Classical population genetics shows that varying permutations of genes and risk factors permit or disallow the effects of causative agents, depending on circumstance. For example, genes and environment determine whether a fox kills black or white rabbits on snow or black ash covered islands. Risk promoting effects are different on each island, but obscured by meta-analysis or GWAS data from both islands, unless partitioned by different contributory factors. In Alzheimer's disease, the foxes appear to be herpes, borrelia or chlamydial infection, hypercholesterolemia, hyperhomocysteinaemia, diabetes, cerebral hypoperfusion, oestrogen depletion, or vitamin A deficiency, all of which promote beta-amyloid deposition in animal models—without the aid of gene variants. All relate to risk factors and subsets of susceptibility genes, which condition their effects. All are less prevalent in convents, where nuns appear less susceptible to the ravages of ageing. Antagonism of the antimicrobial properties of beta-amyloid by Abeta autoantibodies in the ageing population, likely generated by antibodies raised to beta-amyloid/pathogen protein homologues, may play a role in this scenario. These agents are treatable by diet and drugs, vitamin supplementation, pathogen detection and elimination, and autoantibody removal, although again, the beneficial effects of individual treatments may be tempered by genes and environment.
If there is one factor common to complex polygenic diseases it is the heterogeneity in both gene and risk factor association studies.
Although these have discovered key genes and risk factors, the results for most are invariably confounded by conflicting data [
Viruses and other pathogens have been implicated as risk factors in many diseases, although again, conflicting evidence leads to scepticism in many areas. For example, the involvement of the Epstein-Barr virus in multiple sclerosis is hotly contested [
Gene-gene and gene-environment interactions may play an important role in such inconsistency. For example, the risk promoting effects of genes can be better explained when using pathway analysis or combining the effects of genes with common function, rather than by studying single genes in isolation [
Complex diseases are also composed of many endophenotypes or underlying pathologies, and different genes or risk factors may contribute to any of these. Many different processes contribute to cell death in Alzheimer’s disease, for example, beta amyloid, glutamate, calcium, or free radical mediated toxicity [
A summary of the KEGG pathway analysis of Alzheimer’s disease susceptibility genes. The number of genes in each pathway is shown in brackets (see
Immune system and pathogen defence | Pathogen entry pathways | Structural and DNA repair |
---|---|---|
Cytokine-cytokine receptor interaction (13) | Chagas disease (17) | Regulation of actin cytoskeleton (8) |
Hematopoietic cell lineage (11) | Hepatitis C (13) | Endocytosis (8) |
Complement and coagulation cascades (11) | Malaria (12) | Protein processing in endoplasmic reticulum (8) |
Natural killer cell-mediated cytotoxicity (10) | Amoebiasis (11) | Nucleotide excision repair (4) |
Chemokine signaling pathway (9) | Microbial metabolism in diverse environments (10) | Spliceosome (4) |
Phagosome (9) | Leishmaniasis (9) | DNA replication (3) |
Lysosome (8) | Viral myocarditis (6) | Homologous recombination (3) |
T cell receptor signaling pathway (8) | Staphylococcus aureus infection (6) | RNA transport (2) |
Toll-like receptor signaling pathway (8) | Bacterial invasion of epithelial cells (4) | Mismatch repair (2) |
NOD-like receptor signaling pathway—(7) | Pathogenic Escherichia coli infection (3) | Base excision repair (2) |
Systemic lupus erythematosus (7) | Epithelial cell signaling in Helicobacter pylori infection (2) | |
B cell receptor signaling pathway (6) | Shigellosis (2) | Apoptosis (10) |
Graft-versus-host disease (6) | Drug metabolism cytochrome P450 (6) | |
Cytosolic DNA-sensing pathway (5) | Oxidative phosphorylation (14) | Glutathione metabolism (5) |
Antigen processing and presentation (5) | Arginine and proline metabolism (7) | Metabolism of xenobiotics by cytochrome P450 (5) |
Intestinal immune network for IgA production (5) | Glycolysis/gluconeogenesis (5) | Peroxisome (3) |
Type I diabetes mellitus (5) | Valine, leucine, and isoleucine degradation (4) | Drug metabolism—other enzymes (2) |
Salivary secretion (5) | One carbon pool by folate (3) | |
Adipocytokine signaling pathway (5) | Terpenoid backbone biosynthesis (3) | MAPK signalling (35) |
Fc epsilon RI signaling pathway (4) | Pyruvate metabolism (3) | Calcium signaling pathway (13) |
Allograft rejection (4) | Citrate cycle (TCA cycle) (3) | PPAR signaling pathway (12) |
TGF-beta signaling pathway (4) | Glycine, serine, and threonine metabolism (3) | Neurotrophin signaling pathway (12) |
Autoimmune thyroid disease (4) | Protein digestion and absorption (3) | Wnt signaling pathway (10) |
RIG-I-like receptor signaling pathway (4) | Tyrosine metabolism (3) | Insulin signaling pathway (9) |
Jak-STAT signaling pathway (4) | Steroid hormone biosynthesis (3) | VEGF signaling pathway (7) |
Fc gamma R-mediated phagocytosis (3) | Steroid biosynthesis (3) | Vascular smooth muscle contraction (6) |
Leukocyte transendothelial migration (3) | Glycerolipid metabolism (3) | Notch signaling pathway (5) |
Asthma (3) | Porphyrin and chlorophyll metabolism (3) | ABC transporters (5) |
Primary immunodeficiency (2) | Histidine metabolism (2) | Renin-angiotensin system (4) |
Sphingolipid metabolism (2) | Cardiac muscle contraction (4) | |
Cysteine and methionine metabolism (2) | mTOR signaling pathway (3) | |
Purine metabolism (2) | ErbB signaling pathway (3) | |
Tryptophan metabolism (2) | Aldosterone-regulated sodium reabsorption (3) | |
Lysine degradation (2) | Progesterone-mediated oocyte maturation (3) | |
Primary bile acid biosynthesis (2) | GnRH signaling pathway (2) | |
Hedgehog signaling pathway (2) |
In genetic association studies, the drive has been to increase statistical power by increasing the numbers of subjects enrolled. This has resulted in the discovery of important genes and rare genetic variants, but has not delivered genes that confer a high degree of risk in the majority of patients. However, as illustrated below, more could perhaps be gained by a reanalysis of existing data in relation to other genetic and risk factor variables that could result in elucidation of the causes rather than the risks.
Alzheimer’s disease susceptibility genes and risk factors are stocked in an online database at
The overall results of this analysis are shown in Table
These were identified by literature survey and the most directly relevant are shown in Table
The relationships of Alzheimer’s disease susceptibility genes with vitamin A. NF = none found.
Gene | Name | Relationships with vitamin A |
---|---|---|
ALB | Albumin | Together with retinol binding protein forms the retinol transporter [ |
APOE | Apolipoprotein E | Expression regulated by LXR/RXR dimers [ |
TTR | Transthyretin (prealbumin, amyloidosis type I) | Carrier protein for the retinol binding protein [ |
APOA1 | Apolipoprotein A-I | RORA target [ |
HSPG2 | Perlecan: (heparan sulfate proteoglycan 2) | Binds to transthyretin [ |
A2M | Alpha-2-macroglobulin | Synthesis decreased in vitamin-A- deficient rats [ |
ABCA1 | ATP-binding cassette, subfamily A (ABC1), member 1 | 22R-hydroxycholesterol and 9-cis-retinoic acid induce ABCA1 expression and cholesterol efflux in brain cells and decrease Beta-amyloid secretion [ |
CLU | Clusterin (APOJ) LRP2 ligand | The clusterin promoter contains a RARE sequence: Expression is suppressed by all-trans-retinoic acid [ |
LRP2 | Low density lipoprotein-related protein 2 (clusterin receptor) | Mediates the endocytosis of retinol via binding to retinol binding proteins and transthyretin [ |
LRPAP1 | Low density lipoprotein receptor-related protein associated protein 1 | Regulates the uptake of retinol by LRP2 [ |
ALDH2 | Aldehyde dehydrogenase 2 family (mitochondrial) | Exhibits low NAD(+)-dependent retinaldehyde activity [ |
CYP46A1 | Cytochrome P450, family 46, subfamily A, polypeptide 1 | Synthesises 24-S hydroxycholesterol, a ligand for RARA and RARG [ |
GSTM1 | Glutathione S-transferase M1 | Weakly catalyses the enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid [ |
GSTP1 | Glutathione S-transferase pi | Catalyses the enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid [ |
LIPA | Lipase A, lysosomal acid, cholesterol esterase (Wolman disease) | Metabolises carotenoid mono- and diesters providing a source of free carotenoids in the gut [ |
LPL | Lipoprotein lipase | Metabolises retinyl esters [ |
LRAT | Lecithin retinol acyltransferase (phosphatidylcholine—retinol O-acyltransferase) | Lecithin retinol acyltransferase (phosphatidylcholine—retinol O-acyltransferase) |
MEF2A | Myocyte enhancer factor 2A | Regulates beta-carotene 15,15′-monooxygenase 1 which cleaves beta-carotene to all-trans retinal and is the key enzyme in the intestinal metabolism of carotenes to vitamin A [ |
CHD4 | Chromodomain helicase DNA binding protein 4 | Binds to RORG [ |
ESR1 | Estrogen receptor 1 | Dimerises with RAR and RXRA [ |
KLF5 | Kruppel-like factor 5 (intestinal) | Binds to RARA [ |
NPAS2 | Neuronal PAS domain protein 2 | RAR alpha and RXR alpha bind to CLOCK and NPAS2 [ |
NR1H2 | Nuclear receptor subfamily 1, group H, member 2: liver X receptor beta | LXRs form obligate heterodimers with retinoid X receptors RARA, RXRA, RXRB, RXRG (Entrez gene) |
PARP1 | Poly (ADP-ribose) polymerase family, member 1 | Interacts with RARB [ |
PIN1 | Protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1 | RARalpha directly interacts with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARalpha [ |
POU2F1 | POU class 2 homeobox 1 | Binds to RXR [ |
PPARA | Peroxisome proliferator-activated receptor alpha | Dimerises with RXRA and RXRG receptors [ |
PPARG | Peroxisome proliferator-activated receptor gamma | Dimerises with RXRA receptors [ |
RXRA | Retinoid X receptor, alpha | Retinoic acid receptor |
THRA | Thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian) | Dimerises with RXRA [ |
UBQLN1 | Ubiquilin 1 | Binds to retinoic acid receptor alpha [ |
VDR | Vitamin D (1,25-dihydroxyvitamin D3) receptor | Heterodimerises with RXR and RARG [ |
APP | Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | A gamma 57 gamma secretase cleavage product suppresses retinoid signalling [ |
BACE1 | Beta-site APP-cleaving enzyme 1 | Regulated by all-trans-retinoic acid [ |
NCSTN | Nicastrin | Blocks the effects of retinoic acid on neurogenesis [ |
PSEN1 | Presenilin 1 (Alzheimer disease 3) | Regulated by and regulates the effects of retinoic acid on neuronal differentiation [ |
PSEN2 | Presenilin 2 (Alzheimer disease 4) | Activated by all-trans-retinoic acid in osteoblasts [ |
CDK5 | Cyclin-dependent kinase 5 | Activated by retinoic acid [ |
GSK3B | Glycogen synthase kinase 3 beta | SH-SY5Y cells differentiate to neuron-like cells when treated with Retinoic acid/BDNF leading to increases in tau and tau phosphorylation, mediated primarily by GSK3B [ |
MAPT | Microtubule-associated protein tau | Phosphorylation of tau at the 12E8 (Ser-262/Ser-356) epitope decreased in retinoic acid treated cells: increased at Ser-195/Ser-198/Ser-199/Ser-202) and (Ser-396/Ser-404) [ |
CARD8 | Caspase recruitment domain family, member 8 | NF |
CD14 | CD14 molecule | Expression regulated by retinoids [ |
CD86 | CD86 molecule | Expression modulated by and the viral DNA minic polyriboinosinic:polyribocytidylic acid [ |
CST3 | Cystatin C | NF antimicrobial peptide [ |
DEFB122 | Defensin, beta 122: Antimicrobial peptide | NF |
EIF2AK2 | Eukaryotic translation initiation factor 2-alpha kinase 2: (PKR activated by viral DNA) | Upregulated by retinoic acid in HL-60 leukemia cells [ |
GBP2 | Guanylate binding protein 2, interferon inducible | NF |
MEFV | Mediterranean fever | NF |
MPO | Myeloperoxidase | Antimicrobial peptide [ |
PIN1 | peptidylprolyl cis/trans isomerase, NIMA-interacting 1 | Binds to and negatively regulates IRF3 [ |
TF | Transferrin | Antimicrobial peptide [ |
TRAF2 | TNF receptor-associated factor 2 | Infection with RNA viruses activates the cytoplasmic retinoic acid-inducible gene-I (RIG-I) pathway which activates transcription factor IRF-3 which in turn induces many antiviral genes. It also induces apoptosis via TRAF2 [ |
TLR4 | Toll-like receptor 4 | Expression suppressed by retinoic acid [ |
PVRL2 | Poliovirus receptor-related 2 (herpesvirus entry mediator B) | NF: herpes simplex receptor |
ZBP1 | Z-DNA binding protein 1: DNA-dependent activator of interferon regulatory factors | NF |
ABCA1 | Retinol transporter (see above) | |
ABCG1 | ATP-binding cassette, subfamily G (WHITE), member 1 | Expression regulated by 9-cis retinoic acid and 22-hydroxycholesterol [ |
APOA5 | Apolipoprotein A-V | Regulated by RORA [ |
APOC2 | Apolipoprotein C-II | Expression regulated by 9-cis-retinoic acid [ |
APOC3 | Apolipoprotein C-III | RORA target [ |
APOC4 | Apolipoprotein C-IV | Expression regulated by RXR ligands [ |
APOD | Apolipoprotein D | Expression regulated by RARA [ |
CETP | Cholesteryl ester transfer protein, plasma | Expression induced by 9-cis retinoic acid (RXR agonist) [ |
FDPS | Farnesyl diphosphate synthase (farnesyl pyrophosphate synthetase, dimethylallyltranstransferase, geranyltranstransferase) | Activated by the LXR/retinoid X receptor dimer [ |
LPA | Lipoprotein, Lp(a) | Isotretinoin reduces LPA serum levels [ |
LDLR | Low-density lipoprotein receptor (familial hypercholesterolemia) | NF |
LRP1 | Low-density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor) | NF |
LRP2 | See above (retinol receptor) | |
LRP6 | Low-density lipoprotein receptor-related protein 6 | Expression induced by retinoic acid [ |
LRP8 | Low-density lipoprotein receptor-related protein 8, apolipoprotein e receptor | NF |
NPC1 | Niemann-Pick disease, type C1 | NF |
NPC2 | Niemann-Pick disease, type C2 | NF |
OLR1 | Oxidized low-density lipoprotein (lectin-like) receptor 1 | NF |
RFTN1 | Raftlin, lipid raft linker 1 | NF |
SOAT1 | sterol O-acyltransferase 1: cholesterol acyltransferase | NF |
SREBF1 | Sterol regulatory element binding transcription factor 1 | Liver X receptor/RXR target [ |
VLDLR | Very-low-density lipoprotein receptor | All-trans retinoic acid increases expression in adenocarcinoma cells [ |
AGER | Advanced glycosylation end product-specific receptor | Expression upregulated by retinol and vitamin A [ |
ALOX5 | Arachidonate 5-lipoxygenase | RORA target [ |
CCL2 | Chemokine (C-C motif) ligand 2 | All-trans-retinoic acid suppresses bacterial lipopolysaccharide-induced expression and release in astrocytes [ |
CCL3 | Chemokine (C-C motif) ligand 3 | See CCL2 above |
CCR2 | Chemokine (C-C motif) receptor 2 | Expression regulated by 9-cis-Retinoic acid [ |
IL10 | Interleukin 10 | All trans-retinoic acid increases IL10 production in monocytes and macrophages [ |
IL18 | Interleukin 18 (interferon-gamma-inducing factor) | Differentiation of SH-SY5Y neuroblastoma cells by all-trans retinoic acid activates IL18 [ |
IL1A | Interleukin 1, alpha | Retinoic acid decreases expression in thymic epithelial cells [ |
IL1B | Interleukin 1, beta | Intraperitoneal retinoic acid reduces IL-1 |
IL33 | Interleukin 33 | NF |
IL6 | Interleukin 6 (interferon, beta 2) | Retinoic acid increases expression in thymic epithelial cells [ |
IL8 | Interleukin 8 | Retinoid administration decreases polymorphonuclear neutrophilic leukocyte accumulation in mammary alveoli activated by lipopolysaccharide, and decreases IL-8 serum levels [ |
IL1RN | interleukin 1 receptor antagonist | Retinoic acid enhances IL-1 beta and inhibited IL-1ra production in 4beta phorbol 12beta-myristate-13alpha acetate - and lipopolysaccharide-activated human alveolar macrophages [ |
PTGS2 | Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | Suppressed by RARB [ |
TGFB1 | Transforming growth factor, beta 1 | Repressed by RXRA.PPARG dimers [ |
TNF | Tumor necrosis factor (TNF superfamily, member 2) | LPS from bacterial pathogens activates Retinoic inducible gene RIG-I which plays a key role in the expression of TNF-alpha in macrophages in response to LPS stimulation [ |
FAS | Fas (TNF receptor superfamily, member 6) | Retinoic acid increases the expression of FAS in adipocytes: all-trans retinoid acid reduces FAS expression in HELA cells |
C4A | Complement component 4A (Rodgers blood group) | Complement C4 levels correlate with those of retinol in plasma [ |
C4B | Complement component 4B (Chido blood group) | See above |
CFH | Complement factor H | Expression controlled by RAR beta [ |
CLU | Clusterin | See above |
CR1 | Complement component (3b/4b) receptor 1 (Knops blood group) | NF |
CRP | C-reactive protein, pentraxin related | Serum CRP levels negatively correlate with vitamin A levels [ |
CD33 | CD33 molecule | NF |
CD36 | CD36 molecule (thrombospondin receptor) | RORA target [ |
HLA-A | Major histocompatibility complex, class I, A | Upregulated by differentiation of teratoma cells into neuronal cells by retinoic acid [ |
HLA-A2 | Major histocompatibility complex, class I, A2 | Upregulated by interferon alpha-2b and retinoic acid combined treatment in cervical cancer cells [ |
MICA | MHC class I polypeptide-related sequence A | Expression upregulated by retinoic acid in hepatic carcinoma cells [ |
AR | Androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease) | |
ESR1 | See above | |
ESR2 | Estrogen receptor 2 (ER beta) | 9-cis retinoic acid stimulates expression in breast cancer cells [ |
CYP19A1 | Cytochrome P450, family 19, subfamily A, polypeptide 1: aromatase: estrogen synthase | Activated by RORA [ |
HSD11B1 | Hydroxysteroid (11-beta) dehydrogenase 1 | NF |
BDNF | Brain-derived neurotrophic factor | Expression regulated by RARalpha/beta and vitamin A [ |
CSK | C-src tyrosine kinase | CSK negatively regulates RAR functions in relation to neurite differentiation [ |
FGF1 | Fibroblast growth factor 1 (acidic) | Protects fibroblasts from apoptosis induced by retinoid CD437 [ |
GAB2 | GRB2-associated binding protein 2 | Gab2 silencing results in hypersensitivity to retinoic acid -induced apoptosis in neuronal cells [ |
IGF1 | Insulin-like growth factor 1 (somatomedin C) | Pulmonary expression reduced in RORalpha knockout mice [ |
NTRK1 | Neurotrophic tyrosine kinase, receptor, type 1 | Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin-A-deprived rats, partly by upregulating NTRK1 (TrkA) [ |
NTRK2 | Neurotrophic tyrosine kinase, receptor, type 2 | All-trans retinoic acid reduces BDNF and TrkB gene expression in SH-SY5Y cells [ |
VEGFA | vascular endothelial growth factor A | Expression regulated by retinoid acid [ |
Other signalling | ||
DKK1 | Dickkopf homolog 1 (Xenopus laevis) | Expression regulated by retinoic acid in stem cells [ |
DPYSL2 | Dihydropyrimidinase-like 2 | Upregulated in cortex and hippocampus by Vitamin A depletion [ |
BLMH | Bleomycin hydrolase | Hydrolyses homocysteine thiolactone [ |
CBS | Cystathionine-beta-synthase | Converts homocysteine to cystathionine suppressed by all-trans-retinoic acid [ |
MSRA | methionine sulfoxide reductase A | Regulated by retinoic acid via two promoters including RARA [ |
MTHFD1L | Methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like | NF |
MTHFR | 5,10-methylenetetrahydrofolate reductase (NADPH) | Methylenetetrahydrofolate reductase activity is suppressed in retinol-fed rats [ |
MTR | 5-methyltetrahydrofolate-homocysteine methyltransferase | In rats, a retinol-rich diet enhances the folate-dependent oxidation to CO2 of formate and histidine. The activity of hepatic methylenetetrahydrofolate reductase, which regulates liver folate metabolism, is suppressed, leading to decreased 5-methyltetrahydrofolate synthesis [ |
MTRR | 5-methyltetrahydrofolate-homocysteine methyltransferase reductase | NF |
PON1 | Paraoxonase 1 | Hydrolyses homocysteine thiolactone [ |
COX1 | Mitochondrially encoded cytochrome c oxidase I | 9-cis retinoic acid treatment increases mitochondrial DNA transcription, including ND1, ND6, and COX1 [ |
COX2 | Mitochondrially encoded cytochrome c oxidase II | Expression increased by all-trans retinoic acid [ |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase | Retinoic acid target [ |
GSTM3 | Glutathione S-transferase M3 (brain) | Contains a retinoid X receptor-binding site [ |
HBG2 | Hemoglobin, gamma G | Vitamin A increases haemoglobin concentrations in children [ |
HFE | hemochromatosis | Neuroblastoma cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid [ |
HMOX1 | Heme oxygenase (decycling) 1 | The increase in the expression of heme oxygenase-1 and the growth arrest and DNA damage-inducible transcription factor 153 caused by reactive oxygen species is blocked by aRARalpha-specific antagonist AGN194301 in retinal epithelial cells [ |
ND1 | NADH dehydrogenase subunit 1 | 9-cis retinoic acid treatment increases mitochondrial DNA transcription, including ND1, ND6, and COX1 [ |
ND4 | NADH dehydrogenase subunit 4 | Upregulated by all-trans retinoic acid in neutrophils [ |
ND6 | NADH dehydrogenase subunit 6 | 9-cis retinoic acid treatment increases mitochondrial DNA transcription, including ND1, ND6, and COX1 [ |
NFE2L2 | Nuclear factor (erythroid-derived 2)-like 2 | Inhibited by retinoic acid via RARalpha resulting in lack of expression of Nrf2 target genes [ |
NOS1 | Nitric oxide synthase 1 (neuronal) | Expression regulated by retinoic acid [ |
NOS2 | Nitric oxide synthase 2, inducible | Ditto |
NOS3 | Nitric oxide synthase 3 (endothelial cell) | Ditto |
NQO1 | NAD(P)H dehydrogenase, quinone 1 | Retinoic acid (RA) and 12-O-tetradecanoylphorbol acetats are able to induce Nrf2 and its target gene NAD(P)H quinone oxidoreductase 1 in the SH-SY5Y neuroblastomacell line [ |
SOD2 | Superoxide dismutase 2, mitochondrial | All-trans-retinoic acid induces manganese superoxide dismutase in a human neuroblastoma cell line [ |
PCK1 | Phosphoenolpyruvate carboxykinase 1 (soluble) | Three RXR-binding elements (retinoic acid response element (RARE)1/PCK1, RARE2, and RARE3/PCK2) are located in the promoter of Pck1 [ |
PON2 | Paraoxonase 2 | NF |
PON3 | Paraoxonase 3 | NF |
TFAM | Transcription factor A, mitochondrial | Levels are increased by vitamin A [ |
DNAJC28 | DnaJ (Hsp40) homolog, subfamily C, member 28 | NF |
HSPA1B | Heat shock 70 kDa protein 1B | NF |
HSPA5 | Heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa) | Endoplasmic reticulum stress is increased in hepatocarcinoma cells by all-trans retinoic acid, characterised by increased expression of HSPA5 (grp78), GADD153, and XBP1[ |
ADRB1 | Adrenergic, beta-1-, receptor | RARA target [ |
ADRB2 | Adrenergic, beta-2-, receptor, surface | Expression regulated by all-trans retinoic acid [ |
COMT | Catechol-O-methyltransferase | Expression stimulated by all-trans retinoic acid [ |
PNMT | Phenylethanolamine N-methyltransferase | Retinoic acid differentiates embryonic carcinoma cells into neuronal cells, 70% of which stain for tyrosine hydroxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase [ |
CHAT | Choline acetyltransferase | Expression controlled by retinoic acid [ |
CHRNA3 | Cholinergic receptor, nicotinic, alpha 3 | Expression increased by retinoid acid [ |
CHRNA4 | Cholinergic receptor, nicotinic, alpha 4 | Expression decreased by retinoic acid [ |
CHRNB2 | Cholinergic receptor, nicotinic, beta 2 (neuronal) | Expression increased by retinoid acid [ |
GRN | Granulin | All-trans retinoic acid increases expression in myeloid cells [ |
ACAN | Aggrecan | Expression modulated by 13-cis retinoic acid in fibroblasts [ |
ICAM1 | Intercellular adhesion molecule 1 (CD54), human rhinovirus receptor | All-trans retinoic acid downregulates ICAM1 expression in bone marrow stromal cells [ |
COL11A1 | Collagen, type XI, alpha 1 | Expression controlled by all-trans-retinoic acid [ |
DSC1 | Desmocollin 1 | Retinoic acid decreases expression in oral keratinocytes [ |
LMNA | Lamin A/C (nuclear) | Promoter contains a retinoic acid-responsive element (L-RARE) [ |
UBD | Ubiquitin D | All-trans retinoic acid activated the ubiquitin/proteasome pathway in human acute myeloid leukemia cell lines [ |
UBE2I | Ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast) | See above |
XRCC1 | X-ray repair complementing defective repair in Chinese hamster cells 1 | N-[4-hydroxyphenyl] retinamide induces apoptosis in bladder cancer cell line and downregulates XRCC1 [ |
CDC2 | Cell division cycle 2, G1 to S, and G2 to M | Activated by retinoic acid [ |
ACAD8 | Acyl-coenzyme A dehydrogenase family, member 8 | Catalyzes the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. The encoded protein is a mitochondrial enzyme that functions in catabolism of the branched-chain amino acid valine. |
ALDH18A1 | Aldehyde dehydrogenase 18 family, member A1 | NF the encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. |
ARSA | Arylsulfatase A: hydrolyzes cerebroside sulfate to cerebroside and sulphate | Increased urinary excretion of both arylsulfatases A and B is increased in cases of severe vitamin A deficiency coupled with malnutrition [ |
ELAVL4 | ELAV (embryonic lethal, abnormal vision, drosophila)-like 4 (Hu antigen D) | Inhibition reduces retinoic acid-induced neuronal differentiation of mouse embryonal carcinoma P19 cells [ |
SGPL1 | Sphingosine-1-phosphate lyase 1 | Treatment of F9 embryonal carcinoma cells with retinoic acid induces differentiation to primitive endoderm (PrE). This effect is attenuated by SGPL1 knockout [ |
CELF2 | CUGBP, Elav-like family member 2 | Splicing regulated by retinoic acid [ |
CUBN | Cubilin (intrinsic factor-cobalamin receptor) | Expression regulated by all-trans-retinoic acid [ |
F13A1 | Coagulation factor XIII, A1 polypeptide | Vitamin A reduces factor XIII levels in rats fed an atherogenic diet [ |
HHEX | Hematopoietically expressed homeobox | All-trans retinoic acid enhances expression in normal and tumorous mammary tissue [ |
NEDD9 | Neural precursor cell expressed, developmentally downregulated 9 | Downstream target of all-trans retinoic acid and its receptors in the human SH-SY5Y neuroblastoma cell line [ |
RELN | Reelin | Retinoic acid-induced differentiation of NT2 cells to hNT neurons increases reelin expression [ |
RNR1 | RNA, ribosomal 1 | NF |
RPS3A | Ribosomal protein S3A | Downregulated by retinoid-induced differentiation of HL-60 cells [ |
RUNX1 | Runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) | RUNX1 knockdown inhibits retinoid-induced differentiation of HL-60 myeloid leukaemia cells [ |
SEPT3 | Septin 3 | Expressed in SH-SY5Y, after retinoic acid-induced differentiation [ |
SNCA | Synuclein, alpha (non-A4 component of amyloid precursor) | Vitamin A, beta-carotene and coenzyme Q10 inhibit the formation of synuclein fibrils [ |
SYN3 | Synapsin III | Synapsins including SYN3 are upregulated by retinoic acid-induced differentiation of NTera-2cl.D1 cells [ |
TARDBP | TAR DNA binding protein | NF |
VCP | Valosin-containing protein | Retinoic acid receptor responder (RARRES1) regulates VCP expression in human prostatic epithelial cells [ |
This is an adaptation of Lees’s classical population genetics example of the peppered moth, whose dark or pale colouring confers advantage or disadvantage depending upon the degree of industrial pollution that covers trees with soot. It has served to illustrate the concept of natural selection where, over time, dark genes become more common in polluted areas, an effect that could eventually lead to speciation [
On two islands one covered in snow and the other in black volcanic ash live an equal number of black and white rabbits and a family of foxes, who will find it easier to trap the black rabbits on the snowy island and the white rabbits on the island covered in black ash. Gene association studies would correctly identify the black and white genes as being protective or risk promoting depending upon the environment. The snow, the ash, or the fox, being equally present on each island, regardless of the toll of dead rabbits, could not be considered as risk factors. Genetic meta-analysis or pooled GWAS data would also rule out any genetic involvement, leaving no susceptibility genes, no risk factors, and no cause. However, a GWAS study, apportioning the genetic data in relation to ash, snow, and fox would be able to correctly surmise that the white gene is a risk factor on the ash-covered island, and the black gene a risk factor on the snowy island, as would have D. R. Lees. Again the fox is undetectable, being present in all compartments.
On other similar islands, live further populations of black and white rabbits with no fox, an equal number of deaths due to old age, and no reason to investigate either genes or risk factors. However, it is only by including this island, again partitioning GWAS data in relation to all variables, that the genes, the risk factors, and the cause can be correctly allotted their respective roles.
In this example, the genes and environmental variable are risk or protective factors for the cause as well as for the deaths, depending on circumstance. The genes or risk factors are not killing the rabbits, but are allowing the cause to do so. Nonstratified association studies would thus seem to be ill-suited to find important genes, risk factors, or causes, and the pursuit of greater statistical power may well be futile, although such strategies can find rare variants that may cause disease in a minority of patients, which is evidently useful. However, for the majority of cases, much could perhaps be gained from a reappraisal of existing data and by partitioning GWAS data in relation to the many known risk factors in each disease.
The situation is evidently more complex in polygenic diseases, where hundreds of interacting genes, many risk factors, and probably many causes are present. This is already appreciated, and several groups have analysed the statistical problems involved due to the mass of genes and risk factors [
From the above, it would appear that a cause can be present in equal proportion in control and disease populations but should be able to produce the pathological features of the disease, and the disease incidence should be reduced where the causes are few. A cause can kill regardless of the genes (black or white) or risk factors (snow or volcanic ash) but its effects are tempered by a combination of the two (fox + snow + black gene or fox + ash + white gene = death and fox + snow + white gene or fox + ash + black gene, or no fox and any combination = life). The genes and risk factors are, however, both able to influence the cause.
In relation to Alzheimer’s disease, beta-amyloid deposition can be produced by herpes simplex [
The risk factors in Alzheimer’s disease include herpes simplex infection [
The genes implicated in Alzheimer’s disease are related to the herpes simplex life cycle [
The genes, risk factors and agents known to increase beta-amyloid deposition all concur, suggesting that Alzheimer’s disease is multifactorial with many foxes, each with their respective genes and risk factors, any of which can lead to beta-amyloid deposition in multifarious ways. Each risk factor can act independently of any gene or other risk factor variant, in animal models—as with the fox. This in turn might suggest that it is not the risk promoting polymorphisms in the Alzheimer’s disease patients that are crucial, as the risk factors can in any case promote beta-amyloid deposition, but the equivalent polymorphisms in the control group, that are providing protection; a subtle distinction that awaits characterisation of the functional effects of many different gene variants. The reasoning also suggests that beta-amyloid deposition is the consequence and not the cause of the many factors able to promote Alzheimer’s disease. Anoxia, ischaemia, hypoglycaemia, hypercholesterolaemia, and vitamin A deficiency are all able to kill neurones, in some cases including cholinergic neurones, without the aid of beta amyloid.
In relation to Alzheimer’s disease, there is an island where longevity is increased, related to the nun study [
There are few strategies that have been shown to reduce the severity of Alzheimer’s disease, once established. It has, however, been shown that
A number of epidemiological studies have shown that the incidence of Alzheimer’s disease can be reduced, although, once the disease is established, there is little evidence for any curative effects of any treatment other than the above. These protective factors are in most cases the obverse of the risk factors and include diets rich in fish or polyunsaturated fatty acids [
Four major genes have been discovered prior to and from GWAS studies, APOE4, clusterin, complement receptor 1, and PICALM [
An environmental risk factor-gene interactome in Alzheimer’s disease. Risk factors diminished in Alzheimer’s disease (vitamin A deficiency, NGF levels, immune competence, and glutathione depletion) are shown in blue and those increased in red. Solid lines indicate a positive, and dashed or dotted lines a negative effect of risk factor X on risk factor Y. All risk factors feed into increased beta-amyloid deposition. A selection of susceptibility genes relevant to each process is shown (see Table
Hypercholesterolaemia can evidently be related to other dietary risk factors such as saturated fat consumption, and to atherosclerosis. Docosahexaenoic acid increases total plasma cholesterol levels in hymans, but only in APOE4 carriers, an effect that may negate the cardioprotective effects of fish oil supplementation [
In both coronary artery disease and carotid artery atherosclerosis, high plasma levels of homocysteine are positively correlated with
The growth of C. Neoformans is attenuated by diethylstilbestrol and oestradiol but not by progesterone or testosterone [
These complex interactions, of which there are likely many more, suggest that in addition to epistasis and gene-environment interactions, environment-environment interactions have to be factored in to an already complex equation (cf. vitamin E).
Factors known to reactivate herpes simplex include heat [
Fevers induced by diverse infections might thus be expected to reactivate herpes simplex, as well as cerebral hypoperfusion. IL6 plasma and CSF levels have been reported to be increased in Alzheimer’s disease and the secretion of IL6 from monocytes is increased [
As so many other risk factors seem able to reactivate the virus, this may be a key precipitant for the final curtain. Herpes simplex viral DNA is present in Alzheimer’s disease plaques [
Low vitamin A levels are a problem in the ageing population, and even in successfully ageing persons can be observed in 50% of the population over the age of 80–85 [
The vitamin A derivative, retinoic acid, inhibits herpes simplex replication [
Vitamin A levels are in fact higher in hypercholesterolemia patients [
A large number of Alzheimer’s disease genes are related to vitamin A (Table
Beta-amyloid is a potent antimicrobial peptide. Although not tested against
As shown in Table
Viral, bacterial, and fungal protein homology with beta-amyloid; beta-amyloid segments were compared with Borrelia Burgdorferi, C. Neoformans, C. Pneumoniae, H. Pylori, P. Gingivalis, and herpes viruses (HSV1, HHV6, and cytomegalovirus) proteomes by BLAST analysis. The B cell and T cell antigenicity indices are shown, and those above the server set threshold of 0.35 (B cell epitope) or 0.5 (T cell epitope) are highlighted in bold. The first column shows the amino acid sequence of beta-amyloid1-42 and the alignments with pathogen proteins are shown. Spaces represent nonidentical amino acids and + signs amino acids with similar physicochemical properties. Only highly antigenic regions of pentapeptides or more were processed. The VGGVV sequence, antibodies to which label beta-amyloid in brain tissue, despite relatively low antigenicity, has already been reported to be identical to proteins expressed by 69 viruses including HSV-1, HSV-2, and HHV6 [
B cell | T cell | Alignments | |
---|---|---|---|
D | 0.04 | +AE HDSG+ C. Neoformans DAE F H+SG EV Borrelia burgdorferi DAEF H. Pylori DA FRH H. Pylori +AE RH HSV-1 D FR DS HHV-6 +AEFR P. Gingivalis DA EFRHD and +AEFR +SG C. Pneumoniae | |
A | AEFR D GY+V C. Neoformans AEF D S YE H. pylori AE+RH+ H. pylori AEF H+ Borrelia burgdorferi AEFR HD Cytomegalovirus AE R SG HSV-1 AE+ HD HHV-6 A+F H+S and AEFR P. Gingivalis AEF DSG C. Pneumoniae | ||
E | 0.02 | EFRHD H. Pylori EF DSG HHV-6 EFR DS Borrelia Burgdorferi EF R DS YE C. Neoformans E R DSGY V P. Gingivalis EF SGYEV C. Pneumoniae | |
F | FRHDS C. Neoformans +RH SGY++ Borrelia burgdorferi F HD EV H. Pylori F H+SG H. Pylori FR SGY Cytomegalovirus +RHDS P. Gingivalis F H+SGY C. Pneumonia | ||
R | 0.05 | R D GYEV C. Neoformans R SGYE H. pylori RHDS Y V H. pylori RH+ GY Borrelia burgdorferi RHDSG Cytomegalovirus RHD YE cytomegalovirus RH SG HSV-1 RHDS HHV-6 R+DS Y+ P. Gingivalis | |
H | 0.14 | HDSGY C. Neoformans HD G EV H. pylori +DSGY H. pylori H+SG Y+V Borrelia burgdorferi H+SG HSV-1 HDSG P. Gingivalis ++SGY+V C. Pneumoniae | |
D | 0.03 | DSGY+V C. Neoformans +SG+EV H. pylori DSGY HSV-1 DSG+EV P. Gingivalis DSGY V C. Pneumoniae | |
S | 0.02 | SGYEV P. Gingivalis SGYE H. pylori SGY++ C. Neoformans SG+EV C. Pneumoniae | |
G | 0.04 | GYEVH H. pylori GYE V KL+ Borrelia Burgdorferi GYE LV and GY++ + LV C. Neoformans GYEV P. Gingivalis GYEV and GY HH C. Pneumoniae | |
Y | YE HH and YE+ HQ and Y++H Q and YE HHQ H. pylori YEVH Cytomegalovirus YE+ KL Borrelia Burgdorferi YE + QK FC. Neoformans Y++H H+K P. Gingivalis Y+V +Q LV C. Pneumoniae | ||
E | 0.02 | EV +QK H. pylori EV HQ L Cytomegalovirus EV +KL Borrelia Burgdorferi EV Q LV C. Neoformans EV KLV P. Gingivalis EV QKLV C. Pneumoniae | |
V | 0.35 | .+H QK H. pylori V HQ LV Cytomegalovirus VH QK+V HHV-6 VH KL Borrelia Burgdorferi +HH LV C. Neoformans VH + LV P. Gingivalis V HQKL C. Pneumoniae | |
H | −0.17 | 0.10 | HHQK H. pylori and C. Pneumoniae HH KL Cytomegalovirus HH KL P. Gingivalis |
H | −0.66 | 0.11 | HQKL+ Borreli Burgdorferi HQKL C. Pneumoniae and HSV-1 +QKLV P. Gingivalis |
Q | −1.03 | 0.03 | QKLV C. Neoformans and P. Gingivalisand C. Pneumoniae |
K | −1.47 | KLVFF H. pylori: Cryptococcus neoformans Borrelia Burgdorferi Chlamydophila pneumoniae KLVF Human herpesvirus 1 | |
L | −1.34 | LVFF Human herpesvirus 5: Human herpesvirus 6 | |
V | −1.20 | ||
F | −0.93 | ||
F | −0.98 | ||
A | −0.82 | 0.05 | |
E | −0.31 | 0.05 | |
D | 0.23 | 0.11 | |
VGSNK Borrelia burgdorferi Cryptococcus neoformans Porphyromonas gingivalis +GSNK Cytomegalovirus VGSN Helicobacter pylori Chlamydophila pneumoniae | |||
0.03 | GSNK Helicobacter Pylori Chlamydophila pneumoniae | ||
0.03 | |||
0.03 | |||
0.30 | |||
G | 0.30 | 0.10 | |
A | −0.24 | 0.05 | |
I | −0.58 | 0.07 | |
I | −1.00 | 0.13 | |
G | −1.14 | 0.03 | |
L | −1.19 | ||
M | −1.23 | 0.13 | |
V | −1.16 | 0.23 | VGGVV 69 viruses/phages |
G | −0.97 | 0.03 | |
G | −1.02 | 0.03 | |
V | −0.63 | 0.23 | |
V | −0.45 | 0.33 | |
I | −0.80 | ||
A | −1.06 |
Several other autoantibodies have been reported in Alzheimer’s disease, including targets such as nerve growth factor [
The classical population genetics example of the foxes and rabbits illustrates how genes and risk factors can differentially permit or disallow the effects of a causative agent, depending on a permutation of circumstance. Applying this model to Alzheimer’s disease also suggests that many of the environmental risk factors in Alzheimer’s disease are in fact causative agents, at least in terms of an ability to produce beta-amyloid deposition,
Many of these risk factors are avoidable or amenable to therapy. Diet is already known to be an important risk/protective factor with regard to the incidence of Alzheimer’s disease. For example there is clear evidence that the omega-3 fatty acid docosahexaenoic acid (DHA), a component of fish and the Mediterranean diet, also protective factors [
Given the fact that the potential causes of Alzheimer’s disease appear to be multifactorial, perhaps a multifactorial therapeutic effort is also needed. Such approaches might include a greater attention to diet, homocysteine and cholesterol levels, vitamin A supplementation where necessary, and the regular detection and elimination of herpes simplex,