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Meta-Analysis of Amyloid and Cognition: Supplement -- 1

Meta-Analysis of Amyloid-Cognition Relations in Cognitively Normal Older Adults

Trey Hedden1,2, Hwamee Oh4, Alayna P. Younger1,3, and Tanu A. Patel4

1Athinoula A. Martinos Ctr. for Biomed. Imaging, Dept. of Radiology, Massachusetts Gen. Hosp., Charlestown, MA; 2Dept. of Radiology, 3Dept. of Psychiatry, Massachusetts Gen. Hosp., Harvard Medical School, Boston, MA; 4Helen Wills Neuroscience Institute, Univ. of California, Berkeley, Berkeley, CA

Supplementary Materials


e-Methods

Methodological Assumptions. Our analysis incorporates two primary simplifying

assumptions. First, that amyloid pathology can be detected via histopathological, CSF

or plasma assays, or imaging biomarkers and all of these methods indicate the

presence of potentially toxic forms of amyloid. To assess this assumption, we compared

the effects of each broad class of measurement on cognition. Second, that individual

tests of cognitive domains provide similar assessments of that domain. Because of the

wide variability in tests, this assumption is relatively difficult to test. We examined

episodic memory (including both verbal and spatial assessments), executive function (a

broad category including tasks involving directed attention, inhibition, task-switching,

and working memory), working memory (as a subdomain of executive function; this was

the only subdomain reported in a sufficient number of studies to allow separate

examination), processing speed, visuospatial function, semantic memory (including

vocabulary and language tests), and global cognition.

Search Strategy: Selection criteria and the search strategy were defined in advance and

were not modified during the search process. Keyword searches were performed on the

PubMed database using the joint keyword search: (amyloid) AND ((“Pittsburgh

Compound B” OR PIB OR florbetapir OR AV-45 OR florbetaben OR flutemetamol OR

PET) OR (CSF OR plasma OR Abeta40 or Abeta42) OR (neuropathology)) AND

(normal OR nondemented OR aging OR older OR Alzheimer’s OR dementia OR

“cognitive impairment” OR MCI) AND (cognitive OR cognition OR memory OR

executive OR speed OR visuospatial OR semantic). Filters were applied to limit


searches to human studies in the English language and to include all dates through

November 19, 2012. Database searching identified 1275 records (309 of which were

reviews), with an additional 30 records from other sources (reviews, citations, and

author contact), for a total of 1305 records to be screened after removal of duplicates.

Of these, 1188 were excluded on the basis of title or abstract or as reviews, leaving 117

screened via full-text. Fifty-three of these were excluded because no specific cognitive

domains were reported, a separate group of cognitively normal individuals could not be

identified or separately assessed, because insufficient information was not provided or

not available from the authors to compute effect sizes, or the selection criteria were not

otherwise met. This left 64 studies meeting selection criteria to be included in the meta-

analysis.

Amyloid Assessment. Histopathological methods included modified Bielschowsky,

Hedreena, Hirano and Gallyas silver stains, thioflavine S & fluorescence microscopy,

luxol fast blue, Nissle/hematoxylin and eosin staining methods. Also included were

immunohistochemical procedures with anti-amyloid-beta antibodies (A; monoclonal

antibody 10-D-5 and 6-E-10). Histopathological studies for which relations between

cognition and joint amyloid plaque and neurofibrillary tangle assessments, but not a

separable amyloid measure, were available were not included e1, e2. CSF and plasma

assay methods included measurement of A40 and A42 monomers and the ratio of

A40/A42 via enzyme-linked immunosorbant assay or xMAP Luminex technology

(Luminex Corporation). PET amyloid imaging agents included were Pittsburgh

Compound B (PIB), florbetapir, and florbetaben. No studies meeting the selection


criteria were found for flutemetamol. Studies using FDDNP e3-e6 as an imaging agent

were not included because this agent appears to have different properties from other

amyloid imaging agents and labels both amyloid and tau pathology. Estimates of

amyloid binding in PET studies were used from global cortex, large aggregate cortical

regions, or precuneus and posterior cingulate regions (if no global or aggregate

measure was reported).

Neuropsychological Assessment: Individual tasks classified as belonging to the memory

domain were: Alzheimer’s Disease Assessment Scale — Cognitive Behaviour Section:

delayed word recall, Associate Learning, Benton Visual Retention Test: recall, California

Verbal Learning Test, East Boston Story, Face-Name Associative Memory Exam, Free

and Cued Selective Reminding Test, Fuld Object-Memory Evaluation, International

Shopping List Test, Logical Memory, Memory Capacity Test, One Card Learning

(CogState), Paired Associate Learning (CogState), Rey Auditory-Verbal Learning Test,

Rey-Osterrieth Complex Figure: recall, Selective Reminding Test, Visual Reproduction,

and the Visual Association Task: recall. For the executive function domain, tasks were:

Delis-Kaplan Executive Function System, Hayling task, Identification (Cogstate), Letter

Fluency or Phonemic Fluency, Mental Control, Stroop: color-dot or color-word, Trail-

Making Test B or B-A, and all tasks categorized in the subdomain of working memory.

For the working memory subdomain, tasks were: Digit Span Forward & Backward,

Letter-Number Sequencing, Listening Span,1-Back Task (CogState), and the N-Back

Task. For the processing speed domain, tasks were: A Quick Test of Cognitive Speed,

Conceptual Comparisons, Crossing-off, Detection (CogState), Digit Symbol, Number


Comparison, Number Matching, Pattern Matching, Perceptual Comparisons,

Sensorimotor Speed, Stroop: color and word subtests, Symbol Digit Modalities Test and

Trail-Making Test A. For the visuospatial function domain, tasks were: Benton Visual

Form Discrimination Test, Benton Visual Retention Test: copy, Rey-Osterrieth Complex

Figure: copy, Block Design, Constructional Praxis and the Card Rotations Test. For the

semantic memory domain, tasks were: Boston Naming Test, Category Fluency,

Information, Similarities, the Visual Association Task: picture naming, and vocabulary

scales. For global function, tasks were: Alzheimer’s Disease Assessment Scale—

Cognitive Behaviour Section: total score, Activities of Daily Living, Blessed Dementia

Scale – Cognitive Portion, Clinical Dementia Rating – Sum of Boxes, Mini-Mental State

Examination, Modified Mini-Mental State, Short Blessed Test, and the Short Portable

Mental Status Questionnaire. Composite scores were assigned to domains by

evaluating the contribution of tasks to the composite score.

e-Results

Homogeneity Analysis and Evaluation for Outliers. Figure 1 (main text) displays funnel

plots showing the distribution of effect sizes as a function of study weighting. When

examining independent cohorts using PIB only or when examining independent cohorts

using all amyloid assessment methods, no cognitive domain exhibited significant

inhomogeneity (all ps > .11). Although episodic memory did not exhibit significant

inhomogeneity, one study stands out as a large outlier for this domain: Fuld et al.,

198739; because of its small size, if this study is excluded, no significant changes in the

results are observed. Although some domains did exhibit studies with effect sizes

outside the boundaries of the funnel plots, we kept all of these cases in the analyses


because none of these domains exhibited significant inhomogeneity and this approach

maximizes the available data; if any of these outlier studies are excluded, the

substantive results are unchanged.

One potentially important source of inhomogeneity may be differences among

the wide array of test variables included in each cognitive domain. For example, tasks

classified as measuring executive function encompass multiple component processes

including directed attention, inhibition, task switching, and working memory. Similarly,

semantic memory encompasses multiple types of language tasks, including picture

naming and category fluency. As noted above, none of the domains exhibited significant

inhomogeneity in the independent cohorts analyses, suggesting that task variation was

not a major source of variability in the reported effect sizes for any domain.

Effect of Assessment Method, Study Design, and Control Variables. Using the

sample of studies with independent cohorts for all amyloid assessments, we examined

the effects of amyloid assessment method (CSF/plasma, histopathology, or PET

imaging), study design (cross-sectional or longitudinal), and whether control variables

were included or not by conducting separate weighted one-way ANOVAs for each

cognitive domain. For assessment method, no significant effects were observed. There

were no CSF/plasma studies for working memory or visuospatial function, hence only

histopathology and PET imaging studies were compared for these domains. Although it

did not meet the significance threshold, there was a trend for working memory (Q(1,9) =

3.35, p = .07) such that higher effect sizes were observed with histopathological


measures (z(r) = .15, SE = .05) than for PET imaging measures (z(r) = .02, SE = .04).

When PIB was directly contrasted against all other assessment methods (including

other PET ligands), no domain reached the FDR-corrected significance threshold.

However, this comparison showed a trend for executive function (p = .08), working

memory (p = .02), and speed (p = .03). Note that these results are in the context of non-

significant effect sizes for both working memory and speed. Nonetheless, these results

may provide an indication of greater variability across assessment methods in executive

function, its subdomains, and speed than in other cognitive domains. However, we note

that all but one of the studies using other assessment methods and showing a large

positive effect size (r > .2) for any of these domains have sample sizes of fewer than

100 subjects, so it will be important to examine these differences across assessment

methods in subsequent larger studies.

For study design, no significant effects were observed. There were no

longitudinal studies in the independent cohorts analysis for working memory, and only

one longitudinal study each for executive function and processing speed; hence no

statistics could be computed for these domains. Because of the low number of

longitudinal datasets available, even modest effect size differences due to study design

are unlikely to be detected.

There was little consistency across studies in the control variables entered,

although age was the most common control variable. We coded whether age

(regardless of whether it was accompanied by other control variables) was entered into

the analysis of the relation between amyloid burden and cognition. Whether control

variables were included in the analysis or not was not significant for any domain.


Results in All Studies. As exploratory analyses to provide the possible range of effect

sizes if more power were available, we examined the data from all available studies, not

limited to those with independent cohorts. Studies could contribute both a cross-

sectional and longitudinal dataset to this analysis, under the assumption that the two

measurements capture different information. Removing this assumption and allowing

each study to contribute only one dataset does not materially alter any result. The

reported subject count (Table e-2) is adjusted so that such studies are only represented

once. When all studies, representing a maximum of 7018 subjects, are included, all

cognitive domains except visuospatial function had a significant mean effect size (Table

e-2). Notably, the observed effect sizes are very consistent with or somewhat inflated

relative to the independent cohorts analysis reported in the main text; the extent of

these relative changes across analyses can be visualized in the shift from the solid to

the dashed lines in Figure 1 in the main text for each domain. However, one-way

ANOVAs examining the mean effect sizes in studies selected as independent cohorts

versus studies not so selected found no significant effects of selection (all ps > .11),

indicating that the non-independence of samples was unlikely to be a major contributor

to the meta-analytic findings. Studies selected as independent cohorts tended to have

the largest, and therefore most heavily weighted, samples in the meta-analysis.

Nonetheless, results from the non-independent cohorts analysis should be interpreted

with caution.


Table e-1. Study Characteristics and Effect Sizes for All Studies Meeting Selection Criteria

Author Year Cohort Method C/L Controlled n EM EF WM PS VS SM GF

Balasubramanian e7

2012 90+AS Pathology C 0 49 .02 .10

Balasubramanian

e72012 90+AS Pathology L 0 49 .11 .10

Mormino e8 2008 ADNI PIB C 0 17 -0.14

Schott e9 2010 ADNI A42 C 0 105 0.03 0.29 0.13 0.04 -0.09

Ewers e10, a 2011 ADNI PIB; A42 L 0 124 0.01 0.11

Vemuri e11 2011 ADNI A42 C 1 109 0.04 0.11 0.00

Pike e12, b 2007 AIBL PIB C 1 32 0.40

Rowe e13 2007 AIBL PIB C 0 27 0.29

Villemagne e14 2008 AIBL PIB C 0 33 0.69

Bourgeat e15 2010 AIBL PIB C 0 95 0.18

Chetelat e16 2010 AIBL PIB C 1 44 -0.02 -0.06 -0.14 -0.03 0.24

Chetelat e17 2011 AIBL PIB C 1 93 0.26

Pike e18 2011 AIBL PIB C 0 177 0.19 0.03 0.10 -0.01 0.08

Villemagne e19 2011 AIBL PIB C 0 104 0.26 0.04

Villemagne e19 2011 AIBL PIB L 0 104 -0.15 0.01

Villemagne e19 2011 AIBL PIB L 0 34 0.67 0.40


Lim e20 2012 AIBL PIB C 0 141 .14 .07 0.08 0.00 0.01

Lim e20 2012 AIBL PIB L 1 141 .21 .14 0.22 0.05

Lim e21 2012 AIBL PIB C 0 44 .16 -.20 -0.05 0.12

Lim e21 2012 AIBL PIB L 1 44 .34 .07 0.08 0.07

Tolboom e22 2009 AMSTR PIB C 0 15 0.03 -0.05 -0.05 -0.07 -0.29 -0.06

Doraiswamy e23 2012 AV45 Florbetapir C 0 69 0.25 0.31 0.11 -0.04

Doraiswamy e23 2012 AV45 Florbetapir L 1 67 0.15 0.12 0.01 0.13

Sperling e24 2012 AV45 Florbetapir C 1 78 0.27 0.10 0.01 0.22

Mormino e8 2008 BAC PIB C 0 20 0.18 0.29 0.36

Marchant e25 2012 BAC/UCD PIB C 0 54 0.11 0.00

Mormino e26 2011 BAC PIB C 1 44 0.19 0.08

Mormino e27 2012 BAC PIB C 0 45 -0.02 -0.05 -0.07 0.40

Oh e28 2011 BAC PIB C 0 52 0.06 -0.02 -0.03 -0.01 0.21

Oh e29 2012 BAC PIB C 1 52 0.12 0.07 0.12 -0.19

Oh e30 2012 BAC PIB C 1 52 0.13 0.00 0.03 -0.11

Perrotin e31 2012 BAC PIB C 1 39 0.22 0.06 0.12 0.19

Driscoll e32 2006 BLSA Pathology L 0 39 -0.16 -0.04 0.03

Resnick e33 2010 BLSA PIB L 0 51 0.29 0.34 0.45

Sojkova e34 2011 BLSA PIB C 0 24 0.15 0.31


Sojkova e34 2011 BLSA PIB L 0 24 0.32 0.38

Stomrud e35 2010 CMRU A42 C 0 37 0.30 0.49 0.15

Stomrud e35 2010 CMRU A42 L 0 37 0.37 0.40

Rodrigue e36, c 2012 DLBS Florbetapir C 1 88 0.01 0.16 0.16 0.31 -0.02 0.05

Hulette e37 1998 DUKE Pathology C 0 12 0.11 0.00 0.30 0.28 0.15

Barthel e38 2011 EUR Florbetaben C 0 69 0.03 0.03

Fuld e39 1987 FULD Pathology C 0 9 1.19

Rolstad e40 2011 GOTH A42 C 1 60 0.28 0.28 0.39

Jack e41, d 2008 MCSA PIB C 0 20 0.02 0.00

Jack e42 2012 MCSA PIB C 0 263 0.13 0.14 0.10 0.14 0.25

Kantarci e43 2012 MCSA PIB C 1 408 0.14 0.12 -0.13 0.13 0.18

Knopman e44 2012 MCSA PIB C 0 171 -0.02 0.12 0.01 0.06 0.12

Mielke e45, e 2012 MCSA PIB C 0 483 0.08 0.08 0.04 0.08 0.10

Hedden e46 2009 MGH1 PIB C 1 38 0.10 -0.15 -0.06 -0.05

Hedden e47 2012 MGH1 PIB C 1 49 -0.21 -0.10 -0.05

Sperling e48 2009 MGH2 PIB C 1 22 -0.08

Rentz e49 2010 MGH2 PIB C 0 66 0.18 -0.18 -0.15 -0.11 0.23 0.06 0.00

Gomperts e50, f 2012 MGH2 PIB C 1 84 0.06 -0.13 -0.12 -0.04 -0.11Vannini e51 2012 MGH2 PIB C 0 40 0.33 -0.02 0.02 0.19


Rentz e52 2011 MGH-HAB PIB C 1 45 0.23 -0.10

Hedden e53 2012 MGH-HAB PIB C 1 109 0.18 0.00 0.06 0.03 0.11

Okereke e54 2009 NHS A40/42 C 1 481 0.06 0.09

Okereke e54 2009 NHS A40/42 L 1 481 0.06 0.10

Aizenstein e55 2008 PITT PIB C 0 38 -0.25 0.08 0.01 0.04 -0.01 -0.12

Bennett e56 2006 ROS/MAP Pathology C 1 134 0.27 0.13 0.13 0.07 -0.07 0.20 0.07

Bennett e57 2012 ROS/MAP Pathology C 1 296 0.11 0.12 0.12 0.00 0.01 -0.01 0.12

Schmitt e58 2000 UK-ADC Pathology C 0 59 0.07 0.16

Riley e59, g 2011 UK-ADC Pathology C 1 114 0.04 -0.14 0.15 0.05 0.20

Riley e59 2011 UK-ADC Pathology L 1 116 0.16 0.09 0.22 0.19 0.16

Jicha e60 2012 UK-ADC Pathology C 0 85 0.07 -0.04 0.01 0.21

Li e61 2007 UWA A42 C 0 72 0.00 0.08 0.24 0.00

Cosentino e62 2010 WHICAP A40 L 1 478 0.07 0.04 0.01 0.07

Gu63, h 2012 WHICAP A40/42 C 0 813 0.05

Morris e64 1996 WU-ADRC Pathology C 0 19 0.32 0.04 0.02 0.29 0.17 0.46 0.35

Goldman e65 2001 WU-ADRC Pathology C 0 14 -0.25 -0.07 -0.04 0.15 0.00 0.02 -0.10

Mintun e66 2006 WU-ADRC PIB C 0 29 -0.04 -0.05 0.00 0.27

Roe e67 2008 WU-ADRC PIB C 1 156 0.11 0.09 0.00 0.05

Price e68 2009 WU-ADRC Pathology C 0 97 0.59 0.26 0.22 0.21 0.02


Storandt e69 2009 WU-ADRC PIB C 0 135 0.09 -0.03 -0.03 -0.02 0.05

Storandt e69 2009 WU-ADRC PIB L 0 135 0.04 0.17 0.17 0.17 0.04

Storandt e70 2012 WU-ADRC A42 C 1 220 0.11 0.09 -0.07 -0.02

Storandt e70 2012 WU-ADRC PIB C 1 220 0.18 0.06 -0.01 0.08

Studies are grouped by cohort, with each cohort given a unique abbreviation. Studies listed more than once contributed

multiple datasets to the analysis. Effect sizes are Fisher-z transform of r. The weight w for each study is n – 3. Bold

values were selected to represent the cohort in the independent cohorts analysis. Italicized studies indicate that effect

sizes were computed in part from additional unpublished information provided by the authors. aEwers et al., 2011 e10 used

imputed PIB values estimated from CSF A42. bPike et al., 2007 e12 was included in the AIBL cohort because the authors

indicated that most subjects in this study were later enrolled into AIBL (C. Rowe, personal communication). cEffect sizes

for Rodrigue et al., 2012 e36 were computed using only the subsample of adults aged 60+ so as to be most comparable to

the other studies (K. Rodrigue, personal communication). dJack et al., 2008 e41 was included in the MCSA cohort because

the authors indicated these subjects were enrolled in the MCSA (C. Jack, personal communication). eEffect sizes for

Mielke et al., 2012 e45 were computed using the 1.5 PIB threshold. fOnly 47 subjects had available data for the memory

measure in Gomperts et al., 2012 e50 (S. Gomperts, personal communication). fCross-sectional data for Riley et al., 2011

e59 had a smaller sample size than the longitudinal data due to greater missing-ness at baseline. hEffect size for Gu et al.,

2012 e63 was computed by comparing the highest and lowest A tertiles. EM = episodic memory, EF = executive function,


WM = working memory, PS = processing speed, VS = visuospatial function, SM = semantic memory, GF = global

function.


Table e-2. Effect Size Statistics for Exploratory Analysis of Non-independent Cohorts.

All Studies

Cognitive Domain N n r SD Z

Episodic Memory 76 7018 .12 .12 7.89*

Executive Function 47 4229 .08 .10 5.71*

Working Memory 23 1457 .09 .10 3.55*

Processing Speed 30 2047 .06 .12 2.42*

Visuospatial 17 2876 .04 .09 1.51

Semantic Memory 38 4202 .07 .10 4.05*

Global Cognition 47 4997 .10 .09 7.78*

N = number of analytic datasets, n = number of subjects across datasets; r = weighted mean effect size (calculated with

inverse Fisher-z transform); SD = weighted standard deviation. *pFDR < .05


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Supplemental Figure Legend

Figure e-1. Mean effect sizes for each cognitive domain in studies using PIB

imaging. This was the largest and most methodologically homogeneous subset

of studies. Effect size is the Fisher-z transform of r. Dots indicate weighted mean

effect size; bars indicate weighted standard error of the mean. Brackets indicate

significant differences between episodic memory and the other domains. *pFDR

< .05, one-tailed

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