Diet is a promising intervention target to prevent or slow Alzheimer's disease (AD). Early (predementia) stages of AD offer a unique opportunity for dietary interventions. Nutritional assessment methods to estimate nutrient intake have, however, not been validated in clinical populations. Hence, we assessed the association between nutrient intake assessed by food frequency questionnaire (FFQ) and nutrient status measured by nutritional biomarkers in blood in a clinical sample of controls, mild cognitive impairment (MCI), and patients with AD

de Leeuw, Francisca A.

de van der Schueren, Marian A.E.

Doorduijn, Astrid S.

Fieldhouse, Jay L.P.

Kester, Maartje I.

Scheltens, Philip

Teunissen, Charlotte E.

van de Rest, Ondine

van den Heuvel, Ellen G.H.M.

van der Flier, Wiesje M.

Visser, Marjolein

English

Leeuw, F.A. de

Rest, O. van de

Doorduijn, A.S.

Fieldhouse, J.L.P.

Schueren, M.A.E. de van der

Visser, M.

Heuvel, E.G.H.M. van den

Scheltens, P.

Teunissen, C.E.

Kester, M.I.

Flier, W.M. van der

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Associations Between Nutrient Intake and Corresponding Nutritional Biomarker Levels in Blood in a Memory Clinic Cohort: The NUDAD Project

VU Research Portal

VU Research PortalAssociations Between Nutrient Intake and Corresponding Nutritional Biomarker Levelsin Blood in a Memory Clinic Cohortde Leeuw, Francisca A.; van de Rest, Ondine; Doorduijn, Astrid S.; Fieldhouse, Jay L.P.;de van der Schueren, Marian A.E.; Visser, Marjolein; van den Heuvel, Ellen G.H.M.;Scheltens, Philip; Teunissen, Charlotte E.; Kester, Maartje I.; van der Flier, Wiesje M.published inJournal of the American Medical Directors Association2020DOI (link to publisher)10.1016/j.jamda.2020.04.031document versionPublisher's PDF, also known as Version of recorddocument licenseArticle 25fa Dutch Copyright ActLink to publication in VU Research Portalcitation for published version (APA)de Leeuw, F. A., van de Rest, O., Doorduijn, A. S., Fieldhouse, J. L. P., de van der Schueren, M. A. E., Visser,M., van den Heuvel, E. G. H. M., Scheltens, P., Teunissen, C. E., Kester, M. I., & van der Flier, W. M. (2020).Associations Between Nutrient Intake and Corresponding Nutritional Biomarker Levels in Blood in a MemoryClinic Cohort: The NUDAD Project. Journal of the American Medical Directors Association, 21(10), 1436-1438.https://doi.org/10.1016/j.jamda.2020.04.031General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.E-mail address:vuresearchportal.ub@vu.nlDownload date: 27. May. 2021JAMDA 21 (2020) 1436e1438JAMDAjournal homepage: www.jamda.comResearch LetterAssociations Between NutrientIntake and CorrespondingNutritional Biomarker Levels inBlood in a Memory ClinicCohort: The NUDAD ProjectTo the Editor:Diet is a promising intervention target to prevent or slowAlzheimer’s disease (AD).1,2 Early (predementia) stages of AD offer aunique opportunity for dietary interventions.2 Nutritionalassessmentmethods to estimate nutrient intake have, however, notbeen validated in clinical populations. Hence, we assessed theassociation between nutrient intake assessed by food frequencyquestionnaire (FFQ) and nutrient status measured by nutritionalbiomarkers in blood in a clinical sample of controls, mild cognitiveimpairment (MCI), and patients with AD.MethodsFrom the Nutrition, the Unrecognized Determinant in Alzheimer’sDisease (NUDAD) studywe included 90 participants: 29 patientswithAD, 22 patients with MCI, and 39 individuals with subjectivecognitive decline (SCD) who served as controls.3 All participantscompleted a FFQ and had at least 1 nutritional biomarker measure-ment. Written informed consent was obtained from all participantsand the local Medical Ethics Committee approved the study.Usual dietary intake was measured using the semiquantitative238-item HELIUS FFQ with a reference period of 4 weeks.4 Inaddition, participants reported their nutritional supplement use. Ifthe nutrient dosage could not be obtained from participants orthe (online) instructions leaflet (n ¼ 11), it was imputed withthe nutrient dosage of the most frequently used comparablesupplement in this study.All nutritional biomarker were measured in fasting plasma,serum, or whole blood samples, except for folic acid and vitamin B12,which were measured in nonfasting samples, and vitamin A, whichwas measured in both fasting (89%) and nonfasting (11%) samples.To investigate associations of nutrient intake with nutritionalbiomarker levels, we used linear regression analyses. Furthermore,we assessed whether associations differed per diagnostic group(controls/MCI/AD). Lastly, we performed sensitivity analysesexcluding supplement users for each nutrient separately.https://doi.org/10.1016/j.jamda.2020.04.0311525-8610/ 2020 AMDA e The Society for Post-Acute and Long-Term Care Medicine.ResultsOverall, mean age was 67  9 years, 42 (47%) were female, andvitamin and mineral supplement use was observed in 40 (44%)participants.Table 1 shows the associations between nutrient(diet þ supplement) intake and their corresponding nutritionalbiomarker levels in blood. Intake and blood levels were associatedfor vitamin B1, vitamin B6, vitamin B12, vitamin C, folate, andeicosapentaenoic acid, and trendswere observed for retinol activityequivalents, total omega-3 fatty acids, and docosahexaenoic acid(DHA). No associations were found for zinc.Subsequently, we evaluated if associations differed perdiagnostic group. Interactions (P < .10) were found betweendiagnostic group and nutrient intake for vitamin B6, vitamin C, totalomega-3 fatty acids, and DHA. Stratification by diagnostic groupshowed associations for vitamin B6 in all diagnostic groups [B(SE)controls; 0.78 (0.06), MCI; 1.05 (0.20), AD; 0.45 (0.14), P < .01], foromega-3 fatty acids and DHA in controls [B(SE) controls; 0.50(0.20), P ¼ .021, 0.38 (0.13), P ¼ .009, MCI; 0.38 (0.30),P ¼ .230, 0.13 (0.27), P ¼ .646, AD; 0.25 (0.17), P ¼ .166, 0.27(0.25), P¼ .285] and for vitamin C in AD [B(SE) controls; 0.22 (0.15),P ¼ .152, MCI; 0.03 (0.27), P ¼ .927, AD; 0.75 (0.11), P < .001].Finally, we re-analyzed the data in the total cohort excludingsupplement users for each nutrient separately. Associationsremained comparable in effect size for most nutrients, butattenuated for DHA, vitamin B1, B6, and B12 [(B(SE)0.07(0.15), 0.41(0.60), 0.31(0.23), 0.22(0.47), P > .05].DiscussionThe main finding of this study is that nutrient intake ofomega-3 fatty acids, A, B and C vitamins, as assessed by theHELIUS FFQ and self-reported supplement use, is moderatelyassociated with their corresponding nutritional biomarker levelsin a memory-clinic cohort of controls and patients with MCI orAD. Associations were largely similar across diagnostic groups,except for total omega-3 fatty acids and DHA that were onlyassociated in controls, and vitamin C that was only associated inAD. Almost one-half of the participants used nutritionalsupplements.In the subgroup of nonsupplement users, associations betweennutrient intake and nutritional biomarker levels remained largelycomparable to our findings in the total cohort.Among the strengths of this study is that we used a wellcharacterized, clinical population with different stages of cognitivedecline. A potential limitation is that the FFQ used in this study hasa reference period of 4 weeks, which is relatively short to assesshabitual diet. The burden of memory, however, may be less incomparison to other FFQs that use a reference period up to a year,Table 1Associations between Nutrient Intake and Nutritional Biomarker Levels in BloodDeterminants Outcome AllNutrient intake Nutritional biomarker B(SE) P nRetinol activityequivalents, mcg/dVitamin A, mmol/L 0.23 (0.12) .057 87Vitamin B1*, mg/d Vitamin B1, nmol/L 0.48 (0.09) <.001 79Vitamin B6*, mg/d Vitamin B6, nmol/L 0.71 (0.07) <.001 79Vitamin B12, mcg/d Vitamin B12, pmol/L 0.35 (0.10) <.001 77Vitamin C, mg/d Vitamin C, mmol/L 0.49 (0.09) <.001 78Folate equivalents, mcg/d Folate, nmol/L 0.49 (0.09) <.001 77Zinc, mg/d Zinc, mmol/L 0.10 (0.11) .373 79Omega-3 fatty acids, % oftotal fatty acids intakeOmega-3 fatty acids, % ofplasma total fatty acids0.21 (0.12) .101 79DHA, % of total fattyacids intakeDHA, % of plasmatotal fatty acids0.19 (0.12) .102 79EPA, % of total fatty acidsintakeEPA, % of plasma totalfatty acids0.41 (0.11) <.001 79EPA, eicosapentaenoic acid; SD, standard deviation.The HELIUS FFQ was not designed to measure these nutrients.Linear regression analyses adjusted for sex, age, diagnosis, and total energy intakewere used, using separate models for each nutritional biomarker. Data were log-transformed and converted to z scores before data analysis. Effect size is changeof SD nutritional biomarker blood level per 1 SD increase in nutrient intake.Research Letter / JAMDA 21 (2020) 1436e1438 1437which could be an advantage in a cohort of cognitively impairedindividuals. Moreover, most plasma and serum biomarkers reflectrelatively short-term intake. Future studies should includenutritional biomarkers in adipose tissue or erythrocytes that assesslonger-term intake.5In conclusion, nutrient intake and nutrient status weremoderately associated and largely similar across diagnostic groups.Our findings indicate that the HELIUS FFQ provides valid estimatesof nutrient intake in a memory-clinic cohort.AcknowledgmentsThe Alzheimer Center Amsterdam is supported by StichtingAlzheimer Nederland and Stichting VUmc fonds. The clinical databasestructure was developed with funding from Stichting Dioraphte.Research of the Alzheimer Center Amsterdam is part of theneurodegeneration research program of Amsterdam Neuroscience.W.F. is recipient of a donation by stichting Equilibrio, and of a ZonMWMemorabel grant (#733050814). F.L., A.D., M.K., and J.F. are appointedat the NUDAD project, which is funded by NWO-FCB (project number057-14-004). W.F. holds the Pasman chair.We acknowledge members of the NUDAD project team:Amsterdam University Medical Center location VUmc: Wiesje vander Flier, Maartje Kester, Philip Scheltens, Charlotte Teunissen,Marian de van der Schueren, Francien de Leeuw, Astrid Doorduijn,Jay Fieldhouse, Heleen Hendriksen, José Overbeek, and Els Dekkers;Vrije Universiteit Amsterdam: Marjolein Visser; WageningenUniversity and Research: Ondine van de Rest and Sanne Boesveldt;DSM: Peter van-Dael and Manfred Eggersdorfer; Nutricia Research:John Sijben, Nick van Wijk, Amos Attali, and Martin Verkuijl:FrieslandCampina: Rolf Bos, Cecile Singh-Povel, Ellen van denHeuvel, and Martijn Veltkamp.The authors would like to thank Eva Anne Hartman for her helpwith the administration and cleaning of the nutritional supplementdata. F.L., O.R., A.D., J.F., M.S., M.V. and M.K. report no disclosures.E.H. is an employee of FrieslandCampina, P.S. has receivedconsultancy/speaker fees (paid to the institution) from Novartis,Vivoryon, Genentech and EIP Pharma. C.T. has a collaborationcontract with ADx Neurosciences, performed contract research orreceived grants from Probiodrug, Biogen, Esai, Toyama, Janssenprevention center, Boehringer, AxonNeurosciences, Fujirebio, EIPfarma, PeopleBio, and Roche. Research programs of W.F. have beenfunded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland,CardioVascular Onderzoek Nederland, Health~Holland, TopsectorLife Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds,stichting Equilibrio, Pasman stichting, Biogen MA Inc, BoehringerIngelheim, Life-MI, AVID, Roche BV, Janssen Stellar, Combinostics.W.F. has performed contract research for Biogen MA Inc andBoehringer Ingelheim. W.F. has been an invited speaker atBoehringer Ingelheim and Biogen MA Inc. All funding is paid to herinstitution.References1. Gustafson DR, Clare Morris M, Scarmeas N, et al. New perspectives onAlzheimer’s disease and nutrition. J Alzheimers Dis 2015;46:1111e1127.2. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention,and care. Lancet 2017;390:2673e2734.3. Doorduijn AS, de van der Schueren MAE, van de Rest O, et al. Olfactory andgustatory functioning and food preferences of patients with Alzheimer’s diseaseand mild cognitive impairment compared to controls: The NUDAD project.J Neurol 2020;267:144e152.4. Beukers MH, Dekker LH, de Boer EJ, et al. Development of the HELIUSfood frequency questionnaires: Ethnic-specific questionnaires to assess the diet ofa multiethnic population in The Netherlands. Eur J Clin Nutr 2015;69:579e584.5. Corella D, Ordovas JM. Biomarkers: Background, classification and guidelines forapplications in nutritional epidemiology. Nutr Hosp 2015;31:177e188.Francisca A. de Leeuw, MDAlzheimer Center Amsterdam, Department of NeurologyAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsOndine van de Rest, PhDDivision of Human Nutrition and HealthWageningen University and ResearchWageningen, The NetherlandsAstrid S. Doorduijn, MScAlzheimer Center AmsterdamDepartment of NeurologyAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsDepartment of Nutrition and DieteticsPublic Health research instituteVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsJay L.P. Fieldhouse, MScAlzheimer Center AmsterdamDepartment of NeurologyAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsMarian A.E. de van der Schueren, PhDDepartment of Nutrition and HealthHAN University of Applied SciencesNijmegen, The NetherlandsMarjolein Visser, PhDDepartment of Health SciencesFaculty of ScienceResearch Letter / JAMDA 21 (2020) 1436e14381438Vrije Universiteit Amsterdam and the Amsterdam Public HealthResearch InstituteAmsterdam, The NetherlandsEllen G.H.M. van den Heuvel, PhDFriesland CampinaAmersfoort, The NetherlandsPhilip Scheltens, MD, PhDAlzheimer Center AmsterdamDepartment of NeurologyAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsCharlotte E. Teunissen, PhDNeurochemistry Laboratory and BiobankDepartment of Clinical ChemistryAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsMaartje I. Kester, MD, PhDDepartment of NeurologyFlevoziekenhuisAlmere, The NetherlandsWiesje M. van der Flier, PhDAlzheimer Center AmsterdamDepartment of NeurologyAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The NetherlandsDepartment of Epidemiology and BiostatisticsAmsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdam UMC, Amsterdam, The Netherlands

Associations Between Nutrient Intake and Corresponding Nutritional Biomarker Levels in Blood in a Memory Clinic Cohort:The NUDAD Project

Leeuw, de, Francisca A.

Rest, van de, Ondine

Schueren, de van der, Marian A.E.

Heuvel, van den, Ellen G.H.M.

Flier, van der, Wiesje M.

https://research.vu.nl/files/127963244/Associations_Between_Nutrient_Intake_and_Corresponding_Nutritional_Biomarker_Levels_in_Blood_in_a_Memory_Clinic_Cohort_The_NUDAD_Project.pdf

Associations Between Nutrient Intake and Corresponding Nutritional Biomarker Levels in Blood in a Memory Clinic Cohort:The NUDAD Project

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