Table 1.
New genes linked to Alzheimer’s disease and their physiological and pathological roles.
| Gene/Location | Physiological Role * | Molecular Mechanisms Implicated in AD | Ref. |
|---|---|---|---|
| ADAM10 (15q21.3) | It is the most important α-secretase in the brain and contributes to the non-amyloidogenic pathway of APP metabolism. | Alteration in APP metabolism (through non-amyloidogenic pathway), synaptic plasticity, and hippocampal neurogenesis. | [33,34,35] |
| ABCA7 (19p13.3) |
Modulates lipid metabolism, phagocytosis, apoptosis, and phagocytic of Aβ by microglia. | Alteration in Aβ processing and regulation of APP by β-secretase. | [64,65,66] |
| BIN1 (2q14.3) |
Participates in immune response, calcium homeostasis, apoptosis, endocytosis of synaptic vesicles, and plasma membrane dynamic. | Contributes to Amyloid (through β-secretase activity) and Tau pathology and is related to inflammation, apoptosis, and calcium homeostasis. | [67,68,69] |
| CD2AP (6p12.3) |
Regulates actin cytoskeleton and membrane trafficking through endocytosis and cytokinesis. | Associated with increased Aβ production, Tau neurotoxicity, abnormal modulation of the neurite structure, and altered integrity of the BBB. | [52,70,71] |
| EPHA1 (7q34) |
Plays a role in synaptic development and plasticity, modulating cell migration, angiogenesis, cell proliferation, and apoptosis. | Alterations in immune response and endocytosis, as well as disruption of BBB integrity. | [29,72] |
| PICALM (11q14.2) |
Modulates autophagy, membrane metabolism, internalization of cell receptors, synaptic transmission, removal of apoptotic cells, and endocytic pathways for APP processing. | Dysfunction of Aβ metabolism and APP processing. Possible association with tauopathy, synaptic dysfunction, and altered lipid metabolism. | [36,37,38,73,74] |
| SORL1 (11q24.1) |
Plays a role in endocytosis. | Restricts delivery of precursors to endocytic compartments that promote amyloidogenic clearance. | [75,76] |
| MS4A6A (11q12.2) |
Regulates Ca2+ entry and signal transduction of several proteins. | Its variants affect the processing of the TREM2 microglial receptor increasing the risk of AD. | [71,77] |
| CR1 (1q32.2) |
Facilitates the capture and clearance of complement-opsonized pathogens by erythrocytes, monocytes, macrophages, and microglia. | Decreases complement-mediated clearance of Aβ42. Metabolism and clearance of Aβ and its interaction with APOE-4 are related to cognitive impairment and the appearance of LOAD. | [78,79,80] |
| CLU (8p21.1) |
Participates in lipid metabolism, cell proliferation, apoptosis, immune response, and neuronal differentiation. | Alteration in Aβ aggregation, lipid metabolism, regulation of cell cycle and neuronal apoptosis, and neuroinflammation. | [40,41,81] |
| CD33 (19q13.3) |
Involved in the inhibition of immune cell function and cytokine production. | Modulates microglial activation (neuroinflammation) and Aβ clearance through microglial cells. | [49,50,82] |
| TREM2 (6p21.1) |
This microglia receptor regulates proliferation, survival, phagocytosis, and inflammation. | Related to microglial dysfunctions, stress of the endoplasmic reticulum, Tau and amyloid pathology, and neuroinflammation. | [83,84,85] |
| TOMM40 (19q13.32) |
Plays a role in the stabilization of the mitochondrial membrane respiratory chain (Complex I). | Dysfunction of the mitochondrial membrane and subsequent oxidative stress. | [86,87,88] |
| MAPT (17q21.21) |
Related to the assembly and stability of microtubules and neuronal polarity. | Encoding for the Tau protein that is involved in the microtubule disassembly during AD. | [89,90] |
| FERMT2 (14q22.1) |
Participates in cell differentiation, biogenesis, and connection between extracellular matrix adhesion sites and the actin cytoskeleton. | Associated with increasing levels of mature APP at the cell surface, resulting in increased Aβ-peptide production. | [91,92] |
| CASS4 (20q13.31) |
Associated with cell adhesion, cell spreading, calcium signaling, and microtubule stabilization. | Involved in the formation of neuritic plaques and NFT, neuroinflammation, and dysfunction in synapsis, calcium signaling, and microtubule stabilization. | [93,94] |
| PTK2B (8p21.2) |
Involved in the regulation of calcium flux, LTP, neurite growth, synapsis, and angiogenesis. | Contributes to hypoperfusion, vascular permeability, and Tau toxicity. | [93,94,95] |
| INPP5D (2q37.1) |
Participates in the regulation of microglia gene expression. | Involved in microglia with deficient phagocytic capacity, resulting in increased Aβ deposition. | [96,97] |
| SLC10A2 (13q33.1) |
Has an important role in encoding the sodium/bile acid cotransporter, as well as in cholesterol metabolism. | Associated with LOAD by dysfunctional cholesterol metabolism, neuronal death, memory impairment, and increased Aβ generation. | [58,59] |
| COBL (7p12.1) |
Regulates actin cytoskeleton reorganization and neuron morphogenesis and increases the branching of axons and dendrites. | Reduction in the number of dendritic branch points and neurites. | [59] |
| UNC5C (4q22.3) |
Favors apoptosis and directs axon extension and cell migration during neural development. | Contributes to neuronal death, Tau pathology, and Aβ-associated pathways. | [98,99] |
| PLD3 (19q13.2) |
Hydrolysis of membrane phospholipids, which influences the processing of APP. | Promotes the generation of amyloid plaques and cognitive decline. | [100,101] |
| SLC24A4/RIN3 (14q32.12) | Plays a role in calcium transport and lipid and glucose metabolism. | Associated with Aβ loading and Tau pathology. | [102] |
| HLA-DRB5/DRB1 (6p21.32) |
Encodes proteins for MHC and plays an important role in the immune response, including antigen processing and presentation, and self-recognition by immune cells. | It is associated with the presence of capillary β-amyloid and the development of cerebral Amyloid angiopathy. It also induces microglial activation. | [103,104] |
| DSG2 (18ql2.1) |
Encodes adhesion molecule proteins to promote contact between epithelial cells and other cells. | Mediates APOE-associated Aβ aggregation in neurons. | [105] |
| MTHFR (1p36.3) | The regulatory connection between the folate and methionine cycles. | Associated with high levels of homocysteine and subsequent vascular damage and neuroinflammation. | [63,106] |
| CST3 (20p11.21) | Promotes neurogenesis, reduces Aβ deposition, and inhibits fibril formation. | Involved with amyloid angiopathy and cell death induced by oligomeric and fibrillar Aβ. | [107,108,109] |
| BCHE (3q26.1) | Contributes to acetylcholine inactivation and hydrolysis of neurotoxic organophosphate esters. | Related to NFT and neuritic plaque formation. | [16,110,111] |
| CTSD (11p15.5) | Favors the activation/degradation of polypeptide hormones and growth factors. | Implicated in the processing of APP/Aβ deposition and autophagy dysfunction. | [112,113] |
| ZCWPW1 (7q22.1) | Regulation of the DNA metabolic process. Additionally, it is involved in epigenetic modulation. | Suppresses insulin resistance. It may activate the PI3K signaling pathway in neurons. | [60] |
| MEF2C (5q14.3) | Involved in vascular development, neurogenesis, inflammatory processes, and hippocampal-dependent learning and memory. | Promotes neuroinflammation, cell apoptosis, Aβ aggregates, synaptic plasticity dysfunction, and increases the oxidative stress level. | [114,115,116] |
| ABI3 (17q21.32) | Regulates actin cytoskeleton organization, cytokinesis, migration, endocytosis, and phagocytosis. | Associated with alterations in microglial migration and phagocytosis, Aβ accumulation, and neuroinflammation. | [117,118] |
| PLCG2 (16q24.1) | Regulates divergent microglial functions through TREM2 signaling and is involved in the transition to a microglial state. | Correlation with amyloid plaque density, expression levels of microglial marker genes, and neuroinflammation. | [119,120,121,122] |
| SCIMP (17p13.2) | Regulates MHC-II signaling in B cells and the host’s innate immune responses to danger signals. | Associated with alteration in TLR-mediated microglial phagocytosis via MHC II. | [123] |
| SHARPIN (8q24.3) | Induces NF-kB activation and regulation of inflammation, and cell death. Furthermore, it regulates angiogenesis and NLRP3 activation. | Associated with neuroinflammation, and defective Aβ clearance that leads to pathogenic Aβ accumulation. | [124,125,126,127,128] |
| MINK1 (17p13.2) | Controls glutamate receptor signaling, synaptic density, dendrite complexity, actin cytoskeleton reorganization, cell-matrix adhesion, cell–cell adhesion, and cell migration. | It is related to glutamatergic synapse impairment, dysfunction of axon regeneration, neuronal degeneration, neuroinflammation, and increased ROS levels. | [129,130,131] |
| APH1B (15q22.2) | Serves as a scaffold for the assembly of γ-secretase complex; therefore, it cleaves APP. It also favors excitatory synaptic transmission and plasticity. | Decreases excitatory synapsis and promotes Aβ aggregation and spine formation. | [132,133,134] |
| HS3ST1 (4p15.33) | Modulates stem cell differentiation and neuronal targeting. | Promotes Tau spreading mediated by Tau binding to the cell surface heparan sulfate. | [135,136] |
| ECHDC3 (10p14) | Involved in fatty acid biosynthesis in mitochondria and insulin sensitivity. | Alterations in lipid and cholesterol metabolism, such as cognitive functions. | [137,138] |
| ACE (17q23.3) | Regulates blood pressure, electrolyte homeostasis, synaptic plasticity, and Aβ metabolism. | Associated with cognitive decline, oxidative stress, neuroinflammation, and higher levels of Aβ and Tau load. | [139,140,141] |
| PILRA (7q22.1) | Involved in immune system regulation and plays a key role in the life cycle of HSV-1. | Correlation between AD and HSV-1. In addition, it is related to a decrease in the inhibition of microglial activation. | [54,55] |
| SPI1 (11p11.2) | Regulates the immune response and learning-related neuronal activity in the cerebral cortex. | Alters the microglial phenotype and transcriptome, involving interferon pathways. | [47,48] |
| IGF1 (12q23.2) | Inhibits abnormal Tau phosphorylation and Aβ deposition. Stimulates neurogenesis and prevents apoptosis in the hippocampus. | Associated with Tau and Aβ pathology. | [142,143] |
| INSR (19p13.2) |
The insulin-INSR signaling pathway regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids, and proteins. | Can activate GSK-3β by initiating the PI3K-AKT signaling pathway and lead to Aβ accumulation and Tau phosphorylation. | [57] |
| LKB1 (19p13.3) | Plays a role in cell metabolism, cell polarity, apoptosis, and the response to DNA damage by regulating AMPK activity. | Autophagy dysfunction, Aβ accumulation, and Tau phosphorylation. | [57] |
Abbreviations: ABCA7: ATP-binding cassette subfamily A member 7; ABI3: ABI gene family member 3; ACE: Angiotensin-converting enzyme; ADAM10: Disintegrin and metalloproteinase domain-containing protein 10; AMPK: AMP-activated protein kinase; APH1B: Gamma-secretase subunit APH-1B; APOE-4: Apolipoprotein E allele 4; APP: Amyloid beta precursor protein; Aβ: Amyloid beta peptide; BBB: Blood–brain barrier; BCHE: Butyrylcholinesterase; BIN1: Bridging integrator 1; Ca2+: Calcium; CASS4: Cas scaffolding protein family member 4; CD2AP: CD2-associated protein; CD33: Myeloid cell surface antigen CD33; CLU: Clustered mitochondria protein homolog; COBL: Protein cordon-bleu; CR1: Complement receptor type 1; CST3: Cystatin-C; CTSD: Cathepsin D; DSG2: Desmoglein-2; ECHDC3: Enoyl-CoA hydratase domain-containing protein 3, mitochondrial; EPHA1: Ephrin type-A receptor 1; FERMT2: Fermitin family homolog 2; GSK-3β: glycogen synthase kinase 3; HLA-DRB5: HLA class II histocompatibility antigen, DR beta 5 chain; HS3ST1: Heparan sulphate glucosamine 3-O-sulfotransferase 1; HSV-1: Herpes simplex virus type 1; IGF1: Insulin-like growth factor 1; INPP5D: Inositol polyphosphate-5-phosphatase D; INSR: Insulin receptor; LKB1: Liver kinase B1 LOAD: Late-onset Alzheimer’s disease; LTP: Long-term potentiation; MAPT: Microtubule-associated protein tau; MEF2C: Myocyte-specific enhancer factor 2C; MHC II: MHC Class II; MHC: Major histocompatibility complex; MINK1: Misshapen-like kinase 1; MS4A6A: Membrane-spanning 4-domains, subfamily A, member 6A; MTHFR: Methylenetetrahydrofolate reductase; NF-kB: Nuclear factor kappa-light-chain enhancer of activated B cells; NFTs: Neurofibrillary tangles; NLRP3: NLR family pyrin domain containing 3; PICALM: Phosphatidylinositol-binding clathrin assembly protein; PI3K: Phosphoinositide 3-kinase; PILRA: Paired immunoglobulin-like type 2 receptor alpha; PLCG2: Phospholipase C gamma 2; PLD3: Phospholipase D family member 3; PTK2B: Protein-tyrosine kinase 2-beta; ROS: Reactive oxygen species; SCIMP: SLP adapter and CSK-interacting membrane protein; SHARPIN: SHANK-associated RH domain interactor; SLC10A2: Solute carrier family 10 member 2; SLC24A4: Solute carrier family 24 (sodium/potassium/calcium exchanger) member 4; SORL1: Sortilin-related receptor 1; SPI1: Transcription factor PU.1; TLR: Toll-like receptor; TOMM40: Translocase of outer mitochondrial membrane 40; TREM2: Triggering receptor expressed on myeloid cells 2; UNC5C: Netrin receptor UNC5C; ZCWPW1: zinc finger CW-type PWWP domain protein 1. * Data source: UniProt.org (accessed on 20 December 2022).