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These tables include selected references for positive studies demonstrating association between the gene described and Alzheimers disease. The referencing is not comprehensive and negative studies are not included. A complete referencing of all positive and negative studies is available at the Alzgene database. Genes that have also been associated with atherosclerosis or hypercholesterolemia are also referenced and summarised in the first table. Where available, expression changes and functional studies in Alzheimer's disease are annotated.  A brief summary of the role of the gene and its relationship to other genes implicated in Alzheimer's disease and to cholesterol and lipoprotein function is also provided.  Linkage data refer to the chromosomal region rather than the gene. The first column is  linked to the ENTREZ gene database. PUBMED links, where shown,  are designed to retrieve general  references in relation to Alzheimer's disease or atherosclerosis,  rather than specific association data.Protein interaction data are from the Biogrid database. KEGG pathway data is provided by the Kanehisa Laboratories (www.kegg.org). For KEGG licensing conditions, please contact Pathway Solutions Inc. (www.pathway.jp). Kegg pathway maps containing these genes are available here. GeneCards links are with the kind permission of GeneCards.org. Relationships of these genes with the Herpes virus (HSV-1) are also annotated. Environmental risk factors are listed here

Latest publications Last update: May 8, 2008

 

 

 

 

 

Genes associated with both atherosclerosis/hypercholesterolaemia and Alzheimer's

Family Gene
Cholesterol and lipoprotein-related A2M, ABCA1, APOA1, APOA4, APOC1, APOC2, APOC3, APOE, CD36, CETP, HMGCR, LDLR, LIPA, LRP1, LRP6, LPA, LPL, OLR1, SREBF1
Cytokines CCL2, CCR2, IL1B, IL1RN, IL6,IL18, TGFB1, TNF
Oxidative stress ALDH2, GSTM1, GSTT1, HFE, MPO, NOS3, PON1, PON2
Nuclear receptor and related CYP19A1, ESR1, PPARA
Proteases ACE, CST3, MMP1, MMP3, SERPINE1
Miscellaneous BCHE, CBS, CD14, CRP, GNB3, HLA-A2, HTR6, ICAM1, MEF2A, MTHFR, PTGS2, TLR4

CYP2C cluster (in progress) Liu et al, 2007.

 Table 1:  Components of the cholesterol shuttle and cholesterol and lipoprotein related genes that have been associated with Alzheimer's disease.

Gene

Chr and linkage

Alzheimer’s disease 

Atherosclerosis/ hypercholesterolemia Modifications in AD Relationships with other gene products HSV-1
ACAD8 acyl-Coenzyme A dehydrogenase family, member 8 Kegg Bile acid biosynthesis GeneCards 11q25 Blacker et al, 2003 Wollmer et al, 2007        
DHCR24 24-dehydrocholesterol (desmosterol) reductase (seladin) Kegg (1.3.1.72 and DWF1) GeneCards Metabolome 1p33-p31.1 Lamsa et al, 2007 Pubmed  

Downregulated in AD temporal cortex Livonen et al, 2002

Relatively high proportion of desmosterol in AD brain Wender et al, 1994

    
FDPS farnesyl diphosphate synthase Kegg (2.5.1.1 and 2.5.1.10) GeneCards 1q22 Wollmer et al, 2007          
HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase BIOGRID Kegg (1.1.1.34) GeneCards 5q13-q14

Licastro et al 2006

PUBMED

Hubacek et al, 1999

PUBMED

 

 

 No mRNA change Yasojima et al, 2002 Rate limiting enzyme for cholesterol biosynthesis. Transcription controlled by SREBF1 and PPARA Narce and Poisson 2002.Transcription/activityrepressed by 24 and 25-OHcholesterol (CYP46A1, CH25H)Saucier etal ,1989 Nishimura et al,2005. Induced by homocysteine in endothelial cells Li et al, 2002 (cf MTHFR, MTR, MTRR) HSV-1 entry into Vero cells is lipid raft dependent and is blocked by nystatin Bender et al, 2003
HMGCS2 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 mitochondrial Kegg ketones Kegg PPAR GeneCards 1p13-p12 Wollmer et al, 2007     Provides the substrate for HMGCR  

A2M alpha-2-macroglobulin Biogrid Kegg complement

Kegg Alzheimer GeneCards		 12p13.3
-p12.3 12p13-q22  cited in
(Liang et al. 2005)		 (Zappia et al. 2002)

PUBMED

Related to atherosclerosis in circle of Willis Larionov et al, 2006 a risk factor for Alzheimer's disease Roher et al, 2003

PUBMED

 

 

 No change in CSF protein (Blennow et al. 2000) Ligand for LRP1 (Strickland et al. 1990. ). Binds to APOE (Krimbou et al. 1998)Binds to growth factors including BDNF (Wolf and Gonias 1994); Binds to beta amyloid  and mediates degradation and transport of amyloid beta peptides via A2M associated proteases and  LRP (Fabrizi et al. 2001). Binds to lecithin cholesterol acyl transcerase (LCAT)  (Krimbou et al. 2001) Binds to HSV-1 Alonso et al, 2001
LPA lipoprotein, Lp(a) BIOGRID GeneCards 6q26-q27 6q25-27 reviewed by (Bertram and Tanzi 2004) (Compton et al. 2002)
PUBMED 		(Kronenberg et al. 1999)
PUBMED

Increased serum levels(Kuriyama et al. 1992) Lp(a) serum levels

are associated  with an increased risk for AD, independently

of apolipoprotein E genotypes (Solfrizzi et al. 2002)

Binds to APOE (Bard et al. 1992)Binds to LDLR, LRP1, VLDLR and gp330 lipoprotein receptors (Niemeier et al. 1999;Reblin et al. 1997)  
APOA1 BIOGRID GeneCards

11q23-q24

11q23 reviewed by (Bertram and Tanzi 2004)

 (Vollbach et al. 2005)
PUBMED 		 (Spiridonova et al. 2001b)
PUBMED
  		Promotes cholesterol efflux from tissues to the liver for excretion, and it is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. Inhibits HSV-1 induced cell fusion Srinivas et al, 1991 The Herpes simplex virus binds to all classes of lipoprotein (LDL, HDL, VLDL), via glycoprotein B (UL27) Huemer et al, 1988, the use of individual lipoproteins or lipoprotein receptors for herpes viral entry has not been closely examined.
APOA4 Biogrid GeneCards

11q23

11q23 reviewed by (Bertram and Tanzi 2004)

 (Csaszar et al. 1997)
PUBMED 		 (Ganan et al. 2004)
PUBMED
  		Potent activator of LCAT(Emmanuel et al. 1994)
Substrate for ABCA1(Remaley et al. 2001) 		 
APOC1
apolipoprotein C-I Biogrid GeneCards		 19q13.2 19q13 reviewed by (Bertram and Tanzi 2004) (Ki et al. 2002)
PUBMED 		(Hubacek et al. 2004)
PUBMED

Astrocytic protein levels increased in Alzheimer's disease

frontal cortex and hippocampus: mRNA decreased (Petit-Turcotte et al. 2001)

Activates LCAT, inhibits CETP (Shachter 2001):Elevated serum cholesterol, triglycerides and free fatty acids in transgenic mice expressing hAPOC1(Jong et al. 1998;Shachter et al. 1996)Transported by ABCA1 (Remaley et al. 2001). Inhibits APOE mediated binding of VLDL to LRP1 and VLDLR (Jong et al. 1999b)  
APOC2
apolipoprotein C-II Biogrid GeneCards

19q13.2 19q13 reviewed by (Bertram and Tanzi 2004)

 (Schellenberg et al. 1987)

 PUBMED 		 (Kawano et al. 2002),
PUBMED 		No change in blood APOC2 levels (Adunsky et al. 2002) Transported by ABCA1 (Remaley et al. 2001). Binds to and activates  LPL (Shen et al. 2002;MacPhee et al. 2000)Reduces APOB binding to LDLR (Clavey et al. 1995)  
APOC3 Apolipoprotein C III Biogrid GeneCards 11q23.1-
q23.2 11q23 reviewed by (Bertram and Tanzi 2004) 		(Sun et al. 2005b)
PUBMED 		(Waterworth et al. 2000)
PUBMED 		No change in blood APOC3 levels(Adunsky et al. 2002) Transported by ABCA1 (Remaley et al. 2001). Binds to LDLR, inhibits LPL (Jong et al. 1999a).  
APOD Apolipoprotein D Biogrid GeneCards 3q26.
2-qter 3q28 described as a locus in Finnish cases (Hiltunen et al. 2001) and in dementia in the Amish population (Hahs et al. 2006) 		 (Desai et al. 2003)
PUBMED
 PUBMED 		Localised in amyloid deposits (Navarro et al. 2003)Increased protein levels in hippocampus frontal cortex and CSF (Glockner and Ohm 2003;Thomas et al. 2003;Terrisse et al. 1998) Role in Cholesteryl ester exchange: Binds to and activates LCAT(Holmquist 1989). Release from astrocytes stimulated by 25-hydroxycholesterol (CH25H) (Patel et al. 1995). Binds cholesterol, progesterone, arachidonic acid, bilirubin (Nakagawa et al. 2002)  
APOE
apolipoprotein E Biogrid GeneCards		 19q13.2 MIM #104310 (Rubinsztein and Easton 1999)

PUBMED
 		 (Horejsi and Ceska 2000)
PUBMED

Reduced CSF levels with evidence for increased oxidation of lipoproteins

(of which APOE is the major constituent)(Neely and Montine 2002;

Schippling et al. 2000;Yamauchi et al. 1999)


 

Major Cholesterol carrier (Swertfeger and Hui 2001). Ligand for  LDLR, LRP1 (Raussens et al. 2002), (Myklebost et al. 1989), LRP8(APOER2) (Kim et al. 1996), LDLR and and VLDLR (Liu et al. 2002): Amyloid beta binds to APOE  (Strittmatter et al. 1993) APOE4 and HSV-1 infection combine to increase AD risk Itzhaki and Wozniak,2006APOE-derived peptides have anti infective activity(HSV-1 and 2) Dobson et al, 2006. APOE4 favours HSV-1 cerebral entry Burgos et al, 2003 APOE isoforforms modify HSV-1 viral latency and immediate early gene expressionMiller and Federoff, 2008 Pubmed
ABCA1
ATP-binding cassette, sub-family A (ABC1), member 1 Biogrid Kegg GeneCards		 9q31.1 Reviewed by Kamboh, 2004. (Wollmer et al. 2003a)
 PUBMED 		(Lutucuta et al. 2001),
PUBMED 		Increased hippocampal mRNA(Blalock et al. 2004) ABCA1 induction reduces beta and gamma secretase activity (Sun et al. 2003) and increases the secretion of amyloid beta 40 and 42. (Fukumoto et al. 2002b) Transports cholesterol (Knight 2004). Transports lipoproteins APOA-II, APOA4, APOC1, APOC2, APOC3, APOE (Remaley et al. 2001)  
ABCA2 ATP-binding cassette, sub-family A (ABC2), member 2 Biogrid Kegg GeneCards 9q34 Reviewed by Kamboh, 2004. (Mace et al. 2005)
PUBMED

Expression in CHO cells increases LDLR expression (Chen et al. 2004)  
ABCG1 ATP-binding cassette, sub-family G (WHITE), member 1 Biogrid GeneCards 21q22.3 Blacker et al, 2003 Wollmer et al, 2007 Pubmed     Involved in macrophage cholesterol and phospholipid transport. Transports 7-beta-hydroxycholesterol Engel et al, 2007, a product of APP  
NPC2 Niemann-Pick disease, type C2 Biogrid GeneCards 14q24.3 Avramopoulos et al, 2005 Wollmer et al, 2007     regulates the transport of cholesterol through the late endosomal /lysosomal system  
OPRS1
Sigma receptor 1Biogrid GeneCards		 9p13.3 (Uchida et al. 2005) PUBMED  
 PUBMED
  		Sigma 1 ligand inhibits cholesterol biosyntheis at the sterol isomerase step (Labit-Le Bouteiller et al. 1998) Regulates lipid transport from endoplasmic reticulum to plasma membrane Hayashi and Su,2003   
APP Amyloid beta (A4) precursor protein Biogrid Kegg Alzheimer GeneCards 21q21.3 OMIM #
104760 		(Goate et al. 1989)
APP
AICD
Abeta1-42
Abeta1-40

 		APP cholesterol
APP lipoprotein 		Major component of senile plaques Abeta40 reduces cholesterol synthesis via HMGCR inhibition Grimm et al, 2005 Oxidises cholesterol to 7beta-Hydroxycholesterol Nelson and Alkon, 2005, a substrate of HSDB11. Binds to LRP1 via interactions with LRPAP1 and APBB1 Kinoshita et al, 2001. Cleaved by BACE and gamma secretase. Binds to APBB1, APBB2, APBB3, APOE,MAPK8IP1, SNCA, TGFB1,(see gene info). C-terminal AICD induces GSK3B via APBB1 and TFCP2 Kim et al, 2004 Abeta fibrils stimulate the entry of HSV-1 and other enveloped viruses Wojtowicz et al, 2002. APP is involved in the anteroggrade transport of HSV-1 Satpute-Krishnan et al, 2003. HSV-1 infection increases intracellular beta-amyloid productionWozniak et al, 2007
LDLR Low density lipoprotein receptor Biogrid GeneCards 19p13.3 19p13.3 described as a susceptibility locus in a Finnish study (Hiltunen et al. 2001) Poduslo et al. 2004)
 PUBMED 		(Bertolini et al. 2004)
PUBMED 		Increased hippocampal mRNA(Blalock et al. 2004) Binds to LPA(Reblin et al. 1997), APOB, APOE (Defesche 2004). Mediates the increase in the astrocytic expression of APOE induced by beta-amyloid (LaDu et al. 2000). AICD interacts with ARH an adaptor protein for LDLR(Noviello et al. 2003) Major role in cholesterol uptake via binding to APOB and APOE containing particles (Defesche 2004) HSV-1 infection increases LDLR expression and transcription in arterial smooth muscle cells Hsu et al, 1995

LRP6 low density lipoprotein receptor-related protein 6 Biogrid

Kegg Wnt Pathway GeneCards

 12p11-p13 DeFerrari et al, 2007 Mani et al, 2007   Cleaved by gamma-secretase-like activity releasing an intracellular fragment that inhibits GSK3B Mi and Johnson, 2007  
LRP8 (APOER2) Biogrid GeneCards 1p34 (Ma et al. 2002)
PUBMED
 PUBMED 		Decreased hippocampal mRNA(Blalock et al. 2004) Cleaved by gamma secretase (Kinoshita et al. 2003). Brain localised APOE receptor(Kim et al. 1996)Associated with LRPAP1 (Andersen et al. 2003)  
HSPG2
heparan sulfate proteoglycan 2 (perlecan) Biogrid Kegg GeneCards		 1p36.
1-p34 1p36 reviewed by (Bertram and Tanzi 2004) 		(Iivonen et al. 2003)
PUBMED
 PUBMED 		No change in hippocampal mRNA expression (Maresh et al. 1996) Bind to beta amyloid and promotes fibrilogenesis (Castillo et al. 1997),. Binds and internalises low density lipoproteins enriched in LPL (Fuki et al. 2000) Glycoproteins B and C of Herpes simplex bind to Heparan sulfate proteoglycans Bender et al, 2005
LRPAP1: Low density lipoprotein receptor-related protein associated protein 1 (RAP) Biogrid GeneCards 4p16.3 (Sanchez et al. 2001)
PUBMED 		-PUBMED
  		Universal low density lipoprotein receptor antagonist and chaperone (LDLR, LRP1,LRP8, VLDLR) (Bu 1998;Bu 2001;Medh et al. 1995) Controls APP/LRP1 association (Goto and Tanzi 2002)   
LRP1
low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor) Biogrid Kegg Kegg Alzheimer GeneCards		 12q13-q14 D12S1042;D12S368 define a large region between 12p11.23 and 12q13.13 (Liang et al. 2005) (Bi et al. 2001)

PUBMED 		(Schulz et al. 2002)

PUBMED

Associated with senile plaques(Arelin et al. 2002)Increased

protein levels in frontal cortex(Qiu et al. 2001)

APOE receptor (Myklebost et al. 1989)Binds A2M,  LPL and VLDL (Nykjaer et al. 1993). Associated with APP(Rebeck et al. 2001) Exports amyloid/A2M complexes(Shibata et al. 2000) Cleaved by gamma secretase and BACE1 (Lleo et al. 2005;May et al. 2003;von Arnim et al. 2005)  
OLR1
oxidised low density lipoprotein (lectin-like) receptor 1 (LOX1; SCARE1) Biogrid Kegg GeneCards		 12p13.2-
p12.3 12p13-q22  cited in (Liang et al. 2005) 		(Lambert et al. 2003)
PUBMED 		(Chen et al. 2003)

PUBMED

Decreased expression in lymphocytes in individulals with the

Alzheimer’s associated polymorphism (Lambert et al. 2003)

Oxidised LDL Receptor (Moriwaki et al. 1998;Yamada et al. 1998) HSV-1 increases OLR1 expression in endothelial cells Chirathaworn et al, 2004

SORL1 sortilin-related receptor, (LDLR class) A repeats-containing OMIM Biogrid GeneCards

 11q23.2-q24.2

Rogaeva et al, 2007

Pubmed

 PUBMED

Reduced expression in lymphocytes and

cerebral tissue Scherzer et al, 2004

Mediates the uptake of APOE-enriched lipoproteins Taira et al, 2001. Binds to LRPAP1 Jacobsen et al, 1996 and BACE1 Spoelgen et al, 2006.Regulates APP processing Andersen et al, 2005 Gamma-secretase substrate Nyborg et al, 2006 Binds to PLAUR and PAI-1 (SERPINE1)Gliemann et al, 2004

  
VLDLR
very low density lipoprotein receptor Biogrid GeneCards 		9p24 (Yamanaka et al. 1998)

PUBMED 		PUBMED

Localised in senile plaques (Vassar et al. 1999)  

Decreased hippocampal mRNA(Blalock et al. 2004)

Binds APOE, Lipoprotein (a) (LPA), LPL, and serpin/protease complexes. Also binds to LRPAP1 (Rettenberger et al. 1999)and APOC1 (Jong et al. 1999b)  
LPL
lipoprotein lipase Biogrid Kegg Alzheimer GeneCards
  		8p22 (Baum et al. 1999)

PUBMED 		(Peacock et al. 1992)

PUBMED 		Increased hippocampal mRNA(Blalock et al. 2004) Bridging factor for lipoprotein receptor mediated lipoprotein uptake. Binds to LRP1 (Williams et al. 1994)and gp330 (Kounnas et al. 1993)Activated by APOC2 (Fitzharris et al. 1981)Inhibited by APOE(Jong et al. 1997). Cholesterol prevents APOC2 binding to LPL (Arimoto et al. 1998)Increases the capture of HDL cholesteryl esters in the liver via binding to heparan sulphate proteoglycans (Rinninger et al. 1998a;Rinninger et al. 2001;Rinninger et al. 1998b)
Localised to astrocytes , microglia and hippocampal pyramidal  neurones (Blain et al. 2004;Yacoub et al. 1990) 		 

CH25H cholesterol  25 hydroxylase Biogrid GeneCards

Metabolome		 10q23 See Alzgene for large region of 10q linked to AD (Papassotiropoulos et al. 2004)

PUBMED 		PUBMED
 Increased hippocampal mRNA(Blalock et al. 2004) 25-hydroxycholesterol stimulates APOD secretion from astrocytes (Patel et al. 1995) and of APOE in a human astrocytoma cell line (Gueguen et al. 2001). 25-hydroxycholesterol suppresses transcription of cholesterol synthetic enzymes and increases  HMGCR degradation (Taylor 1992).  
CYP46A1
cytochrome P450, family 46, subfamily A, polypeptide 1 Biogrid GeneCards Metabolome		 14q32.1 D14S1015  (Kamboh 2004) (Papassotiropoulos et al. 2003)

PUBMED
 24-(s)hydroxycholesterol and atherosclerosis 

Shift of localisation from neurones to glia in AD brain

(Bogdanovic et al. 2001)Increased CSF levels of the

product 24S-hydroxycholesterol (Schonknecht et al. 2002)

Major cholesterol metabolising enzyme in brain (Lund et al. 2003). The CYP46 polymorphism is associated with increased brain beta-amyloid load and increased CSF levels(Papassotiropoulos et al. 2003)  
HSD11B1 11-beta-Hydroxysteroid Dehydrogenase Type 1 Biogrid GeneCards 1q32-q41 (de Quervain et al. 2004)

PUBMED 		 PUBMED
  
 7-beta-hydroxycholesterol, the product of cholesterol oxidation by APP is metabolised by type 1 11-hydroxysteroid dehydrogenase(s) (HSD11B1) to the corresponding keto derivative (Hult et al. 2004)  
LIPA lipase A, lysosomal acid, cholesterol esterase Biogrid GeneCards 10q23.2-
q23.3 D10S583(10q23.33)(Bertram et al. 2000) 		(Li et al. 2004a)
PUBMED 		 (Bian et al. 2004)

PUBMED,  		 
  
Catalyzes the hydrolysis of cholesteryl esters and triglycerides 		 
CETP cholesteryl ester transfer protein Biogrid GeneCards 16q21 (Rodriguez et al. 2005) PUBMED  (Boekholdt et al. 2004)
PUBMED 		High astrocytic expression in white and gray matter (Yamada et al. 1995)  Expression controlled by SREBF1 (Gauthier et al 1999)  
SOAT1:
sterol O-acyltransferase (acyl-Coenzyme A: cholesterol acyltransferase) 1 Biogrid GeneCards		 1q25 1q23-31 reviewed by (Bertram and Tanzi 2004) (Wollmer et al. 2003b)
PUBMED
 PUBMED 		 
 Modulates Abeta production via control of cholesterol/cholesteryl ester ratio (Puglielli et al. 2001): Metabolises cholesterol and oxysterols to  esters (Cases et al. 1998;Zhang et al. 2003): Inhibitors reduce plasma cholesterol levels (Miyazaki et al. 2003)

  		 
PPP1R3A
protein phosphatase 1, regulatory (inhibitor) subunit 3A (glycogen and sarcoplasmic reticulum binding subunit, skeletal muscle) (PP1G; PPP1R3) Biogrid GeneCards		 7q31.1 Reviewed by Kamboh (Kamboh 2004) (Liolitsa et al. 2002)