Molecular genetics of Alzheimer's disease and the amyloid beta peptide precursor gene

Topic: Amyloid, tau and blood-test diagnosis

Alzheimer's disease is a neurodegenerative disorder characterized by global cognitive decline. An autopsy of the Alzheimer patient's brain reveals two major neuropathological lesions: neurofibrillary tangles, and amyloid deposits in the form of senile plaques and cerebrovascular accumulations. While tangles appear to be a universal hallmark of dying neurons in several neurodegenerative diseases, amyloid plaques occur in only three conditions including Alzheimer's disease, Down syndrome, and to a limited extent, normal aging. The frequency of senile plaques appears to correlate well with the degree of dementia in the Alzheimer's patient. It remains unclear, however, whether amyloid formation represents one of the final stages of a long neuropathological process in the brain, or initially participates in promoting neuronal dysfunction. To address this question, we have isolated the gene encoding the precursor of the principle component of the plaque, the amyloid beta peptide. We have mapped this gene to chromosome 21, the same chromosome in which we have detected linkage between anonymous DNA markers and the familial form of Alzheimer's disease. Employing direct genetic linkage analysis, we have shown that the amyloid gene and the familial Alzheimer's disease gene represent two separate and distinct genetic loci. Here we present further information on the location of the familial Alzheimer's disease gene on chromosome 21. We also discuss the recent discovery of an alternate form of the amyloid beta peptide precursor gene which encodes a serine protease inhibitor in the Kunitz family. The presence of a protease inhibitor domain within the amyloid beta peptide precursor, itself, has profound implications for its possible role in the process of amyloid formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Key findings

• Employing direct genetic linkage analysis, we have shown that the amyloid gene and the familial Alzheimer's disease gene represent two separate and distinct genetic loci.

Why it matters

This genetic study mapped the amyloid beta precursor gene to chromosome 21 and showed through linkage analysis that the amyloid gene and the familial Alzheimer's disease gene are separate genetic loci. It clarifies the genetics of Alzheimer's disease but does not provide a treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3109/07853898909149191
• PubMed: 2504259
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{tanzi1989-2504259,
  author  = {Tanzi, R. E.},
  title   = {{Molecular genetics of Alzheimer's disease and the amyloid beta peptide precursor gene}},
  journal = {Annals of medicine},
  year    = {1989},
  doi     = {10.3109/07853898909149191},
  pmid    = {2504259},
  url     = {https://doi.org/10.3109/07853898909149191}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor Nature · 1987-02-01 · usefulness score 58/100 · Disease mechanisms
• Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus Science (New York, N.Y.) · 1987-02-01 · usefulness score 57/100 · Down syndrome and Alzheimer's
• Amyloid plaque core protein in Alzheimer disease and Down syndrome Proceedings of the National Academy of Sciences of the United States of America · 1985-06-01 · usefulness score 56/100 · Down syndrome and Alzheimer's
• Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides Proceedings of the National Academy of Sciences of the United States of America · 1987-06-01 · usefulness score 45/100 · Down syndrome and Alzheimer's

Later studies that cite this one

1 study in the alzhub library lists this one in its references.

• Diagnosis and Management of Dementia: Review JAMA · 2019-10-01 · usefulness score 59/100 · Getting a diagnosis

Related studies in Down syndrome and Alzheimer's

• Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer's disease Proceedings of the National Academy of Sciences of the United States of America · 2001-08-21 · usefulness score 36/100
• Mapping of the gene encoding the beta-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21 Proceedings of the National Academy of Sciences of the United States of America · 1988-11-01 · usefulness score 44/100
• Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch) Science (New York, N.Y.) · 1990-06-01 · usefulness score 41/100
• The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences Brain research. Molecular brain research · 1991-02-01 · usefulness score 37/100
• Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease Cold Spring Harbor perspectives in medicine · 2017-06-01 · usefulness score 38/100
• Measurement of amyloid peptide precursor of Alzheimer disease in human blood by double antibody immunoradiometric assay Alzheimer disease and associated disorders · 1991-01-01 · usefulness score 36/100

Also tagged “down”

527 studies in the library carry the topic tag “down”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 527 tagged studies.

• Alzheimer's disease in Down's syndrome: clinicopathologic studies Neurology · 1985-07-01 · usefulness score 61/100 · Getting a diagnosis
• Emerging roles for intersectin (ITSN) in regulating signaling and disease pathways International journal of molecular sciences · 2013-04-10 · usefulness score 39/100 · Down syndrome and Alzheimer's
• The evolution of ovarian oocyte decline with aging and possible relationships to Down syndrome and Alzheimer disease Experimental gerontology · 1994-05-01 · usefulness score 35/100 · Down syndrome and Alzheimer's

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• The Genetics and Mechanisms of Alzheimer's Disease in Down Syndrome 2026 · Down syndrome and Alzheimer's
• Genetic studies support a neuronal origin for the beta amyloid polypeptide 1989 · Down syndrome and Alzheimer's
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• Molecular mapping of Alzheimer-type dementia in Down's syndrome 1998 · Risk genes beyond APOE

More on Down syndrome and Alzheimer's

• A review that covers this ground A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide--the first step of a fatal cascade Journal of neurochemistry · 2004-11-01 · usefulness score 36/100
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