1) (As of December 2018) and the Latest GWAS of AD (2

SUPPLEMENTARY FIGURES

downstream intergenic ncRNA_exonic upstream ●936 ●918 group downstream intergenic ncRNA_exonic upstream group exonic exonicintronicintronic ncRNA_intronic ncRNA_intronicUTR3 UTR3

3.8% 1.2%1.5%1.9% 3.8% 5.4%5.4% 750 0.3% 3.8%1.2%1.5%1.9% ●700 5.4% ●670 0.3%

500

45.8% 40.240.2% % 45.8% ●329

●274 250 ●223

Number (GWAS SNPs/studies) Number (GWAS ●128 ●105 45.8% ●54 ●57 ●58 ●48 ●42 ●46 ●50 ●30 ●3740.2% ● ●17 ●25 ●4 ●6 ●12 0 ● 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Year

Supplementary Figure S1. GWAS of AD since 2007. The figure is based on data from the GWAS Catalog (1) (as of December 2018) and the latest GWAS of AD (2). The green area shows the total number of AD-associated SNPs, and the purple area shows the total number of GWAS of AD. The insert chart shows the proportions of different types of all 936 AD-associated SNPs.

1 100 200 RPS27A TGFB2 BIN1 C4BPB MSH2 PROC UGT1A1 RAB1A TTN DISC1 50 PDCL3 COL4A3 CD55 ERCC3 100 USP21 C4BPA ITSN2 PTPRF MPZ FMN2 INPP5D CEP85 FNBP1L CSF1 CD46 ADAMTS4 PRKRA SPRED2 0 CTNNA2 DGKD ADCY10 ZAP70 LIMS2 PDE1A PROX1 0 CHRNB2 CR1 HSPG2 SH3BGRL3 DAB1 CTBS FCER1G MAP3K2

AD risk score or log10(P value) IL6R CDC73 CD34 AD risk score or log10(P value) −50 B4GALT3 IL19

0 50 100 150 200 250 0 50 100 150 200 Chromosome 1 (Mb) Chromosome 2 (Mb)

ATP2B2 LTF ARF4 MECOM PAK2 EPHB1 40 VHL PRSS42 ARL6IP5 150 COL25A1 TDGF1

RPSA CCR2 CCR1 IL1RAP IRAK2 20 PTPRG 100 FLNB TF CX3CR1 IL17RD SH3RF1

FGG FANCD2 LIMD1 CCR5 50 0 WDR1 PDGFRA

EIF4E FGB AD risk score or log10(P value) AD risk score or log10(P value) 0 FGA HMGB2 −20 0 50 100 150 200 0 50 100 150 Chromosome 3 (Mb) Chromosome 4 (Mb)

75 BAG6 HSPA1B SYNGAP1

F2R NOTCH4 SNX9 75 HSPA1A PSMB8 RAD50 MAML1 SQSTM1 SGK1 50 TFEB MEF2C C4B AGER RPS6KA2 SERINC5 CSF2 HBEGF DDX41 50 C4A CD2AP PJA2 SLC35A1 FGF10 IQGAP2 GLRA1 CANX 25 GNMT CDKAL1 IL3 TIAM2 25 FNIP1 PDLIM7 TMEM30A APOM TREM2 CUL7 ATF6B C2 DHFR 0 MAP3K1 HINT1 B4GALT7 TMED9 HLA−DRA 0 CFB CSNK2B

AD risk score or log10(P value) CAMK4 AD risk score or log10(P value) SPARC MSX2 PSMB9 −25 0 50 100 150 0 50 100 150 Chromosome 5 (Mb) Chromosome 6 (Mb)

40 PDGFA LMTK2 RELN WEE2 PTK2B EXOC4 CNTNAP2 ELMO1 CLU AZGP1 GPC2 60 SCIN TNFRSF10B TFR2 EPHA1 20 SLC25A13 DLC1 CYCS NME8 ZYX ESCO2 GGH SGK3 PCOLCE KEL 30 HDAC9 LAMTOR4 PBK ADCY8 ADRA1A PTPRZ1 TRIP6 TTPA TP53INP1 0 0 AD risk score or log10(P value) AD risk score or log10(P value)

−20 0 50 100 150 0 50 100 Chromosome 7 (Mb) Chromosome 8 (Mb)

50 ABCA1 KIAA1432 PCSK5 PAX2 40 GRIN1 60

TSPAN15 30 CASP7 NSMF 40 WAC 20 NFIB MUSK

20 NRG3 10 VPS13A ATP5C1 KIF5B

0 0 AD risk score or log10(P value) AD risk score or log10(P value)

−10 0 50 100 0 50 100 Chromosome 9 (Mb) Chromosome 10 (Mb)

40 ERBB3 ULK1 FOLH1 SORL1 PRICKLE1 100 PSMC3 PICALM CASP4 KRAS BRSK2 RRAS2 30 TESC NR1H3 B3GAT3 ATM CNTN1 DLG2 A2M PTPRJ AICDA EIF2B1 DEAF1 CHID1 50 PACSIN3 SHANK2 CHEK1 20 HMGA2 DYNC2H1 PDE3B 10 SYTL2 CASP12 0 UBXN1 IRF7 AP2A2 LRP4 RAPSN 0 TENM4 MMP3

AD risk score or log10(P value) GNG3 AD risk score or log10(P value) TOLLIP NDUFS3 GANAB −50 −10 0 50 100 0 50 100 Chromosome 11 (Mb) Chromosome 12 (Mb)

2 30 PCID2 SNX6

FARP1 40 ERO1L SLITRK1 20 ADPRHL1 PSMC6 RNF6 ATXN3 20 10 STYX

GPR68

0 0 AD risk score or log10(P value) AD risk score or log10(P value)

25 50 75 100 20 40 60 80 100 Chromosome 13 (Mb) Chromosome 14 (Mb)

PYCARD CDH13 USP8 PDPK1 STX4 RNF40 100 40 PLCG2 JPH3 APH1B TRIM72 RHBDF1 STX1B SPPL2A ADAM10 CDH1 MAP2K5 PRSS8 PIAS1 20 USP10 50 DUOX1 CLN6 EEF2K AKAP13 KAT8 CDH3 HERC2 SNX1 PCSK6 SORD ALDH1A2 0 NMB AD risk score or log10(P value) LINGO1 AD risk score or log10(P value) 0 SKOR1 RORA RPS27L

40 60 80 100 0 25 50 75 Chromosome 15 (Mb) Chromosome 16 (Mb)

80 USP6 SPPL2C PHB ACE TIMP2 60 CDK5RAP3 PSMC5 PMAIP1 MAPT TMC8 ALOX12 GRB2 60 TRIM37 40 CRHR1 GH1 MALT1 NSF SUMO2 40 ENO3 OSBPL7 BCAS3 DUSP3 20 STRADA PLD2 20 NMT1 RNF43 RPTOR

AD risk score or log10(P value) AD risk score or log10(P value) 0

20 40 60 80 0 20 40 60 Chromosome 17 (Mb) Chromosome 18 (Mb)

APOE BAX APOC1 APOC2 100 FGF22 ABCA7 MARK4 CALM3 CST3 QPCTL STK11 BCL3 100 0 CBLC CYTH2 TMEM259 BSG RELB CSNK2A1 PTPN1 AURKA −100 SPHK2 ERCC2 50 ASIP PLCG1 RBCK1 −200 TBC1D20 ADNP AHCY

AD risk score or log10(P value) AD risk score or log10(P value) EDEM2 0 ANGPT4 −300

0 20 40 0 20 40 Chromosome 19 (Mb) Chromosome 20 (Mb)

SYNJ1 TMPRSS6 CYP2D6 MAPK12 40 30 NCF4 ABCG1 ARSA PDE9A SREBF2 30 CSF2RB MLC1 20 COL18A1 IL2RB 20 CCT8 SIK1 10 10

0 0 AD risk score or log10(P value) AD risk score or log10(P value)

−10 25 30 35 40 45 20 30 40 50 Chromosome 21 (Mb) Chromosome 22 (Mb)

Supplementary Figure S2. GWAS AD SNPs, AD risk regions, AD risk gene candidates, and predicted AD risk genes in each human autosome. Green dots below the black dashed line represent GWAS AD SNPs and their log10P values. Above the black dashed line, gray dots represent AD risk gene candidates, and red ones predicted AD risk genes (labelled with gene symbols). The red dashed line marks the threshold for AD risk gene prediction based on the stringent training. AD risk genes below this threshold were predicted with the lenient training gene set. Vertical lines represent AD risk regions: red for risk regions with AD risk genes, blue for risk regions with only AD risk gene candidates, gray for risk regions without any AD risk gene candidates.

3 Color Key

Color Key

−3 −2 −1 0 1 2 3 Z Score Islet cells Bladder Placenta CD105+ Endothelial Esophagus Small intestine Colon Uterus

HINT1 NDUFS3 ATP5C1 −3 −2 −1 0 1 2 3 CYCS HERC2 TRIM37 PSMC5 Z Score DDX41 SUMO2 NMT1 EIF2B1 ES cells Stem cells B cells T cells Myeloid cells CNS Thyroid Pancreas Muscle Heart Kidney Liver Adipose Airway Skin Salivary gland Stomach Appendix Ovary Breast Testis PCID2 Conjunctiva PRKRA RAD50 MSH2 HMGB2 CCT8 RNF6 PSMC6 EIF4E TMEM30A USP8 SLC35A1 ARL6IP5 MAML1 ADNP ITSN2 PIAS1 SORL1 KRAS HINT1 WAC NDUFS3 PBK ATP5C1 AURKA CYCS GGH HERC2 DHFR TRIM37 CHEK1 PSMC5 CSNK2A1 DDX41 PSMC3 SUMO2 GANAB NMT1 BSG EIF2B1 AHCY PCID2 PHB PRKRA RPS27L RAD50 TMED9 MSH2 RRAS2 HMGB2 FLNB CCT8 PTK2B RNF6 B3GAT3 PSMC6 ULK1 EIF4E SPHK2 TMEM30A AP2A2 USP8 USP21 SLC35A1 PLCG1 ARL6IP5 LIMS2 MAML1 PDE9A ADNP CDK5RAP3ITSN2 ERCC3 PIAS1 UBXN1 SORL1 STRADA KRAS ABCA7 WAC DGKD PBK PDPK1 AURKA AKAP13 GGH KIF5B DHFR F2R CHEK1 HMGA2 CSNK2A1 CYTH2 PSMC3 CD34 GANAB RNF40 BSG CLN6 AHCY CUL7 PHB B4GALT7 RPS27L ERCC2 TMED9 PMAIP1 RRAS2 IQGAP2 FLNB CD55 PTK2B BCL3 B3GAT3 CSF2RB ULK1 RELB SPHK2 B4GALT3 AP2A2 SH3BGRL3USP21 PYCARD PLCG1 EDEM2 LIMS2 INPP5D PDE9A NCF4 CDK5RAP3 PTPN1 ERCC3 MALT1 UBXN1 STX4 STRADA SNX6 ABCA7 PSMB8 DGKD PSMB9 PDPK1 RBCK1 AKAP13 PAK2 KIF5B IRF7 F2R CASP4 HMGA2 BAX CYTH2 WDR1 CD34 ADAM10 RNF40 GRB2 CLN6 USP10 CUL7 IL2RB B4GALT7 ZAP70 ERCC2 ATM PMAIP1 RORA IQGAP2 SPRED2 CD55 SLC25A13 BCL3 ABCA1 CSF2RB CD2AP RELB CASP7 B4GALT3 ABCG1 SH3BGRL3 CANX PYCARD ARF4 EDEM2 RAB1A INPP5D SGK1 NCF4 HBEGF PTPN1 TNFRSF10BMALT1 CD46 STX4 CDC73 SNX6 CTBS PSMB8 SNX1 PSMB9 HLA−DRA RBCK1 PLCG2 PAK2 TFEB IRF7 TIMP2 CASP4 PICALM BAX FCER1G WDR1 CCR1 ADAM10 NR1H3 GRB2 C2 USP10 ERO1L IL2RB TREM2 ZAP70 CSF1 ATM MEF2C RORA HDAC9 SPRED2 MARK4 SLC25A13 BCAS3 ABCA1 VPS13A CD2AP USP6 CASP7 PDE1A ABCG1 PJA2 CANX NSF ARF4 SYNJ1 RAB1A ELMO1 SGK1 MLC1 HBEGF BIN1 TNFRSF10B CX3CR1 CD46 PTPRZ1 CDC73 LRP4 CTBS SHANK2 SNX1 DEAF1 HLA−DRA GNG3 PLCG2 ATP2B2 TFEB MAPT TIMP2 CNTNAP2 PICALM CTNNA2 FCER1G GRIN1 CCR1 SREBF2 NR1H3 RELN C2 EPHB1 ERO1L DLG2 TREM2 BRSK2 CSF1 CNTN1 MEF2C JPH3 HDAC9 NOTCH4 MARK4 CHRNB2 BCAS3 PLD2 VPS13A TOLLIP USP6 NMB PDE1A CLU PJA2 A2M NSF APOE SYNJ1 APOC1 ELMO1 TF MLC1 PCSK6 BIN1 TSPAN15 CX3CR1 ERBB3 PTPRZ1 FOLH1 LRP4 PDGFA SHANK2 SQSTM1 DEAF1 DUSP3 GNG3 ZYX ATP2B2 PDLIM7 MAPT ALDH1A2 CNTNAP2 ACE CTNNA2 APH1B GRIN1 FNBP1L SREBF2 SORD RELN CDH1 EPHB1 PRSS8 DLG2 DUOX1 BRSK2 TRIP6 CNTN1 COL18A1 JPH3 RHBDF1 NOTCH4 HSPG2 CHRNB2 PCOLCE PLD2 PDGFRA TOLLIP SPARC NMB NFIB CLU RPS6KA2 A2M PTPRF APOE FARP1 APOC1 CDH13 TF DLC1 PCSK6 PTPRG TSPAN15 DYNC2H1 ERBB3 FOLH1 CFB PDGFA OSBPL7 SQSTM1 CRHR1 DUSP3 VHL ZYX GLRA1 PDLIM7 LMTK2 ALDH1A2 ADRA1A ACE MUSK APH1B PTPRJ FNBP1L LIMD1 SORD ASIP CDH1 ADCY10 PRSS8 TTPA DUOX1 MSX2 TRIP6 TGFB2 COL18A1 MAP3K1 RHBDF1 FGF22 HSPG2 MAPK12 PCOLCE MPZ PDGFRA DAB1 SPARC QPCTL NFIB COL4A3 RPS6KA2 CYP2D6 PTPRF SCIN FARP1 PAX2 CDH13 ANGPT4 DLC1 RAPSN PTPRG GPR68 DYNC2H1 MAP2K5 CFB CAMK4 OSBPL7 ATF6B CRHR1 TIAM2 VHL PDE3B GLRA1 PCSK5 LMTK2 DISC1 ADRA1A IL6R MUSK MAP3K2 PTPRJ CDKAL1 LIMD1 ATXN3 ASIP IL1RAP ADCY10 CR1 TTPA SYTL2 MSX2 CSF2 TGFB2 IL3 MAP3K1 PACSIN3 FGF22 TTN MAPK12 ENO3 MPZ TESC DAB1 TFR2 QPCTL APOM COL4A3 STK11 CYP2D6 KEL SCIN LTF PAX2 AZGP1 ANGPT4 GNMT RAPSN RNF43 GPR68 EPHA1 MAP2K5 CDH3 CAMK4 ALOX12 ATF6B AICDA TIAM2 MMP3 PDE3B IL19 PCSK5 CBLC DISC1 TMPRSS6 IL6R ARSA MAP3K2 PROX1 CDKAL1 AGER ATXN3 C4BPA IL1RAP PROC CR1 C4BPB SYTL2 FGG CSF2 FGA IL3 FGB PACSIN3 TTN ES cells HSC fetal blood CD34+ CD38 HSC cord blood CD34+ CD38 HSC cord blood CD34+ CD38 HSC bone marrow CD34+ CD38 HSC fetal blood CD34+ CD38+ HSC cord blood CD34+ CD38+ HSC cord blood CD34+ CD38+ CD33 bloodHSC periph CD34+ CD38+ HSC bone marrow CD34+ CD38+ HSC bone marrow CD34+ CD38+ CD33 Bone marrow CD34+ B cells cord blood CD34+ B cells Pro B cells PreI B cells PreII B cells immature B cells CD19+ Tonsils Lymph node Thymus T cells cord blood CD34+ Thymic CD34+ Thymic CD34+CD38+ CD1A Thymic CD34+CD38+ CD1A+ Thymic CD4+CD8 Thymic CD4+CD8+CD3 Thymic CD4+CD8+CD3+ Thymic SP CD4+ T cells Peripheral naive CD4+ T cells Th1 Th2 Thymic SP CD8+ T cells Peripheral CD8+ T cells Tonsils CD4+ T cells T cells BAFF+ T cells CD57+ T cells central memory T cells effector memory T cells gammadelta Treg NK CD56+ DC Immature DC LPS 6h DC LPS 48h DC DC BAFF+ Myeloid CD33+ Monocyte CD14+ Derived Macrophage 16h Macrophage Macrophage LPS 4h Mast cell Mast cell IgE Spleen Blood Neutrophils RBC Whole brain Fetal brain Frontal cortex Prefrontal cortex Parietal Lobe Occipital lobe Temporal lobe Cingulate cortex Caudate nucleus Globus pallidus Thalamus Subthalamic nucleus Hypothalamus Hippocampus Amygdala Cerebellum Cerebellum peduncles Pons Medulla oblongata Spinal cord Olfactory bulb Trigeminal ganglion ganglion Ciliary Dorsal root ganglion ganglion cervical Superior Adrenal gland Pituitary Thyroid Fetal thyroid Pancreas Skeletal muscle Tongue Smooth muscle Cardiac myocytes Cardiac muscle left ventricle Heart Atrioventricular node Islet cells Kidney Bladder Liver Fetal liver Preadipocyte subcutanous Adipocyte Lung Fetal Lung Broncho epithelial Trachea Placenta Skin Endothelial CD105+ gland Salivary Esophagus Stomach Small intestine Appendix Colon Ovary Uterus corpus Uterus Breast Testis Testis Leydig cell Testis cell germ Testis intersitial Testis seminiferous tubule Prostate Conjunctiva ENO3 TESC TFR2 APOM STK11 KEL LTF AZGP1 GNMT RNF43

− EPHA1 CD3 CDH3 ALOX12

− − AICDA MMP3 IL19 − CBLC − − −

CD33 TMPRSS6

− ARSA CD33 PROX1 AGER

− − C4BPA PROC − − C4BPB FGG FGA FGB ES cells HSC fetal blood CD34+ CD38 HSC cord blood CD34+ CD38 HSC cord blood CD34+ CD38 HSC bone marrow CD34+ CD38 HSC fetal blood CD34+ CD38+ HSC cord blood CD34+ CD38+ HSC cord blood CD34+ CD38+ CD33 bloodHSC periph CD34+ CD38+ HSC bone marrow CD34+ CD38+ HSC bone marrow CD34+ CD38+ CD33 Bone marrow CD34+ B cells cord blood CD34+ B cells Pro B cells PreI B cells PreII B cells immature B cells CD19+ Tonsils Lymph node Thymus T cells cord blood CD34+ Thymic CD34+ Thymic CD34+CD38+ CD1A Thymic CD34+CD38+ CD1A+ Thymic CD4+CD8 Thymic CD4+CD8+CD3 Thymic CD4+CD8+CD3+ Thymic SP CD4+ T cells Peripheral naive CD4+ T cells Th1 Th2 Thymic SP CD8+ T cells Peripheral CD8+ T cells Tonsils CD4+ T cells T cells BAFF+ T cells CD57+ T cells central memory T cells effector memory T cells gammadelta Treg NK CD56+ DC Immature DC LPS 6h DC LPS 48h DC DC BAFF+ Myeloid CD33+ Monocyte CD14+ Derived Macrophage 16h Macrophage Macrophage LPS 4h Mast cell Mast cell IgE Spleen Blood Neutrophils RBC Whole brain Fetal brain Frontal cortex Prefrontal cortex Parietal Lobe Occipital lobe Temporal lobe Cingulate cortex Caudate nucleus Globus pallidus Thalamus Subthalamic nucleus Hypothalamus Hippocampus Amygdala Cerebellum Cerebellum peduncles Pons Medulla oblongata Spinal cord Olfactory bulb Trigeminal ganglion ganglion Ciliary Dorsal root ganglion ganglion cervical Superior Adrenal gland Pituitary Thyroid Fetal thyroid Pancreas Skeletal muscle Tongue Smooth muscle Cardiac myocytes Cardiac muscle left ventricle Heart Atrioventricular node Islet cells Kidney Bladder Liver Fetal liver Preadipocyte subcutanous Adipocyte Lung Fetal Lung Broncho epithelial Trachea Placenta Skin Endothelial CD105+ gland Salivary Esophagus Stomach Small intestine Appendix Colon Ovary Uterus corpus Uterus Breast Testis Testis Leydig cell Testis cell germ Testis intersitial Testis seminiferous tubule Prostate Conjunctiva − CD3 − − − − − − CD33 − CD33 − − − −

Supplementary Figure S3. Expression of AD risk genes in different tissues. Genes were clustered according to their expressions among different tissues. Three black boxes indicate gene clusters and corresponding tissues in which they are more transcriptionally active. 64 AD risk genes were not included due to the lack of data from the Gene Enrichment Profiler (http://xavierlab2.mgh.harvard.edu/EnrichmentProfiler/help.html).

4 ● ● ● ● 100 ● ● A 80 ● Frontal cortex Visual cortex Cerebellum ● Adult brain ● 80 ● ● ●

● ● ● ● 75 ● ● 75 ● 60 ● ● ● ● 60 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 50 ● ● ● ●● 50 ●● ● 40 ● 40 ● ● ●● ●●● ● ● ● ● ●● ●● ● ●●● ● ● ● ●●●●● ●● ●●● ● ●● ●● ● ●● ● ●●●●●● ●●●● ●● ●●● ●● ●● ●●● ●●● ●● ● 25 ●● ●● ●●● ●● 25 ●● 20 ●●●● ●● 20 ● ●●●● ●● ● ●● ● ●● ●●● ●● ●● ● ● ●● ● ● ●●●● ●● ●● ●● ●●●●●● ●●●● ● ●● ●●●●●● ●● ● ●●● ●●●● ● ● ●●● ● ●● ● ●●●● ●●●● ●●● ● ●●●● ●●●● ●● ● ●● ●●●●●●● ● ● ●●● Expression in cell type (%) ● Expression in cell type (%) ● Expression in cell type (%) ● Expression in cell type (%) ● ●● ● ● ●●● ● ●● ● ●●●● ● ●●● ● ●●● ● ●●●● ● ●●● ● ●● ● ● ● ● ● 0 ● 0 ● 0 ● 0 ● 0 20 40 60 80 0 20 40 60 0 25 50 75 100 0 25 50 75 Mean Bootstrap Expression Mean Bootstrap Expression Mean Bootstrap Expression Mean Bootstrap Expression

● ● ● 100 ● B 100 100 100 ● Frontal cortex ● Visual cortex Cerebellum ● ● Adult brain ● ● ● ● ● ● ● ●

●

● ● ● ● ● 75 ● 75 75 75 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 50 50 50 ● ● 50 ●●● ● ●● ● ● ●● ● ●● ● ● ●● ●● ● ●●● ● ●● ● ● ●● ●● ● ●● ●●●● ●●● ● ● ●●● ● ● ●● ● ●●● ●●● ●● ●● 25 ● 25 ● 25 ●● 25 ● ● ● ●● ●● ● ● ●●●● ● ●●●● ●●● ●●● ●● ●● ● ● ●● ●● ● ● ●● ●● ● ● ●● ●●●● ● ●●●●●●● ●●● ●● ● ●●●●● ●●●● ●● ●●●●● ●● ● ●●● ●●●● ●● ● ●●● ●●●● ●● ● ● ●● ●●● ●● ● ●●● Expression in cell type (%) ● Expression in cell type (%) ● Expression in cell type (%) ● Expression in cell type (%) ● ●● ●● ● ●●● ●●●● ●● ● ●●●● ●●●●●● ●● ● ●●● ● ●● ● ●●● ● ●●● ● ● ● ●●●● ● ● 0 ● 0 ● 0 ● 0 ● 0 25 50 75 0 20 40 60 80 0 25 50 75 100 0 25 50 75 Mean Bootstrap Expression Mean Bootstrap Expression Mean Bootstrap Expression Mean Bootstrap Expression

Supplementary Figure S4. Enriched expression of AD risk genes in endothelia and microglia from different brain regions. (A) Endothelia. (B) Microglia. The plot shows the actual level of expression of AD risk genes against the mean expression level of the ith most expressed gene in a bootstrapping analysis of the same number of genes. If the expression of AD risk genes was randomly distributed for a cell type from a brain region, the dots would be expected to fall along the red line. See Skene and Grant (3) for method details.

5 BM_10− AD peason correlation−0.7 BM_10− Normal peason correlation−0.7

● ● ● ● ● ● ● ● ● MEF2C ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● MAPT ● ● ● ● ● ● ● ● BM10 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● RAB1A ● ● RAB1A ● ● ● ● ● ● ● ● ● ● ● ● ● ● MSH2● PJA2 ● ● ● ● MSH2● PJA2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● CYCS ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● HINT1 ● ● HINT1 ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● TRIM37 ● TRIM37 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● SYNGAP1 ● ● SYNGAP1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● AP2A2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● SUMO2 MAML1 ● ● ● ● ● ● ● ● ● ● ● ●CCT8 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ARL6IP5 ● ● ● ● GRIN1 ● ● ● ● ● ● ● ● ● ● ● TMEM30A ● TMEM30A● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ULK1 ● ● ● ● ● ● ● ULK1 ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● JPH3 ● STX1B● ● ● ● ● ● ATP5C1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● LMTK2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● CHRNB2 ● ● ● ● ● ● CAMK4 ● ● ● CAMK4 ● ● ● ● ● PSMC6 ● ● ● PSMC6 ● ● ● ● ● RPTOR● ● LINGO1 ●● ● ● ● ● CNTNAP2 ● ● ● ● ● ● ● ● ● ● ● ● ● CNTN1 ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● BM_22− AD peason●GGH OSBPL7● correlation−0.7 BM_22− Normal peasonNSF● ●● correlation−0.7 KRAS●● ● ● ●

● ● ● ● ● ● MEF2C ● ● ● ● ● ● ● MEF2C● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● BM22 ● ● ● ● MAPT ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PJA2 ● ● ● ● MSH2● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● HINT1 ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● SYNJ1 ● ● SYNJ1 ● ● ● ● ●

● ● ● ● ● TRIM37 ● ● ● TRIM37 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● TOLLIP ● TOLLIP ● ● ● ● TRIP6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● RNF6 ● ● ● ● ● ● CSF1 ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● TNFRSF10B ● ● VPS13A ● ● ● VPS13A ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● EIF4E ● ● ● ● ● ● ● ● ● ● ● ● ● ● WDR1● PRICKLE1● ● ● PRICKLE1● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● GRIN1● ● ● ● ● ● ● ● ● ● ● ● ● SPPL2A ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● STX1B● ● ● ● ● TIAM2 ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ATP2B2 ● ● ● ● ● ● ● ATP2B2 ● ● ● ● ● ● ● ● ● PTK2B ● ● LMTK2 ● ● LMTK2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● CHRNB2 CALM3● ● CALM3 ● ●● ● CAMK4 ● ● ●● ● ● ● CAMK4 ● ● ● ● ● ● ● ● ●● ● ● ● ● CNTNAP2 ● ● CNTNAP2 ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● DLG2 ● ● ● ● NSF● ● ● ● NSF ● ● ● ●● ● ● BN_36− AD peason●KRAS correlation−0.7 BN_36− Normal peason●● correlation−0.7

● ● ● ● ● MEF2C● ● ● ● ● ● ● ● ● ● ● MARK4 ● ● ●●● ● ● ● ● ● ●● ● ● ● ● ● ● BM36 ● ● ● ● MAPT ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● RAB1A ● ● ● ●● ● ● ●● ● ● ● ● PJA2 ● ● ● ● ● ● MSH2 ● ● ● MSH2● PJA2 ● SNX6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● MAP3K2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● HINT1 ● ● ● TENM4 ●● ● ● ● ● ● ● ● ● ● ● ● SYNJ1 ● ● ● ● ●● ● ● ● ● ● ● TRIM37 TP53INP1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● HERC2 ● ● ● ● ● ● ● ● SYNGAP1 ● ● ● ● TOLLIP TOLLIP ● ● ● ● ● ● ● USP8 ●● ● ● ● ● ● ● ● ● ●● BRSK2 ● ● ● ● ● ● ● ● ● ● ● ● ● AP2A2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● MAML1 ● VPS13A ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● EIF4E ● ● ● ● ● ● ● ● ● ● ● ● ● ● PRICKLE1● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● GRIN1 ● ● ● ● ● ● ● ● ●● TMEM30A ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ULK1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● JPH3 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ATP2B2 ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● PTK2B ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● CANX ● ● ● ● ● ● ● ● CALM3 ● ● ● ● ● CAMK4 ●● ● ● ● ● ● PSMC6 ● ● ● ● ● ● LINGO1 ●● ●● ● ● ●● ● ●● ● CNTNAP2 ● ● ● ● ● ●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● NSF ● ● ● ● BM_44− AD peasonKRAS●● correlation−0.7 BM_44− Normal peason●● correlation−0.7

● ● ● ● ● ● ● ● ● MEF2C● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● BM44 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● RAB1A ● ● ● ● ● ● CDH13 ● ● ● ● ● PJA2 ● ●● ● ● ● ● ● ● ●PJA2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● HINT1 ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● SYNJ1 ● SYNJ1 ● ● ● ● ● ● ● TRIM37 ● ● ● ● ● ● ● TRIM37 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● TOLLIP ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● AP2A2 ● ● RNF6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● MAML1 ● ● ● ● ● ● CCT8 ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● NDUFS3 ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● EIF4E ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PRICKLE1● ● ● ● ● PRICKLE1● ●● ● ● ● ● ● ● ● ● ARL6IP5 ● ● ● ● GRIN1● ● ● ● ● ● ● ● ● ● ● ● ● TMEM30A ● SPPL2A ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● TIAM2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ATP2B2 ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● LMTK2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● CHRNB2 CALM3● ● ● ● CAMK4 ●● ● ● ● ● ● ● ● ● ● ● ● PSMC6 ● ● ● ● ●● ● CNTNAP2 ● ●● CNTNAP2 ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● PAK2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● DLG2 ● ● ● ● ● ● ●● ● NSF● ● NSF● ● ● ● ●KRASGGH● ● ●

AD Normal

Supplementary Figure S5. Co-expression networks of AD risk genes in both AD patients and normal controls. Networks were constructed using the Pearson's correlation coefficients (> 0.7). Positive and negative correlations are denoted by gray and green lines, respectively. The size of a node is proportional to the connectivity of the gene. The network hub genes are colored orange or yellow.

6 BM10 ● 40 BM22 ● 30 ● ●

● ● PJA2 ● ● ● ● ● EIF4E ● 30 ● ● MAML1 ● ● ● ATP5C1● MSH2 KRAS ● ● ● ● 20 SUMO2 ● ● ● GGH ● ● TIAM2 DLG2 ● ● ● ● ● ● ● ● CCT8 ARL6IP5 ● CYCS ● RNF6● HINT1● PTK2B ● MEF2C 20 ● OSBPL7 KRAS ● ● ● ● NSF ● ● ● ● ● ● CNTN1 ● ● ● ● STX1B MAPT ● CNTNAP2 ● ● ● ● ● ● ● ● ● ● LINGO1 GRIN1 ● STX1B 10 ● ● RPTOR ● ● JPH3 ● ● ● ● ● ● ● ● Conectivity in AD network ● Conectivity in AD network TRIP6 ● ● AP2A2 10 ● ● ● ● ●● ●● ● ● ● ● GRIN1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● CHRNB2 ● ● ●●● ● ● ● ● ● ● ● ● CHRNB2 ●● ● ● ● ● LMTK2 ● ● CSF1 ● ●● ●● ● ● ● ● ●● ● ● ● ●●● ● ● ● ● ● ● ●● ●●●● ● ● ●● ● ● TNFRSF10B ● ● ● ● ● ● ●● ●● ● ● ● ● ●●●●●● ● ●● ● ● ●● ● ● ●●● ●●●● ● ● ●● ●● ● ● ●● ● ● ● ● SPPL2A ●●●●●●● ● ● ● ● ● ●● ● ● ● ●●●●●●●●●●●●●● ● ●● ● ● ●●●●●●●●●●●●●●●● ●●●●●●● ●● ● ● 0 ●●●●●●●●●●●●● ●● ● ● ● 0 ●●●●●●●●●●●●●●●●●● ●● ●● ● ● ● ● WDR1 MAPT 0 10 20 0 10 20 30 40 50 Conectivity in control network Conectivity in control network

40 BM36 ● BM44 ● CAMK4 ● TRIM37 VPS13A ● ● ● MEF2C● ● 30 ● SYNJ1 ● EIF4E EIF4E ● ● CNTNAP2● 30 KRAS ● ● KRAS TIAM2 TP53INP1 NSF ● ● HINT1 HINT1 ● ● ● MAML1 ● ● ● ● ● ● ARL6IP5 RNF6 ● ● ● ATP2B2 PRICKLE1 ● ● RAB1A CCT8 RAB1A● CALM3 TMEM30A PSMC6 ● 20 LINGO1 ● GGH NDUFS3 ● MSH2 PTK2B ● ● ● ● ● TMEM30A ● ● ● ● ● GRIN1 20 ● ● ● MEF2C ● ● ● ● ● ● CYCS VPS13A CDH13 ● ● ● MAML1 PSMC6 ● ● CALM3 ● ● ● ● JPH3 ● BRSK2 DLG2 ● ● ● ● ● ● ● ● ● ● ● ● AP2A2 ● ● ● ● ● ATP2B2 ● ● ● PTK2B ● SYNGAP1 ● ● ● 10 ● ● ● ● ● ● ● CHRNB2 ● ● ● LMTK2 Conectivity in AD network ● ●●● ● MARK4 Conectivity in AD network 10 ● ● MAPT ● ● ● ● ● ● ● ● ● ● CAMK4 ● ● ● ● ● ●● ●● ULK1 ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● TENM4 SNX6 ● ● TOLLIP ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ●●●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● CANX ●● ● ● ● GRIN1 PAK2 ●●● ●●●● ● ● ● ● ● ● ●●● ●● ● ● ●●● ● ●● ● ● ● ● ●● ●● ● ● ● ● HERC2 ●● ● ● ● ● ● ●●●●●●●● ● ● ● ● ● ● ● ●●●● ●●● ● ● ● ●● ● ● ●MAPT ● ●●●● ● ● ● ●●● ●● ●● ● ● ● ●●●●●●●●●●● ●●●●● ● ● ● ● ● ●●●●●●●●●●●●●●● ● ●● ● ●●●● ● ● ● AP2A2 0 ●●●●●●●● ● ● ● ● ● ● USP8 MAP3K2 0 ●●●●●●●●●●●●●●●● ●●● ●●● ● ● ● ● ● ● ● SPPL2A 0 10 20 30 40 0 10 20 30 40 50 Conectivity in control network Conectivity in control network

Supplementary Figure S6. Network connectivity of AD risk genes in co-expression networks of both AD patients and normal controls. Each dot represents an AD risk gene. The gray dashed line marks the threshold for network hub genes either in the co- expression network of AD patients or normal controls. Blue and green dots represent network hub genes only in the co-expression network of AD patients and only in the co- expression network of normal controls, respectively.

7 FC AD pearson correlation−0.7 Control pearson correlation−0.7

● MAPT ● GNG3 ● GGH ● ● ● ● ● ● ● ● ● GRB2 ● DLG2 ● ● ●● ●●● ● ● ● ● ● ● ● ● ● ●●MAP2K5 GRIN1 ● ● ● RPTOR CDK5RAP3 ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● RPS27L ● ● ● ● ● ● ● ● ● SCIN ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● HINT1● ● ● ● ● CD55 ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● BIN1 AP2A2 ● ● PSMB8 ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● VPS13A ● ● ELMO1● ● ● ● ● ● ● TF SH3BGRL3 ●● ● ● ● ● ● ● AHCY ●FLNB ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ●● ADAM10 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●

● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● TSPAN15 ● ● CTNNA2● SHANK2 ● ● CTNNA2● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ARL6IP5 ● ● ● ● ●● ● ● ● KRAS TBC1D20 ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● SYTL2 ● ● ● ● ● ● CANX ● ● ● ● ● ● C4BPA COL25A1 ● ● ● ● ●● ●PTPRZ1 ● ● ● KIF5B ● ●● ● ● CST3 ● ● SNX6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● EXOC4 ● ● ● ● ● ● ● PACSIN3 ●● ● ●

ACG AD pearson correlation−0.7 Control pearson correlation−0.7

● ● ● ● ● ● ● ● PHB ● ● ● ● ● ● ● ● ● ● CYCS FLNBLINGO1 ● PHB ● ● ● RAD50 ● ● ●FLNB ●● ● ● ● ● ● ● ● ● ● ● FOLH1 ● ● ● ● ● ● ● ● ● FOLH1 ● ● ● ● ● ● ● ● ● ● ● ● ● ●SORD ● ● ● ● ● ● SNX9 ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● SPARC ● ● ● ● ● ● ● ● ● ● SNX6 ● ● ● ● ●

● ● ● ● B3GAT3 ● ● ● ● ● ● ● ● ● ●● ATP5C1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● KIF5B ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● GNG3 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● TSPAN15 ● ● ● ● ● ● ● ● ● ● ● ● ● GRB2 ● ● ●

CAMK4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ARL6IP5 ● ● ● ● ● ● ● PACSIN3 ● ● ● ● ● ADAM10 ● ● ● ● ● ● ● ● AP2A2 ● ● AP2A2 ● ● ● ● ● ●● ● ITSN2 ● ● ● ● ● ● ● ● ● ● ARF4 ● CRHR1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● SYNGAP1 ● ● ● ● ● ● SYNGAP1● ● ● ● ● ● ● ●SH3RF1 ERO1L ● ● ● ●EIF2B1 STX1B ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● PTK2B ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●ELMO1 ● ● ● ● ● ELMO1 ● ENO3● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● AD Control

Supplementary Figure S7. Co-expression networks of AD risk genes products in both AD patients and normal controls. Co-expression networks were constructed using protein data and the Pearson's correlation coefficients (> 0.7). Positive and negative correlations are denoted by gray and green lines, respectively. The size of a node is proportional to the connectivity of the gene. The network hub genes are colored orange or yellow.

8 FC ACG

CANX PSMB8 LINGO1 60 ● ● ARF4 ● SYTL2 RPTOR 40 ● ● ● EXOC4 ● ● ARL6IP5 KIF5B SNX6 RPS27LVPS13A● ● PACSIN3 ● ● ● ● CYCS ● ● ● ● COL25A1 MAP2K5 ● ● ATP5C1 ● ● ● MAPT ● SNX9 ● PTPRZ1 B3GAT3 ● ● ● ADAM10 GGH SCIN ● ● ● ● TBC1D20 TSPAN15 ● HINT1 ● ● C4BPA●● ●● 30 ● ● ●● ● ● SH3BGRL3 ● ● RAD50 GRB2 ● ● 40 ● ● ● KRAS KAT8 ● ● ● CAMK4 ● ● ● ● ● BIN1● ● ● ● ● SHANK2 GNG3 ● NDUFS3 ● ● ● ● ● ● ● TF ● ●● ● ● ELMO1 ●● ● ● ● ● ●ADAM10 ● ● CDK5RAP3 GRIN1 ● ● ● ● ● ● ● 20 ● ● SORD ● ● ●● ● ●● ● ● ● ● AHCY ● ● ● ● ● ● SNX6 ● ● ● ● AP2A2● ITSN2 ●● ● ● KIF5B ● ● ● CST3 ● ● ● ● ● ● ● ● ● ● GNG3 ●● DLG2 ● ● ● ● PACSIN3TSPAN15 ● ● 20 ● ● ● ● ERO1L● ● ● ● ● ● ● ● ● ● ● ● ● ● ● CD55 ● ● ● ● ● ● ● BIN1 ● ● ● ● STX1B ● ● ● ●● ● ● Conectivity in AD network ● Conectivity in AD network ● ● ● ● ● ● ● ● ● ● ● 10 ● ● CRHR1 SH3RF1 ●●●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● GRB2 ARL6IP5 ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ●●● ● ● ● ●● ● ●● ● ● ●● ● ● ● ● ● ● ●●● ● ● SPARC ● ● ●●● ● FLNB ● ●● ● ● ● ● ●● ●● ●● ● ● ●● ● ● ●● ● RRAS2 EIF2B1 ●●● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ●●●●●●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ●● ● ENO3 ● ● ● ● ●●● ● ● ● ● ● ● CNTNAP2 ● ● ● ●● ● ● ● ● ●● PTK2B 0 ● ● ● ● ● 0 ●

0 10 20 30 0 10 20 30 40 Conectivity in control network Conectivity in control network

Supplementary Figure S8. Network connectivity of AD risk genes in protein-based co-expression networks of both AD patients and normal controls. Each dot represents an AD risk gene. The gray dashed line marks the threshold for network hub genes either in the co-expression network of AD patients or normal controls. Blue and green dots represent network hub genes only in the co-expression network of AD patients and only in the co-expression network of normal controls, respectively.

9 Increased Suppressed A1C STC ITC VFC HIP IPC S1C OFC CBC M1C A1C STC ITC VFC HIP IPC S1C OFC CBC M1C

0.5 0.15 0.14 0.11 0.19 0.15 0.14 0.18 0.17 0.21 0.17 40yrs 0.29 0.26 0.28 0.28 0.45 0.23 0.33 0.31 0.49 0.45 40yrs

0.3 0.4 0.1 0.15 0.17 0.13 0.13 0.07 0.15 0.15 0.15 0.18 36yrs 0.12 0.05 0.06 0.2 0.04 0.22 0.18 0.18 0.09 0.11 36yrs 0.3 0.32 0.2 0.24 0.33 0.2 0.3 0.24 0.27 0.18 0.2 30yrs 0.25 0.18 0.21 0.24 0.15 0.2 0.12 0.24 0.08 0.1 30yrs 0.2 0.2 0.31 0.34 0.26 0.23 0.32 0.36 0.28 0.26 0.26 0.26 23yrs 0.06 0.25 0.18 0.09 0.14 0.14 0.07 0.11 0.06 0.1 23yrs 0.1 0.1 0.14 0.14 0.26 0.13 0.16 0.12 0.17 0.11 0.07 0.19 19yrs 0.07 0.06 0.08 0.04 0.06 0.03 0.05 0.04 0.04 0.04 19yrs 0.0

Supplementary Figure S9. Spatiotemporal expression patterns of AD risk genes during brain development. Both the active (red) and the suppressed (blue) gene expression were analyzed, using the same approach as in Lin et al. (4). Each heat maps shows gene expression at five developmental stages, in a chronological order, in ten brain regions. The shade of the color is proportional to the ratio of genes that manifest active (or suppressed) transcriptional activities, in the corresponding brain region and at the developmental stage, to the total number of AD risk genes. Abbreviations: A1C, primary auditory cortex (core); STC, posterior superior temporal cortex; ITC, inferior temporal cortex; VFC, ventrolateral prefrontal cortex; HIP, hippocampus; IPC , posteroventral (inferior) parietal cortex; S1C, primary somatosensory cortex (area S1, areas 3,1,2); OFC, orbitofrontal cortex; CBC, cerebellar cortex; M1C, primary motor cortex (area M1, area 4).

10 A PHB MAPK12 IL1RAP 1.00 1.00 1.00

0.75 0.75 0.75

0.50 0.50 0.50 + + + + 0.25 + 0.25 0.25 + Survival probability + High expression Survival probability + High expression Survival probability + High expression + Low expression + Low expression + Low expression 0.00 0.00 0.00 50 60 70 80 90 50 60 70 80 90 50 60 70 80 90 Age (years) Age (years) Age (years)

● 5.2 ● ● 6.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 5.0 ● ● 4.8 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 5.5 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 4.4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 5.0 ● ● ● ● ● ● ● 4.5 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Gene expression ● Gene expression ● Gene expression ● ● ● ● ● ● 4.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● AD ● ● ● AD 4.5 ● AD ● ● ● ● ● ● ● ● ● 4.0 ● ● Control ● Control ● Control● ● ● 3.6 ● ● ● 60 70 80 90 60 70 80 90 60 70 80 90 Age (years) Age (years) Age (years) B IL1RAP PMAIP1 STRADA SGK3 1.00 1.00 1.00 1.00

0.75 0.75 0.75 0.75

0.50 0.50 0.50 0.50 + + + + + 0.25

0.25 0.25 0.25 Survival probability Survival probability + High expression + Survival probability + High expression Survival probability + High expression + + High expression + + Low expression + Low expression + Low expression + Low expression 0.00 0.00 0.00 0.00 50 60 70 80 90 50 60 70 80 90 50 60 70 80 90 50 60 70 80 90 Age (years) Age (years) Age (years) Age (years)

● ● ● ● ● ● ● ● ● ● ● 4.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 6.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 3.5 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 5.6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 3.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 5 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Gene expression ● ● ● ● Gene expression −2 ● Gene expression ● Gene expression 5.2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● AD ● ● ● ● ● AD 2.5 AD ● AD ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Control ● ● Control ● Control ● Control ● ● −4 ● ● 4.8 ● 4 60 70 80 90 60 70 80 90 60 70 80 90 60 70 80 90 Age (years) Age (years) Age (years) Age (years)

Supplementary Figure S10. AD survival curves and gene expression trajectories accompany with age. (A) BM10. (B) BM22. There are additional six genes, not shown in Figure 5, whose expression affects the survival of AD patients with low and high expression levels and shows opposite expression trajectories with age in AD patients and normal controls.

11 A 1.0

0.9

0.8

PrimateAI score 0.7

BIN1 FGG ABCA1ABCA7APOE CANXCD2AP CST3DDX41EPHA1FARP1 GLRA1HSPG2 ITSN2JPH3KIF5BLIMS2 PTK2B SGK3 SKOR1SNX6SPARC SYNJ1TTPAUSP21USP6 B4GALT3 CHRNB2COL18A1 GANAB IQGAP2 MAML1MARK4PICALMPSMC5 RAPSN SH3RF1 SREBF2

0.6 0.5 0.4 0.3 0.2

ExPecto score (neuro tissue) ExPecto TF ACE BIN1 F2R GH1 ABCA7 APOC1 CCR5 CST3 PTPRF SPARC SPHK2 USP6 COL25A1 PICALM

0.6

0.4

0.2 ExPecto score (all tissue) ExPecto TF ACE BIN1 F2R GH1 ABCA7 APOC1 AZGP1 CCR5 CDH1 CDH3 CST3 EPHA1 PLCG1 PTPRF RRAS2 SPARC SPHK2 SYTL2 USP6 CDKAL1COL25A1 PICALM PMAIP1

1.00 0.95 0.90 0.85 0.80 LINSIGHT score

DRA − C4AC4B CFB IL3 NSF ASIPATF6BBCL3BIN1 CSF1CSF2CTBS ENO3 FLNBFNIP1GPC2 IL6RKAT8KIF5B MAPTNMT1 RELB RPSA SNX1 STX4SYTL2TFR2TRIP6USP6 ADAM10ADRA1A CHRNB2CRHR1 ELMO1EPHA1ERCC3ERO1L GANAB HSPG2 MAP2K5MEF2CNOTCH4OSBPL7PACSIN3PCOLCEPDGFRAPICALMPSMB8PSMC5PTK2BPTPN1PTPRFPTPRJRAB1ARAD50RNF40SKOR1 SPPL2CSTRADASTX1BSUMO2 VPS13A CDK5RAP3 HLA LAMTOR4 PRICKLE1 SLC25A13 Genes

B 150 predicted casual variants

32 reported 21.3% 46% eQTL

69 Motif change

Supplementary Figure S11. Predicted AD casual variants. (A) AD risk genes, casual variants, and their functional scores. For promoter variants, we used ExPecto scores from both all or neuro tissues. (B) Functional annotation of predicted casual variants. ~57% (85/150) of them are either known eQTLs or predicted to change TFBS motifs.

12 REFERENCES

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