Alzheimer's & Dementia: The Journal of the Alzheimer's Association - Articles in Press

Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging - Corrected Proof

2012-04-26

Abstract: Background: Increasing evidence suggests a role of atherosclerosis in the pathogenesis of cognitive impairment and dementia. Calcification volume measured with computed tomography (CT) is a valid marker of atherosclerosis. This study investigates associations of atherosclerosis (measured using CT) at four locations with cognition and brain changes on magnetic resonance imaging (MRI).Methods: To quantify calcification volume, 2414 nondemented people from the Rotterdam Study underwent CT of the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. To assess global cognition and performance on memory, executive function, information processing speed, and motor speed, they also underwent neuropsychological tests. In a random subgroup of 844 participants, brain MRI was performed. Automated segmentation and quantification of brain MRI scans yielded brain tissue volumes in milliliters. Diffusion tensor imaging was used to measure the microstructural integrity of the white matter. Relationships of atherosclerotic calcification with cognition, brain tissue volumes, and diffusion tensor imaging measures were assessed with linear regression models and adjusted for relevant confounders.Results: With larger calcification volumes, lower cognitive scores were observed. When calcification volumes were larger, total brain volumes were also smaller. Specifically, larger coronary artery calcification volumes related to smaller gray matter volumes, and extracranial and intracranial carotid calcification volumes related to smaller white matter volumes. Larger calcification volume in all vessel beds was accompanied by worse microstructural integrity of the white matter.Conclusions: Larger calcification volume is associated with worse cognitive performance. It also relates to smaller brain tissue volumes and worse white matter microstructural integrity, revealing possible mechanisms through which atherosclerosis may lead to poorer cognition.

Antihypertensive drug use and the risk of dementia in patients with diabetes mellitus - Corrected Proof

2012-04-23

Abstract: Background: Diabetes and hypertension are independent risk factors for dementia, and hypertension may increase this risk in patients with diabetes. It is unclear whether antihypertensive drugs are associated with risk of dementia in these patients.Methods: A retrospective study using a national cohort of beneficiaries of the Department of Veterans Affairs who have diabetes examined incidence of dementia over a 2-year follow-up period. Multivariate Cox proportional hazards regression model was used to estimate the unique effects of comorbid hypertension and antihypertensive medications on risk of dementia, after adjusting for several potential confounders.Results: In all, 377,838 patients were studied (mean age: 75.53 ± 6.07 years). After adjustments were made for sociodemographic factors, duration of diabetes, comorbidity, and comedications, hypertension was associated with increased risk of developing dementia (hazard ratio [HR] = 1.08; 95% confidence interval [CI] = 1.03, 1.14). Antihypertensive medications decreased risk, ranging from 24% for angiotensin receptor blockers (ARBs) to 4% for β-blockers. In a stratified analysis of patients without hypertension, angiotensin-converting enzyme inhibitors (HR = 0.81; 95% CI = 0.69, 0.94) and ARBs (HR = 0.55; 95% CI = 0.34, 0.88) continued to show protective effects.Conclusions: Comorbid hypertension was associated with increased risk of dementia, whereas antihypertensive medications, especially angiotensin-converting enzyme inhibitors and ARBs, were associated with reduced risk, even among patients without hypertension. Consequently, these agents may have potential therapeutic roles in delaying the onset of dementia in patients with diabetes.

Gaining precision on the Alzheimer’s Disease Assessment Scale-cognitive: A comparison of item response theory-based scores and total scores - Corrected Proof

Steve Balsis, Alexis A. Unger, Jared F. Benge, Lisa Geraci, Rachelle S. Doody — 2012-04-05

Abstract: Background: The Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) is a commonly used measure for assessing cognitive dysfunction in patients with Alzheimer’s disease (AD). The measure has 11 subscales, each of which captures an important aspect of cognitive dysfunction in AD. Traditional scoring of the ADAS-cog involves adding up the scores from the subscales without regarding their varying difficulty or their strength of relationship to AD-associated cognitive dysfunction. The present article analyzes problems associated with this approach and offers solutions for gaining measurement precision by modeling how the subscales function.Methods: We analyzed data collected at the Baylor College of Medicine Alzheimer’s Disease and Memory Disorders Clinic from 1240 patients diagnosed with varying degrees of dementia. Item response theory was used to determine the relationship between total scores on the ADAS-cog and the underlying level of cognitive dysfunction reflected by the scores.Results: Results revealed that each total score corresponded to a spectrum of cognitive dysfunction, indicating that total scores were relatively imprecise indicators of underlying cognitive dysfunction. Furthermore, it was common for two individuals with the same total score to have significantly different degrees of cognitive dysfunction.Conclusions: These findings suggest that item response theory scoring of the ADAS-cog may measure cognitive dysfunction more precisely than a total score method.

Fire in the ashes: Can failed Alzheimer’s disease drugs succeed with second chances? - Corrected Proof

Robert E. Becker, Nigel H. Greig — 2012-04-05

Abstract: Background: Since Cognex, more than 200 Alzheimer’s disease (AD) drug candidates have failed. Investigations have identified vulnerabilities of these AD drug developments to methodological errors. (−)-Phenserine has been discussed as possibly failing due to flawed methods and practices in development.Methods: We analyzed documentation of (−)-phenserine’s development for vulnerabilities to errors and designed interventions for a redevelopment that could provide fair or unbiased assessments of (−)-phenserine target engagement, target relevance for human diseases, and adequate presumptive evidence of efficacy as a therapeutic for one or more diagnoses to justify registration-required clinical trials.Results: Similar to studies of 40 other AD developments, with (−)-phenserine, we found little evidence of preemptive interventions against potentially invalidating errors, grounds to judge progress in development through stages as not scientifically justifiable, and variance excess and placebo group improvements as capable of accounting for outcomes from various studies in the development. We propose to compare a redevelopment resourced to counter these deficiencies with the original development as historical control to evaluate further our hypothesis that errors in development accounted for the (−)-phenserine failure, specifically, and other AD drug failures, potentially.Conclusions: We find support for our earlier proposal that (−)-phenserine did not fail, but the methods of development did fail, to provide conditions where efficacy could be tested. We propose that redevelopment under conditions aimed to correct methodological deficiencies common in AD drug developments will successfully test efficacy for (−)-phenserine and hopefully lead to a disease-modifying addition to the AD therapeutic armamentarium.

Butyrylcholinesterase genotype and gender influence Alzheimer’s disease phenotype - Corrected Proof

Roger M. Lane, Yunsheng He — 2012-03-09

Abstract: Retrospective data are presented to support a spectrum of early Alzheimer’s disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed.

Global gray matter changes in posterior cortical atrophy: A serial imaging study - Corrected Proof

2012-02-27

Abstract: Background: Posterior cortical atrophy (PCA) is a neurodegenerative condition predominantly associated with Alzheimer’s disease (AD) pathology. Cross-sectional imaging studies have shown different atrophy patterns in PCA patients compared with typical amnestic Alzheimer’s disease (tAD) patients, with greatest atrophy commonly found in posterior regions in the PCA group, whereas in the tAD group, atrophy is most prominent in medial temporal lobe regions. However, differential longitudinal atrophy patterns are not well understood.Methods: This study assessed longitudinal changes in brain and gray matter volumes in 17 PCA patients, 16 tAD patients, and 18 healthy control subjects. Both patient groups had symptom durations of approximately 5 years.Results: Progressive gray matter losses in both PCA and tAD patients were relatively widespread throughout the cortex, compared with control subjects, and were not confined to areas related to initial symptomatology. A multivariate classification analysis revealed a statistically significant group separation between PCA and tAD patients, with 72.7% accuracy (P < .01).Conclusion: Progression from an initially focal presentation to a more global pattern suggests that these different clinical presentations of AD might converge pathologically over time.

Analysis of case management programs for patients with dementia: A systematic review - Corrected Proof

2012-01-30

Abstract: Background: People suffering from dementia are particularly vulnerable to the gaps between the health and social service systems. Case management is a professional field that seeks to fill in these gaps and remedy this fragmentation.Methods: We report the results of a systematic literature review of the impact of case management programs on clinical outcomes and the utilization of resources by persons with dementia. We focused on randomized controlled trials (RCTs) and attempted to identify the factors that might contribute to greater program efficacy. Because the evaluation methods in these studies varied, we used the effect size method to estimate the magnitude of the statistically significant effects reported.Results: Our search strategy identified 17 references relating to six RCTs. Four of these six RCTs reported moderately statistically significant effects (effect size, 0.2–0.8) on their primary end point: the clinical outcome in three and resource utilization in one. Two of the RCTs reported weak or no effects (effect size, <0.2) on their primary end point. Because of the wide variety of the end points used, an overall effect size could not be calculated. Parameters that appear to be related to greater case management efficacy are the integration level between the health and social service organizations and the intensity of the case management.Conclusions: Integration and case management intensity seem to determine the magnitude of the clinical effects in this new professional field. Further studies are needed to clarify the economic impact.

Amyloid imaging in dementias with atypical presentation - Corrected Proof

2012-01-30

Abstract: Background: With the potential emergence of disease specific therapies, an accurate biomarker of Alzheimer’s Disease pathology is needed in cases in which the underlying etiology is uncertain. We explored the potential value of amyloid imaging in patients with atypical presentations of dementia.Methods: Twenty-eight patients with atypical dementia underwent positron emission tomography imaging with the amyloid imaging tracer Pittsburgh compound B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible Alzheimer’s disease (AD), focal dementias (e.g., posterior cortical atrophy [PCA]), or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology). Patients were classified as PiB-positive, PiB-negative, or PiB-intermediate, based on objective criteria. Anterior–posterior and left–right indices of PiB and [18F]fluoro-2-deoxy-D-glucose uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype.Results: Eleven patients (39%) were PiB positive, 16 were PiB negative (57%), and one (4%) was PiB intermediate. By diagnostic category, three of 10 patients (30%) with dementia of uncertain etiology, one of five (20%) with primary progressive aphasia, three of five (60%) with PCA, and four of seven (57%) with possible AD were PiB positive. Brain metabolism of both PiB-positive and PiB-negative patients was generally similar by phenotype, but appeared to differ from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared with typical AD, consistent with their atypical phenotype.Conclusions: AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications.

Impact of the Food and Drug Administration’s antipsychotic black box warning on psychotropic drug prescribing in elderly patients with dementia in outpatient and office-based settings - Corrected Proof

Vibha C.A. Desai, Pamela C. Heaton, Christina M.L. Kelton — 2012-01-30

Abstract: Background: Most patients with dementia also suffer from behavioral and psychological symptoms of dementia, for which there is no Food and Drug Administration-approved treatment.Objectives: To determine whether the Food and Drug Administration’s black box warning in April 2005 has led to a decline in prescriptions of atypical antipsychotics for behavioral and psychological symptoms of dementia, as well as whether prescriptions for other psychotropic drugs, including antidepressants, anxiolytics, and antiepileptics, as substitutes, have increased.Methods: Data on outpatient visits by elderly dementia patients were obtained from two large national surveys from 2003 to 2008. Any psychotropic drug mentions were identified. Percentage utilization statistics were calculated.Results: The percentage of visits mentioning an atypical antipsychotic decreased from 12.5% prewarning to 11.5% postwarning. Postwarning, 34.4% of patients were taking none of the study medications, as opposed to 26.1% prewarning.Conclusion: After the warning, there was a small decline in the use of atypical antipsychotics and no evidence of substitution of other psychotropic medications.

Vascular risk factors, apolipoprotein E, and hippocampal decline on magnetic resonance imaging over a 10-year follow-up - Corrected Proof

2012-01-16

Abstract: Background: Decline of hippocampal volume on magnetic resonance imaging (MRI) may be considered as a surrogate biomarker of accumulating Alzheimer disease (AD) pathology. Previously, we showed in the prospective population-based Rotterdam Scan Study that a higher rate of decline of hippocampal volume on MRI precedes clinical AD or memory decline. We studied potential risk factors for decline of hippocampal volume.Methods: At baseline (1995–1996), 518 nondemented elderly subjects were included, and the cohort was re-examined in 1999 and in 2006. At each examination, hippocampal volume was determined using an automated segmentation procedure. In all, 301 persons had at least two three-dimensional MRI scans to assess decline in hippocampal volume.Results: Persons carrying the apolipoprotein E (APOE) ɛ4 allele had lower hippocampal volumes than persons with the ɛ3/ɛ3 genotype, but the rate of decline was not influenced by APOE genotype. In persons who did not use antihypertensive treatment, both a high (>90 mm Hg) and a low (<70 mm Hg) diastolic blood pressure were associated with a faster decline in hippocampal volume. Also, white matter lesions on baseline MRI were associated with a higher rate of decline in hippocampal volume.Conclusions: In a nondemented elderly population, persons with the APOE ɛ4 allele have a smaller hippocampal volume but not a higher rate of decline. Rate of decline of hippocampal volume was influenced by white matter lesions and diastolic blood pressure, supporting their hypothesized role in the pathogenesis of AD.

Cardiovascular fitness is associated with altered cortical glucose metabolism during working memory in ɛ4 carriers - Corrected Proof

2012-01-09

Abstract: Background: The possibility that ɛ4 may modulate the effects of fitness in the brain remains controversial. The present exploratory FDG-PET study aimed to better understand the relationship among ɛ4, fitness, and cerebral metabolism in 18 healthy aged women (nine carriers, nine noncarriers) during working memory.Methods: Participants were evaluated using maximal level of oxygen consumption, California Verbal Learning Test, and FDG-PET, which were collected at rest and during completion of the Sternberg working memory task.Results: Resting FDG-PET did not differ between carriers and noncarriers. Significant effects of fitness on FDG-PET during working memory were noted in the ɛ4 carriers only. High fit ɛ4 carriers had greater glucose uptake in the temporal lobe than the low fit ɛ4 carriers, but low fit ɛ4 carriers had greater glucose uptake in the frontal and parietal lobes.Conclusions: We demonstrate that fitness differentially affects cerebral metabolism in ɛ4 carriers only, consistent with previous findings that the effects of fitness may be more pronounced in populations genetically at risk for cognitive decline.

Association of environmental tobacco smoke with dementia and Alzheimer’s disease among never smokers - Corrected Proof

Ruoling Chen — 2011-12-26

Abstract: Background: Environmental tobacco smoke (ETS) is known to be harmful; however, its association with dementia remains controversial and with Alzheimer’s disease (AD) is unknown.Methods: Using a standard interview method, the author carried out a multicenter cross-sectional study of dementia in China by examining 2692 never-smoking people aged ≥60 years. Relative risks (RRs) of AD and all dementia, as diagnosed by psychiatrists, in relation to ETS were calculated in a multivariate regression model.Results: The adjusted RR for all dementia was 1.78 (95% confidence interval [CI]: 1.18–2.68). The increased risk was mainly from exposure to ETS at home (1.87, 95% CI: 1.19–2.93), and it was associated with exposure duration. The adjusted RR for AD was 2.28 (95% CI: 1.82–2.84); the matched figure for ETS exposure at home, at work, and at other places was 2.15 (95% CI: 1.69–2.74), 2.04 (95% CI: 1.72–2.42), and 1.80 (95% CI: 0.96–3.38), respectively. The association of the increased risk with a total cumulative exposure dose was at borderline significance.Conclusions: The risk of dementia and AD increased with ETS exposure. Banning smoking in public areas may help reduce a dementia epidemic worldwide.

Some evolutionary perspectives on Alzheimer’s disease pathogenesis and pathology - Corrected Proof

Daniel J. Glass, Steven E. Arnold — 2011-12-05

Abstract: There is increasing urgency to develop effective prevention and treatment for Alzheimer’s disease (AD) as the aging population swells. Yet, our understanding remains limited for the elemental pathophysiological mechanisms of AD dementia that may be causal, compensatory, or epiphenomenal. To this end, we consider AD and why it exists from the perspectives of natural selection, adaptation, genetic drift, and other evolutionary forces. We discuss the connection between the apolipoprotein E (APOE) allele and AD, with special consideration to APOE ɛ4 as the ancestral allele. The phylogeny of AD-like changes across species is also examined, and pathology and treatment implications of AD are discussed from the perspective of evolutionary medicine. In particular, amyloid-β (Aβ) neuritic plaques and paired helical filament tau (PHFtau) neurofibrillary tangles have been traditionally viewed as injurious pathologies to be targeted, but may be preservative or restorative processes that mitigate harmful neurodegenerative processes or may be epiphenoma of the essential processes that cause neurodegeneration. Thus, we raise fundamental questions about current strategies for AD prevention and therapeutics.

Safety profile of Alzheimer’s disease populations in Alzheimer’s Disease Neuroimaging Initiative and other 18-month studies - Corrected Proof

2011-12-05

Abstract: Background: Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer’s disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials.Methods: We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer’s Disease Neuroimaging Initiative study.Results: AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%–5.8% of patients), headache (4.0%–5.5%), constipation (4.3%–4.7%), nausea (2.0%–5.8%), joint swelling (3.6%–3.7%), vomiting (3.6%–3.7%), and anxiety (3.2%–3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%–33.0% vs 8.2%–21.0%) and greater discontinuations due to AEs (9.5%–11.6% vs 2.7%–3.2%). Rates of death (1.8%–2.4%) and SAEs (19.9%–21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%–4.0%) where SAEs were reported.Conclusions: In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer’s Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.

Clinical and neurobiological correlates of soluble amyloid precursor proteins in the cerebrospinal fluid - Corrected Proof

2011-11-07

Abstract: Background: According to a widely accepted hypothesis, the amyloid precursor protein (APP) is processed by two competing pathways: the amyloidogenic β-secretase–mediated pathway or the nonamyloidogenic α-secretase–mediated pathway. APP is cleaved preferentially through the nonamyloidogenic pathway in normal brain, whereas the balance shifts to the amyloidogenic pathway in Alzheimer’s disease (AD). The levels of the α-secretase–cleaved soluble APP (sAPPα) and β-secretase–cleaved soluble APP (sAPPβ) in cerebrospinal fluid (CSF) are likely to reflect these competing mechanisms.Methods: We investigated the levels and the relationship between sAPPα and sAPPβ in the CSF of 64 patients with mild AD, 76 patients with mild cognitive impairment, and 12 cognitively healthy control subjects, as well as the effect of apolipoprotein E genotype and sex on soluble APP levels.Results: There was a significant positive correlation between sAPPα and sAPPβ levels in all three groups. sAPPα and sAPPβ concentrations were higher in patients with mild cognitive impairment compared with patients with AD. In the AD group, females exhibited higher sAPPα and sAPPβ levels than males. No influence of the apolipoprotein E genotype on soluble APP concentrations was detected.Discussion: The positive correlation between sAPPα and sAPPβ challenges the hypothesis that AD is caused by an imbalance of the α- and β-secretase APP proteolysis through competing mechanisms. Moreover, the differences in CSF levels of sAPPα and sAPPβ between male and female patients with AD may reflect a “sexual dimorphism” in the activity of the two APP processing pathways in AD.

Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels - Corrected Proof

2011-11-03

Abstract: Background: β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer’s disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations.Methods: The current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies.Results: The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect.Conclusion: These results will help guide clinical trial design for Alzheimer’s disease therapy.

Is Alzheimer’s disease amyloidosis the result of a repair mechanism gone astray? - Corrected Proof

Tyler A. Kokjohn, Chera L. Maarouf, Alex E. Roher — 2011-11-03

Abstract: Here, we synthesize several lines of evidence supporting the hypothesis that at least one function of amyloid-β is to serve as a part of the acute response to brain hemodynamic disturbances intended to seal vascular leakage. Given the resilient and adhesive physicochemical properties of amyloid, an abluminal hemostatic repair system might be highly advantageous, if deployed on a limited and short-term basis, in young individuals. However, in the aged, inevitable cardiovascular dysfunction combined with brain microvascular lesions may yield global chronic hypoperfusion that may lead to continuous amyloid deposition and consequential negative effects on neuronal viability. A large body of experimental evidence supports the hypothesis of an amyloid-β rescue function gone astray. Preventing or inducing the removal of amyloid in Alzheimer’s disease (AD) has been simultaneously successful and disappointing. Amyloid deposits clearly play major roles in AD, but they may not represent the preeminent factor in dementia pathogenesis. Successful application of AD preventative approaches may hinge on an accurate and comprehensive view of comorbidities, including cardiovascular disease, diabetes, and head trauma.

Effects of n-3 fatty acids on cognitive decline: A randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients - Corrected Proof

Johanna M. Geleijnse, Erik J. Giltay, Daan Kromhout — 2011-10-04

Abstract: Background: Epidemiological studies suggest a protective effect of n-3 fatty acids derived from fish (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) against cognitive decline. For α-linolenic acid (ALA) obtained from vegetable sources, the effect on cognitive decline is unknown. We examined the effect of n-3 fatty acid supplementation on cognitive decline in coronary heart disease patients.Methods: The analysis included 2911 coronary patients (78% men) aged 60 to 80 years who participated in a double-blind placebo-controlled trial of n-3 fatty acids and cardiovascular diseases (Alpha Omega Trial). By using a 2 × 2 factorial design, patients were randomly assigned to margarines that provided 400 mg/d of EPA–DHA, 2 g/d of ALA, both EPA–DHA and ALA, or placebo for 40 months. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at baseline and after 40 months. The effect of n-3 fatty acids on change in MMSE score was assessed using analysis of variance. Logistic regression analysis was used to examine the effects on risk of cognitive decline, defined as a decrease of 3 or more points in MMSE score or incidence of dementia.Results: Patients in the active treatment groups had an additional intake of 384 mg of EPA–DHA, 1.9 g of ALA, or both. The overall MMSE score in this cohort was 28.3 ± 1.6 points, which decreased by 0.67 ± 2.25 points during follow-up. Changes in MMSE score during intervention did not differ significantly between EPA–DHA and placebo (−0.65 vs −0.69 points, P = .44) or between ALA and placebo (−0.60 vs −0.74 points, P = .12). The risk of cognitive decline was 1.03 (95% confidence interval: 0.84–1.26, P = .80) for EPA–DHA (vs placebo) and 0.90 (0.74–1.10, P = .31) for ALA (vs placebo).Conclusion: This large intervention study showed no effect of dietary doses of n-3 fatty acids on global cognitive decline in coronary heart disease patients.