Supplemental Data

Supplemental methods Methods e-1: Search strategy and selection criteria The keywords used for the Pubmed search were: APOE, Apolipoprotein E, MRI, white matter, leukoaraiosis, infarct, infarction, brain infarct, brain infarction, silent infarct, silent infarction, cerebral infarct, cerebral infarction, lacunar infarct, lacunar infarction, microbleed, microhemorrhage. We restricted the search to studies in humans. We reviewed abstracts of identified articles in all languages. For those potentially meeting the inclusion criteria, the full paper was reviewed. Only papers in peer-reviewed journals were considered for analysis (not including abstracts or conference summaries). For studies with more than one publication describing results among overlapping groups of subjects, with the same outcome measure, we included only the dataset that was most recent, with the largest number of patients and with numerical results. The same approach was used when unpublished results on a larger dataset were available (Framingham Heart Study). Methods e-2:Variable definition We excluded studies on white matter lesions occurring in inflammatory or neurodegenerative conditions such as multiple sclerosis, autoimmune disorders, as well as studies on WMH in monogenic cerebrovascular diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Whenever possible we used results for global WMH, but when only PVH and DWMH were available, we used PVH in our primary meta-analysis. It has indeed been shown that although PVH and DWMH volumes are both strongly associated with global WMH burden, there is a steeper slope of change in PVH volume with increasing total WMH volume.e1 Methods e-3: Statistical analyses When only separate results for APOE4 homozygous and heterozygous carriers were available (and not for APOE4+ status), we used the results for APOE4 heterozygous carriers, in order to combine with results of studies using APOE4+ status as a predictor variable, given the low frequency of APOE4 homozygotes. The sample size weighted z-score based meta-analysis accounts for the fact that WMH burden was measured on different scales (microliters or grade) and analyzed either quantitatively or qualitatively across studies. Instead of combining coefficients and standard errors it combines each cohort's z-statistic, weighted by their sample size, but does not provide a measure of effect size.

Supplemental Figures Figure e-1: Meta-analysis of studies testing the association between APOE4+ and BI, using a fixed effects model

Figure e-2: Meta-analysis of studies testing the association between APOE44 and BI, using a random effects model

Figure e-3: Meta-analysis of studies testing the association between APOE2+ and CMB, using a fixed effects model

Figure e-4: Meta-analysis of studies testing the association between APOE4+ and WMH burden using a random effects model Association between APOE4+ and continuous WMH

Association between APOE4+ and dichotomous WMH

Figure e-5: Meta-analysis of studies testing the association between APOE44 and WMH burden using a random effects model Association between APOE44 and continuous WMH

Association between APOE44 and dichotomized WMH

Figure e-6: Meta-analysis of studies testing the association between APOE4+ and BI using a random effects model

Figure e-7: Meta-analysis of studies testing the association between APOE4+ or APOE44 and CMB using a random effects model Figure e-7a: Association between APOE4+ and CMB

Figure e-7b: Association between APOE44 and CMB

Figure e-8: Meta-analysis of studies testing the association between APOE2+ and WMH burden using a random effects model Association between APOE2+ and continuous WMH

Association between APOE2+ and dichotomized WMH

Figure e-9 Meta-analysis of studies testing the association between APOE2+ and BI using a random effects model

Figure e-10: Meta-analysis of studies testing the association between APOE2+ and CMB using a random effects model

Supplemental Tables

Table e-1: Quality criteria of the included articles See Separate File.

10

Table e-2: Cross sectional associations between APOE4+ and WMH burden, in the general population
Reference e2 e3 65* 396 e4 235 e6 Austria 59.9 USA 72.3 SE, DE (+T2) T1, T2, PD Q SQ N 106 74 75 origin Finland Denmark Age 72.9 82.3 Sequence FLAIR T2, PD Qn SQ SQ WMH definition 3 grades (<4, 5-7, >8) WMH score: addition of PVH and DWMH scores volumes (cm3) lacunes and/or WMH: presence or absence association 4-heterozygous: RR=085 (0.45-1.40, p=0.57) 4-homozygous: RR=1.31(0.39-2.26, p=0.59) WMH score in 4-carriers: 11(3-27) in 4-non-carriers: 7.5(0-22), p<0.05 4-carriers: SMD=0.60 (0.09, 1.11) WMH vol in 4-carriers: 4457, in 4-non-carriers: 4.16.1, NS 4-carriers : 0.05 (-0.19, 0.29) (from Paternoster et al.)5 34: OR=1.39 (0.62-3.10), p=0.44 Ref group 4-nc 4-nc 33 4-nc (24 excluded) 33 AV age, sex, edu n.a. Age, edu, head size Age, arterial HTN, diabetes, cardiac disease, plasma fibrinogen levels age, sex, SS, BMI, PAD, diabetes

829 e7

NL

72.6

T1, T2, PD

SQ

DWMH: mean volume; PVH: mean grade

e8 e9 e10

432 411 309 1,758* 1,404* 3,480 3,244* 2,487* 92 56

Australia France USA (W & AA) USA (C & AA) Sweden USA Iceland Australia

62.6 72.4 71.0

FLAIR T1, T2 T2, SD

SQ + Q Q SQ

total WMH volume (cm3) : continuous variable WML volume (cm3, mean values) Dichotomized severity of WMH: grade <3 or >3 Dichotomized severity of DWMH: high or low 3 grades Volumes (log-transformed) Volumes (log-transformed) Volumes

4-carriers with PVH: adjusted mean difference: 0.1 (-0.2,0.5) 4-carriers with DWMH: adjusted mean difference 0.5 (0.2-0.8) DWMH: 4-carriers: SMD HTN+=0.35 (0.14, 0.55), HTN-=0.01 (-0.20, 0.22)* PVH: 4-carriers: SMD HTN+=0.05 (-0.15, 0.25), HTN-=-0.06(-0.27, 0.15)* 4-carriers with WMH vol: =0.081 (NS) in men, =-0.006 (NS) in women 4-carriers: SMD=0.02 (-0.20, 0.24), p=0.8587 4-homozygous: SMD=-0.05 (-0.86, 0.76), p=0.9053 Total WML: 4-noncarriers: mean vol=5.64, 4-heterozygous: mean vol=5.41, 4-homozygous: mean vol=9.14, p=0.003 no association 4-carriers: OR=1.09 (0.92, 1.29), p=0.299 4 homozygous: OR=1.79 (0.99, 3.22), p=0.054 4-carriers: OR=1.40 (0.52, 3.72), p=0.68* 4-carriers : OR=2.51 (0.83, 7.57), p= 0.17* No association (p=0.33) 4-carriers : SMD=-0.19 (-0.59, 0.21) 4-carriers : 6.94% difference (p=0.01) 4-carriers: SMD=0.09 (0.02, 0.15)* 4-carriers: SMD=-0.11 (-0.32, 0.09), p=0.2863 4-homozygous: SMD=-0.01 (-0.70, 0.69), p=0.9897

33 ( 24 excluded)

4-nc ( 24 in 4+) 4-nc 4-nc 4-nc (24 in 4carriers) 4-nc 4-nc 33* 4-nc 4-nc ( 24 in 4+) 4-nc 4-nc (24 excluded) 33

ICV, age ICV, age age, sex, education level, TIV age, sex, edu

73.6 74.2 58.9 76.3 78.8

e11 e12 e13 e14 Sydney MAS, unpublished , 2011 FHS, unpublished, 2012 144 125 4,303 518 406 2,353 1,574

T2, FLAIR, PD T2, FLAIR FLAIR T1, T2, FLAIR T1, FLAIR

SQ SQ Q Q Q

n.a. none Age, sex, htn Age, sex age, sex, ICV ICV, age

USA

64.4

T1, T2, PD

Volumes (log-transformed and 4-carriers: =0.06273 (0.04851), p=0.19612 normalized to intracranial size) 4-homozygous: =-0.0783 (0.15336), p=0.60980

Age, sex, familial relationships

AA: African-American, APOE: apolipoprotein E genotype, AV: adjustment variable, C: Caucasian, CHD: coronary heart disease, DE: double echo, DWMH: deep white matter hyperintensities, edu: education, FHS: Framingham Heart Study, FLAIR: fluid attenuated inversion recovery, GP: general population, HTN: hypertension, ICV: intracranial volume, ILL: infarction-like lesions, MAS: Memory and Ageing Study, N: number of subjects, n.a.: not available, nc: noncarriers, NL: the Netherlands NS: not significant, OR: odds ratio, PAD: peripheral artery disease, PD: proton density, PVH: periventricular hyperintensities, Q: quantitative, Qn: quantification, Ref: reference, RR: relative risk, SE: spin echo, SMD: standardized

mean difference, SQ: semi-quantitative, SS: study site, TIV: total intracranial volume, USA: United States of America, vol: volume, W: white, WM: white matter, WMH: white matter hyperintensities, WML: white matter lesions, yr: year, *: computed by authors of meta-analysis from published raw numbers (and used in the meta-analysis ), : computed by authors of meta-analysis from raw data provided by authors of the original article (and used in the meta-analysis), : p value for the general model (2 degrees of freedom)

Table e-3: Cross sectional associations between APOE4+ and WMH burden, in high risk populations
Reference e15 e16 N 117 90 342 207* e17 67 acute lacunar infarct, HC ICH depressed, HC AD, VaD China 70.7 T2 Q Condition hypertensive TIA or IS Origin NL Belgium Age 63.3 71.0 Sequence FLAIR FLAIR Qn Q SQ WMH definition log transformed WML volume, percentage of intracranial volume WMD severity, dichotomized into absent or mild versus moderate to severe WMC volume (mL) dichotomized as severe versus mild WMC 3 grades (0/1, 2, 3) Grades 2/3 vs 0/15 Grade 3 vs others* mean WML volume (mL) Association 4 heterozygous: mean difference= -0.01 (-0.37,0.36), p=0.97 4 homozygous: mean difference= 0.31 (-0.27,0.88), p=0.29 4-carriers: OR= 0.96 (0.59,1.6), no p value 4-homozygous vs E3/3: OR=1.75 (0.34, 8.91), p=0.7484* 4-carriers OR=4.7 (1.4,16), p=0.003 4-carriers: SMD=0.24 (-0.33, 0.81)* Ref group 4-nc 4-nc (24 in 4+) 33* 4-nc AV age, sex. Family relationship for p values age, sex, HTN, diabetes, stroke history, CAD, smoking, cholesterol, scan type age

101 e18 245 e19 245* 187* 131 e20 72* 71 e21

Austria USA

70.0 70.2

T1, T2, T2* D-E, FSE

SQ SA

Japan

73.5

T2, FLAIR

SQ

AD, LB, VaD

GB

77.8

T2, PD, FSE

SQ

no association 4-carriers OR=0.69 (0.26, 1.84) (from Paternoster et al.)5 4-carriers: OR= 0.70 (0.23, 2.15)* 4-carriers B= -1.364 (for depressed n=145) and B= -0.7545 (for nondepressed n=100), both ns 4-carriers: SMD=0.10 (-0.18, 0.38) 4-homozygous: SMD=0.72 (0.04, 1.39) WMH were 4-carriers OR=1.00 (0.58, 1.73) for 1 increase in 4 allele dichotomized as present 4-carriers ORadjusted=1.06 (0.53-2.14) for 1 increase in 4 allele or absent 4-carriers OR=0.87 (0.36-2.08) for presence versus absence of 4 allele 4-carriers: OR=0.95 (0.47-1.89)* 4-homozygous : 1.16 (0.30, 4.51), p=0.8335* PVH and DWMH Mean PVH score in 4-noncarriers=3.3, in 4-heterozygous=3.1, in 4scores homozygous=2.9 (p=0.83) for all groups Mean DWMH score in 4-noncarriers=5.3, in 4-heterozygous=4.9, in 4homozygous=4.9 (p=0.79) for all groups Score as sum of PVH, DWMH and BG scores (ranging from 0 to 48) ApoE genotype with DWMH: F(2.51)=3.79, p<0.05 ApoE genotype with PVH: F(2.51)=5.15, p<0.01 4-homozygous associated with DWMH (p<0.01 compared to 3/4, p<0.02 compared to 3/3) 4-homozygous associated with PVH when compared to 3/4 (p<0.01) but not when compared to 3/3 (p=0.15) 4-carriers OR = 1.09, p>0.99

24 excluded 4-noncarriers5 4-noncarriers* 33 (2-carriers excluded) 33 4-nc* 33* 4-nc

n.a. none5 none* age, sex, race, edu, MMSE score, vascular conditions, TBV, and gray matter lesion vol demographic factors, dementia severity, vascular risk factors, presence of lacunar infarcts (matching on age, sex, age at onset of illness, duration of illness, and cognitive function) age, degree of dementia

56 e22

AD

Sweden

63.6

T2, PD

SQ

33 (24 excluded)

55 e23

AD

Japan

71.1 80.6

T2

SQ

WMH were dichotomized as present or absent

4-nc

none

Reference

Condition

Origin

Age

Sequence

Qn

WMH definition

Association

Ref group

AV

83 e24

probable AD

USA

72.0

T1, T2

SQ Scheltens score: PVH total score, total WMH score, total BGH score, total IH score

Results as comparisons of mean Scheltens scores according to number of 4 alleles carried (none, 1 or 2) 4 with PVH score: r=0.079, p=0.42 / 4 with WMH score: r=0.115, p=0.25 4 with BGH score: r=0.122, p=0.22 / 4 with IH score: r=0.017, p=0.86 4-carriers : SMD=0.35 (-0.07, 0.78) (from Paternoster et al.)5 4-homozygous: SMD=0.32 (-0.24, 0.88)* no association

4-nc

n.a.

51* 195 e25 96 e26 82 e27 96 e28 815 e29 740 e30 944 e31 633* AD, MCI, CAA AD USA 73.077.7 AD, VaD, M/A, mixed, HC MCI, dementia, HC probable AD USA China Italy 76.9 74.2 71.9 T1, T2 Ql

WML score (PV WML and CS WML, each on a 4-point scale) FLAIR log transformed WMH 4-carriers : B=-0.26 (0.24), p=0.27 volume after division by total cranial volume T2, SQ WMC global score (0 to no association FLAIR, PD 18) 4-carriers: OR=1.41 (0.57, 3.45)* T1, FLAIR Q log transformed WMH normalized to intracranial size

4-nc 4-nc 4-nc 4-nc

age, dementia severity, and duration of disease educational level and sex Age, sex, education n.a.

4-carriers and AD/MCI patients: B=-0.02, p>0.2 4-carriers and CAA patients: B=-0.06, p>0.2 (bivariate)

USA, CA, 70.8 FLAIR DE, GR 75.0 75.3 58.468.8 T1, T2* T2

probable USA, CA AD, MCI, HC Leukoaraiosi HU s, HC

SQ 0 (no WMH) to 100 4-carriers: p=0.0068 mm (most extensive 4-carriers: =0.3455 (0.1239242643) WMH), log transformed WMH Q WML volume (log4-carriers: B=0.025 (0.033), p=0.44 (FDR p=0.44) transformed) SQ Dichotomized (leukoaraiosis vs HC) 4-carriers: OR=0.93 (0.67, 1.31), p=0.69* 44: OR=1.28 (0.30, 5.42), p=0.7336*

4-nc

sex, age at MRI, ethnicity, AD affection status, duration of disease (years) age, sex, HTN, edu, alcohol, smoking, and PC 1 & 2 none

n.a. 4-nc (24 excluded) 33*

AAMI: age-related memory impairment, AD: Alzheimer disease, APOE: apolipoprotein E genotype, AV: adjustment variable, BGH: basal ganglia hyperintensities, CA: Canada, CAA: cerebral amyloid angiopathy, CAD: coronary artery disease, CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, CS: centrum semiovale, CSWML: cortico subcortical white matter lesions, DE: Germany, D-E: double echo, DWMH: deep white matter hyperintensities, edu: education, FDR: false discovery rate, FLAIR: fluid attenuated inversion recovery, FSE: fast spin echo, GB: Great Britain, GR: Greece, HC: healthy controls, HTN: hypertension, HU: Hungary, ICA: intracranial cross-sectional area, ICH: intracerebral hemorrhage, IH: infratentorial hyperintensities, IS: ischemic stroke, LB: lewy bodies, M/A: mild/ambiguous, MCI: mild cognitive impairment, MMSE: mini mental state examination, MRI: magnetic resonance imaging, N: number of subjects, n.a.: not available, nc: noncarriers, NL: the Netherlands, NS: not significant, OR: odds ratio, PC: principal components, PD: proton density, PVH: periventricular hyperintensities, PVMWL: periventricular white matter lesions, Q: quantitative, Ql: qualitative, Qn: quantification, Ref: reference, SH: subcortical hyperintensities, SMC: subjective memory complaints, SNP: single nucleotide polymorphism, SQ: semi-quantitative, TIA: transient ischemic attack, TBV: total brain volume, USA: United States of America, VaD: vascular dementia, vol: volume, vs: versus, WMC: white matter change, WMD: white matter disease, WMH: white matter hyperintensities, WML: white matter lesions , yr: year, *: computed by authors of meta-analysis from published raw numbers (used in the meta-analysis), : value provided by author (and used in the meta-analysis), : computed by authors of meta-analysis from raw data provided by authors of the original article (and used in the meta-analysis)

Table e-4: Longitudinal associations between APOE4+ and WMH burden, in the general population

Reference

N 1319

Origin France

Age 72.4

Sequence T1 T2

Qn Q

WMH definition WML volume change (cm3, mean values)

Association Total WML: 4-noncarriers: mean vol=+1.32, 4-heterozygous: mean vol=+1.48, 4-homozygous: mean vol=+3.46, p=0.01

Ref group 4-nc

AV age, sex, education level, TIV age, sex, white matter grade at initial scan, and time between scans sex, age at the first NP/MRI assessment, time interval between the risk factor assessment and the first NP/MRI assessment, and education for cognitive outcomes.

e9 952 e32 USA 74.0 T1 T2 SQ

Worsening of white 4-carriers: OR=1.46 (1.00, 2.14), p=0.052 matter grades (none, 1, or 2 or more) WMH volume (logtransformed) no association

4-nc

1,352 e33

USA

61.0

T1 T2

4-nc

APOE: apolipoprotein E genotype, AV: adjustment variable, DWMH: deep white matter hyperintensities, GP: general population, MRI: magnetic resonance imaging, N: number of subjects, nc: noncarriers, NP: neuropsychological test battery, OR: odds ratio, PVH: periventricular hyperintensities, Q: quantitative, Qn: quantification, Ref: reference, SQ: semi-quantitative, TIV: total intracranial volume, USA: United States of America, vol: volume, WMH: white matter hyperintensities, WML: white matter lesions, yr: year

Table e-5: Cross sectional associations between APOE4+ and BI, in the general population and in high risk populations
Reference N Condition Origin Age Sequenc e SE, DE T1, T2 BI definition Association Ref group AV

General population 396 e4 214 e34 3,480 3,271~ 2,508~ 1,802 1,771~ 1,771 ~ 1,555~ 2,353 1,893

USA Austria

72.3 60.5

evidence of stroke TI or lacunes

no association (p=0.08) 4-carriers: OR=1.57 (0.92, 2.70), p=0.1315* 4-carriers p=0.64 for TI 4-carriers: p=0.47 for lacunes Lacunes 4-carriers: OR=1.84 (0.34, 9.84), pfisher=0.6137* No association 4-carriers: OR=0.95 (0.80, 1.13 ), p=0.5510 4 homozygous: OR=0.69 (0.35, 1.37), p=0.2954 4-carriers: OR=1.02 (0.68, 1.52), p=0.9386 4-homozygous: OR=0.624 (0.082, 4.746), p=0.6489 4-homozygous: OR=0.644 (0.085, 4.908), p=0.6714 4-carriers: OR=1.16 (0.87, 1.55), p=0.31538 4-homozygous: OR=0.19 (0.03, 1.40), p=0.10316

4-nc (24 excluded) 4-nc

n.a. n.a.

e10

USA (W & AA) France

71.0 72.8

T1, T2 T1, T2

ILL Presence of BI

4-nc (24 in 4-carriers) 4-nc (24 excluded) ~ 33 4-nc (24 excluded)

3C-Dijon study, unpublished, 2011 FHS, unpublished, 2012 High risk populations e15 117 73 101 e18 82 e27

Age, education and sex Age and sex

USA

64.4

T1, T2, PD

Presence of BI

Age, sex, familial relationships age, sex. Family relationship for p values n.a. Age, sex, education level

Hyperten- NL sive ICH probable AD Austria Italy

63.3

FLAIR

presence of LI

4-heterozygous: OR=0.39 (0.10, 1.52), p=0.18 4-homozygous: OR=4.77 (1.18, 19.32) no association 4-carriers : OR= 1.33 (0.49, 3.59)* no association

4-nc

70.0 71.9

T2 T2, FLAIR, PD

Presence of lacunes presence of lacunes

24 excluded 4noncarriers* 4-nc

AA: African-American, AD: Alzheimer disease, APOE: apolipoprotein E genotype, AV: adjustment variable, BI: brain infarct, DE: double echo, FHS: Framingham Heart Study, FLAIR: fluid attenuated inversion recovery, GP: general population, ICH: intracerebral hemorrhage, ILL: infarct-like lesions, LI: lacunar infarct, N: number of subjects, n.a.: not available, nc: noncarriers, NL: the Netherlands, OR: odds ratio, PD: proton density, Ref: reference, SE: spin echo, TI: thromboembolic infarct, USA: United States of America, W: white, yr: year, *: computed by authors of meta-analysis from published raw numbers (and used in the meta-analysis), : computed by authors of meta-analysis from raw data provided by authors of the original article (and used in the meta-analysis), : participants with prevalent stroke, dementia or brain tumor were excluded from the analysis

Table e-6: Cross sectional associations between APOE4+ and CMB, in the general population

Reference

N 3,141

Condition

Origin NL

Age 60.3

Sequence 3DT2*GRE

Association 4-carriers: ORMB=1.35 (1.10, 1.65), ORSLMB=1.37 (1.08, 1.74), ORDIMB=1.37 (0.97, 1.93) 4-homozygous: ORMB=1.32 (0.76, 2.31), ORSLMB=1.43 (0.76, 2.69), ORDIMB=1.11 (0.40, 3.12) 4-homozygous associated with CMB: p=0.01 4-carriers vs 3/3: OR=1.09 (0.79, 1.51)* 4-homozygous vs 3/3- : OR=2.38 (1.11, 5.11)* 4-carriers : OR= 1.53 (0.87, 2.70), p=0.13918 4-homozygous: OR=2.16 (0.45 , 10.31), p=0.33584

Ref group 33

AV age

e35 2815e36 2986e36

1,725 e37 FHS, unpublished, 2012 1255* 521 402

Iceland

76.0

T2*

4/4- (24 excluded) 33

age and sex

USA

73.4

T2*

Age, sex and familial relationships

AV: adjustment variable, APOE: apolipoprotein E genotype, CMB: cerebral microbleed, FHS: Framingham Heart Study, GP: general population, GRE: gradient echo, N: number of subjects, n.a.: not available, OR: odds ratio, ORDIMB: OR deep or infratentorial microbleed, ORMB: OR microbleed, ORSLMB: OR strictly lobar microbleed, Ref: reference, USA: United States of America, yr: year, *: computed by authors of meta-analysis from published raw numbers (and used in the meta-analysis)

Table e-7: Cross sectional associations between APOE4+ and CMB, in high risk populations
Reference N 129 90 284 e16 207* 246 e36 248 e36 condition Origin Age 63.3 71.0 Sequence Association T2* T2* 4-heterozygous : OR=0.96 (0.37, 2.48), p=0.94 4-homozygous : OR=1.99 (0.50, 7.94), p=0.33 4-carriers: p=0.74 for increased MB in the MB group 4-carriership was not associated with corticosubcortical MB 4-carriers: OR=0.95 (0.53, 1.70), p=0.9699* 4-homozygous: OR=5.59 (0.99, 31.38), p=0.05* 4-carriers for lobar CMB : OR=0.92 (0.42, 2.02) (from Maxwell et al.)36 4-carriers for nonlobar CMB : OR=0.97 (0.45, 2.09)36 ICH Austria 70.0 T2* no association 4-carriers : OR= 1.54 (0.53, 4.49)* 4-carriers: ORMB=1.22 (0.72, 2.08), ORLMB=1.35 (0.75, 2.45), ORNLMB=1.05 (0.60, 1.83) 4-carriers: X=0.19, p=0.67 4-carriers: OR=0.97 (0.54, 1.75) (from Maxwell et al.)36 4-carriers for lobar CMB : OR=1.47 (0.65, 3.31)36 4-carriers for not strictly lobar CMB : OR=0.62 (0.27, 1.44)36 4-homozygous: OR=16.0 (0.9-276.0) 4-heterozygous: OR=1.6 (0.1-19) Ref group 4-nc 4-nc (24 in 4+) 33, 24 excluded* 3336 AV age, sex. Family relationship for p values age, sex, HTN, diabetes, stroke, CAD, smoking, cholesterol

hypertensive NL TIA or IS Belgium

e15

88 e18 414 368 e36 273 e36 362 e36 438 379 e36 355 e36 352 e36 63 e40

24 excluded 33* 33

n.a.

e38

neurologic Korea abnormalities

62.1 T2* 69.7

none

e39

AD, VaD, MCI, OTD, OD, SC

NL

n.a.

T2*

4-nc 3336

age sex, and arterial HTN

AD with NL >=8MB, AD without MBs

73.0

T2*

4-nc

age, sex, WMH, and MTA

AD: Alzheimer disease, APOE: apolipoprotein E genotype, AV: adjustment variable, CAD: coronary artery disease, CMB: cerebral microbleed, HTN: hypertension, ICH: intracerebral hemorrhage, IS: ischemic stroke, MB: microbleed, MCI: mild cognitive impairment, MTA: medial temporal atrophy, N: number of subjects, n.a.: not available, nc: noncarriers, NL: the Netherlands, OD: other disorders, OR: odds ratio, ORLMB: OR for lobar microbleed, ORMB: OR for microbleed, ORNLMB: OR for non-lobar microbleed, OTD: other types of dementia, Ref: reference, SC: subjective complaint, TIA: transient ischemic attack, VaD: vascular dementia, WMH: white matter hyperintensities, yr: year, *: computed by authors of meta-analysis from published raw numbers (and used in the meta-analysis)

Table e-8: Longitudinal associations between APOE4+ and CMB, in the general population and in high risk populations
Reference General population 654 e41 NL 68.5 3DT2* 4-carriers: ORMB=1.19 (0.69-2.05), ORSLMB=1.58 (0.82-3.07), ORDIMB=0.70 (0.28-1.78) 4-homozygous ORMB=4.43 (1.44, 13.64), ORSLMB=6.60 (1.90, 22.89), ORDIMB=2.07 (0.25-17.13) 4-carriers : OR=1.5 (0.6-3.8) 33 age, sex, and scan interval N Condition Origin Age Sequence Association Ref group AV

High risk populations 197 e42 AD, SC, OD NL 66.0 69.0 T2* 4-noncarriers none

AD: Alzheimer disease, ApoE: apolipoprotein E, AV: adjustment variable, (C)MB: (cerebral) microbleed, GP: general population, N: number of subjects, NL: the Netherlands, OD: other disorders, OR: odds ratio, ORDIMB: OR for deep or infratentorial microbleed, ORMB: OR for microbleed, ORSLMB: OR for strictly lobar microbleed, Ref: reference, SC: subjective complaints, yr: year

Table e-9: Cross sectional associations between APOE2+ and WMH burden, in the general population and in high risk populations
Reference N Condition Origin Age Sequence Qn WMH definition Association Ref group AV

General population 221 e6

Austria

59.9

T1, T2, PD

SQ

lacunes and/or early confluent or confluent WMH: presence or absence Volume

2 /3: OR= 3.00 (1.35-6.69), p=0.01

33

144 e13 112 411 e8 SydneyMAS, unpublish ed, 2011 3C-Dijon study, unpublish ed, 2011 FHS, unpublish ed, 2012 518

USA

58.9

FLAIR

Australia Australia

62.6 78.8

FLAIR T1, FLAIR T1, T2

SQ +Q Q

Total WMH Volume

No association In secondary analyses, significant association of 2 with large frontal WMH was found (p=0.03) 2-carriers: SMD=0.09 (-0.41, 0.58) 2-carriers: SMD=0.23 (-0.04, 0.50) 2-carriers: SMD=0.02 (-0.22, 0.25)

Age, aterial HTN, diabetes, cardiac disease, plasma fibrinogen levels n.a age, sex ICV, age ICV, age

33 33 2-nc 2-nc

1,802 1,667 2,353

France

72.8

Log-transformed WMH

2-carriers: SMD=0.02 (-0.02, 0.06)

2-nc (24 excluded) 2-nc (24 excluded)

Age, sex, white matter volume Age, sex, familial relationships

USA

64.4

T1, T2, PD

WMH volume (logtransformed and normalized to intracranial volume) WMD severity, dichotomized into absent or mild versus moderate to severe 3 grades (0/1, 2, 3) Grade 3 vs others log transformed normalized WMH (nWMH=WMH volume of the subject/mean ICA of the population)

2-carriers: =0.04385 (0.05754), p=0.44616

High risk populations 342 TIA or IS e16 101 e18 96 e28 AD, MCI, CAA ICH

Belgium

71.0

FLAIR

SQ

2-carriers : OR= 2.63 (1.48, 4.7)

Austria

70.0

T1, T2, T2* T1, FLAIR

SQ

no association 2-carriers : OR=1.00 (0.28, 3.55)* 2-carriers and AD/MCI patients: B=-0.09, p>0.2

2-nc (24 in age, sex, HTN, 2+) diabetes, stroke, CAD, smoking, cholesterol 24 excluded n.a. 2noncarriers* 2-nc Intracranial size

USA

73.077.7

944 e31

Leukoaraiosis, HC

Hungary

58.468.8

T2

SQ

2-carriers and CAA patients: B=-0.24, p=0.13(bivariate) 2-carriers and CAA patients: B=-0.38, p=0.018(multivariate) Dichotomized (leukoaraiosis 2-carriers : OR=1.42 (0.96, 2.10), p=0.08* vs controls)

2-nc (24 excluded)

n.a.

AAMI: age-associated memory impairment, AD: Alzheimers Disease, APOE: apolipoprotein E genotype, AV: adjustment variable, CAA: cerebral amyloid angiopathy, CAD: cervical artery disease, DWMH: deep white matter hyperintensity, FHS: Framingham Heart Study, FLAIR: fluid attenuated inversion recovery, GP: general population, HC: healthy controls, HTN: hypertension, ICA: intracranial cross-sectional area , ICH: intracerebral hemorrhage, IS: ischemic stroke, MAS: Memory and Ageing Study, MCI: mild cognitive impairment, N: number of subjects, n.a.: not available, nc: noncarriers, OR: odds ratio, PD: proton density, PVH: periventricular ICV: intracranial volume, hyperintensities, Q: quantitative, Qn: quantification, Ref: reference, SH: subcortical hyperintensities, SMC:

subjective memory complaint, SMD: standardized mean difference, SNP: single nucleotide polymorphism, SQ: semi-quantitative, TIA: transient ischemic attack, vs: versus, WMD: white matter disease, WMH: white matter hyperintensities, yr: year, *: computed by authors of meta-analysis from published raw numbers (and used in the meta-analysis), : computed by authors of meta-analysis from raw data provided by authors of the original article (and used in the meta-analysis), : participants with prevalent stroke, dementia or brain tumor were excluded from the analysis

Table e-10: Cross sectional association between APOE2+ and BI, in the general population and in high risk populations
Reference N Condition Origin Austria Age 59.9 Sequence T1, T2, PD BI definition lacunes and/or early confluent or confluent WMH: presence or absence Presence of BI 2-carriers OR=1.2 (0.74, 1.93), p=0.4753 USA 64.4 T1, T2, PD Presence of BI 2-carriers OR=1.33 (0.95, 1.86), p=0.08493 Association 2/3 : OR= 3.00 (1.35-6.69), p=0.01 Ref group 33 AV n.a.

General population 221 e6

3C-Dijon Study, unpublished, 2011 FHS, unpublished, 2012

1,802 1,771 2,353

France

72.8

T1, T2

2-nc (24 excluded)* 2-nc (24 excluded)

Age and sex

Age, sex, familial relationships n.a.

High risk populations 101 e18

ICH

Austria

70.0

T2

Presence of lacunes

no association 2carriers: OR = 1.40 (0.42, 4.60)*

24 excluded 2noncarriers*

APOE: apolipoprotein E genotype, AV: adjustment variable, BI: brain infarct, FHS: Framingham Heart Study, GP: general population, ICH: intracerebral hemorrhage, N: number of subjects, n.a.: not available, OR: odds ratio, PD: proton density; Ref: reference, WMH: white matter hyperintensities, yr: year; *: computed by authors of meta-analysis from published raw numbers (and used in the meta-analysis), : computed by authors of meta-analysis from raw data provided by authors of the original article (and used in the meta-analysis), : participants with prevalent stroke, dementia or brain tumor were excluded from the analysis

Table e-11: Cross sectional associations between APOE2+ and CMB, in the general population and in high risk populations
Reference N Condition Origin Age Seq Association Ref group AV

General population 2,611 e35 2340e36 2482e36

NL

60.3

2-carriers: ORMB=1.05 (0.80, 1.38), ORSLMB=1.07 (0.78, 1.46), 3DT2 ORDIMB=1.02 (0.64, 1.61) * 2-homozygous: ORMB=2.44 (0.91, 6.57), ORSLMB=3.09 (1.08, 8.79), ORDIMB=1.28 (0.16, 10.31) T2* T2* 2-carriers : OR=1.04 (0.64, 1.68) p=0.96* 2-carriers : OR= 0.63 (0.29, 1.36), p=0.23574 2-carriers: p=0.09 (median 2 vs 3) in the MB group 2-carriership was not associated with corticosubcortical MB 2-carriers: OR=1.06 (0.53, 2.10), p=0.9831* 2-homozygous : OR=5.58 (0.50, 62.86), p=0.1775* 2-carriers for lobar CMB : OR=1.08 (0.44, 2.68) (from Maxwell et al.)36 2-carriers for nonlobar CMB : OR=1.04 (0.42, 2.57)36 no association 2-carriers : OR= 2.19 (0.55, 8.71)* 2-carriers: ORMB=1.41 (0.74, 2.70), ORLMB=1.62 (0.79, 3.29), ORNLMB=1.01 (0.51, 2.04) 2-carriers: X=1.68 p=0.21 2-carriers: OR=1.75 (0.72, 4.27) (from Maxwell et al.)36 2-carriers for lobar CMB : OR=2.62 (0.83, 8.23)36 2-carriers for nonlobar CMB : OR=1.12 (0.30, 4.15)36

33

age

1,410 e37 FHS, 487 unpublished, 2012 High risk populations 252 e16 TIA or IS 218 e36 219 e36 e18 e38 81 414 335 e36 249 e36 329 e36 438 213 e36 196 e36 198 e36 ICH

Island USA

76.0 73.4

33* 33

None* Age, sex, familial relationships

Belgium

71.0

T2*

2-nc (24 in 2+) 24 excluded* 33* 3336 24 excluded 33* 33

age, sex, HTN, diabetes, stroke, CAD, smoking, cholesterol n.a. none

Austria

70.0 62.1 69.7 n.a.

T2* T2*

neurologic abnormali- Korea ties AD, VaD, MCI, OTD, OD, SC NL

e39

T2*

2-nc 3336

Age, sex, and arterial HTN

AD: Alzheimer disease, APOE: apolipoprotein E genotype, AV: adjustment variable, CAD: coronary artery disease, (C)MB: (cerebral) microbleed, FHS: Framingham Heart Study, GP: general population, HTN: hypertension, IS: ischemic stroke, MCI: mild cognitive impairment, N: number of subjects, n.a.: not available, nc: noncarriers, NL: the Netherlands, OD: other disorders, OR: odds ratio, ORDIMB: OR for deep or infratentorial microbleed, ORLMB: OR for lobar microbleed, ORMB: OR for microbleed, ORNLMB: OR for non-lobar microbleed, ORSLMB: OR for strictly lobar microbleed, OTD: other types of dementia, Ref: reference, SC: subjective complaints, Seq: sequence, TIA: transient ischemic attack, VaD: vascular dementia, vs: versus, yr: year, *: computed by authors of metaanalysis from published raw numbers (and used in the meta-analysis)

Table e-12: Longitudinal association between APOE2+ and CMB, in the general population and in high risk populations

Reference

Condition

Origin NL

Age 68.5

Sequence 3DT2*

Association 2-carriers: ORMB=1.20 (0.60-2.37), ORSLMB=1.11 (0.44-2.80), ORDIMB=1.29 (0.50-3.30) 2-carriers : OR=4.2 (1.4, 12.5), p<0.01

Ref group 33

AV age, sex, and scan interval

General population 563 e41

High risk populations 197 AD, SC, e42 OD

NL

66.0 69.0

T2*

2noncarriers

none

AD: Alzheimer Disease, APOE: apolipoprotein E genotype, (C)MB: (cerebral) microbleed, GP: general population, N: number of subjects, NL: the Netherlands, OD: other disorders, OR: odds ratio, ORDIMB: OR for deep or infatentorial microbleed, ORMB: OR for microbleed, ORSLMB: OR for strictly lobar microbleed, SC: subjective complaints, yr: year

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