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FB2025_04
,
released October 2, 2025
This report describes Alzheimer disease 1 (AD1), which is a subtype of Alzheimer disease; AD1 is inherited as an autosomal dominant. The human gene implicated in this disease is APP, amyloid beta A4 precursor protein. Peptides derived from APP are the major component of amyloid plaques found in the brains of Alzheimer patients; the most common of these is amyloidβ42 (Aβ42). The human APP gene is also implicated in a second disease, cerebral amyloid angiopathy, APP-related (MIM:605714; FBhh0000544). There is a single fly ortholog of APP, Dmel\Appl, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Appl is orthologous to two additional human genes, APLP1 and APLP2, neither of which is implicated in human disease.
Multiple different UAS constructs of the human Hsap\APP gene have been introduced into flies, expressing the wild-type protein, the APP protein with introduced modification, or a subset of APP amyloid peptides. Many studies use constructs that encode the amyloid peptide Aβ42. Drosophila has also been used to investigate the role of the larger APP C-terminal fragment, APP-C99 (precursor of Aβ42), in amyloid plaque formation.
Some Alzheimer disease models use Hsap\APP in combination with other genes thought to impact the disease, such as Hsap\BACE1 (FBhh0000580) and Hsap\MAPT (FBhh0000101). Phenotypic assays using the human gene have allowed characterization of genetic interactions with numerous other genes.
Variants implicated in this human disease have been assessed using transgenic constructs of the human APP gene or constructs that encode only the amyloid peptide Aβ42; see the 'Disease-Implicated Variants' table below. The frequently used 'Arctic' variant is designated APP:p.Glu693Gly (in the context of the whole APP gene) or APP(A& bgr:42 peptide):p.Glu22Gly (n the context of the amyloid peptide) by FlyBase.
Variants of APP associated with cerebral amyloid angiopathy have been introduced into flies and are available, but have not been characterized. See the disease report for cerebral amyloid angiopathy, APP-related (FBhh0000544).
Animals homozygous for a loss-of-function mutation in the Dmel\Appl gene exhibit learning and memory defects and neuroanatomy defective phenotypes. Physical interactions of the Dmel\Appl protein product have been described; see below and in the FlyBase gene report for Dmel\Appl. Phenotypic assays using the fly gene have allowed characterization of genetic interactions.
[updated Jan. 2022 by FlyBase; FBrf0222196]
Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from MIM:104300; 2016.01.08]
Memory loss is the most common sign of Alzheimer disease. As the disorder progresses, some people with AD experience personality and behavioral changes; other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. Total care is usually required during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]
Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]
[ALZHEIMER DISEASE, FAMILIAL, 1; AD1](https://omim.org/entry/104300)
[NITRIC OXIDE SYNTHASE 3; NOS3](https://omim.org/entry/163729)
[PLASMINOGEN ACTIVATOR, URINARY; PLAU](https://omim.org/entry/191840)
[MYELOPEROXIDASE; MPO](https://omim.org/entry/606989)
[AMYLOID BETA A4 PRECURSOR PROTEIN; APP](https://omim.org/entry/104760)
Alzheimer disease 1 (AD1) is characterized by typical symptoms of Alzheimer disease (described above).
Alzheimer disease 1 is inherited as an autosomal dominant; it is associated with heterozygous mutations in the APP gene [from MIM:104300; 2016.01.08]
In the amyloidogenic pathway associated with Alzheimer disease, the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques (Pera et al., 2017; pubmed:29018038).
Peptides derived from the amyloid beta A4 precursor protein (APP) are the major component of amyloid plaques found in the brains of Alzheimer patients. [from MIM:104760; 2016.01.08]
Many to one: 3 human to 1 Drosophila. Three human genes, APP, APLP2 and APLP1, are orthologous to the fly gene Dmel\Appl.
Ortholog of human APP (reciprocal best hit), APLP2 and APLP1 (1 Drosophila to 3 human). Dmel\Appl shares 23-25% identity and 36-42% similarity with the 3 human genes.