Table 1
A quick reference guide for select AD susceptibility factors.
Name Major functions Expression Disease associations Innate immune reactivity and inflammatory response NLRP1 A sensor of intracellular PAMPs and DAMPs; the sensor component of the NLRP1 inflammasome; triggers inflammation in response to microbial products, particulates, crystals (e.g., cholesterol and urate crystals), silica, asbestos, Aβ, prions, mutant SOD1, etc. Broad; abundant in immune and epithelial cells AD, chronic peripheral inflammatory and autoimmune disorders TLR4 A major sensor of extracellular PAMPs and DAMPs; triggers inflammation upon recognition of various ligands, including LPS, viruses, bacteria, oxLDLs, saturated fatty acids, heat shock proteins, Aβ, fibronectin, fetuin-A, and β-defensins Predominantly in cells of myeloid origins AD, macular degeneration, Crohn’s disease, ulcerative colitis, tonsillitis, infections CD33 A receptor for sialic-acid SAMPs (self-associated molecular patterns); functions in cell-cell interactions, endocytosis; suppresses activation of immune cells when engaged with cognate SAMPs Predominantly in innate immune cells AD TREM2 A cell-surface receptor; involved in initiation and suppression of inflammatory responses in innate immune cells; functions in phagocytosis Broad; augmented in brain, lung, and adipose tissues AD, COPD, GI injury, infections, Nasu-Hakola disease CR1 A cell surface immune adherence receptor (complement system); phagocytosis of cells, debris, and pathogens opsonized by complement factors, e.g., C1q, C3b, and C4b Erythrocytes, monocytes, leucocytes, neutrophils, but not in brain cells AD, chronic peripheral inflammatory and autoimmune disorders, infections INPP5D A phosphatidylinositol phosphatase; involved in signaling of cell surface receptors; regulates multiple functions in immune cells, including chemotaxis, activation, homeostasis, and phagocytosis High in immune cells, bone marrow, lymphoid tissues AD RIN3 A Ras effector and Rab5-directed guanine nucleotide exchange factor; cell signaling; endocytosis, migration, synaptic functions, immune responses Broad; abundant in mast cells AD, Paget’s disease PICALM Phosphatidylinositol-binding clathrin assembly protein; endocytosis Broad AD, acute leukemias Cell-cell and cell-matrix adhesions and communications DSG2 Desmosomal cadherin, an integral component of intercellular junctions; mediates functional cell-cell adhesions; links plaque proteins and cytoskeleton; regulates EMT and barrier functions High in epithelial cells, cardiomyocytes, cancer AD, arrhythmogenic right ventricular dysplasia, cancer ANK-1 Ankyrins link membrane proteins and adhesion molecules to cytoskeleton; involved in integrating cells into tissues and regulation of cell motility, activation, proliferation, and EMT RBCs, bone marrow, lymphoid tissue, brain AD, spherocytosis, hereditary hemolytic anemia NEDD9 A scaffold of the Cas protein family with functions in cell adhesions, cell attachment, migration, and invasion; regulates EMT; metastatic marker in multiple cancers Broad AD, cancer, hemochromatosis CASS4 A scaffold of the Cas family of proteins; functions in cell attachment, migration, and motility via regulation of focal adhesion kinases in focal adhesions Abundant in lungs, spleen, and leucocytes AD, atopic asthma, cystic fibrosis, lung cancer CD2AP A scaffolding molecule that mediate attachment of cell surface receptors to the cytoskeleton; functions in the formation of adherens junctions and EMT; involved in maintaining integrity and permeability of barriers, including BBB, via control of adherens junctions Broad; low in brain; high in kidneys, endothelial and epithelial cells AD, renal disease FERMT2 A member of the fermitin family of focal adhesion proteins; involved in integrin activation, integrin signaling, and cell adhesion; functions in adherens junctions and plays a role in wound healing, tissue repair, angiogenesis; overexpressed in cancers where it promotes EMT and invasion Broad; high in endothelial cells AD, cancer EPHA1 A member of the cell surface ephrin receptor family that mediate contact-dependent bidirectional cell-cell communications. Eph receptors are involved in shaping tissues during development and injury, and support functions and homeostasis of mature tissues; upregulated at sites of injury and inflammation; involved in the control of endothelial, blood-brain, and intestinal barrier permeability, EMT, neural development, plasticity, and regeneration; overexpressed in carcinomas Broad AD, cancer, chronic inflammatory disorders APP A cell surface receptor with functions in axonal guidance, neuronal adhesions, and synaptogenesis; regulates neurite outgrowth through binding to ECM components (heparin and collagens); signals to nucleus via conserved YAP and TAZ transcription factors that control EMT Moderate in the brain, low in GI and other epithelia AD, cancer ADAM10 A broad specificity membrane metalloprotease that cleaves and sheds extracellular domains of transmembrane proteins; a key α-protease in APP processing; regulates cell-cell adhesions, migration, communications; may function in EMT; substrates: Notch, APP, N-/E-cadherins, Klotho, VEGF, TNF-α and IL6 receptors, ephrins, and many other molecules Broad, widely in most immune cells AD, breast cancer Presenilin-1 A key component of the γ-secretase complex that catalyzes intramembrane cleavage of integral membrane proteins; involved in regulation of cell adhesions, fate, migration, neurite outgrowth, synaptogenesis; substrates: Notch, APP, DSG2, N-/E-cadherins, SORL1, LRP1, Klotho, HLA; VEGF, IL1 and IL6 receptors, ephrins, insulin receptor, and many other molecules Broad, high in cerebral cortex, thyroid gland, respiratory and GI systems AD, FTD, Pick’s disease, cardiomyopathy, cancer Cell metabolism and detoxification MTHFR, MTR, MTRR, CBS Enzymes of folate-dependent one-carbon metabolism (OCM), a central hub of the basic cellular metabolism; OCM supports a large variety of metabolic pathways and reactions utilized in biosynthesis of proteins, lipids, nucleic acids, and neurotransmitters. OCM is essential for tissue and cell repair, cell proliferation, DNA repair, detoxification, and antioxidant defenses MTHFR, MTR, MTRR- broad; CBS - predominantly in liver, hepatocytes, and CNS AD, and neurological, psychiatric metabolic, cardiovascular, immune and hematological disorders; homocystinuria, cancer ApoE A multifunctional apolipoprotein with a best-known role in lipid metabolism, and trafficking and redistribution of lipids and cholesterol within and between cells and tissues, particularly in the brain; functions as a stress factor (chaperon/scavenger) secreted upon injury; Aβ chaperon High in the brain, liver, adrenals, low to moderate elsewhere AD, FTD, Pick’s disease, TBI, atherosclerosis, coronary heart disease, infections ApoJ A member of the small heat shock protein family; a generic stress factor (chaperon/scavenger); upregulated and secreted upon cell stress/injury; functions in lipid metabolism/transport, cell adhesion, apoptosis; ApoJ and ApoE are primary chaperons in Aβ clearance from the brain Broad AD, HD, atherosclerosis, cancer, cardiovascular and metabolic disorders ABCA7 An ATP-binding cassette transporter; functions in lipid transport and homeostasis (predominantly in immune cells), and macrophage-mediated phagocytosis High in leukocytes, bone marrow, thymus, spleen AD SORL1 A multifunctional endocytic, transport, and sorting receptor; mediates uptake of lipoproteins and proteases; involved in APP trafficking and sorting High in the brain, low to moderate elsewhere AD, vascular disease COMT Methylase; targets reactive catechol compounds for degradation and clearance;substrates: epinephrine, norepinephrine, catechol-estrogens, drugs, other compounds Broad AD, impaired cognition, behavioral and psychiatric disorders MAO-A Monoamine oxidase; oxidative deamination of monoamines; substrates: serotonin, melatonin, dopamine, epinephrine, norepinephrine, other compounds Broad AD, neurological and psychiatric disorders For details, references, abbreviations, and additional risk factors, see Appendix, Figure 2, and discussion in the text.