%0 Journal Article %J J Alzheimers Dis %D 2021 %T B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment. %A Jakubowski, Hieronim %A Zioła-Frankowska, Anetta %A Frankowski, Marcin %A Perła-Kaján, Joanna %A Refsum, Helga %A de Jager, Celeste A %A Smith, A David %B J Alzheimers Dis %V 84 %P 1039-1055 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-215085 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Homocysteine and Dementia: An International Consensus Statement. %A Smith, A David %A Refsum, Helga %A Bottiglieri, Teodoro %A Fenech, Michael %A Hooshmand, Babak %A McCaddon, Andrew %A Miller, Joshua W %A Rosenberg, Irwin H %A Obeid, Rima %K Cognition %K Cognitive Dysfunction %K Consensus %K Dementia %K Dietary Supplements %K Homocysteine %K Humans %K Meta-Analysis as Topic %K Review Literature as Topic %K Risk Factors %K Vitamin B Complex %X

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

%B J Alzheimers Dis %V 62 %P 561-570 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad171042?id=journal-of-alzheimers-disease%2Fjad171042 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480200?dopt=Abstract %R 10.3233/JAD-171042 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Kynurenine Pathway Metabolites in Alzheimer's Disease. %A Giil, Lasse Melvaer %A Midttun, Øivind %A Refsum, Helga %A Ulvik, Arve %A Advani, Rajiv %A Smith, A David %A Ueland, Per Magne %X

BACKGROUND: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results.

OBJECTIVE: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition.

METHODS: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05.

RESULTS: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 -0.47; p-values <0.001 -0.01). Pyridoxal 5'phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5'phosphate + Pyridoxal)) increased with age (β 0.31 -0.51; p-values <0.001 -0.006). Xanthurenic acid decreased with age (β: -0.42, p < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (β 0.21, p < 0.001).

CONCLUSION: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients.

%B J Alzheimers Dis %V 60 %P 495-504 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869479?dopt=Abstract %R 10.3233/JAD-170485 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. %A Oulhaj, Abderrahim %A Jernerén, Fredrik %A Refsum, Helga %A Smith, A David %A de Jager, Celeste A %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Neuropsychological Tests %K Treatment Outcome %K Vitamin B Complex %X

A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.

%B J Alzheimers Dis %V 50 %P 547-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757190?dopt=Abstract %R 10.3233/JAD-150777 %0 Journal Article %J PLoS One %D 2010 %T Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. %A Jones, Lesley %A Holmans, Peter A %A Hamshere, Marian L %A Harold, Denise %A Moskvina, Valentina %A Ivanov, Dobril %A Pocklington, Andrew %A Abraham, Richard %A Hollingworth, Paul %A Sims, Rebecca %A Gerrish, Amy %A Pahwa, Jaspreet Singh %A Jones, Nicola %A Stretton, Alexandra %A Morgan, Angharad R %A Lovestone, Simon %A Powell, John %A Proitsi, Petroula %A Lupton, Michelle K %A Brayne, Carol %A Rubinsztein, David C %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Morgan, Kevin %A Brown, Kristelle S %A Passmore, Peter A %A Craig, David %A McGuinness, Bernadette %A Todd, Stephen %A Holmes, Clive %A Mann, David %A Smith, A David %A Love, Seth %A Kehoe, Patrick G %A Mead, Simon %A Fox, Nick %A Rossor, Martin %A Collinge, John %A Maier, Wolfgang %A Jessen, Frank %A Schürmann, Britta %A Heun, Reinhard %A Kölsch, Heike %A van den Bussche, Hendrik %A Heuser, Isabella %A Peters, Oliver %A Kornhuber, Johannes %A Wiltfang, Jens %A Dichgans, Martin %A Frölich, Lutz %A Hampel, Harald %A Hüll, Michael %A Rujescu, Dan %A Goate, Alison M %A Kauwe, John S K %A Cruchaga, Carlos %A Nowotny, Petra %A Morris, John C %A Mayo, Kevin %A Livingston, Gill %A Bass, Nicholas J %A Gurling, Hugh %A McQuillin, Andrew %A Gwilliam, Rhian %A Deloukas, Panos %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Singleton, Andrew B %A Guerreiro, Rita %A Mühleisen, Thomas W %A Nöthen, Markus M %A Moebus, Susanne %A Jöckel, Karl-Heinz %A Klopp, Norman %A Wichmann, H-Erich %A Rüther, Eckhard %A Carrasquillo, Minerva M %A Pankratz, V Shane %A Younkin, Steven G %A Hardy, John %A O'Donovan, Michael C %A Owen, Michael J %A Williams, Julie %K Alzheimer Disease %K Apolipoproteins E %K Cholesterol %K Chromosome Mapping %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Immune System %K Polymorphism, Single Nucleotide %X

BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

%B PLoS One %V 5 %P e13950 %8 2010 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21085570?dopt=Abstract %R 10.1371/journal.pone.0013950