The Genetics of Alzheimer's disease

Genetics is changing extremely rapidly with the greatly increased ease of reading genetic code.  The most common genetic abnormality in late-onset Alzheimer's, by far the most common type, is the e4 polymorphism of apolipoprotein-E (APOE-4).  Other gene variants which increase the risk of Alzheimer's include a variant of the CYP46 Brain Cholesterol Breakdown Gene and a variant of the Fibroblast Growth Factor 1 Gene.

Variants of the beta-amyloid precursor protein (APP) gene (on chromosome 21), Presenilin 1 (PS1) gene (on chromosome 14) and Presenilin 2 (PS2) gene (on chromosome 1) are responsible for most cases of autosomal dominant early-onset Alzheimer's disease.  Early-onset Alzheimer's disease makes up only 1-5% of all Alzheimer's disease.  These mutations result in overproduction of a toxic A- beta-amyloid 42 fragment which then accumulates in the nervous system. 

Mutations of the transmembrane protein BRI-2 gene also causes early onset AD type dementia.

Undoubtedly, many more less common gene variants (polymorphisms) will be discovered that are responsible for small numbers of cases or play a contributing role.  Very likely, many of these polymorphisms are influenced by environmental factors, which appear to play a major role in the development of Alzheimer's disease.  For instance, a variant of the gene that helps with cholesterol breakdown in the brain increases the risk of dementia in certain individuals with another genetic abnormality.  This causes a cholesterol build up, but perhaps keeping cholesterol low by diet and medication can reduce this risk in these individuals.

Genes deteriorate as we age.  Some of these deteriorations cause dementia.  Disease factors and bad habit can cause genetic deterioration which magnifies the deterioration of normal aging.  Mitochondrial genetic deterioration is a common finding in Alzheimer's.  

Genetic studies are becoming more and more numerous as our tools for measuring genes are becoming better.  It is hard to keep up with the studies and sometimes not easy to understand all of the complexities.  It is also discouraging to spend the time reading them, since at the present time there is not much you can do about it.  That will change someday.

Amyloid Cleared by CPHPC: Serum amyloid P probably exacerbates amyloid deposits. Nature May 16, 2003, reported a pyrrolidine caroxylic acid binds two amyloids which causes the liver to mark it for excretion. U New Mexico.

Amyloid Turns Off Memory Genes: U S. Fla. J Neuroscience 6/15/03, Morgan, found at least 6 of 30 genes associated with memory and learning turned off in microarray analysis by amyloid in both genetically engineered mice and humans suffering from AD.

APOE e4, Male Sex Chromosome Version, Lack Mental Illness Decrease AD: Chance of longevity with Alzheimer's is higher if there were no mental disorders in youth and early adulthood, absence of e4 version of apolipoprotein-E (APOE-4), and if the patient carries a particular version of a gene on the male sex chromosome. In a study of 100 mentally healthy elderly over age 89 and 100 young adults ages 18-25 matched ethnically and 100 deceased who had AD, 42% of AD had the e4 genetic variation, 12% of young adults, and 7% of healthy elderly. The healthy elderly group had half the level of mental illness in youth and younger adulthood than did the controls. George Zubenko, Univ. Pittsburgh 10/02 American Journal of Geriatric Psychiatry.

APOEThe three most important Alzheimer's risk factors are increasing age, a family history of the disease, and the presence of the ε4 allele of the Apolipoprotein E (APOE) gene. Every person has one maternally and one paternally inherited APOE allele of type ε2, ε3, or ε4. The ε4 allele confers increased susceptibility to the development of Alzheimer's. The presence of one ε4 allele increases the risk 200-300%, while having two ε4 alleles increases the risk 1500%. The ε4 allele is found in approximately 15 percent of the population and more than half of clinically diagnosed Alzheimer's patients. A.D. Roses, "Apoliopoprotein E Affects the Rate of Alzheimer Disease Expression: Beta-Amyloid Burden Is a Secondary Consequence Dependant on APOE Genotype and Duration of Disease," Journal of Neuropathology and Experimental Neurology 53, no. 5 (1994): 429-437; and L.A. Farrer et al., "Effects of Age, Sex, and Ethnicity on the Association between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-Analysis," Journal of the American Medical Association 278, no. 16 (1997): 1349-1356.

APOE Testing: People Testing Positive for APOE e4 Much More Likely to Purchase Long-Term Care Policies: In a study of 148 cognitively normal adults with family histories of Alzheimer's, some were informed and other not informed on how they tested on a APOE genetic test for Alzheimer's disease. Those who tested positive for an increased risk were 476% more likely to purchase long-term care insurance policies than those who tested positive and were not informed.  This adverse selection tendency on a national scale could effect the rates that insurance companies would have to charge.  Almost 17% of those who tested positive subsequently changed their long-term care insurance coverage in the year after APOE disclosure, compared with 2% of those who tested negative and 4% of those who did not receive APOE disclosure. C. Zick et al. Univ Utah, Health Aff. 2005; 24 (2): 483-490

BRI-2 Transmembrane Protein Mutations Cause Early-Onset Dementia: Transmembrane proteins BRI2 and APP co-localize with Ass amyloid lesions in sporadic Alzheimer's disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral haemorrhage. BRI2 interacts with APP and regulates Abeta production. BRI2 is a type-II transmembrane protein encoded by the single gene BRI2 (also known as ITM2B and E25B) located on the long arm of chromosome 13. BRI2 belongs to an evolutionary conserved multigene family comprising at least three homologues in both mouse and humans all bearing the same genomic organization. BRI2 is broadly expressed in peripheral organs as well as in the brain, Fotinopoulou et al. University of Athens. J Biol Chem. 2005 Jul 18

Cytochrome B Genetic Mutation Protective: A 2001 Italian study showed that healthy centenarians have a high incidence of a certain mutation which is part of the energy-production system in the mitochondria. Douglas Wallace of UC-Irvine found another longevity group in England with the same mutation. Mitochondria produce free radicals with damage DNA and proteins and those with this mutation producer fewer radicals and are less susceptible to Alzheimer's. New Scientist 1/17/04 

CYP46 Brain Cholesterol Breakdown Gene Variant: A gene, CYP46, is involved in production of an enzyme that helps break down excess cholesterol in the brain. Variation might hamper production of the enzyme, resulting in a buildup in the brain of cholesterol and beta amyloid. 40% adults in Zurich study had a CYP46 variant. If an individual has both the CYP46 variant and APOE-4, the risk of AD increased 10-fold. Andreas Papassotiropoulos, Univ Zurich, Arch Neurol 1/03 

Environment More Important Factor for Late Life Alzheimer's: A Karolinska Institute Swedish study of 662 twin pairs over age 49 with five years of follow-up found that of the identical twin pairs, in only five of 26 pairs developing Alzheimer's were both affected. Only 2 of 44 fraternal twin pairs with Alzheimer's were both twins affected. The researchers conclude that while genetics still plays a role in late life Alzheimer's, it is much more important in early life dementia. Nancy Peterson, Ann Neurol 2/2004;55

Fibroblast Growth Factor 1 Gene Polymorphism Increases Risk of AD: Fibroblast growth factor 1 (FGF1) protects selective neuronal populations against neurotoxic effects such as those in Alzheimer's disease (AD) and HIV encephalitis. In a study of 100 Japanese autopsy-confirmed late-onset AD patients and 106 age-matched non-demented controls, researchers examined the FGF1 and apolipoprotein E (APOE) genes. The promoter polymorphism (-1385 A/G) was significantly associated with AD risk. The odds ratio for AD associated with the GG vs non-GG genotype was 2.02, while that of s4 vs non-е┌4 in APOE4 gene was 5.19. The odds ratio for APOEP4 and FGF1 GG carriers was 20.5. Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease. Yamagata H, Chen Y, Akatsu H, Kamino K, Ito J, Yokoyama S, Yamamoto T, Kosaka K, Miki T, Kondo I. Ehime University, Japan. Biochem Biophys Res Commun. 2004 Aug 20;321(2):320-3

FoxM1B Gene Lack Involved in Ageing: FoxM1B controls a key enzyme needed to help cells pull apart at the end of mitosis, the final step in cell division. Dr Costa, UI, Chic, said: "These results clearly link FoxM1B with the failure of tissues to mend. "And in old age, the FoxM1B gene is essentially out of action. 12/31/02 BBC News

Genes on Chromosome 10: Science 12/22/00 three articles point to gene or genes on 10. Previous studies have found abnormal apolipoprotein E gene on 19 a risk factor. Some reports show a gene on 12 a risk factor. Insulin degrading enzyme on 10 is involved in degrading beta amyloid; APOE epsilon 4 allele was associated with shorter survival in men but not in women. RR 2.7.Hopkins. Neurology 2002 Apr 9;58(7):1045-50

Glutathione S-Transferase Omega-1 or GSTO1 Linked to Early Onset AD and Parkinson's Disease: Duke Univ. researchers studied 1,773 patients with Alzheimer's disease and 635 patients with Parkinson's disease. Dec. 15, 2003, Human Molecular Genetics

Lipoprotein System Gene Defects Cause Some AD: When there are genetic defects in the lipoprotein system, they frequently result in increase in atherosclerosis, xanthomatosis, and AD. Olson, U S. Fla., J Nutr 2/98

Memory 50-80% Genetic, Linked to Alzheimer's: Joseph H. Lee, and Richard Mayeux of Columbia University 1,036 people from 266 families in the Dominican Republic and Puerto Rico. Most of the families had more than one person living with Alzheimer's disease in the extended family. Memory performance was found to be strongly influenced by genetics. Mayeux reports that about half of the variation in memory performance among individuals is due to genetics.  The other half is due to environmental factors such as education. Considering that even with dominant traits, such as a genetic mutation that leads to early onset Alzheimer's, the genetic influence actually amounts to about 80 percent. Neurology 2/10/04

Naprilysin Gene Therapy Helps in Mice: Naprilysin is a protein that normally breaks down beta-amyloid. Using an HIV modified vector, the naprilysin gene was injected and successfully decreased beta-amyloid levels by 50%. Salk Institute, J Neurosci 3/15/03

Neuregulin-1 Polymorphisms Linked to Late Onset Alzheimer's with Psychosis: Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, researchers found a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. The NRG1 SNP (single nucleotide polymorphism), rs392499, was linked with ADP, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families. Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses. Go RC, et al. University of Alabama, Birmingham, Alabama. Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4

Pin1 Shortage May Cause Tangles: In Alzheimer's disease, the tau protein acquires too many extra phosphate groups, changes its shape and collects into tangles, which destroy neurons. The Pin1 gene underfunctions in the hippocampus of AD victims and underproduces a protein to modify tau. Pin1 functioning prevents age-related neurodegeneration. Kun Ping Lu, Harvard, Nature 7/31/03

Presenilin 1 Gene, Although Rare, Associated with Depression and Alzheimer's: In a study of 33 asymptomatic Mexican women (17 PS1 mutation carriers and 16 non-carriers) who were unaware of their genetic status, the rare PS1 mutation carriers scored significantly higher than did non-carriers on the Beck Depression Inventory (14.4 versus 6.5, respectively). Nearly twice as many mutation carriers (24%) than non-carriers (12.5%) had sought help from a psychologist or psychiatrist. Mutation carriers also performed more poorly on the Mini-Mental State Examination, the Wechsler memory scale associative learning subtest-immediate recall, and the Wechsler adult intelligence scale block design. Members of these rare families with PS1 mutations, though they develop the neuropathology characteristic of Alzheimer's disease, can also have features atypical of the more common form of Alzheimer's disease (faster progression of illness, paraparesis, early seizures and myoclonus). John M. Ringman. UCLA. J Neurol Neurosurg Psychiatry 2004;75:500-502.

Presenilin-1 Gene Mutation Causes a Familial Alzheimer's with Spastic Paraplegia: A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD. Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Moretti P, Lieberman AP, Wilde EA, Giordani BI, Kluin KJ, Koeppe RA, Minoshima S, Kuhl DE, Seltzer WK, Foster NL. University of Michigan. Neurology. 2004 May 25;62(10):1865-8

Presenilin-1: Abnormal Presenilin-1 Associated with Familial Frontotemporal Dementia: Dement Geriatr Cogn Disord 2002;14(1):13-21. Kluver-Bucy Syndrome is associated with arginine substitution on a codon of presenilin. First check for tau mutations.

TorsinA Folding Gene: Early onset dystonia, a severe hereditary movement disorder, is caused by a gene that normally helps manage protein folding. The mutated gene, TOR1A (or DYT1), was linked to the disorder in 1997, but the role of its protein, torsinA, was unveiled in the February 1, 2003, issue of Human Molecular Genetics. TorsinA and the family of torsin proteins are normally neuroprotective, used by cells as a quality control mechanism to clear proteins that have misfolded. It may play role in Parkinson’s, Huntington’s, and AD. University of Alabama/the Howard Hughes Institute 1/31/03