

A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer's disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD.

High monounsaturated fatty acids intake protects against age-related cognitive decline.

OBJECTIVE: To study the relationships between dietary macronutrient intakes and age-related changes in cognitive functions. METHODS: We investigated these associations in the prevalence survey (1992 through 1993) of the Italian Longitudinal Study on Aging (ILSA). The population-based sample of 5,632 subjects of the ILSA, age 65 to 84 years, was identified from the electoral rolls of eight Italian municipalities. In this study, standardized test batteries assessing global cognitive functions (Mini-Mental State Examination [MMSE]), selective attention (Digit Cancellation Test [DCT]), and episodic memory (Babcock Story Recall Test), and a semi-quantitative food frequency questionnaire evaluating macronutrient energy intakes, were performed on 278 nondemented elderly subjects from the randomized cohort of Casamassima, Bari (n = 704). RESULTS: There was an inverse relationship between monounsaturated fatty acids (MUFAs) energy intake and cognitive decline (MMSE < 24). The effect of education on the odds of having a MMSE score <24 decreased exponentially with the increase of MUFA intakes (over 2,400 kJ; odds ratio, 0.69). Moreover, a significant inverse association was observed between MUFA intakes and DCT score (odds ratio, 0.99). No association was found between nutritional variables and episodic memory. CONCLUSIONS: In an elderly population of Southern Italy with a typical Mediterranean diet, high MUFA intakes appeared to be protective against age-related cognitive decline. Prospective clinical trials are needed to evaluate the impact of specific dietary macronutrient intakes on the age-related changes of cognitive functions.

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.

Impact of aging on the relationships between impairment of "Orientation" and "Recall" items of MMSE and mild to moderate mood disorders.

The association of depression and dementia is far more common than the masking of depression by dementia, i.e., pseudodementia. The impact of aging was investigated on the relationships between mood disorders, evaluated by means of Hamilton Depression Rating Scale (HDRS) and early cognitive impairments, measured by using the Mini Mental State Examination (MMSE) in 100 aged subjects (age range 60-84 years). In our population of mildly to moderately depressed elderly people, the aging was associated with a loss of MMSE item "Orientation" and a loss of MMSE item "Recall"; this could be explained by an association of cognitive impairment and mild to moderate depressive disorders which are worsening with aging.

Analysis of some aspects of learning and memorization processes in an adult population.

This study evaluated the impact of aging, gender and education on learning function and memory process. Hundred-six normal subjects, in the age range 20-79 years were recruited, and their following functions were evaluated as inclusion criteria: (i) global cognitive performance by using the Mini Mental State Examination (MMSE > or = 24), (ii) depressive disorders by using the Hamilton Depression Rating Scale (HDRS < 14); (iii) intelligence and "problem solving" ability by means of the Raven's Colored Progressive Matrices (PM 47 > or = 9). The prospective memory and the working memory, the incidental memory, as well as the immediate and delayed visuo-verbal association of these subjects were evaluated in the daily life conditions with the aid of a personal computer. Statistical analysis was performed by a model of multiple linear regression. The results suggested that prospective memory and working memory was influenced by age and education in both sexes. The percental loss of visuo-verbal association was not influenced by education, but was by gender and age. Test exploring incidental memory evidenced a worsening of performance in both sexes, being influenced only by the age.

A rehabilitation program for mild memory impairments.

Eight subjects, 60-75 years of age, with at least 5 years of education and mild memory impairments were recruited for a rehabilitation program. Other 8 subjects, not exposed to the rehabilitative training and with the same neuropsychological profile, represented a control group. In the first day of this program an evaluation of cognitive/behavioral functions was performed. Our program consisted of a neuropsychological rehabilitative intervention along 12 weeks, with a 5-day-period of domiciliary training with a set of home exercises and a 1-day training in our Center with rehabilitative exercises administered with the aid of a personal computer, each week. Rehabilitative training administered in our Center was aimed at stimulating visuo-verbal, verbal and spatial memory and the utilization of "memory strategies". After 4, 8 and 12 weeks of therapeutic program, other evaluations of the cognitive functions with the same battery tests were performed to evaluate possible improvements: the results indicated an improvement of memory test scores that demonstrated the positive effect of neuropsychological training on memory performances. There was no improvement in the control group.

Correlation between neuropsychometric tests and semiquantitative evaluation of the regional cerebral blood flow (rCBF) in a group of outpatients affected by cognitive impairment.

In order to evaluate the correlation between the cognitive-behavioral performances and the regional blood-perfusion deficits of the brain, 18 elderly subjects affected by dementia of probably primary degenerative character have been studied. The patients were first examined by psychometric tests and then submitted to brain Single Photon Emission Computed Tomography (SPECT) using [(99m)Technetium]-d,l-hexamethyl-propylene-amine-oxine (Tc-HMPAO) for regional blood flow evaluation (rCBF). The cognitive-behavioral functions have been estimated by Mini Mental State Examination (MMSE), Randt Memory Test, Rey's 15 Words, Corsi's Block Tapping Test, Word Fluency Test, Sentence Construction, Sketch Copy, Toulouse-Pieron's test. Digit Symbol Test from Wechsler Adult Intelligence Scale, and the Progressive Matrices 1947 (PM 47). The cerebral blood flow reduction in left occipital lobe and left frontal lobe explained 67% of the visuo-verbal memory impairment of the patients. These results suggest that the decrease of cognitive functions is related to some extent to a lower cerebral blood perfusion.

[Age-related cognitive decline: evaluation and prevention strategy]. / Declino cognitivo età-correlato: valutazione e strategie per la prevenzione.

The age-related decline of cognitive functions generally refers to a mild deterioration in memory performance, executive functions, and speed of cognitive processing. The terms "age-related cognitive decline" (ARCD) and "aging-associated cognitive decline" have been proposed recently to indicate an objective decline in cognitive functioning associated to the ageing process but within normal limits given the person's age. Whether ARCD is expression of a normal ageing process or represents a distinct clinical entity or, eventually, is a continuum with dementia is, at present, difficult to establish. The causes of ARCD are unknown, but some studies have suggested that it may be prevented. Avoidance of cardiovascular and other chronic diseases, high educational level, and maintenance of vision and hearing have been identified as protective factors from ARCD. On the contrary, hypertension, effects of altered metabolism of steroid hormones, smoking, low-complexity occupation, higher density of persons/bedroom in home, and low level of physical activity have been identified as risk factors for ARCD. Recent findings suggest a possible role of diet in the ARCD. In fact, in an elderly 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. Dietary antioxidants, specific macronutrients, estrogens, and anti-inflammatory drugs, may act synergistically with other protective factors, opening new therapeutic interventions for cognitive decline.

Short-term effects of high-intensity laser therapy versus ultrasound therapy in the treatment of low back pain: a randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a common musculoskeletal disorder that is highly prevalent in the general population. Management of this pathology includes numerous interventions depending on pain severity: analgesic, nonsteroidal anti-inflammatory drugs, steroid injections. However, the effect size and duration of symptom relief are limited. Physical therapy (ultrasound [US], laser therapy, manual therapy, interferential current therapy, Back School, aerobic work, therapeutic aquatic exercise acupuncture) have been reported often with mixed results. AIM: To evaluate the short-term effectiveness of high-intensity laser therapy (HILT) versus ultrasound (US) therapy in the treatment of LBP. DESIGN: Randomized clinical trial. SETTING: University hospital. POPULATION: Thirty patients with LBP were randomly assigned to a HILT group or a US therapy group. METHODS: Study participants received fifteen treatment sessions of HILT or US therapy over a period of three consecutive weeks (five days/week). RESULTS: For the 30 study participants there were no between-group differences at baseline in Visual Analogic Scale (VAS) and Oswestry Low Back Pain Disability Questionnaire (OLBPDQ) scores. At the end of the 3-week intervention, participants in the HILT group showed a significantly greater decrease in pain (measured by the VAS) and an improvement of related disability (measured by the OLBPDQ) compared with the group treated with US therapy. CONCLUSION: Our findings obtained after 15 treatment sessions with the experimental protocol suggested greater effectiveness of HILT than of US therapy in the treatment of LBP, proposing HILT as a promising new therapeutic option into the rehabilitation of LBP.

Different models of frailty in predementia and dementia syndromes.

Dementia is an increasingly common disease in the aging population, and the numbers are expected to rise exponentially in coming years. Therefore, there is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. Despite a substantial increase in the epidemiological and clinical evidence on frailty, there is no consensus on its definition or on what criteria should be used to identify older individuals with frailty. Frailty appears to be a nonspecific state of vulnerability, which reflects multisystem physiological change. In fact, current thinking is that not only physical but also psychological, cognitive and social factors contribute to this multidimensional syndrome and need to be taken into account in its definition and treatment. Cognition has already been considered as a component of frailty, and it has been demonstrated that it is associated with adverse health outcomes. In a recent population-based study, physical frail demented patients were at higher risk of all-cause mortality over 3- and 7-year follow-up periods. Several studies have also reported that physical frailty is associated with low cognitive performance, incidence of Alzheimer's disease (AD), and mild cognitive impairment, and AD pathology in older persons with and without dementia. Most frailty instruments use a dichotomous scoring system classifying a person as either frail or not frail, while a continuous or an ordinal scoring system on multiple levels would be preferable to be used as an outcome measure. Recently, a Multidimensional Prognostic Index (MPI), derived from a standardized comprehensive geriatric assessment, was effective in predicting short- and long-term mortality risk in hospitalized patients with dementia. Overall taken together these findings supported the concept that outcome measures linked to multidimensional impairment may be extremely important in making clinical decisions, especially for monitoring drug treatment in randomized clinical trials also for predementia and dementia syndromes.

Interacting with γ-secretase for treating Alzheimer's disease: from inhibition to modulation.

Drugs currently used for the treatment of Alzheimer's disease (AD) produce limited clinical benefits, and there is no disease-modifying therapy yet available. Compounds that inhibit or modulate γ-secretase, the pivotal enzyme that generates ß-amyloid (Aß), are potential therapeutics for AD. This article briefly reviews the profile of γ-secretase inhibitors and modulators that have reached the clinic. Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aß concentrations. However, scanty data are available on the effects of these compounds on brain Aß deposition after prolonged administration. γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and alterations in hair color in experimental animals and in man, effects believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. These detrimental effects were mainly ascribed to the inhibition of the processing of an unknown substrate of γ-secretase. It has been also hypothesized that the detrimental cognitive effects observed after semagacestat administration are due to the accumulation of the neurotoxic precursor of Aß (the carboxy-terminal fragment of amyloid precursor protein, APP, or CTFß) resulting from the block of the γ-secretase cleavage activity on APP. Some non-steroidal anti-inflammatory drugs and other small organic molecules have been found to modulate γ-secretase shifting its cleavage activity from longer to shorter Aß species without affecting Notch cleavage. However, two large Phase III studies in mild AD patients with tarenflurbil, a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New more selective γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks. Further understanding of the reasons of the failures of these γ-secretase-based drugs in AD may be important for the future research on effective treatments for this devastating disease.

Mediterranean diet in predementia and dementia syndromes.

There is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. Only recently higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline although the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggested a possible association among fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA) and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and Alzheimer's disease (AD), while for vascular dementia, cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supported a protective role of these macronutrients against cognitive decline, dementia, and AD. Moreover, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD, and decreased all-causes mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk for AD, but also for predementia syndromes and their progression to overt dementia. Nonetheless, at present, no definitive dietary recommendations are possible. However, high levels of consumption of fats from fish, vegetable oils, non-starchy vegetables, low glycemic fruits, and diet low in foods with added sugars and with moderate wine intake should be encouraged. In fact, this dietary advice is in accordance with recommendations for lowering the risk of cardiovascular disease, obesity, diabetes, and hypertension and might open new ways for the prevention and management of cognitive decline and dementia.

Metabolic syndrome, mild cognitive impairment, and dementia.

At present, the search for preventive strategies for cognitive decline and dementia appears to be of crucial importance, given that the therapeutic options currently available have demonstrated limited efficacy. Cumulative epidemiological evidence suggested that vascular and vascular-related factors may be important for the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). Among vascular-related factors, metabolic syndrome (MetS) has been associated with the reduced risk of predementia syndromes (ARCD and MCI), overall dementia, and VaD, but contrasting findings also exist on the possible role of MetS in AD. In the next future, trials could then be undertaken to determine if modifications of these risks including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. If MetS is associated with increased risk of developing cognitive impairment, then early identification and treatment of these individuals at risk might offer new avenues for disease course modification. Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor management could be decisive in delaying the onset of dementia syndromes or in preventing the progression of predementia syndromes.