n–3 Fatty acid erythrocyte membrane content, APOE ε4, and cognitive variation: an observational follow-up study in late adulthood
01 Feb 2008-The American Journal of Clinical Nutrition (American Society for Nutrition)-Vol. 87, Iss: 2, pp 449-454
TL;DR: Evidence of a gene environment interaction for cognitive aging is found and trials of n–3 PUFA supplements in cognitive aging and dementia prevention are relevant, and they support heterogeneity in Cognitive aging and, possibly, in Alzheimer disease.
About: This article is published in The American Journal of Clinical Nutrition.The article was published on 2008-02-01 and is currently open access. It has received 174 citations till now. The article focuses on the topics: APOE*4 Allele & Cognitive decline.
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TL;DR: Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between individuals, and factors affecting general bodily ageing also influence cognitive functions in old age.
Abstract: Introduction: Age-associated cognitive decline—or normal (non-pathological, normative, usual) cognitive ageing—is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. Areas of agreement and controversy: The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed ‘cause’ of cognitive ability in old age. Emerging areas for developing research: Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.
928 citations
TL;DR: Additional controlled clinical trials are needed to document whether long-term consumption or supplementation with eicosapentaenoic acid/docosahexaenoic Acid or the plant-derived counterpart (alpha-linolenic acid) results in better quality of life.
Abstract: Attention to the role of n-3 long-chain fatty acids in human health and disease has been continuously increased during recent decades. Many clinical and epidemiologic studies have shown positive roles for n-3 fatty acids in infant development; cancer; cardiovascular diseases; and more recently, in various mental illnesses, including depression, attention-deficit hyperactivity disorder, and dementia. These fatty acids are known to have pleiotropic effects, including effects against inflammation, platelet aggregation, hypertension, and hyperlipidemia. These beneficial effects may be mediated through several distinct mechanisms, including alterations in cell membrane composition and function, gene expression, or eicosanoid production. A number of authorities have recently recommended increases in intakes of n-3 fatty acids by the general population. To comply with this recommendation a variety of food products, most notably eggs, yogurt, milk, and spreads have been enriched with these fatty acids. Ongoing research will further determine the tissue distribution, biological effects, cost-effectiveness, and consumer acceptability of such enriched products. Furthermore, additional controlled clinical trials are needed to document whether long-term consumption or supplementation with eicosapentaenoic acid/docosahexaenoic acid or the plant-derived counterpart (alpha-linolenic acid) results in better quality of life.
693 citations
TL;DR: A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer's Disease Cooperative Study as discussed by the authors.
Abstract: Context Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. Objective To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. Design, Setting, and Patients A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study. Intervention Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. Main Outcome Measures Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102). Results A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm 3 (95% CI, 21.4-28.0 cm 3 ) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm 3 (95% CI, 20-28 cm 3 ) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79). Conclusion Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease. Trial Registration clinicaltrials.gov Identifier: NCT00440050
637 citations
01 Jan 2016
TL;DR: A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (MiniMental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer's Disease Cooperative Study as discussed by the authors.
Abstract: Context Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. Objective To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. Design, Setting, and Patients A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (MiniMental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study. Intervention Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. Main Outcome Measures Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n=102).
557 citations
TL;DR: The existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD).
Abstract: Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.
330 citations
References
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TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
8,669 citations
TL;DR: A protective effect of the ε2 allele, in addition to the dose effect ofThe ε4 allele in sporadic AD, is demonstrated, which further support the direct involvement of APOE in the pathogenesis of AD.
Abstract: Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.
1,797 citations
TL;DR: It is reported that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid produce a novel family of bioactive 17R-hydroxy-containing di- and tri-Hydroxy-docosanoids termed resolvins.
Abstract: Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R- containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17 R -hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17 R -hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17 R -HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA‐derived 17 R -hydroxy-DHA into two sets of novel diand trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC 50 � 50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40‐80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17 R -hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.
1,608 citations
TL;DR: In the largest twin study to date, heritability for AD is high and that the same genetic factors are influential for both men and women, however, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset.
Abstract: ronmentalinfluences,adjustingforage,werederivedfrom the twin data. Results: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantlygreaterindizygoticthaninmonozygoticpairs,suggesting genetic influences on timing of the disease. Conclusions: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset. Arch Gen Psychiatry. 2006;63:168-174
1,436 citations
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