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1 Supplementary Online Content Chew EY, Clemons TE, Agrón E, et al; Age-Related Eye Disease Study 2 Research Group. Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial. JAMA. doi: /jama eappendix. Methods for Cognitive Function Tests and Others That Were Administered to the Age-Related Eye Disease Study 2 Participants etable 1. The Number of Interviews (Cognitive Function Testing) Conducted During the Age-Related Eye Disease Study 2 (AREDS2) etable 2. Baseline Characteristics of AREDS2 Participants Included vs Excluded in the Cognitive Function Analysis etable 3. Baseline Scores for All the Cognitive Function Tests for All Participants of the AREDS2 Ancillary Cognitive Function Study Included in the Analyses of the Various Nutrient Supplementations etable 4 (A,B,C). Cognitive Function Tests Scores at Baseline by Treatment efigure. Study Flow of Participants This supplementary material has been provided by the authors to give readers additional information about their work.

2 eappendix. Methods for Cognitive Function Tests and Others That Were Administered to the Age-Related Eye Disease Study 2 Participants They were administered in the following order: 1. The Hearing Handicap Inventory 1 is given first to evaluate the participant s hearing as the interview is conducted by telephone. 2. The Center for Epidemiologic Studies Depression Scale (CES-D) 2 is a test that the Center for Epidemiologic Studies of the National Institute of Mental Health developed as a short self-report scale designed to assess symptoms of depression in the general population. It asks the participant to report the frequency with which each of twenty events was experienced during the previous week (5 minutes to administer). It is used as an adjustor in this study. 3. Telephone Interview Cognitive Status-Modified (TICS-M) 3 is a version of the Mini Mental State Examination. This telephone interview was designed specifically for facilitating registration, executive function, current events, serial subtraction, counting and other functions (approximately 10 to 15 minutes). TICS also included 10 words that are given early and tested for and immediate and delayed recall. The TICS ranges from 0 to 39 points. A dichotomous outcome from the TICS is defined as follows: 1) TICS total < 30 points defines low cognitive function and 2) TICS total >30 defines normal cognitive function. The TICS words recall list ranges from 0 to Animal Category 4 is used together with letter fluency and alternating fluency to assess language and executive function. Participants are asked to name as many animals as possible in 1 minute. Score is the total number of animals named, ranging from 0 to as many named.. 5. Letter Fluency 4 is used as described above with animal and alternating fluency. Participants are asked to name as many words starting with the letter F: as possible in 1 minute. The score is the total number of words. This is repeated for letters A and S. Again the score is from 0 to as many words named. 6. Alternating fluency 4 is used with animal and letter fluency as described above. Participants are instructed to alternately name a word beginning with the letter C and a food category in 1 minute. One point is given for each correct pair of words. This and above 2 tests take approximately 8 minutes. The score ranges from 0 to as many words named. 7. Wechsler Memory Scale Third Edition (WMS-III), Logical Memory Part I and Part II) 5 measures both immediate and delayed recall of two stories. The test assesses two domains of cognitive function: attention and memory. Two brief paragraphs are read aloud to the participant (Logical Memory 1) and after each, the participant is asked to recall as much as possible about each story. Delayed report is tested 30 minutes later, when the participant is asked again to recall each story from memory. The Logical Memory Part I scores range from 0 to 75 and the Logical Memory Part II scores range from 0 to 50. This takes approximately 5 minutes. 8. Digits Backwards 6 is a task used to test the speed of processing task where the participant is asked to count as fast as they can backwards starting from 100 for 30 seconds. The score is the total number of correct numbers reported after adjusting for number of errors and skipped numbers, ranging from 0 to number counted correctly. 9. Delayed recall of the WMS-III Recall paragraph, see number 7 above. 10. TICS-M Recall of the 10 letters read at the administration of TICS, ranging from 0 to 10. References: 1 Newman CW, Weinstein BE, Jacobson GP, Hug GA. Test-retest reliability of the hearing handicap inventory for adults. Ear and Hearing. 1991;12: Radloff LS. The CES-D Scale C a self report depression scale for research in the general population. Appl Psychol Meas. 1: , Brandt J, Spencer M, Folstein M. The Telephone Interview for Cognitive Status. Neuropsychiatry Neuropsychol Behav Neurol. 1988;1: Rosen WG. Verbal fluency in aging and dementia. J Clin Neuropsychol. 2: , Weschler D. A standardized memory scale for clinical use. J of Psychology. 19:87-95, Meyerson J, Hale S, Wagstaff D, Poon LW, Smith GA. The information-loss model: A mathematical theory of age-related slowing. Psychological Review. 1990;97:

3 etable 1. The Number of Interviews (Cognitive Function Testing) Conducted During the Age-Related Eye Disease Study 2 (AREDS2) #interviews Short 1 Long 2 Visit N % N % Baseline years years TOTAL Number of times administered N % TOTAL Short interview includes the Hearing Handicap Inventory, CES-D, and TICS (approximately 10 to 15 minutes to administer) 2 Long interview includes all the tests described above in Appendix 1 Number of participants with at least 1 long interview: 2991 (85.4% of 3501) Number of participants with only short interviews: 510 (14.6% of 3501)

4 etable 2. Baseline Characteristics of AREDS2 Participants Included vs Excluded in the Cognitive Function Analysis Included in Analysis Excluded in Analysis (N=3073) (N=1130) P-value Baseline Characteristic N (%) N (%) Age, mean (SD), y 72.7 (7.7) 74.3 (7.6) <.001 Female 1767 (57.5) 620 (54.9) 0.43 Race White 2986 (97.2) 1072 (94.9) 0.09 Black 35 (1.1) 19 (1.7) Asian 18 (0.6) 16 (1.4) American Indian 5 (0.2) 1 (0.1) Native Hawaiian or Other Pacific Islander 3 (0.1) 0 (0) Other 26 (0.8) 22 (1.9) Education High school or less 898 (29.2) 439 (41.7) <.001 At least some college 1493 (48.6) 431 (41.0) Post-graduate 682 (22.2) 182 (17.3) Smoking status Never 1313 (42.7) 511 (45.2) 0.24 Former 1558 (50.7) 539 (47.7) Current 202 (6.6) 80 (7.1) Aspirin use 1502 (48.9) 555 (49.1) 0.92 Statin use 1358 (44.2) 508 (45.0) 0.77 History of: Hypertension 1774 (57.7) 695 (61.8) 0.12 Congestive heart failure 108 (3.5) 39 (3.5) 0.93 Coronary heart disease 284 (9.3) 121 (10.8) 0.18 Myocardial infarction 190 (6.2) 103 (9.1) <.001 Stroke 152 (5.0) 59 (5.3) 0.72 Treatment DHA/EPA main effect No 1526 (49.7) 530 (46.9) 0.07 Yes 1547 (50.3) 600 (53.1) Lutein/Zeaxanthin main effect No 1563 (50.9) 517 (45.8) 0.08 Yes 1510 (49.1) 613 (54.2) High zinc main effect No 1141 (50.0) 373 (49.3) 0.74 Yes 1139 (50.0) 383 (50.7) Beta-carotene No 1008 (49.7) 333 (50.3) 0.80 Yes 1019 (50.3) 329 (49.7) Abbreviations: AREDS2, Age-Related Eye Disease Study 2; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; SD, standard deviation; CES-D, Center for Epidemiologic Studies Depression Scale. P-values are from χ 2 tests.

5 etable 3. Baseline Scores for All the Cognitive Function Tests for All Participants of the AREDS2 Ancillary Cognitive Function Study Included in the Analyses of the Various Nutrient Supplementations Analyses of omega-3 LCPUFAs and lutein/zeaxanthin Analyses of zinc Analyses of beta-carotene N Mean (SD) N Mean (SD) N Mean (SD) Composite score (5.3) (5.3) (5.2) TICS Total (3.4) (3.4) (3.4) Tics Word List Recall (2.4) (2.4) (2.4) Verbal Fluency Animal (5.1) (5.1) (5.1) Verbal Fluency Letter (14.0) (13.9) (14.0) Verbal Fluency Alternating (2.2) (2.2) (2.2) Wechsler Logical Memory I (14.4) (14.4) (14.3) Wechsler Logical Memory II (11.1) (11.1) (11.0) Backwards Counting (9.0) (9.0) (9.0)

6 etables 4. Cognitive Function Tests Scores at Baseline by Treatment A. Main Effect of Lutein/Zeaxanthin vs. No Lutein/Zeaxanthin Cognitive Function Test No Lutein/Zeaxanthin Lutein/Zeaxanthin P-value Composite Score a N Mean (SD) Z-score 0.4 (5.2) 0.3 (5.3) Mean (SD) difference (95%CI) (-0.63, 0.46) 0.70 Telephone Interview of Cognitive Status (TICS) b N Mean (SD) points 33.0 (3.4) 33.0 (3.4) Mean (SD) difference (95%CI) (-0.32, 0.31) 0.98 a Composite score. A composite score was constructed by including the score of all 8 cognitive tests by converting all test results into z-scores and then adding the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from -22 to 17, with higher scores representing better function. b TICS, Telephone Interview of Cognitive Status; (TICS-M) 3 is a version of the Mini Mental State Examination. The TICS score ranges from 0 to 39 points. The higher score denotes better cognitive function. Abbreviations: SD, standard deviation P-values are from an analysis of covariance comparing the means. B. Main Effect of High Zinc vs. Low Zinc Cognitive Function Test Low Zinc High Zinc P-value Composite Score a N Mean (SD) Z-score 0.2 (5.3) 0.3 (5.2) Mean (SD) difference (95%CI) 0.14 (-0.49, 0.77) 0.58 Telephone Interview of Cognitive Status (TICS) b N Mean (SD) points 33.0 (3.4) 33.0 (3.4) Mean (SD) difference (95%CI) 0.05 (-0.32, 0.42) 0.73 a Composite score. A composite score was constructed by including the score of all 8 cognitive tests by converting all test results into z-scores and then adding the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from -22 to 17, with higher scores representing better function. b TICS, Telephone Interview of Cognitive Status; (TICS-M) 3 is a version of the Mini Mental State Examination. The TICS score ranges from 0 to 39 points. The higher score denotes better cognitive function. Abbreviations: SD, standard deviation P-values are from an analysis of covariance comparing the means. C. Main Effect of Beta-Carotene vs. Beta-Carotene Cognitive Function Test No Beta-carotene Beta-carotene P-value Composite Score a N Mean (SD) Z-score 0.5 (5.2) 0.1 (5.2) Mean (SD) difference (95%CI) (-1.10, 0.22) 0.09 Telephone Interview of Cognitive Status (TICS) b N Mean (SD) points 33.1 (3.4) 33.0 (3.3) Mean (SD) difference (95%CI) (-0.49, 0.28) 0.47 a Composite score. A composite score was constructed by including the score of all 8 cognitive tests by converting all test results into z-scores and then adding the z-scores. The composite score was computed to obtain an overall score for the battery of cognitive function tests, ranging from -22 to 17, with higher scores representing better function. b TICS, Telephone Interview of Cognitive Status; (TICS-M) 3 is a version of the Mini Mental State Examination. The TICS score ranges from 0 to 39 points. The higher score denotes better cognitive function. Abbreviations: SD, standard deviation P-values are from an analysis of covariance comparing the means.

7 e-figure. Study Flow of Participants 5,178 Assessed for Eligibility 975 Excluded 4,203 Randomized Did not meet inclusion criteria Declined participation Other 1,012 Placebo 1,044 Lutein and Zeaxanthin 1,068 DHA and EPA a 1,079 Lutein/Zeaxanthin + DHA and EPA a 1,007 included in the Analysis 31 lost to follow-up 1,038 included in the Analysis 30 lost to follow-up 1,062 Included in the Analysis 38 lost to follow-up 1,069 Included in the Analysis 42 lost to follow-up 19 No AREDS Supplements c 3,036 AREDS Supplements c Randomized d 1,148 AREDS Supplements c Non randomized 659 AREDS 863 No Beta carotene 689 Low Zinc 825 No Beta-carotene and Low Zinc 656 included in the Analysis 21 lost to follow up 858 included in the Analysis 30 lost to follow up 685 included in the Analysis 26 lost to follow up 818 included in the Analysis 28 lost to follow up a DHA+EPA: docosahexanoic acid and eicosapentaneoic acid b AMD: age-related macular degeneration c AREDS (Age-Related Eye Disease Study ) Supplements: vitamins C (500 mg), E (400 international units), beta carotene (15 mg), zinc (oxide 80 mg) and copper (cupric oxide 2 mg). Smokers were not randomized to beta-carotene and are excluded from analyses of the beta-carotene main effect. d Randomization is factorial: original AREDS supplements(as), AS minus beta-carotene, AS with low zinc, or AS with combination of no beta-carotene and low zinc.

The Age-Related Eye Disease Study

What have the Age-Related Eye Disease Study (AREDS) and AREDS2 Taught Us? Emily Y. Chew, MD National Eye Institute/National Institutes of Health On Behalf of the AREDS and AREDS2 Research Groups Presenter