APP

Many variants (also called mutations) in the APP gene can cause early-onset Alzheimer's disease, which begins before age 65. These variants are responsible for less than 10 percent of all early-onset cases of Alzheimer's disease.

The most common APP gene variant changes one of the protein building blocks (amino acids) in the amyloid precursor protein. This variant replaces the amino acid valine with the amino acid isoleucine at protein position 717 (written as Val717Ile or V717I). Variants in the APP gene can lead to an increased amount of the amyloid β peptide or to the production of a slightly longer and stickier form of the peptide. When these protein fragments are released from the cell, they can accumulate in the brain and form clumps called amyloid plaques. These plaques are characteristic of Alzheimer's disease. A buildup of toxic amyloid β peptide and amyloid plaques may lead to the death of neurons and the progressive signs and symptoms of Alzheimer's disease.

Variants in the APP gene have been found to cause hereditary cerebral amyloid angiopathy, a condition characterized by stroke and a decline in intellectual function (dementia), which begins in mid-adulthood. These variants change single amino acids in the amyloid precursor protein. Each of these variants causes a different type of the condition. The Dutch type, the most common of all the types, is caused by the replacement of the amino acid glutamic acid with the amino acid glutamine at position 22 in the protein sequence (written as Glu22Gln or E22Q). The Italian type and Arctic type are also caused by changes to glutamic acid at position 22. In the Italian type, glutamic acid is replaced with the amino acid lysine (written as Glu22Lys or E22K) and in the Arctic type, glutamic acid is replaced with the amino acid glycine (written as Glu22Gly or E22G). The Flemish type is caused by replacement of the amino acid alanine with glycine at position 21 (written as Ala21Gly or A21G). In the Iowa type, the amino acid aspartic acid is switched with the amino acid asparagine at position 23 (written as Asp23Asn or D23N). The Piedmont type of hereditary cerebral amyloid angiopathy is caused by the replacement of the amino acid leucine at position 34 with the amino acid valine (written as Leu34Val or L34V).

The result of all of these variants is the production of an amyloid β peptide that is more prone to cluster together (aggregate) than the normal peptide. The aggregated protein forms amyloid deposits that accumulate in the blood vessels of the brain. The amyloid deposits replace the muscle fibers and elastic fibers that give blood vessels flexibility, causing the blood vessels to become weak and prone to breakage. In the brain, such a break causes bleeding (hemorrhagic stroke), which can lead to brain damage and dementia or be life-threatening. Amyloid deposits in specific parts of the brain can interfere with normal brain function, leading to dementia, seizures, movement problems, and other neurological features in some people with hereditary cerebral amyloid angiopathy.