Table 1.
Confirmed risk gene loci.
| Locus | Gene | Function | References |
|---|---|---|---|
| 9q31.3 | ABCA1 | ATP-binding cassette transporter subfamily A member 1: regulates cholesterol efflux to forming HDL | [476, 604] |
| 19p13.3 | ABCA7 | ATP binding cassette subfamily A member 7: lipid homeostasis of immune cells, efflux of phospholipids, phagocytosis | [541, 542, 557, 558, 569, 605-608] |
| 15q23.3 | ADAM10 | A-disintegrin and metalloproteinase domain-containing protein 10: excitatory hippocampal synapses | [556, 559] |
| 8p11.21 | ANK1 | Ankyrin 1: integral membrane protein in the spectrin-actin cytoskeleton, neuron motility, activation, proliferation, contact | [476, 569, 570] |
| 19q13.32 | APOE | Apolipoprotein E: neuronal cholesterol and triglyceride transport shuttle | [605, 606] |
| 21q21.2 | APP | Amyloid precursor protein: cell surface receptor, cleavage products binding acetyltransferase complex APBB1/TIP60, promoting transcriptional activation | [124, 211, 545, 546] |
| 9q33.1 | ASTN2 | Neuronal protein astrotactin 2: neuron migration and connectivity | [578] |
| 17q25.1 | ATP5H/KCTD2 | Mitochondrial ATP synthase H+ transporting: catalyses ATP synthesis, involved in OXPHOS, mitochondrial energy and cellular stress | [541] |
| 11q23.3 | BACE1 | Beta-secretase 1: transmembrane protease performing first cleavage step for amyloid beta | [547] |
| 2q14.3 | BIN1 | Myc box-dependent-interacting protein 1: involved in synaptic vesicle endocytosis, endosomal vesicle cycling, clathrin-mediated endocytosis, related to tauopathy | [540, 542, 546, 557, 563, 564, 569, 572, 605-607] |
| 19q13.32 | BLOC1S3 | Biogenesis of lysosomal organelles complex1, subunit 3: autophagy and apoptosis | [572] |
| 22q13.1 | CARD10 | Caspase recruitment domain family, member 10: NFkappaB signalling pathway, hippocampal volume, hippocampal neurodegeneration with PARP1 in APOE epsilon3 carriers | [541, 609] |
| 20q13.31 | CASS4 | Cas scaffolding protein family member 4: cytoskeletal stabilisation, axonal transport, binding to CD2AP, involved in APP pathology, tauopathy | [542, 557, 605, 606] |
| 6p12.3 | CD2AP | CD2 associated protein: endosomal vesicle movement/cycling, cytoskeletal reorganisation, modulating with GRB2 metabolism of APP |
[540, 542, 546, 557, 558, 566, 605-607] |
| 19q13.41 | CD33 | CD33 molecule: microglial/immune/inflammatory response, cell-cell interactions, related to cognitive decline, Abeta clearance | [541, 542, 557, 605-607, 610] |
| 10q23.1 | CDH23 | Cadherin related 23: calcium dependent cell-cell adhesion glycoprotein, neuronal differentiation, neuronal transmission | [543, 569] |
| 11p11.2 | CELF1 | CUGBP Elav-like family member 1: regulating pre-mRNA alternative splicing, editing, translation, including MADD MAPK–activating death domain, affecting long-term neuronal viability | [542, 557, 605, 606, 611] |
| 16q13 | CETP | Cholesteryl ester transfer protein: transfer of cholesteryl ester from HDL to other lipoproteins, related to myelination, white matter integrity, MetS components | [541, 612, 613] |
| 1q31.1 | CFHR1 | Complement factor H related 1: controlling complement, facilitating tissue invasion, neuroinflammation with IL-6, neurodegeneration | [541, 614] |
| 8p21.1 | CLU | Clusterin: molecular chaperone, clearing cellular debris and apoptosis, cholesterol and lipid metabolism, regulation of cell proliferation | [541, 542, 546, 567, 605-608] |
| 1q32.2 | CR1 | Complement receptor 1: membrane glycoprotein binding immune complexes, immune response, regulation of complement activation, neuroinflammation | [540, 541, 542, 546, 557, 562, 605-607] |
| Locus | Gene | Function | References |
| 15q21.1 | CYP19A1 | Enzyme aromatase: oestrogen pathway, involved in tauopathy, Abeta cascade, interaction with IL-10 | [544, 615, 616] |
| 14q32.2 | CYP46A1 | Cholesterol 24S-hydroxylase (CYP46A1) promoter: monooxygenase related to synthesis of cholesterol hydroxylase, steroids and other lipids, cholesterol transport through BBB | [617-619] |
| 1p23.3 | DHCR24 | 24-dehydrocholesterol reductase: oxidoreductase catalysing cholesterol biosynthesis, cholesterol efflux | [476, 620, 621] |
| 21q22.3 | DIP2A | Disco interacting protein 2 homolog A: CNS axon patterning | [569] |
| 18q12.1 | DSG2 | Desmoglein 2: calcium-binding transmembrane glycoprotein component of desmosomes, cell-cell junctions, glycoprotein generation, involved in APP processing | [606, 622] |
| 1p36.12 | ECE-1b promoter | Endothelin converting enzyme 1: related to Abeta degradation | [573, 574] |
| 18q12.2-q21.1 | EPG5 | Ectopic P-granules autophagy protein 5 homologue: autophagy | [551, 623] |
| 7q34-35 | EPHA1 | Ephrin receptor: mediating CNS development, modulating cell migration, axon guidance, synapse development and plasticity, cerebral glucose levels, atrophy, endosomal vesicle cycling, immune system | [542, 546, 557, 565, 567, 605-607] |
| 2q33.3 | FASTKD2 | Fas-associated serine/threonine kinase domains 2: mitochondrial inner compartment protein, COX signalling, memory performance | [541, 624-626] |
| 14q22.1 | FERMT2 | Fermitin family member 2: cytoskeletal function and axonal transport, actin assembly and cell shape modulation, cell matrix adhesion structures, activates integrins, related to tauopathy | [542, 557, 605, 606] |
| 9p24.2 | GLIS3 | GLI-similar family zinc finger 3: repressor and activator of transcription, development of pancreatic beta cells, tauopathy, APP metabolism | [19, 541, 627] |
| 3q28 | GMNC | Geminin coiled-coil domain containing: involved chromosomal DNA replication, preferentially expressed in proliferating neurons, related to tauopathy | [19] |
| 6p21.31 | HLA-DRB5/DRB1 | Major histocompatibility complex class II, DRbeta5 and DRbeta1: immuno- competence, encoding human leukocyte antigen, neuroinflammation | [542, 557, 605, 606] |
| 14q32.33 | IGHV1-67 | Immunoglobulin heavy variable 1-67: neuroinflammation | [628] |
| 2q37.1 | INPP5D | Inositol polyphosphate-5-phosphatase: Immune response, gene regulation, posttranslational modification of proteins, microglial and myeloid function, interacting with CD2AP, neuroinflammation | [542, 557, 605, 606] |
| 17q21.31 | KANSL1 | KAT8 regulatory NSL complex subunit 1: involved with histone acetylation, related to MAPT expression | [629] |
| 12q24.31 | KDM2B | Lysine demethylase 2B: phosphorylation-dependent ubiquitination, posttranslational modification | [630] |
| 9q34.12 | LAMC3 | Laminin subunit gamma 3: extracellular matrix glycoprotein related to cellular morphogenesis, in interaction with LRRK2 and MADD related to age-of-onset | [577] |
| 12q12 | LRRK2 | Leucine rich repeat kinase 2: Ras-Raf signalling, cytoplasm and mitochondrial outer membrane, related to age-of-onset | [577] |
| 11p11.2 | MADD | MAP kinase activating death domain: TNFalpha signalling with the death domain of TNFalpha receptor 1, MAPK apoptotic signal transduction, related to age-of-onset | [577, 631, 632] |
| 17q21.31 | MAPT | Microtubule-associated protein tau: neuron stabilisation, transcript undergoes complex, regulated alternative splicing, producing several mRNA species | [546, 629] |
| Locus | Gene | Function | References |
| 5q14.3 | MEF2C | Myocyte enhancer factor 2C: immune response, neural development, synaptic connectivity and plasticity, limiting excessive activity-dependent synapse formation, facilitating hippocampal-dependent learning and memory, neuroinflammation | [557, 605, 606] |
| 3p25.2 | MME/NEP | Membrane metalloendopeptidase/neprisylin: glycoprotein neutral endopeptidase, related to WM hyperintensities, related to cleavage of peptides, related to Abeta degradation, covariation with WM disintegrity | [573, 633, 634] |
| 11q12.2 | MS4A4/MS4A6E | Membrane spanning 4-domains: involved in signal transduction as a component of a multimeric receptor complex, IgE receptor, immune response, neuroinflammation | [540, 542, 546, 605-608, 635] |
| 20q13.33 | MYT1 | Myelin transcription factor: zinc finger transcription factor expressed on neurons, myelination onset, binding to the significant promoter CYP46A1 polymorphism, in haplotypes with CYP46A1, related to REST, MECP2 | [617] |
| 20p11.21 | NANP | N-acetylneuraminic acid phosphatase: implicated in insulin signalling, glycation, related to brain atrophy in neurodegeneration | [630] |
| 20p11.21 | NINL | Ninein-like protein: implicated in dynein-dynactin-interaction, related to stabilisation of microtubuli, tauopathy, related to brain atrophy in non-APOE epsilon4 carriers in haplotype with NANP | [630] |
| 7p14.1 | NME8 | Thioredoxin domain-containing protein 3: implicated in dynein-related microtubular transport function, related to cognitive decline, neurodegeneration | [542, 557, 605, 606] |
| 10q23.1 | NRG3 | Neuregulin 3: EGF-related ligand to transmembrane receptors, implicated in neuroblast proliferation, migration, differentiation, and survival or apoptosis, related to age-of-onset | [579] |
| 12q22 | NTN4 | Netrin 4: EGF-related, responsible for axon guidance, neurite growth, neuron migration, angiogenesis, in haplotype with common variants | [577] |
| 1p35.3 | OPRD1 | Delta-opioid receptor: small cerebral volume, implicated with APP processing | [541, 636-638] |
| 3q28 | OSTN | Osteocrin: primate-specific regulator of synapse formation, restricting activity-dependent dendritic growth, related to transcription factor MEF2 in the SASP (Section 1.4.) | [19, 541, 639] |
| 1q42.12 | PARP1 | Poly(ADP-ribose) polymerase 1: neuron proliferation, hippocampal volume, hippocampal neurodegeneration in APOE epsilon3 carriers | [541, 609] |
| 11q14.2 | PICALM | Phosphatidylinositol binding clathrin assembly protein: membrane recycling, autophagy, endosomal vesicle cycling, trafficking of synaptic vesicle proteins | [7, 540, 541, 542, 546, 557, 561, 606, 607, 640] |
| 19q13.2 | PLD3 | Enzyme phospholipase D: catalysis of membrane phospholipids, influence to processing of APP | [19, 540, 542, 557, 558, 568] |
| 7q31.32 | POT1 | Protection of telomeres protein 1: hyper-phosphorylated tau, inflammatory response IL-6, ventricular dilation, cognitive decline | [541, 575] |
| 2p14 | PPP3R1 | Protein phosphatase 3 regulatory subunit B alpha: calcineurin gene, implicated in cytokine release, TLR4 signalling, related to tauopathy | [567, 607, 641, 642] |
| 8p21.2 | PTK2B | Protein tyrosine kinase 2 beta: related to MAPK signalling, ionotropic receptors, neuron migration, synaptic function, LTP in hippocampal CA1 neurons, implicated in tauopathy | [542, 543, 557, 569, 605, 606, 632] |
| 4q12 | REST | RE1-silencing transcription factor: non-autonomous Wnt signalling, neuroprotection against OS and Abeta, autophagy, longevity | [541, 643] |
| Locus | Gene | Function | References |
| 17q25.1 | RHBDF2 | Rhomboid 5 homolog 2: intramembrane serine protease, related to EGF receptor signalling, age-of-onset | [569] |
| 19q13.33 | RPL13A | 60S ribosomal protein L13a: protein synthesis, close to BAX and IRF3 loci, component of the IFNgamma-activated inhibitor of translation (GAIT) complex, repression of inflammatory genes | [569] |
| 14q32.12 | SCL24A4 | Solute carrier family 24 member 4: Na+/Ca++ exchanger, involved in neural development, hypertension | [542, 557, 605, 606] |
| 14q32.13 | SERPINA3 | Alpha-1 antichymotrypsin: pro-inflammatory protein, related to amyloid plaques | [545] |
| 17p13.1 | SERPINF1 | Pigment epithelium-derived factor: serpin F1 gene, neurotrophic functions, related to hypoxic stress, increases gamma-secretase activity, apoptotic signaling through p38 MAPK pathway | [569] |
| 17p13.3 | SERPINF2 | Alpha 2-antiplasmin: serine protease inhibitor, involved in protein degradation, anti-inflammatory | [569] |
| 2q36.2 | SLC19A3 | Solute carrier family 19 member A3: biotin-thiamine transporter, related to HIF1A, hypoxic stress | [577] |
| 14q24.2 | SLC8A3 | Solute carrier family 8 member A3: Na+/Ca++ exchanger, based in intracellular organelle membranes, related to oligodendrocyte maturation, myelination, involved in memory and sensory pathways | [577, 644] |
| 15q22.31 | SNX1 | Sorting nexin 1: regulating the cell-surface expression of EGF receptor, lysosome formation, autophagy | [546, 645] |
| 6q21 | SNX3 | Sorting nexin 3: involved in intracellular trafficking, regulating phagocytosis, interacting with cargo-selective retromer complex, involved in APP processing | [546, 645] |
| 11q24.1 | SORL1 | Sortilin related receptor 1: neuronal LDL receptor, VPS10 receptor, endosomal vesicle cycling, vesicle trafficking, APP pathology | [1, 542, 546, 548-551, 605, 606, 646] |
| 11p15.2 | SPON1 | Spondin 1: related to reelin signalling, involved in axon guidance, neural cell adhesion and neurite extension, formation of anatomical connectivity, involved in Abeta cleavage | [541, 647, 648] |
| 5p15.33 | TERT | Telomerase reverse transcriptase: serving as template for the telomere repeat, chromosome repair, age-of-onset | [203, 649, 650] |
| 19q13.32 | TOMM40 | Translocase of outer mitochondrial membrane 40: outer mitochondrial membrane protein, protein import, mitochondrial dysfunction | [541, 555] |
| 8q22.1 | TP53INP1 | Tumor protein p53 inducible nuclear protein 1: autophagy, caspase signalling | [628] |
| 6p21.1 | TREM2 | Triggering receptor expressed on myeloid cells 2: microglial cytokine signalling, related to TYRO protein, autophagy, Abeta clearance, neuroinflammation, interacting with IL4 and TYROBP | [540-542, 557, 560, 571, 606, 651] |
| 15q22.31 | TRIP4 | Thyroid hormone receptor interactor 4: containing tetrameric nuclear activating signal co-integrator 1 (ASC-1) complex, associating with transcriptional coactivators, related to intrinsic histone acetyltransferase activity | [557, 650] |
| 2p22.3 | TTC27 | Tetratricopeptide repeat domain 27: scaffolding protein-protein interactions, related to myelin formation, white-matter integrity | [652] |
| 19q13.12 | TYROBP | TYRO protein tyrosine kinase binding protein: transmembrane signalling polypeptide, tyrosine-based immunoreceptor, related to cerebral myelination, neuroinflammation, interacting with CD33, MS4A4A, MS4A6A, TREM2, IL4 | [540, 542, 571, 651] |
| Locus | Gene | Function | References |
| 8p12 | WRN | Werner syndrome RecQ like helicase: DEAH family of DNA and RNA helicases, involved in DNA metabolism, transcription, replication, recombination, repair, age-of onset |
[577] |
| 7q22.1 | ZCWPW1 | Zinc finger CW-type and PWWP domain containing 1: early embryonic development, regulating chromatin methylation, regulating epigenetic modification | [8, 542, 557, 605, 606, 611] |
| 6q14.3 | ZNF292 | Zinc finger protein 292: transcription factor, binding GH promoter, steroid receptor, posttranscriptional modifications, brain atrophy, neurodegeneration |
[640] |
| 19q13.42 | ZNF628 | Zinc finger protein 628: transcription regulator | [541, 653] |
| 4q31.21-q31.22 | ZNF827 | Zinc finger protein 827: transcription regulator, related to tauopathy, haplotype block with NANP and NINL | [630] |
Note: Tabulated are gene loci from GWAS, WES, case-control studies, and pathway analysis studies.