A genetic dichotomy model for the inheritance of Alzheimer's disease and common age-related disorders.

Alzheimer’s disease (AD), already one of the most serious health problems in the U.S., will carry an ever burgeoning impact as the proportion of elderly continues to increase. Clinically, AD is a progressive neurodegenerative disorder characterized by global cognitive decline. Neuropathologically, the brains of AD patients contain abundant amounts of neurofibrillary tangles (NFT) and β-amyloid in the form of senile plaques (SP) and blood vessel deposits. While the etiological events that lead to AD have not been clearly resolved, genetic factors clearly play a major role; there is an emerging consensus that AD is a complex and genetically heterogeneous disorder that is best explained by an age-dependent dichotomous model. On one hand, early-onset (<60) AD is caused by defects in any of three different genes: presenilin 1 (PSEN1) on chromosome 14 (1), presenilin 2 (PSEN2) on chromosome 1 (2), and the amyloid β protein precursor (APP) on chromosome 21 (3). On the other hand, late-onset AD is associated with genetic polymorphisms that appear to operate as risk factors and/or genetic modifiers.

[1]  B. Hyman,et al.  Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells , 1996, Nature Medicine.

[2]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[3]  J. Haines,et al.  ApoE-4 and Age at Onset of Alzheimer's Disease , 1997, Neurology.

[4]  W. Ewens,et al.  A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. , 1998, American journal of human genetics.

[5]  B. Trask,et al.  Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. , 1998, Human molecular genetics.

[6]  N. Laird,et al.  An α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease (reply) , 1999, Nature Genetics.

[7]  N. Cairns,et al.  α-2 macroglobulin polymorphism and Alzheimer disease risk in the UK , 1999, Nature Genetics.

[8]  F. Pasquier,et al.  A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease. , 1998, Human molecular genetics.

[9]  S. DeKosky,et al.  A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease , 1999, Neuroscience Letters.

[10]  J. Haines,et al.  An α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease , 1999, Nature Genetics.

[11]  R. Tanzi,et al.  The gene defects responsible for familial Alzheimer's disease. , 1996, Neurobiology of disease.

[12]  G. Siest,et al.  Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer's disease. , 1994, American journal of medical genetics.

[13]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[14]  K. Welsh-Bohmer,et al.  APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease , 1998, Nature Genetics.

[15]  N M Laird,et al.  A discordant-sibship test for disequilibrium and linkage: no need for parental data. , 1998, American journal of human genetics.

[16]  Steven M. Horvath,et al.  Alpha-2 macroglobulin is genetically associated with Alzheimer disease , 1998, Nature Genetics.

[17]  J. Morris,et al.  A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia , 1998, Nature Genetics.

[18]  R. Sulkava,et al.  Genetic association of α2‐macroglobulin with Alzheimer's disease in a Finnish elderly population , 1999, Annals of neurology.

[19]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[20]  G. Schellenberg,et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus , 1995, Science.

[21]  R. Tanzi,et al.  REVIEWThe Gene Defects Responsible for Familial Alzheimer's Disease , 1996, Neurobiology of Disease.

[22]  M. Albert,et al.  Genetic association of an (α2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease , 1998 .

[23]  J. Haines,et al.  Further evidence linking late-onset Alzheimer disease with chromosome 12. , 1999, JAMA.

[24]  M. Owen,et al.  α-2 macroglobulin gene and Alzheimer disease , 1999, Nature Genetics.