Omega-3 fatty acids intake and risks of dementia and Alzheimer's disease: A meta-analysis

BackgroundWe systematically reviewed the association of omega-3 fatty acids intake with the incidence of dementia and Alzheimer's disease (AD) in this meta-analysis of prospective cohort studies, as evidence from previous studies suggests inconsistent results.MethodsWe identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to June 2013. Prospective cohort studies reporting on associations of dietary intake of long-chain omega-3 fatty acids or fish with the incidence of dementia and AD were eligible.ResultsComparing the highest to lowest category of long-chain omega-3 fatty acids intake and fish intake, the pooled relative risks (RRs) for dementia were 0.97 (95% CI 0.85–1.10) and 0.84 (95% CI 0.71–1.01), respectively. Evidence synthesis for AD risk did not show a statistically significant association with long-chain omega-3 fatty acids intake (RR = 0.89, 95% CI 0.74–1.08). However, a higher intake of fish was associated with a 36% (95% CI 8–56%) lower risk of AD. Dose–response meta-analysis showed that an increment of 100 g per week of fish intake was associated with an 11% lower risk of AD (RR = 0.89, 95% CI 0.79–0.99). There was limited evidence of heterogeneity across studies or within subgroups.ConclusionA higher intake of fish was associated with a lower risk of AD. However, there was no statistical evidence for similar inverse association between long-chain omega-3 fatty acids intake and risk of dementia or AD, nor was there inverse association between fish intake and risk of dementia.     

Ischemic stroke and n-3 fatty acids

The content of fatty acids in subcutaneous adipose tissue was measured to determine whether differences of fatty acids correlate with presence or absence of cerebral infarction in individual patients. Adipose tissue microbiopsies was sampled from 10 patients with computed tomography (CT) verified cerebral infarction and 10 matched control subjects, and assayed for content of fatty acids by gas-liquid chromatographic analysis. There were no differences in levels of n-3 fatty acids of marine origin. Patients with cerebral infarction had statistically significant lower levels of the essential fatty acids linoleic acid (mean+/-SE, 8.9+/-0.4 v 10.7+/-0.5%) (P<.05) and linolenic acid (0.80+/-0.05 v 1.00+/-0.06%) (P<.05) and high levels of palmitoleic acid (8.5+/-0.6% v 5.7+/-0.4%) (P<.005) indicative of increased lipid synthesis de novo, which might explain the depressed levels of fatty acids primarily supplied by the diet. Although significant differences in levels of essential fatty acids were found, no judgment could be made regarding a causal relationship between essential fatty acids and cerebral infarction. The present study does not support the hypothesis of an association between dietary fatty acids (e.g., fish consumption) and ischemic stroke.     

Effects of gender and dementia severity on Alzheimer's disease caregivers' sleep and biomarkers of coagulation and inflammation

Background: Being a caregiver for a spouse with Alzheimer’s disease is associated with increased risk for cardiovascular illness, particularly for males. This study examined the effects of caregiver gender and severity of the spouse’s dementia on sleep, coagulation, and inflammation in the caregiver.Methods: Eighty-one male and female spousal caregivers and 41 non-caregivers participated (mean age of all participants 70.2 years). Full-night polysomnography (PSG) was recorded in each participants home. Severity of the Alzheimer’s disease patient’s dementia was determined by the Clinical Dementia Rating (CDR) scale. The Role Overload scale was completed as an assessment of caregiving stress. Blood was drawn to assess circulating levels of D-dimer and Interleukin-6 (IL-6).Results: Male caregivers who were caring for a spouse with moderate to severe dementia spent significantly more time awake after sleep onset than female caregivers caring for spouses with moderate to severe dementia (p = .011), who spent a similar amount of time awake after sleep onset to caregivers of low dementia spouses and to non-caregivers. Similarly, male caregivers caring for spouses with worse dementia had significantly higher circulating levels of D-dimer (p = .034) than females caring for spouses with worse dementia. In multiple regression analysis (adjusted R² = .270, p < .001), elevated D-dimer levels were predicted by a combination of the CDR rating of the patient (p = .047) as well as greater time awake after sleep onset (p = .046).Discussion: The findings suggest that males caring for spouses with more severe dementia experience more disturbed sleep and have greater coagulation, the latter being associated with the disturbed sleep. These findings may provide insight into why male caregivers of spouses with Alzheimer’s disease are at increased risk for illness, particularly cardiovascular disease.     

Neuropsychiatric symptoms in dementia-frequency, relationship to dementia severity and comparison in Alzheimer's disease, vascular dementia and frontotemporal dementia

Noncognitive behavioral and psychiatric disturbances are common in dementia and help in the clinical differentiation of the various subtypes. We studied the frequency of neuropsychiatric disturbances, their relationship to dementia severity and compared these disturbances in Alzheimer's disease (AD), vascular dementia (VaD) and frontotemporal dementia (FTD) using the 12-item Neuropsychiatric Inventory (NPI). A total of 98 patients (AD-44, VaD-31, FTD-23) were evaluated. All subjects were community dwelling at the time of evaluation. The three groups were comparable on global dementia severity and functional ability. All patients had clinically significant scores on the NPI with apathy, irritability and agitation being very common (>90% of patients). AD and VaD patients in Clinical Dementia Rating (CDR) stage 2 had significantly higher scores on the total NPI, agitation and disinhibition subscales compared to those in CDR stage 1. Mean scores in the domains of aberrant motor behavior, disinhibition and appetite/eating behavior differentiated FTD from AD and VaD. Neuropsychiatric disturbances in dementia appear to be universal with agitation, disinhibition and irritability being more frequent in the later stages. In this cohort disinhibition, aberrant motor behavior and appetite/eating disturbances could reliably differentiate AD and VaD from FTD. There were no significant differences between the neuropsychiatric profiles of AD and VaD.     

Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers

The current rise in the prevalence of Alzheimer's disease (AD) is unfortunately not matched by new treatment options. In the last 10 years, epidemiological, preclinical and clinical data have enlightened the possible preventive action of omega-3 polyunsaturated fatty acids (n-3 PUFA) in AD and other diseases. While the contribution of recent studies to our general knowledge is priceless, many important new questions have been raised. In the present review, we aim at addressing some of these timely interrogations. First, the transport of n-3 PUFA across the blood-brain barrier is underscored based on preclinical data. Second, the relative contribution of two neuroactive n-3 PUFA found in fish oil, docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3), remains unclear and is reviewed. Third, clinical trials on neurodegenerative diseases consistently remind us that treating early is critical, and this is likely to be the case with n-3 PUFA in AD as well. Fourth, we draw attention to the possibility that the current knowledge translation approach to make health recommendations might have to be adapted to non-patentable endogenous compounds like n-3 PUFA. We propose that answers to these critical questions will be instrumental toward a rational use of n-3 PUFA in AD.     

The relationship between cognitive functioning and disease severity with depression in dementia of the Alzheimer's type

This study was conducted to determine the relationship between cognitive and functional impairment in depressed and non-depressed patients with Alzheimer's disease (AD). Subjects (N = 1,486) met NINCDS-ADRDA criteria for possible or probable AD; 183 where diagnosed with a DSM-III-R depressive disorder. All subjects resided in the community. The Mini-Mental States Examination (MMSE) assessed cognitive functioning and the Blessed-Roth Dementia Rating Scale (BRDRS) assessed functional abilities. A depression score was calculated based on the number of endorsed DSM-III-R major depression symptoms. Regression analyses determined the contribution of cognitive (MMSE) and functional severity (BRDRS) in explaining the depression score, while controlling for the effects of: demographic/psychosocial variables, history of depression, and current diagnosis of depression. Cognitive and functional impairment were found to be significantly related to depression. Also, as cognitive impairment and functional abilities worsened, the number of reported depressive symptoms increased. The results of this study underscore the importance of being aware of emotional factors which may compromise cognitive/functional skills in individuals with AD. In addition, depression can be present in all stages of the illness.     

Quantitative magnetic resonance imaging and the severity of dementia in Alzheimer's disease

The T2 component of the magnetic resonance imaging (MRI) signal was measured in 11 brain loci in six elderly patients diagnosed as having probable Alzheimer's disease. T2 values and relative amount of periventricular high-intensity foci were significantly correlated with dementia severity, indicated by the Blessed-Roth Dementia Scale score. Although the mean T2 value for left hemispheric structures was more closely correlated with the dementia score, T2 values did not differ significantly in the right and left hemispheres or in gray and white matter. These findings suggest that more severe dementia in Alzheimer's disease is associated with more water in the brain.     

Association between brain functional failure and dementia severity in Alzheimer's disease: resting versus stimulation PET study

OBJECTIVE: This study tested the hypothesis that regional cerebral glucose metabolism during neuronal activation is a more sensitive index of neuronal dysfunction and clinical severity in Alzheimer's disease than is glucose metabolism at rest. METHOD: The subjects were 15 Alzheimer's disease patients with a wide range of Mattis Dementia Rating Scale scores (23-128). By using positron emission tomography, absolute glucose metabolism was measured in the parietal, occipital (visual areas), and temporal (auditory areas) cortical regions during rest (eyes/ears covered) and audiovisual stimulation. RESULTS: In the parietal cortex, glucose metabolism correlated with dementia severity in both conditions. In contrast, in the relatively preserved visual and auditory cortical regions, glucose metabolism predicted dementia severity during stimulation but not at rest. CONCLUSIONS: These findings suggest that regional cerebral glucose metabolism during stimulation is a more sensitive index of the functional/metabolic failure of neuronal systems than is metabolism at rest.     

The role of dietary n-6 and n-3 fatty acids in the developing brain

The dietary requirements for essential fatty acids and the possibility of a specific role for the polyunsaturated fatty acid docosahexaenoic acid (DHA) is one of the most controversial areas in infant nutrition. DHA is found in unusually high concentrations in the brain and is selectively accumulated during fetal and infant brain growth. DHA can be synthesised through a complex series of chain elongation-desaturation reactions from alpha-linolenic acid, but the efficiency of this process in young infants is not clear. Clinical studies on the potential benefits to neural development of dietary DHA have yielded conflicting results. Recent studies have provided evidence that plasma DHA is available to developing brain and that DHA is involved in dopamine and serotonin metabolism. These findings should guide clinical studies to more sensitive measures of the functional roles of dietary n-3 fatty acids and to clinical conditions where n-3 fatty acids may have benefit.     

Study on the association between SOAT1 polymorphisms, Alzheimer's disease risk and the level of CSF biomarkers

BACKGROUND: In Alzheimer's disease (AD) the beta-amyloid precursor protein is excessively cleaved into Abeta(42), causing the abundant amyloid plaque loads in affected brain areas. Sterol O-acyltransferase 1 (SOAT1) has been found to regulate the production of beta-amyloid precursor protein. METHODS: We genotyped 4 SOAT1 single nucleotide polymorphism (SNP) sites (rs2247071, rs2862616, rs3753526 and rs1044925) in 410 Finnish AD cases and 455 controls and conducted a single allele and genotypic distribution comparison as well as estimating the haplotype frequencies between cases and controls and the level of biomarkers in genotype and haplotype carriers. RESULTS: The CC genotype of rs2247071 was overrepresented in the AD cases (OR = 1.38, 95% CI = 1.01-1.89, p = 0.043, Bonferroni corrected p = 0.172 with 4 tests) independent of gender, age and APOE epsilon4 allele carrier status. We did not find any significant differences between Abeta(42), tau or ptau levels in different allele, genotype or haplotype carrier cases. CONCLUSION: Our findings suggest that SOAT1 gene may possibly be only a minor risk factor in AD.     

Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease

BACKGROUND: Dietary n-3 polyunsaturated fatty acids improve brain functioning in animal studies, but there is limited study of whether this type of fat protects against Alzheimer disease. OBJECTIVE: To examine whether fish consumption and intake of different types of n-3 fatty acids protect against Alzheimer disease. DESIGN: Prospective study conducted from 1993 through 2000, of a stratified random sample from a geographically defined community. Participants were followed up for an average of 3.9 years for the development of Alzheimer disease. PATIENTS: A total of 815 residents, aged 65 to 94 years, who were initially unaffected by Alzheimer disease and completed a dietary questionnaire on average 2.3 years before clinical evaluation of incident disease. MAIN OUTCOME MEASURES: Incident Alzheimer disease diagnosed in a structured neurologic examination by means of standardized criteria. RESULTS: A total of 131 sample participants developed Alzheimer disease. Participants who consumed fish once per week or more had 60% less risk of Alzheimer disease compared with those who rarely or never ate fish (relative risk, 0.4; 95% confidence interval, 0.2-0.9) in a model adjusted for age and other risk factors. Total intake of n-3 polyunsaturated fatty acids was associated with reduced risk of Alzheimer disease, as was intake of docosahexaenoic acid (22:6n-3). Eicosapentaenoic acid (20:5n-3) was not associated with Alzheimer disease. The associations remained unchanged with additional adjustment for intakes of other dietary fats and of vitamin E and for cardiovascular conditions. CONCLUSION: Dietary intake of n-3 fatty acids and weekly consumption of fish may reduce the risk of incident Alzheimer disease.     

Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease

Alzheimer''s disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer''s disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.     

Psychiatric symptoms vary with the severity of dementia in probable Alzheimer's disease

This cross-sectional study examines relationships among the constellation of psychiatric syndromes in Alzheimer's disease (AD) as a function of dementia severity in 1155 patients with probable AD. The frequency of major depression decreased in severe stages, while agitation, aggression, and psychosis were more frequent in late stages. Major depression was associated with anhedonia, sleep disorders, depressed mood, low self-esteem, anxiety, and hopelessness in mild/moderate and severe stages. Agitation was associated with aggression and psychosis in mild/moderate stages, and psychosis was associated with aggression in moderate/severe stages. In addition, there was a constellation of psychiatric symptoms (e.g., anxiety, wandering, irritability, inappropriate behavior, uncooperativeness, emotional lability) associated with agitation, aggression, and psychosis, which varied according to the severity of the dementia, suggesting a progressive deterioration of frontal-temporal limbic structures. Education and race were independently associated with psychosis. However, while education was associated with psychosis in mild/moderate stages, race was associated with psychosis in moderate/severe stages.     

The relationship of agraphia to the severity of dementia in Alzheimer's disease

Impairment of writing ability was studied in 20 patients with mild to moderate dementia caused by early-onset Alzheimer's disease. A multicomponent analysis was made of a brief narrative writing sample obtained from each patient, and this writing proficiency score was compared with results of standard tests of cognitive function as well as ratings of the degree of dementia. In these patients, significant correlations were observed between this brief test of narrative writing ability and the severity of dementia. An analysis of writing proficiency appears to be a simple means of assessing the severity of dementia caused by Alzheimer's disease. Further studies are needed to show the potential usefulness of such measures of agraphia in subtyping this disease.     

Prevalence of apathy, dysphoria, and depression in relation to dementia severity in Alzheimer's disease

Apathy is common in Alzheimer's disease (AD) but may be confused with depression due to overlap in symptoms queried in depression assessments. Depression and dysphoria appear to occur less frequently in AD but are better researched. This study examined the relative frequency of these syndromes and their relation to disease characteristics in 131 research participants with probable or possible AD. Apathy was more prevalent than dysphoria or major depression and was more strongly associated with global disease severity, cognitive impairment, and functional deficits. Accurate differential diagnosis of apathy and depression is key to appropriate family education and effective treatment.     

Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype

Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer's disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The ε4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD. Carriers of the ε4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry ε4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in ε4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype.     

Telling the difference between frontotemporal dementia and Alzheimer's disease

PURPOSE OF REVIEW: A precise diagnosis of the cause of dementia during life is needed for proper management, in order to explain the symptoms to the patient and to the close relatives, and to give appropriate indications on the prognosis and possibly on the genetic risk. Frontotemporal dementia remains under-diagnosed and often misdiagnosed for Alzheimer's disease, the most common cause of dementia. More and more studies explore the differences between the two syndromes. RECENT FINDINGS: Progress in neuropsychological testing improves the ability to distinguish between syndromes and knowledge on brain functioning. More attention has been paid over these last months--or years--on emotion, insight, behavior, artistic creativity and quality of responses. Yet, biomarkers do not improve the diagnostic accuracy of trained clinicians, and do not help to distinguish between histological subtypes of frontotemporal dementia. SUMMARY: Improvement in knowledge on cognitive and emotional impairment in frontotemporal dementia and Alzheimer's disease is essential for the management of the patient--information can be given to the patients and the families that helps them to understand and to behave in consequence.     

Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia

OBJECTIVES: The study aimed to increase understanding of behavioural changes in frontotemporal dementia (FTD) and identify features that best differentiate FTD from Alzheimer's disease (AD) and cerebrovascular dementia (CvD). METHODS: A semi-structured questionnaire was administered to carers of 30 FTD, 75 AD and 34 CvD patients. RESULTS: Behavioural changes that strongly discriminated FTD from AD and to a lesser extent CvD were loss of emotions and insight, selfishness, disinhibition, personal neglect, gluttony and sweet food preference, wandering, motor and verbal stereotypies, loss of pain, echolalia and mutism. Irritability, hyposexuality and hypersomnia did not discriminate. Emotional, eating and stereotyped behaviours correctly classified 95% of patients using regression analysis. CONCLUSIONS: Behavioural characteristics accurately differentiate FTD from AD and CvD. The findings highlight the particular importance of affective change in FTD, and underline the role of the frontotemporal lobes in emotion.