This directory lists genes that have been studied in relation to their role in Alzheimer's disease. The directory provides links to the gene information in the On-line Mendalian Inheritance in Man (OMIM) database. To add entries or comments to this directory, please notify us using the Comments Form

Subcategories

• Familial Alzheimer Disease Genes
• Alzheimer Disease Susceptibility Genes
• APP, APP Processing, Related Proteins
• Amyloidoses
• Apoptosis and Related Proteins
• Cytoskeletal and Related Proteins
• Developmentally Expressed Genes
• Diagnostic Marker Candidates
• Immune System/Glia
• Metabolism
• Mitochondrial Genes
• Neuritic Plaque Components
• Neurotransmission
• Neurotrophic Factors
• Related Disorders
• Signal Transduction

Familial Alzheimer Disease Genes

• ALZHEIMER DISEASE; AD. [OMIM 104300]
  AD is a progressive dementing illness. Clinically a diagnosis of exclusion, it is characterized histopathologically by the presence of amyloid plaques and neurofibrillary tangles.
• AMYLOID BETA A4 PRECURSOR PROTEIN (APP). Gene Map Locus: 21q21.3-q22.05. [OMIM 104760]
  7 mutations on the APP gene have been linked to the development of AD, representing <<1% of AD cases. Age of onset is ranges from 45 to 65 years, and is hypothesized to be caused by increased beta amyloid deposition and/or increased alpha-secretase activity.
• ALZHEIMER DISEASE, FAMILIAL, TYPE 3 (AD3), PRESENILIN-1 (PS1), S182. Gene Map Locus: 14q24.3 [OMIM 104311]
  Numerous mutations throughout PS1 lead to Alzheimer's disease (~8% of AD cases, with age of onset of 28-50 years)-- increasing beta-amyloid elaboration, perturbing calcium regulation and perhaps contributing to g protein-mediated apoptosis.
• ALZHEIMER DISEASE, FAMILIAL, TYPE 4 (AD4), presenilin-2 (PS2), STM2. Gene Map Locus: 1q31-q42 [OMIM 600759]
  A very small percentage (~1%) of familial cases are caused by this chromosome 1 homolog of PS1, working probably through a similar mechanism. Age of onset is 40-55 years. See also Drosophila Presenilin homologue and C. elegans homologue sel 12.
• See also Drosophila Presenilin homologue and C. elegans homologue sel 12.

Alzheimer Disease Susceptibility Genes

• ALZHEIMER DISEASE-2 (AD2). Gene Map Locus: 19cen-q13.2 [OMIM104310]
• APOLIPOPROTEIN E; (ApoE). Gene Map Locus: 19q13.2. [OMIM 107741]
  ApoE allele variations increase susceptibility to late-onset AD phenotype (age of onset 60-85 years), with low penetrance but high incidence. The mechanism may be linkedto vascular damage and/or increased beta amyloid deposition.
• COMPLEX I (mtDNA) [OMIM 516001]
  Mutations in Complex I mtDNA are associated with a subset of late-onset AD cases, and apparently lead to increased reactive oxygen species in the brain.
• MITOCHONDRIAL DNA POLYMORPHISMS [OMIM 502500]
  AD patients have higher numbers of DNA polymorphisms, which are maternally- inherited and account for up to 20% of late-onset AD cases.

APP, APP Processing, Related Proteins

• ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTOR (AGER). RECEPTOR FOR ADVANCED GLYACATION END PRODUCTS (RAGE). Gene Map Locus: 6p21.3. [OMIM 600214]
  This "receptor" may bind the a-beta peptide and serve as a stimulus for the inflammatory response in amyloid plaques.
• ALPHA-CHYMOTRYPSIN; see CHYMOTRPYSINOGEN B (CTRB). Gene map locus: 16q23.2-q23.3. [OMIM 118890]
  Alpha-chymotrypsin, an acute phase protease, may contribute to the inflammatory response in plaques--it seems to preferentially exist in neuritic-type plaques.
• AMYLOID BETA A4 PRECURSOR PROTEIN (APP), Gene Map Locus: 21q21.3-q22.05. [OMIM 104760]
• NON-A-BETA COMPONENT OF ALZHEIMER DISEASE AMYLOID, PRECURSOR OF (NACP) [OMIM 163890]
  A part of the larger protein, various moieities of the b-APP are bioactive--its biological role (neurite growth? Injury amelioration?) has yet to be elucidated.
• AMYLOID BETA A4 PRECURSOR PROTEIN-LIKE (APPL1), Gene Map Locus: 9q31-qter [OMIM 104740]
  The first discovered homolog of b-APP, APLP1 is enriched in neurons' post-synaptic densities and may be associated with neuronal response to injury
• AMYLOID PRECURSOR-LIKE PROTEIN (APLP), Gene Map Locus: 19cen-q13.2 [OMIM 104775]
  The significance of this chromosomal region that bears homology to the b-APP gene is as yet unknown.
• AMYLOID BETA A4 PRECURSOR-LIKE PROTEIN 2 (APLP2). Gene map locus: 11q23-q25. [OMIM 104776]
  Apparently expressed in a pattern similar to b-APP in development, APLP2 is also present in some neuritic plaques in AD.
• APP-BP1 (APP BINDING PROTEIN)
  A protein that specifically interacts with the c-terminus of the b-APP (specifically, the 100 peptide region including b-AP), and may play a role in AD pathobiology.
• CATHEPSIN G (CTSG). Gene Map Locus: 14q11.2. [OMIM 116830]
  Cathepsin D has been implicated as a possible beta-secretase that produces b-AP.
• CATHEPSIN B (CTSB), APP SECRETASE. Gene Map Locus: 8p22. [OMIM 116810]
  Cathepsin B has a high carboxypeptidase activity which may implicate it in generating b- AP fragments.
• SPERM MEMBRANE PROTEIN [OMIM 182879]
• THIMET OLIGOPEPTIDASE 1 (THOP1). Tentative gene map locus 19q13.3. [OMIM 601117]
  A sperm membrane protein is a hyaluronidase; however, a guanylate cyclase protein analagous to sperm membrane g proteins might bind to b-APP.
• THIMET OLIGOPEPTIDASE 1 (THOP1). Tentative gene map locus 19q13.3. [OMIM 601117]
  Another candidate for endoproteolytic cleavage of b-APP into B-AP, THOP1 is located within the linkage region of chromosome 19 that is associated with late-onset AD.

Amyloidoses

• AMYLOIDOSIS VI, HEREDITARY CEREBRAL HEMORRHAGE. Gene Map Locus: 20p11. [OMIM 105150]
  In this disease, usually termed "of Dutch type", a mutation in the b-APP gene is associated with copious deposits of the protein, compromise in cerebrovascular integrity, and massive hemorrhage.
• CYSTATIN 1; HEREDITARY CYSTATIN-C AMYLOID ANGIOPATHY. Gene map locus: 20q13.3 [OMIM 123855]
  A mainly Icelandic variation of amyloid angiopathy in which copious amounts of cystatin C is present in the involved blood vessels.
• GELSOLIN (GSN). Gene Map Locus: 9q34 [OMIM 137350]
  Finnish hereditary systemic amyloidosis (aka Meretoja's disease) involves the systemic deposition of gelsolin. Very different from Alzheimer's disease.
• ISLET AMYLOID POLYPEPTIDE (IAPP). Gene Map Locus: 12p12.3-p12.1. [OMIM 147940]
  A disease of the islet cells of the pancreas, the amyloidogenicity of IAPP is thought to perhaps hold clues about the pathoetiology of Alzheimer's disease.
• PRION PROTEIN (PRNP). Gene Map Locus: 20pter-p12. [OMIM 176640]
  In several disease entities, including Creutzfeldt Jakob and Gerstmann Straussler Schenker disease, the prion protein aggregates in the brain and induces spongiform encephalopathy.
• TRANSTHYRETIN (TTR). Gene Map Locus: 18q11.2-q12.1 [OMIM 176300]
  Transthyretin is thought to inhibit the aggregation of b-AP into fibrils; however, in a disease called familial amyloidotic polyneuropathy, a mutated transthyretin molecule is the amloidogenic component.

Apoptosis and Related Genes

• Also see Apoptosis/Programmed Cell Death Homepage.
• APOPTOSIS-LINKED GENE 2 (ALG2). [OMIM 601057]
  ALG2 is a calcium-binding protein that is required for some receptor-mediated apoptosis, and which is linked through homology to presenilins to the apoptosis hypothesis in AD.
• B-CELL LYMPHOMA 2 (BCL2). Gene map locus 18q21.3. [OMIM 151430]
  Bcl-2 is a protooncogene & transcription factor that increases cell survival in apoptosing paradigms; in Alzheimer's, bcl-2 levels have been shown in separate studies to stay the same or increase in neurons.
• BCL2-ASSOCIATED X PROTEIN (BAX). Gene Map Locus: 19q13.3-q13.4. [OMIM 600040]
  Bax is a "killer" transcription factor whose actions favor apoptosis in different cell systems; in AD, bax expression in increased in vulnerable neurons and neuritic plaques.
• CASPASE 1 (CASP1); INTERLEUKIN-1-BETA CONVERTASE (IL1BC); INTERLEUKIN-1-B CONVERTING ENZYME (ICE); IL1B-CONVERTASE. Gene map locus 11q22.2-q22.3. [OMIM 147678] Also see C. elegans ced-3.
  ICE is a cysteine protease that plays a critical role in apoptosis in many cell lines. Its possible role in AD is not known.
• CASPASE 3, APOPTOSIS-RELATED CYSTEINE PROTEASE (CASP3); PARP CLEAVAGE PROTEASE; APOPAIN; CPP32. Gene map locus: 4q35. [OMIM 600636]
• CASPASE 6, APOPTOSIS-RELATED CYSTEINE PROTEASE (CASP6); APOPTOTIC CYSTEINE PROTEASE MCH2. Gene map locus 4q25-q25. [OMIM 601532]
• CASPASE 7, APOPTOSIS-RELATED CYSTEINE PROTEASE (CASP7); MCH3. [OMIM 601761]
• CASPASE 8, APOPTOSIS-RELATED CYSTEINE PROTEASE (CASP8); MCH5. [OMIM 601763]
• CASPASE 10, APOPTOSIS-RELATED CYSTEINE PROTEASE (CASP10); MCH4. [OMIM 601762]

Cytoskeletal and Related Proteins

• EXTRACELLULAR REGULATED KINASE (ERK), ELK-RELATED TYROSINE KINASE, gene map locus 1p36.1 [OMIM 176946]
  ERK is a cell cycle-related protein kinase that phosphorylates tau protein so as to produce SDS PAGE gel moblility shifts similar to tau proteins from AD brains.
• GLYCOGEN SYNTHASE KINASE (GSK). [Not found in OMIM]
  GSK is a proline-dependent kinase, with normal activity in AD brain, that phosphorylates tau proteins in vitro and may be associated with NFTs.
• MARK, A NOVEL FAMILY OF PROTEIN KINASES THAT PHOSPHORYLATES TAU, MAP2 AND MAP4. [See Cell article summary or full text.]
  MARK protein kinases attach phosphate residues onto microtubule-associated proteins at those proteins' tubulin binding domains, disengaging the molecules and disrupting the microtubules.
• MICROTUBULE-ASSOCIATED PROTEIN TAU (MAPT), gene map locus 17q21 [OMIM 157140]
  Tau protein(s) are a series of alternatively spliced protein products that appear to play a role in microtubule assembly/dissembly. In AD, tau proteins are aberrantly hyperphosphorylated, functionally incompetent, and ultimately polyermize into the PHFs that are the core of neurofibrillary pathology.
• NEUROFILAMENT, HIGH MOLECULAR WEIGHT, HEAVY POLYPEPTIDE, (NFH, NEFH), gene map locus 22q12.2 [OMIM 162230]
  A component of neurofilaments, this protein is aberrantly phosphorylated in AD, especially in NFTs and surrounding neuritic plaques, but is not thought to play an important role in AD pathoetiology.
• NEUROFILAMENT, MEDIUM MOLECULAR WEIGHT (NFM, NEFM) [OMIM 162250]
  A component of neurofilaments, this protein is aberrantly phosphorylated in AD, especially in NFTs and surrounding neuritic plaques, but is not thought to play an important role in AD pathoetiology.
• NEUROFILAMENT, LOW MOLECULAR WEIGHT (NFL, NEFL NF68), gene map locus 8p21 [OMIM 162280]
  A component of neurofilaments, this protein is aberrantly phosphorylated in AD, especially in NFTs and surrounding neuritic plaques, but is not thought to play an important role in AD pathoetiology.
• PROTEIN PHOSPHATASE 2A
  Protein phosphatases 1, 2A, and 2B all appear to dephorphorylate AD hyperphosphorylated tau. Protein phosphatase 2C does not appear to be capable of this dephosphorylation. The overall enzymatic level of PP2A is lower in AD brains in comparison to controls.
  • CATALYTIC SUBUNIT, ALPHA ISOFORM (PPP2CA). Gene map locus 5q23-q31. [OMIM 176915]
  • CATALYTIC SUBUNIT, BETA ISOFORM (PPP2CB). Gene map locus 8p12-p11.2. [OMIM 176916]
  • REGULATORY SUBUNIT B-PRIME (PPP2R4). gene map locus 9q34. [OMIM 600756]
• PROTEIN PHOSPHATASE 3 (FORMERLY 2B)
  • CATALYTIC SUBUNIT, ALPHA ISOFORM (PPP3CA); CALCINEURIN A; CALCINEURIN A1; CALCINEURIN A-ALPHA. Gene map locus Chr 4. [OMIM 114105]
  • CATALYTIC SUBUNIT, BETA ISOFORM (PPP3CB); CALCINEURIN A-BETA; CALCINEURIN A2; CALCINEURIN B. Gene map locus 10q21-q22. [OMIM 114106]
• STRESS ACTIVATED PROTEIN KINASE (SAPK, ERK KINASE 1, SERK1). Gene map locus 17p11.2. [OMIM 601335]
  SAPKs are activated by stress, including cell stimulation by Il-1 and TNF. They are a component of the c-jun cascade, serving to activate other stressor kinases.

Developmentally Expressed Genes

• ALZHEIMER DISEASE, FAMILIAL, TYPE 3 (AD3), PRESENILIN-1 (PS1), S182. Gene Map Locus: 14q24.3 [OMIM 104311]
• ALZHEIMER DISEASE, FAMILIAL, TYPE 4 (AD4), presenilin-2 (PS2), STM2. Gene Map Locus: 1q31-q42 [OMIM 600759]
• DELTA-CATENIN [See Neuroreport abstract.] See also CATENIN, BETA 1 (CTNNB1). [OMIM 116806]
• GROWTH ASSOCIATED PROTEIN 43 (GAP-43). Gene map locus Chr.3 [OMIM 162060]
  GAP-43 is a growth and regeneration-associated protein that is aberrantly expressed in AD. Overall, it is down-regulated, but glia and degenerated "sprout-like" neurites are also immunoreactive for GAP-43.
• NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1 (NTRK1, trkA). Gene map locus 1q21-q22. [OMIM 191315]
  trkA is the high-affinity NGF receptor, so it is highly relevant to cholinergic neurons. In AD, trkA activity decreases dramatically in parallel with the elimination of cholinergic neurons.
• NEUROTROPHIC TYROSINE KINASE RECEPTOR, TYPE 2; TYROSINE KINASE RECEPTOR B (trkB, NTRK2). Gene map locus 9q22.1 [OMIM 600456]
  trkB is a high-affinity receptor for BDNF and neurotrophin 4/5. In AD, there is no, significantly less than trkA, trkB receptor activity in the basal forebrain.
• TYROSINE PROTEIN KINASE (trkC, NTRK3); NEUOTROPHIN-3 RECEPTOR. Gene Map Locus: 15q24-q25. [OMIM 191316]
  trkC is a high-affinity neurotrophic factor receptor that is decreased in AD basal forebrain relative to controls in a manner similar to trkB but less than trkA.
• NOTCH (DROSOPHILA) HOMOLOG 3; NOTCH3. Gene map locus 19p13.2-p13.1. [OMIM 600276]
  Notch3, is a receptor& protooncogene, with human gene on chromosome 19. Mutations on Notch3 cause a syndrome of recurrent subcortical strokes called "CADASIL".
• V-FOS FBJ MURINE OSTEOSARCOMA VIRAL ONCOGENE HOMOLOG (FOS), Gene Map Locus: 14q24.3 [OMIM 164810]
  v-fos is a viral oncogene homolog that is not known to play any role in neurodegenerative diseases. Fos protein, its analog and itself a normal transcription factor, may help play a role in inducing the apoptosis pathway, along with jun protein.

Diagnostic Marker Candidates:

• BLOOD GROUP--MN LOCUS; MN. Gene Map Locus: 4q28.2-q31.1 [OMIM 111300]
  The MN chromosome locus is on the long arm of chromosome two, and has been linked with loci for AD and for colonic polyposis. It encodes glycophorin.
• CLUSTERIN (CLU), APOLIPOPROTEIN J. Gene Map Locus: 8p21-p12. [OMIM 185430]
  Clusterin/Apo J appears to bind b-AP as ApoE does, is present in some amyloid plaques, and may be tied to the inflammatory response; however, there does not appear to be a genetic link with AD as there is with Apo E.
• CORTICOTROPIN-RELEASING HORMONE (CRH). Gene Map Locus: 8q13 [OMIM 122560]
  CRH levels are decreased in AD cerebrospinal fluid, but this is probably not specific to AD per se.
• CRYSTALLIN, ALPHA B (CRYAB). Gene Map Locus: 11q22.3-q23.1 [OMIM 123590]
  Alpha beta-crystallin is a heat-shock protein whose expression is elevated in AD, but it is difficult to know how specific this is.
• DIHYDROLIPOAMIDE S-SUCCINYLTRANSFERASE (DLST). Gene Map Locus: 14q24.3 [OMIM 126063]
  DLSTs act by decarboxylating alpha-keto acids in mitochondria. It was a candidate gene for the chromosome 14-mapping familial AD gene. Comment from John Blass
• GLUTAMINE SYNTHETASE (GLNS). Gene Map Locus: 1q31 [OMIM 138290]
  GLNS activity is a metabolic glial protein whose activities appear to be decreased in AD, possibly secondary to oxidative damage to the molecule. The specificity of this finding is unclear.
• METALLOTHIONEIN 3 (MT3), GROWTH INHIBITORY FACTOR,. Gene Map Locus: 16q13. [OMIM 139255]
  GIF activity and mRNA changes in AD are unclear, as the conflicting reports are present in the literature; hence, this protein's diagnostic powers are probably limited.
• PLATELET MEMBRANE FLUIDITY (PMF) [OMIM 173560]
  Although a somewhat controversial hypothesis, increased platelet membrane fluidity apparently is a risk factor for AD. Some techniques for detecting PMF are inconsistent with the result.
• PHOSPHORIBOSYLGLYCINAMIDE FORMYLTRANSFERASE; (PGFT). Gene Map Locus: 14q24 [OMIM 172460]
  This gene is nearby presenilin 1.
• PROTEIN S-100, BETA SUBUNIT. CALCIUM-BINDING PROTEIN. Gene Map Locus: 21q22.2-q22.3 [OMIM 176990]
  Protein S-100 is a glial-derived protein implicated in the immune inflammatory response in AD. Anit-protein S-100 antibody titers do not provide a good diagnostic criterion for AD.
• TRANSTHYRETIN (TTR). Gene Map Locus: 18q11.2-q12.1 [OMIM 176300]
  See above.
• UBIQUITIN CONJUGATING ENZYME E2L-1 (UBEL1). Gene Map Locus: 14q24.3. [OMIM 600012]
  Another protein that could have been, but is not, AD3.

Immune System/Glia

• ALPHA-1-ANTICHYMOTRYPSIN (AACT). Gene Map Locus: 14q32.1. [OMIM 107280]
  AACT appears to be in neuritic plaques but not diffuse plaques, and may play a role in recruiting inflammatory processes in AD.
• BETA-2-MICROGLOBULIN (B2M). Gene Map Locus: 15q21-q22 [OMIM 109700]
  B2M is a protein elevated in certain pathological states, including Wilson's disease. In some conditions, B2M self-associates into beta-pleated sheets and ergo becomes an amyloidogenic protein. This is not apparently pertinent to neurolopathology.
• COMPLEMENT COMPONENT 4A; C4A [OMIM 120810]
  C4A is a component of the blood-borne complement cascade. Its allelic variation has drawn some attention, and disparate papers have conflicted on its phenotype in AD vs control patients.
• CATHEPSIN G; CTSG [OMIM 116830]
  See above.
• CRYSTALLIN, ALPHA B (CRYAB). Gene Map Locus: 11q22.3-q23.1 [OMIM 123590]
  See above.
• HLA-A2. Gene Map Locus: 6p21.3 [OMIM 142800]
  Possible linkage association between HLA-A2 and AD, which could be consistent with the importance of the immune response in AD.
• PROTEIN S-100, BETA SUBUNIT. CALCIUM-BINDING PROTEIN. Gene Map Locus: 21q22.2-q22.3 [OMIM 176990]
  See above.
• TRANSFORMING GROWTH FACTOR BETA-1 (TGF BETA-1), Gene Map Locus: 19q13.1-q13.3 . [OMIM 190180]
  Glial overproduction of TGF beta-1 leads to increased amyloid deposition in APP transgenic mice, presumably through recruitment of inflammatory mechanisms.

Metabolism (see also Mitochondrial Genes)

• CYTOCHROME P450, SUBFAMILY IID; CYP2D, gene map locus 22q13.1 [OMIM 124030]
  This family is a member of enzymes that metabolize and detoxify body substances. It has been postulated that poor detoxification of pro-oxidants plays a role in the development of Parkinson's disease.
• DIHYDROLIPOAMIDE S-SUCCINYLTRANSFERASE (DLST). Gene Map Locus: 14q24.3 [OMIM 126063]
  DLSTs act by decarboxylating alpha-keto acids in mitochondria. It was a candidate gene for the chromosome 14-mapping familial AD gene. Comment from John Blass

Mitochondrial Genes

• COMPLEX I, SUBUNIT ND1; MTND1 [OMIM 516000]
  One of 7 mtND, encodes proteins involved in first stage of electron transport. In two Caucasion pedigrees with matrilineal inheritance of AD, this gene is mutated.
• COMPLEX IV, CYTOCHROME c OXIDASE
  Three different mitochondrial genes help encode complex IV CO, which is the 3d and final member of the electron transport chain and is found in the mitochondrial membrane. Specific mutations in complex I and II are associated with AD phenotype.
  • SUBUNIT I (MTCO1; COI), CYTOCHROME c OXIDASE I. [OMIM 516030]
  • SUBUNIT II (MTCO2, COII), CYTOCHROME c OXIDASE II. [OMIM 516040]
• TRANSFER RNA, MITOCHONDRIAL, LYSINE (MTTK) [OMIM 590060]
  Mutations in the mitochondrially-encoded tRNA-lysine is associated with the development of the mitochondrial neurological disease MERRF (myoclonus epilepsy with ragged red fibers).
• MITOCHONDRIAL DNA POLYMORPHISMS [OMIM 502500]
  Mutations in specific nucleotides of mt DNA have been associated with AD. These include mutations of CO1&CO2 (see above), ND2 (subunit 2 of NADH dehydrogenase- ubiquinone oxidoreductase, or complex I of the respiratory chain), and others are being actively sought.

Neuritic Plaque Components

• ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTOR (AGER). RECEPTOR FOR ADVANCED GLYACATION END PRODUCTS (RAGE). Gene Map Locus: 6p21.3. [OMIM 600214]
  See above.
• ALPHA-1-ANTICHYMOTRYPSIN (AACT). Gene Map Locus: 14q32.1. [OMIM 107280]
  See above.
• AMYLOID BETA A4 PRECURSOR PROTEIN (APP). Gene Map Locus: 21q21.3-q22.05. [OMIM 104760]
  See above.
• AMYLOID P COMPONENT.
  Normally found in serum, it is also found in NFTs and amyloid plaques. In AD, the serum concentration of AP is apparently lower than in controls.
• APOLIPOPROTEIN E; (ApoE). Gene Map Locus: 19q13.2. [OMIM 107741]
• BETA-2-MICROGLOBULIN (B2M). Gene Map Locus: 15q21-q22 [OMIM 109700]
  See above.
• MICROTUBULE-ASSOCIATED PROTEIN TAU (MAPT), gene map locus 17q21 [OMIM 157140]
  Tau proteins are components of the neuronal cytoskeleton that compose the core of neurofibrillary pathology.
• UBIQUITIN [OMIM 191320]
  Ubiquitin is a remarkably evolutionarily-conserved protein that helps mediate proteolytic reactions and attaches to the paired helical filaments in neurofibrillary pathology.
• TRANSTHYRETIN (TTR). Gene Map Locus: 18q11.2-q12.1 [OMIM 176300]
  See above.

Neurotransmission

• ACETYLCHOLINE RECEPTOR, MUSCARINIC 1 (CHRM1). Gene map locus 11q12-q13. [OMIM 118510]
  M1R are most plentiful in the basal forebrain; M1 receptor-->g protein coupling is disrupted in AD; M1 signalling may regulate b-APP processing; and M1 agonists may have a therapeutic role in AD.
• ACETYLCHOLINE RECEPTOR, MUSCARINIC 2 (CHRM2). Gene map locus 7q35-136. [OMIM 118493]
  M2R, like M1R, are found in greatest concentrations in the basal forebrain, and are therefor compromised in AD. In contrast to M1R, M3R works through cAMP instead of g proteins.
• ACETYLCHOLINE RECEPTOR, MUSCARINIC 3 (CHRM3). Gene map locus 1q41-q44. [OMIM 118494]
  Although not prevalently transcribed in the basal forebrain, M3R signalling may modulate b-APP processing.
• ACETYLCHOLINE RECEPTOR, MUSCARINIC 4 (CHRM4). Gene map locus 11p12-p11.2. [OMIM 118495]
  Another basal forebrain muscarinic receptor, M4R is upregulated in AD vs. control; a m1&m4R-(quasi)-specific agonist has shown to significantly increase some clinical parameters in AD patients.
• ACETYLCHOLINE RECEPTOR, MUSCARINIC 5 (CHRM5). Gene map locus 15q26. [OMIM 118496]
  M5 is something of an "odd man out" in re: relevance to cortical or subcortical neurodegenerative diseases like aD.
• ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC
  • ALPHA POLYPEPTIDE 2. Gene map locus Chr. 8. [OMIM 118502]
  • ALPHA POLYPEPTIDE 3. Gene map locus 15q24. [OMIM 118503]
  • ALPHA POLYPEPTIDE 4. Gene map locus 20q13.2-q13.3. [OMIM 118504]
  • ALPHA POLYPEPTIDE 5. Gene map locus 15q24. [OMIM 118505]
  • ALPHA POLYPEPTIDE 7. Gene map loucs 15q14. [OMIM 118511]
  • BETA-2 SUBUNIT. Gene map locus 1p21. [OMIM 118507]
  • BETA POLYPEPTIDE 3. Gene map locus 8p11.2. [OMIM 118508]
  • BETA POLYPEPTIDE 4. Gene map locus 15q24. [OMIM 118509]
• ACETYLCHOLINESTERASE (ACHE). Gene Map Locus: 7q22. [OMIM 100740]
  AchE is an enzyme that cleaves and deactivates the neurotransmitter acetylcholine.
• BUTYRYLCHOLINESTERASE (BCHE). Gene Map Locus: 3q26.1-q26.2 . [OMIM 177400]
  The K variant of this gene appears to act synergistically with ApoE E4 to raise the risk of late-onset Alzheimer disease.
• VESICULAR ACETYLCHOLINE TRANSPORTER (VACHT). Gene Map Locus: 10q11.2. [OMIM 600336]
  This gene is found within an intron of ChAT and is apparently transcribed simultaneously. Its relevance to disease states is unknown.
• CARNITINE ACETYLTRANSFERASE (CAT1). Gene Map Locus: 9q34.1. [OMIM 600184]
  CAT enzymes transfer acyl groups to carnitine molecules. CAT may be provide a source for acetylcholine. In AD, CAT activity is apparently decreased.
• CHOLINE ACETYLTRANSFERASE (CHAT). Gene Map Locus: 10q11.2. [OMIM 118490]
  ChAT is the enzyme that creates acetylcholine. ChAT activity is decreased in AD dramatically, possibly due to the death of cholinergic cells in which it is transcribed.
• GALANIN (GALN), gene map locus 11q13.3-q13.5 [OMIM 137035]
  GALN is a peptide transmitter found in brain and gut. Although hardly exclusive to cholinergic basal forebrain neurons, galanin appears to hyperinnervate remaining nucleus basalis neurons in AD.
• GALANIN RECEPTOR (GALNR), gene map locus 18q23 [OMIM 600377]
  GALNR is a g protein-type receptor, present in many tissues including gut, heart, and brain.
• GLUTAMATE RECEPTOR-5 (GLR5; GLUR5). [OMIM 138245 ]
  GLUR5 is a glutamate receptor subunit expressed in the ventral horn of humans. Several lines of evidence implicate GLUR5 as a culprit in amyotropic lateral sclerosis (ALS).
• GLUTAMATE RECEPTOR-6. [OMIM 138244 ]
  GLUR6 is a glutamate receptor subunit associated with kainate vulnerability and GLUR6-mediated excitotoxicity may contribute to neuropathology of Huntington's disease.
• GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 1 (GRIA1). [OMIM 138248]
  GRIA1, aka GLUR1, is a glutamate receptor subunit; mutations of mice GRIA1 is associated with neurological changes ('vibrator', 'shaker-2', 'tipsy', and others). AMPA- sensitive receptor subtypes mediate 'fast' ligand-activated cation channels.
• GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 2 (GRIA2). [OMIM 138247]
  GRIA2, aka GLUR2, is another AMPA-related glutamate receptor subunit. In mice, mutations in this gene are associated with earl-onset epilepsy and short life-span.
• GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 3 (GRIA3). [OMIM 305915]
  GTIA3, aka GLUR3, is another AMPA-related glutamate receptor subunit. A recent exciting finding is that autoantibodies vs. GTIA3 may be responsible for Rasmussen disease, a devastating pediatric epileptic syndrome.
• GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 4 (GRIA4). [OMIM 138246]
  GRIA4, aka GLUR4, is another AMPA-relevant glutamate receptor subunit, of unknown significance in re: diseases.
• GLUTAMATE RECEPTOR, IONOTROPIC, KAINATE 3 (GRIK3). [OMIM 138243 ]
  GRIK3, aka GLUR7, is a glutamate receptor subunit subtype that confers sensitivity to the excitotory molecule kainate.
• GLUTAMATE RECEPTOR, IONOTROPIC, KAINATE 4 (GRIK4). [OMIM 600282 ]
  GRIK4, aka KA1, is the "first" of a class of kainate-sensitive glutamate receptor subunit molecules.
• GLUTAMATE RECEPTOR, IONOTROPIC, KAINATE 5 (GRIK5). [OMIM 600283 ]
  GRIK5, aka KA2, is the "second" in the same class as KA1.
• GLUTAMATE RECEPTOR, METABOTROPIC, 3 (GRM3). [OMIM 601115 ]
  GRM3 and GRM8 are two glutamate receptors that are evidently metabotropic, i.e., their stimulation triggers a g protein and intracellular signalling cascade.
• GLUTAMATE RECEPTOR, METABOTROPIC, 8 (GRM8). [OMIM 601116 ]
  See above.
• GLUTAMATE RECEPTOR, IONOTROPIC, NMDA-A (GRINA). [OMIM 138251]
• GLUTAMATE RECEPTOR, IONOTROPIC, NMDA-1 (GRIN1). [OMIM 138249]
• GLUTAMATE RECEPTOR, IONOTROPIC, NMDA-2A (GRIN2A). [OMIM 138253 ]
• GLUTAMATE RECEPTOR, IONOTROPIC, NMDA-2B (GRIN2B). [OMIM 138252 ]
• GLUTAMATE RECEPTOR, IONOTROPIC, NMDA-2C (GRIN2C). [OMIM 138254 ]
• GLUTAMINE SYNTHETASE (GLNS). Gene Map Locus: 1q23 [OMIM 138290]
  GLNS is also called glutamate-ammonia ligase because of its primary action. In at least one report, the presence of GLNS in CSF is a sensitive and specific indicator of AD.
• POTASSIUM CHANNELS.
  It has been reported that TEA-sensitive potassium channels and calcium influx are absent from AD fibroblasts, which could provide both means of diagnosing AD and a pathoetiological mechanism.

Neurotrophic Factors

• BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF). Gene map locus 11p13. [OMIM 113505]
  Expressed in both the peripheral and central nervous systems, particularly in the mossy fibers. Binds to trkB receptor.
• NERVE GROWTH FACTOR, ALPHA SUBUNIT (NGFA). [OMIM 162020 ]
  NGF comprises two alpha, two beta, two gamma subunits. It is particularly relevant to cholinergic neurons, acting as a growth and trophic factor. NGF alpha and beta show homology to kallikrein molecules. NGF activity is decreased in AD brain, presumably in parallel to the elimination of cholinergic neurons.
• 162030 NERVE GROWTH FACTOR, BETA SUBUNIT (NGFB). Gene map locus 1p13.1. [OMIM 162030]
• NERVE GROWTH FACTOR, GAMMA SUBUNIT (NGFG). Gene map locus 19q13.3 [OMIM 162040]
  see above; NGF gamma subunit also has kallikrein-like activity.
• NERVE GROWTH FACTOR RECEPTOR (NGFR). Gene map locus 17q21-q22. [OMIM 162010]
• NEUROTROPHIC FACTOR-3 (NT3). Gene map locus 12p13. [OMIM 162660]
  NT3 is a close relative of NGF and BDNF. It is apparently important for development of peripheral nervous system and heart.
• NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1 (NTRK1, trkA). Gene map locus 1q21-q22. [OMIM 191315]
  More frequently called TrkA, the high-affinity receptor for NGF. This receptor, closely associated functionally with the cholinergic system, is dramatically decreased in AD brain.
• NEUROTROPHIC TYROSINE KINASE RECEPTOR, TYPE 2; TYROSINE KINASE RECEPTOR B (trkB, NTRK2). Gene map locus 9q22.1 [OMIM 600456]
• TYROSINE PROTEIN KINASE (trkC, NTRK3); NEUROTROPHIN-3 RECEPTOR. Gene Map Locus: 15q24-q25. [OMIM 191316]
• NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 4 (NTRK4, trkE). Gene Map Locus: 6p21. [OMIM 601312]
  This protein has not been well-characterized to date; however, it appears to be structurally and functionally related to the other Trk genes.
• ONCOGENE TRK. Gene Map Locus: 1q23-q24 [OMIM 164970]
  This oncogene is the chimeric product of TrkA and non-muscle tropomyosin. It is associated with colon cancer.
• TYROSINE PROTEIN KINASE TRKC (TRKC), NEUROTROPHIN-3 RECEPTOR (NTRK3). Gene map locus 15q24-q25. [OMIM 191316]
  see above

Related Disorders (see also Amyloidoses)

• ALPHA-KETOGLUTARATE DEHYDROGENASE DEFICIENCY. Gene Map Locus: 7p14-p13. [OMIM 203740]
  This is a disease of the TCA metabolic enzyme, OGDH. It is fatal by 30 months. Apparently, the activity of OGDH is also lowered in AD brain and skin fibroblasts.
• AMYOTROPHIC LATERAL SCLEROSIS- PARKINSONISM/ DEMENTIA COMPLEX OF GUAM; ALS-PD [OMIM 105500]
  Thought to be conferred by eating the cycad plant, ALS-PD involves spinal cord and basal forebrain, in addition to many NFTs in the hippocampus without amyloid plaques.
• ARGININOSUCCINICACIDURIA. Gene Map Locus: 7cen-q11.2 [OMIM 207900]
  Arginosuccinate lyase deficiency manifests very early in life as both mental and physical debilitation. It is treatable via diet modification/supplementation. Neuropathology is consistent with hyperammonemia, with the usual astrocytic changes.
• CEREBRAL HEMORRHAGE, FAMILIAL, ICELANDIC; AMYLOIDOSIS VI; HEREDITARY CEREBRAL HEMORRHAGE WITH AMYLOIDOSIS (HCHWA). Gene Map Locus: 20p11 [OMIM 105150]
  Mutation of b-APP causes deposition of b-AP deposition that compromises vascular integrity leading to devastating hemorrhage.
• CEROID-LIPOFUSCINOSIS, NEURONAL 3, JUVENILE (CLN3); AMAUROTIC FAMILY IDIOCY, JUVENILE TYPE; BATTEN DISEASE (BTS); VOGT-SPIELMEYER DISEASE. Gene map locus 16p12.1. [OMIM 204200]
  BTS/CLN3, a ceroid lipofuscinosis, is a pediatric neurological disease that involves rapid deterioration in vision and slower loss of cognitive function, in addition to seizures and psychoses.
• CREUTZFELDT-JAKOB DISEASE (CJD). Gene Map Locus: 20pter-p12. [OMIM 123400]
  CJD is a dementing illness accompanied by myoclonic jerks, and is thought to be caused by infection by a pathogenic form of prion protein. The gene that makes normal prion protein can mutate and produce misshapen prion proteins without any infectious prion transmission from animals. The mutant gene can then be passed on through families to produce hereditary prion disease. 10-15% of CJD cases are familial and are believed to be transmitted in this way.
• DEMENTIA, FAMILIAL, NEUMANN TYPE [OMIM 221820]
  This disease was first referred to as "subcortical gliosis", and is a dementia distinct from other known types. It is apprently inherited in an autosomal dominant pattern, with the responsible gene currently unknown.
• DEMENTIA, FAMILIAL NONSPECIFIC. Gene Map Locus: 3p11.1-q11.2. [OMIM 600795]
  A kindred of Danes have been described with a familial dementia without previously described pathological features. The gene locus responsible has been localized to a 12 cM region on chromosome 3.
• DEMENTIA, HEREDITARY MULTI-INFARCT TYPE, CEREBRAL AUTOSOMAL DOMINANT ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY; CADASIL; CASIL. Gene map locus 19p13.1. [OMIM 125310]
  See above.
• DEMENTIA/PARKINSONISM WITH NON-ALZHEIMER AMYLOID PLAQUES [OMIM 125320]
  A human pedigree with dementia and Parkinsomism was described. Their neuropathology was conspicuous for plaque-like structures that lacked beta-amyloid peptide and prion protein as judged by immunochemical means.
• DEMENTIA, PROGRESSIVE, WITH LIPOMEMBRANOUS POLYCYSTIC OSTEODYSPLASIA [OMIM 221770]
  This dementia afflicts people in their late 30's and is associated with cystic bone lesions. This disease, which is found concentrated in certain kinships, appears to involve breakdown in blood-brain barrier.
• DOWN SYNDROME, TRISOMY 21 [OMIM 190685]
  Trisomy 21 involves an extra copy of the 21st chromosome (on which the beta-amyloid precursor protein gene resides). Individuals with trisomy 21 generally have AD-type neuropathological features by their fourth decade, and the amount of amyloid burden in their brains can be appreciable.
• FRONTOTEMPORAL LOBE DEMENTIA (FLDEM). [OMIM 601630]
  FLDEM involves dementia apparently secondary to degeneration of frontal and anterior temporal lobes, without concomitant development of pathognomonic inclusion bodies. This disease apparently has a polygenetic etiology.
• GERSTMANN-STRAUSSLER DISEASE (GSD). Gene Map Locus: 20pter-p12 . [OMIM 137440]
  Gerstmann-Straussler Scheinker disease is caused by mutations in the prion protein, can involve neuritic plaques without b-AP, and is inherited in autosomal dominant fashion.
• HALLERVORDEN-SPATZ DISEASE [OMIM 234200]
  Hallervoden-Spatz disease is characterized by motor and cognitive deficits, and involves deposits of globus pallidus in the nuclei of basal ganglia. It some, but not other, kindreds, the mutation is mapped to chromosome 20.
• HUNTINGTON DISEASE (HD). Gene Map Locus: 4p16.3 . [OMIM 143100]
  HD is disease characterized by dementia and choreas, and is associated with mutations and triplet repeats in the Huntingtin gene. The most significant neuropathological finding in HD is atrophy of the caudate nucleus of the basal ganglia.
• INCLUSION BODY MYOPATHY (IBM2). Gene Map Locus: 9p1-q1. [OMIM 601073]
  IBM provides an intriguing model of AD pathobiology. IBM is a peripheral nerve disease that includes depositions of b-AP amyloid and neurofibrillary pathology with tau protein PHFs.
• LEWY BODY DEMENTIA [OMIM 127750]
  Lewy Bodies are features of Parkinson's disease when found in the substantia nigra. In Lewy Body dementia, they are found in the neocortex as well, and are associated with dementia in addition to formed visual hallucinations and a progressive but vacillating clinical course.
• METACHROMATIC LEUKODYSTROPHY, LATE-INFANTILE (MLD). Gene Map Locus: 22q13.31-qter. [OMIM 250100]
  MLD, aka arylsulfatase A deficiency, is a devastating neurologicadisease, usually occurs before the age of 5, and involves a disturbance of the white matter. Neurofibrillary pathology has been described in this condition.
• MUSCULAR DYSTROPHY, LATE-ONSET DISTAL. Gene Map Locus: 2p13.3-p13.1. [OMIM 254130]
  Similar to IBM disease, this type of muscular dystrophy involves a peripheral nerve process that includes amyloid, neurofibrillary pathology-like inclusions, and ubiquitin- immunoreactive lesions.
• MYOCLONUS EPILEPSY OF UNVERRICHT AND LUNDBORG, PROGRESSIVE MYOCLONUS EPILEPSY (PME); BALTIC MYOCLONUS EPILEPSY. Gene map locus 21q22.3 [OMIM 254800]
  This pediatric disorder results in seizures, myoclonus, and then dementia. Cerebellum is affected, and the disease is not universally fatal.
• NIEMANN-PICK DISEASE, TYPE C. Gene Map Locus: 18q11-q12 . [OMIM 257220]
  In Neimann-Pick Disease, type C, a disorder of cholesterol/lipoprotein metabolism, pediatric (and sometimes adult) patients undergo progressive neurological degeneration. Neurofibrillary pathology is observed in this condition.
• ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO (OTC). Gene Map Locus: Xp21.1. [OMIM 311250]
  This disease is an inborn defect in metabolism that induces a rise in serum ammonia levels, and is treatable. Symptoms include lethargy, irritability, and gait unsteadiness.
• PICK DISEASE OF BRAIN [OMIM 172700]
  Pick's disease is a form of progressive dementia, often rapid in course and affecting individuals in their 5th-6th decades, that affects the frontal and anterior temporal cortices. "Pick Bodies" are seen, often in the dentate granule cells of the hippocampus.
• PARKINSON-DEMENTIA SYNDROME [OMIM 260540]
  aka "Atypical progressive supranuclear palsy", this syndrome is accompanied by neruofibrillary pathology in the hippocampus and basal forebrain. It is rare.
• PRESENILE DEMENTIA, KRAEPELIN TYPE. [OMIM 176600]
  This is a rare syndrome, affecting patients as early as their third decade. It is present in families, has male-only inheritance, and causes dementia with catatonia. Its other name is "non-specific familial pre-senile dementia".
• PRION PROTEIN (PRNP). Gene Map Locus: 20pter-p12. [OMIM 176640]
  PRNP is a singular protein that can confer and apparently propagate spongiform encephalopathy in numerous mammalian species. Mutations in the protein can also lead to disease phenotype. PRNP is responsible for scrapie, CJD, GSS. A specific mutation in the prion protein gene appears to underlie a hereditary schizophrenic disorder.
• SCHIZOPHRENIA-2 [OMIM 181500]
  Schizophrenia is a complicated psychiatric disorder (like AD) probably induced by many genetic and environmental factors. To date, the evidence of AD-type pathology in schizophrenia per se is not convincing. However, in some neurological conditions with AD-type pathology, schizophrenia like symptoms have been observed.
• SUPRANUCLEAR PALSY, PROGRESSIVE; STEELE- RICHARDSON- OLSZEWSKI SYNDROME. [OMIM 601104]
  PSP affects older people and involves palsy of upward gaze, and then many other neurological sequelae including dementia. Neuropathologically, neurofibrillary pathology is present in the basal ganglia and brain stem and is found in glial cells.

Signal Transduction

• CALMODULIN (CALM3). Gene Map Locus: 19q13.2-q13.3 [OMIM 144183]
  Mediates the transduction of calcium signalling through changes in protein. Calcium-calmodulin protein kinase II, for instance, was an early candidate kinase for causing pathological phosphorylation in AD.
• cGMP-DEPENDENT KINASE. [OMIM 601591]
  Activation of this kinase is thought to be one of the means by which secreted b-APP mediates signalling (as through cGMP-dependent potassium channel activation).
• Fe65.
  A transcriptional activator that binds b-APP (dependent upon phosphorylation state), and is expressed in parts of the human brain most vulnerable to AD pathology.
• Go. [See Yamatsuji , et al. PubMed 8650548]
  In both cell-free and tissue culture paragdigms, b-APP acts as a G(o)-type intramembrane receptor complex, transducing ligand bindign into intracellular signals (e.g. mitogen-activated protein kinase activation).
• NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1 (NTRK1). Gene map locus 1q21-q22. [OMIM 191315]
  See above.
• NEUROTROPHIC TYROSINE KINASE RECEPTOR, TYPE 2
  See above.
• TYROSINE KINASE RECEPTOR B (TRKB, NTRAK2). Gene map locus 9q22.1 [OMIM 600456]
  See above.
• ONCOGENE TRK. Gene Map Locus: 1q23-q24 [OMIM 164970]
  See above.
• TYROSINE PROTEIN KINASE TRKC (TRKC), NEUROTROPHIN-3 RECEPTOR (NTRK3). Gene map locus 15q24-q25. [OMIM 191316]
  See above.
• V-FOS FBJ MURINE OSTEOSARCOMA VIRAL ONCOGENE HOMOLOG (FOS), Gene Map Locus: 14q24.3 [OMIM 164810]
  See above.