Early-onset Alzheimer's disease

Familial AD is inherited in an autosomal dominant fashion.

Familial Alzheimer disease is caused by a mutation in one of at least three genes, which code for presenilin 1, presenilin 2, and APP.[4][5][6]

The presenilin 1 gene (PSEN1 located on chromosome 14) was identified by Sherrington (1995)[7] and multiple mutations have been identified. Mutations in this gene cause familial Alzheimer's type 3 with certainty and usually under 50 years old. This type accounts for 30–70% of EOFAD. This protein has been identified as part of the enzymatic complex that cleaves amyloid-beta peptide from APP.

The gene contains 14 exons, and the coding portion is estimated at 60 kb, as reported by Rogaev (1997)[8] and Del-Favero (1999).[9] The protein the gene codes for (PS1) is an integral membrane protein. As stated by Ikeuchi (2002)[10] it cleaves the protein Notch1 so is thought by Koizumi (2001)[11] to have a role in somitogenesis in the embryo. It also has an action on an amyloid precursor protein, which gives its probable role in the pathogenesis of FAD. Homologs of PS1 have been found in plants, invertebrates and other vertebrates.

Some of the mutations in the gene, of which over 90 are known, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete penetrance, but a common mutation is Glu318Gly and this predisposes individuals to familial AD, with a study by Taddei (2002)[12] finding an incidence of 8.7% in patients with familial AD.

The presenilin 2 gene (PSEN2) is very similar in structure and function to PSEN1. It is located on chromosome 1 (1q31-q42), and mutations in this gene cause type 4 FAD. This type accounts for less than 5% of all EOFAD cases. The gene was identified by Rudolph Tanzi and Jerry Schellenberg in 1995.[13] A subsequent study by Kovacs (1996)[14] showed that PS1 and PS2 proteins are expressed in similar amounts, and in the same organelles as each other, in mammalian neuronal cells. Levy-Lahad (1996)[15] determined that PSEN2 contained 12 exons, 10 of which were coding exons, and that the primary transcript encodes a 448-amino-acid polypeptide with 67% homology to PS1. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).

The mutations have not been studied as much as PSEN1, but distinct allelic variants have been identified. These include Asn141Ile, which was identified first by Rudolph Tanzi and Jerry Schellenberg in Volga German families with familial Alzheimer disease (Levy-Lahad et al. Nature, 1995). One of these studies by Nochlin (1998) found severe amyloid angiopathy in the affected individuals in a family. This phenotype may be explained by a study by Tomita (1997)[16] suggesting that the Asn141Ile mutation alters APP metabolism causing an increased rate of protein deposition into plaques.

Similarly, miR-212-3p, another molecule implicated in Alzheimer's disease, has recently been shown to control inflammation in the brain, which could potentially influence plaque formation and Alzheimer's progression.[17]

Other allelic variants are Met239Val which was identified in an Italian pedigree by Rogaev (1995)[18] who also suggested early on that the gene may be similar to PSEN1, and an Asp439Ala mutation in exon 12 of the gene which is suggested by Lleo (2001)[19] to change the endoproteolytic processing of the PS2.

Processing of the amyloid precursor protein

Mutations to the amyloid beta A4 precursor protein (APP) located on the long arm of chromosome 21 (21q21.3) cause familial Alzheimer disease.[6] Further research into molecules like miR-212-3p might shed new light on potential therapeutic approaches for Alzheimer's disease, possibly alongside interventions targeted at APP.[20]

[21] This type accounts for no more than 10–15% of EOFAD.

As of 2023, the count of known pathogenic APP mutations stands at just over 20.[22] The most prevalent among these mutations - APP V717I, known as the London Mutation - was first identified in 1991 within the family of Carol Jennings by a research team led by John Hardy.[23][24][25] Other notable APP mutations include the Swedish[26] and Arctic mutations.[27] Functional analyses of these mutations have significantly increased the understanding of the disease pathogenesis. Whereas the Swedish mutation, located at the cleavage site for β-secretase, results in an overall higher production of Aβ peptides by increasing the β-secretory cleavage,[28] the London mutation, as well as other mutations in the APP at codon 717, shifts the ratio of toxic Aβ species to the more aggregate-prone 42 amino-acid length peptide,[29] while the Arctic mutation leads to a conformation change of the Aβ peptide and increased formation of toxic Aβ protofibrils.[30]

Histologically, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid can be seen in sections of brain tissue. This amyloid protein forms plaques and neurofibrillary tangles that progress through the brain. Very rarely, the plaque may be unique, or uncharacteristic of AD; this can happen when a mutation occurs in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations.

The underlying neurobiology of this disease is just recently starting to be understood. Researchers have been working on mapping the inflammation pathways associated with the development, progression, and degenerative properties of AD. The major molecules involved in these pathways include glial cells (specifically astrocytes and microglia), beta-amyloid, and proinflammatory compounds. As neurons are injured and die throughout the brain, connections between networks of neurons may break down, and many brain regions begin to shrink. By the final stages of Alzheimer's, this process – called brain atrophy – is widespread, causing significant loss of brain volume. This loss of brain volume affects ones ability to live and function properly, ultimately being fatal.[31]

Beta-amyloid is a small piece of a larger protein called amyloid precursor protein (APP). Once APP is activated, it is cut into smaller sections of other proteins. One of the fragments produced in this cutting process is β-amyloid. β-amyloid is “stickier” than any other fragment produced from cut-up APP, so it starts an accumulation process in the brain, which is due to various genetic and biochemical abnormalities. Eventually, the fragments form oligomers, then fibrils, beta-sheets, and finally plaques. The presence of β-amyloid plaques in the brain causes the body to recruit and activate microglial cells and astrocytes.[32]

Following cleavage by β-secretase, APP is cleaved by a membrane-bound protein complex called γ-secretase to generate Aβ.[33] Presenilins 1 and 2 are the enzymatic centers of this complex along with nicastrin, Aph1, and PEN-2. Alpha-secretase cleavage of APP, which precludes the production of Aβ, is the most common processing event for APP. 21 allelic mutations have been discovered in the APP gene. These guarantee onset of early-onset familial Alzheimer disease and all occur in the region of the APP gene that encodes the Aβ domain.

Genetic testing is available for symptomatic individuals and asymptomatic relatives.[5] Among families with EOFAD, 40–80% will have a detectable mutation in the APP, PSEN1, or PSEN2 gene. Therefore, some families with EOFAD will not have an identifiable mutation by testing.