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 (OMIM: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 peptides. 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.
Variant(s) implicated in human disease tested (as transgenic human gene, APP): K670N.M671L (affects 2 adjacent amino acids; designated Hsap\APP695-Swedish.UAS) and V717F variant forms of the human gene have been introduced into flies. A double mutant, K670N.M671L plus E693G, has been introduced into flies and is available, but has not been characterized.
Variant(s) implicated in human disease tested (as transgenic human amyloid peptide, Aβ42): the E693G (E22G in the amyloid peptide; see alleles designated Hsap\APP[Arctic.xxx]), D671_E673delinsQ (D1_E3delinsQ in the amyloid peptide), and S679D (S8D in the amyloid peptide) variant forms have been introduced into flies. The variant A692G (A21G) has been introduced into flies and is available, but has not been characterized.
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 Mar. 2020 by FlyBase; FBrf0222196]
Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from OMIM: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; AD](https://omim.org/entry/104300)
[HOMEOSTATIC IRON REGULATOR; HFE](https://omim.org/entry/613609)
[NITRIC OXIDE SYNTHASE 3; NOS3](https://omim.org/entry/163729)
[PLASMINOGEN ACTIVATOR, URINARY; PLAU](https://omim.org/entry/191840)
[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).