ALZHEIMER DISEASE; AD

Alternative Terms:

PRESENILE AND SENILE DEMENTIA
ALZHEIMER DISEASE, FAMILIAL; FAD

Clinical Synopsis:

Neuro:
Presenile and senile dementia;
Parkinsonism;
Long tract signs
Misc:
? Excess of Down syndrome and myeloproliferative disorders
Lab:
Neurofibrillary tangles composed of disordered microtubules in neurons;
Some early-onset families due to mutation in the gene for amyloid
precursor protein (104760.0002) on chromosome 21
Inheritance:

Autosomal dominant allele with additional multifactorial component
in late-onset cases

Mini-MIM:

Alzheimer disease is by far the most common cause of dementia. Clinically, it cannot be distinguished from Pick disease (172700).

The histopathological picture is characterized by neurofibrillary tangles and amyloid plaques, which contain a novel amyloid protein, beta protein. It is suggested that the amyloid in Alzheimer disease (and Down syndrome) is formed from a precursor synthesized in neurons, where it produces neurofibrillary tangles, and in microglial cells and brain macrophages from which it is exuded and forms the extracellular amyloid plaques and vascular amyloid deposits (Gajdusek, 1986).

In a study of 70 kindreds, Farrer et al. (1990) found evidence of 2 categories of families: those with mean age of onset less than 58 years (early onset form) and those with mean age of onset greater than 58 years (late-onset form).

Early onset FAD is, in some families, due to a mutation of a gene, AD1, near the centromere on chromosome 21q, that codes for amyloid precursor protein (Lawrence et al., 1992). Other early onset families show linkage to markers on 14q (Van Broeckhoven et al., 1992), and there may be a second locus on 21 (St. George-Hyslop et al., 1990).

In one representative study (van Dujin et al., 1993) the lifetime risk (to age 90) of first degree relatives of early onset cases (less than 65 years) was about 40%; higher in females than males (56 vs. 22%) and in parents than sibs (42 vs. 18%) compared to 14% for controls. The risk at age 70 was about 13% for first-degree relatives versus about 7% for controls.

The situation for late-onset AD is even more complex, involving several loci, and perhaps polygenic and environmental contributions (Haines, 1991). Most, if not all, families with late-onset FAD have mutations on chromosomes other than 21, particularly AD2 (Pericak-Vance et al., 1991). The recently discovered relationship of late-onset AD to the apolipoprotein E type 4 allele on chromosome 19 may clarify the picture (Corder et al., 1993). See 104310. In a series of 42 late-onset families, 20% of affected members had no copies of E4, 47% had one, and 91% had two copies. Mean ages of onset were 84, 76, and 68 years, respectively.

Commentary:

DESCRIPTION

A number sign (#) is used with this entry because of evidence that mutations in at least 4 genes can cause Alzheimer disease: AD1 is caused by mutations in the amyloid precursor gene (104760); AD2 is associated the the APOE*4 allele on chromosome 19 (107741); AD3 is caused by mutation in a chromosome 14 gene encoding a 7-transmembrane domain protein (104311); and AD4 is caused by mutation in a gene on chromosome 1 that encodes a similar 7-transmembrane domain protein (600759). In addition, evidence has been presented suggesting involvement of mitochondrial DNA mutations in Alzheimer disease (502500).

Alzheimer disease, the most common cause of dementia, is inherited as an autosomal dominant trait in some families.

CLINICAL FEATURES

Alzheimer disease is by far the most common cause of dementia. Terry and Davies (1980) pointed out that the presenile form (with onset before age 65) is identical to the most common form of senile dementia. Thus, they recommended the designation senile dementia of the Alzheimer type (SDAT). Clinically, Alzheimer disease cannot be distinguished from Pick disease (172700).

Schottky (1932) described presenile dementia in 4 generations. The diagnosis was confirmed at autopsy in a patient in the fourth generation. Lowenberg and Waggoner (1934) reported a family with unusually early onset in the father and 4 of 5 children. Postmortem findings in 1 case were described. McMenemey et al. (1939) described 4 affected males in 2 generations with pathologic confirmation in one.

Heston et al. (1966) described a family with 19 affected in 4 generations. Dementia was coupled with conspicuous parkinsonism and long tract signs. In a study of the families of Alzheimer disease patients, Heston (1977) found an excess of Down syndrome and of myeloproliferative disorders, e.g., lymphoma and leukemia. Although the mechanism is not clear, Heston (1977) speculated that a disorder of microtubules underlies the association. Microtubules are involved in the spatial orientation of chromosomes and their separation in meiosis and mitosis. Neurons of Alzheimer patients show a neurofibrillary tangle that is made up of disordered microtubules. An identical lesion occurs in the neurons of Down syndrome, at an earlier age than in Alzheimer disease. Leukemia and accelerated aging are also features of Down syndrome. In a large multicenter study of first-degree relatives of Alzheimer disease probands and nondemented spouse controls, Silverman et al. (1994) found only one case of Down syndrome, a relative of a spouse control. On the basis of a study of the families of 188 Down syndrome children and 185 controls, Berr et al. (1989) found no evidence of an excess of dementia cases with insidious onset suggestive of dementia of Alzheimer type in the families of children with classic trisomy 21. One mechanism whereby Alzheimer disease might occur in a parent of a Down syndrome patient is somatic mosaicism in that parent.

Harper et al. (1979) could not confirm that a systemic microtubular defect exists in Alzheimer disease. Cultured skin fibroblasts showed normal tubulin networks. Nordenson et al. (1980) found an increased frequency of acentric fragments in karyotypes from patients with Alzheimer disease. They viewed this as consistent with defective tubulin protein leading to erratic function of the spindle mechanism.

Ball (1980) reported a kindred in which members had the clinical features of familial Alzheimer disease but histologic changes of spongiform encephalopathy of the Creutzfeldt-Jakob type (123400) at autopsy. The clinical course, with dementia for as long as 10 years, was unusual for CJD. Masters et al. (1981) studied 52 families and compared them with familial Creutzfeldt-Jakob disease. The age at death and duration of illness was greater in AD. No maternal effect was evident in the pattern of autosomal dominant inheritance. In 4 families with AD, 1 or more members had died from CJD. In 17 other families with AD, 1 or more members presented with clinical features suggesting CJD. Although a virus causing an experimental spongiform encephalopathy was isolated from the brain of 2 cases of familial AD, brain tissue from most sporadic and familial cases of AD failed to cause disease when inoculated into nonhuman primates.

In the families of 17 of 68 cases, Heyman et al. (1983) found secondary cases in parents and sibs. The cumulative incidence in these relatives was about 14% at age 75. A probable increase in the frequency of Down syndrome was noted: 3.6 per 1,000 as compared with an expected rate of 1.3 per 1,000. A history of thyroid disease was unusually frequent (9 of 46; 19.6%) in the female probands. No excess of hematologic malignancy was found in relatives. Parental age at time of birth of the probands did not differ from the normal. Corkin et al. (1983) also could find no difference in parental age from that in controls.

Joachim et al. (1989) presented evidence suggesting that Alzheimer disease is not restricted to the brain but is a widespread systemic disorder with accumulation of amyloid beta protein in nonneuronal tissues.

In a study of 70 kindreds containing 541 affected and 1,066 unaffected offspring of demented parents, Farrer et al. (1990) found evidence of 2 categories of families: those with mean age of onset less than 58 years (early-onset form) and those with mean age of onset greater than 58 years (late-onset form). At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, leading Farrer et al. (1990) to suggest autosomal dominant inheritance. The lifetime risk in late-onset families was 86%. Farrer et al. (1990) concluded that this form may have at least 2 causes: autosomal dominant inheritance in some families and other genetic or shared environmental factors in other families. Farrer et al. (1990) pointed out that some early-onset families show linkage to markers on chromosome 21, whereas there is evidence against linkage to the same group of markers in late-onset families. By the criteria of the analysis, the Volga Germans (Bird et al., 1988), who are among the unlinked families, were classified as the upper boundary of the early-onset group.

In a complex segregation analysis on 232 nuclear families ascertained through a single proband who was referred for diagnostic evaluation of memory disorder, Farrer et al. (1991) concluded that susceptibility to AD is determined, in part, by a major autosomal dominant allele with an additional multifactorial component. The frequency of the AD susceptibility allele is estimated to be 0.038, but the major locus was thought to account for only 24% of the 'transmission variance,' indicating a substantial role for other genetic and nongenetic mechanisms.

Silverman et al. (1994) used a standardized family history assessment to study first-degree relatives of Alzheimer disease probands and nondemented spouse controls. First-degree relatives of the probands with Alzheimer disease had a significantly greater cumulative risk of Alzheimer disease (24.8%) than did the relatives of spouse controls (15.2%). The cumulative risk for the disorder among female relatives of probands was significantly greater than that among male relatives.

BIOCHEMICAL FEATURES

Glenner and Wong (1984) identified a novel amyloid protein, called beta protein, in Alzheimer disease. The 4.2-kD polypeptide was called beta protein because of its partial beta-pleated sheet structure. It was identified in both amyloid plaque core and in cerebral vascular amyloid; both have an identical 28-amino acid sequence. A cDNA for the beta protein suggested that it is derived from a larger protein expressed in a variety of tissues (Tanzi et al., 1987).

Kang et al. (1987) isolated and sequenced an apparently full-length cDNA clone coding for the A4 polypeptide (the designation they used for the major protein subunit of the amyloid fibril of tangles, plaques, and blood vessel deposits in AD and Down syndrome). The predicted precursor consisted of 695 residues and contained features characteristic of glycosylated cell-surface receptors.

Abraham et al. (1988) identified one of the components of the amyloid deposits seen in Alzheimer disease as the serine protease inhibitor alpha-1-antichymotrypsin. Carrell (1988) speculated that plaque formation in Alzheimer disease is a consequence of proteolysis of the precursor protein; self-aggregation of the cleaved A4 peptides explains the precipitated amyloid, while release of a trophic inhibitory domain explains the interwoven neuritic development. Zubenko et al. (1987) described a biophysical alteration of platelet membranes in Alzheimer disease. They concluded that increased platelet membrane fluidity identifies a subgroup of patients with early age of symptomatic onset and rapidly progressive course.

Zubenko and Ferrell (1988) described monozygotic twins concordant for probable Alzheimer disease and for increased platelet membrane fluid. See 173560. Birchall and Chappell (1988) suggested that individual vulnerability to aluminum might depend on genetic factors influencing intake, transport or excretion, and might be a mechanism for familial Alzheimer disease. The inositol phosphate system may be particularly vulnerable.

Kitaguchi et al. (1988) showed that the amyloid protein precursor contains a domain very similar to the Kunitz family of serine protease inhibitors. All 3 groups found the variable presence of a domain of 56 residues interpolated at residue 289, that is, in the proposed extracellular portion of the amyloid precursor protein. The best-studied member of the protease inhibitor family is bovine pancreatic trypsin inhibitor, also called aprotinin. The newly found amyloid protein sequence was 50% identical to aprotinin and also to the second inhibitory domain of the human plasma protein, inter-alpha-trypsin inhibitor.

OTHER FEATURES

Gajdusek (1986) suggested that the amyloid in Alzheimer disease and Down syndrome is formed from a precursor synthesized in neurons as well as in microglial cells and brain macrophages: that synthesized in neurons produces neurofibrillary tangles, and that synthesized in microglial cells and brain macrophages is exuded from the cell and forms the extracellular amyloid plaques and vascular amyloid deposits. Dying neurons may also contribute to extracellular deposits.

Wolozin et al. (1988) performed immunocytochemical studies of cerebral cortex tissue sections from normal human fetal and neonatal brain, and of brain tissue from individuals with Down syndrome and patients with Alzheimer disease. They used the monoclonal antibody ALZ-50, which recognizes a 68-kD protein. The authors reported that ALZ-50-reactive neurons are found in normal fetal and neonatal human brain as well as in brain tissue from neonates with Down syndrome. The number of reactive neurons decreased sharply after age 2 years, but reappeared in older individuals with Down syndrome and in patients with Alzheimer disease.

INHERITANCE

From an extensive study in Sweden, Sjogren et al. (1952) suggested that whereas Pick disease may be dominant with important modifier genes, Alzheimer disease was multifactorial. However, a dominant pattern of inheritance, more common in presenile cases than in older patients, is well documented and accounts for about one-third of all cases of Alzheimer disease.

Masters et al. (1981) found no maternal effect in the autosomal dominant inheritance pattern of 52 families.

In 7 of 21 families, Powell and Folstein (1984) found evidence of 3-generation transmission. Paternal age was raised, they concluded, in the case of new mutation cases. Age of onset varied from 25 to 85 years. Breitner and Folstein (1984) suggested that most cases of Alzheimer disease are familial. Fitch et al. (1988) found a familial incidence of 43%. They could detect no clinical differences between the familial and sporadic cases. In one-third of the familial cases, the gene was not expressed until after age 70. In a continuing longitudinal study of family members of probands with Alzheimer disease, Breitner et al. (1988) found that the cumulative incidence of Alzheimer disease among relatives was 49% by age 87. The risk was similar among parents and siblings and did not differ significantly between relatives of presenile-onset versus senile-onset probands.

CYTOGENETICS

Percy et al. (1991) described 2 sisters thought to have Alzheimer disease of late onset who also had an unusual chromosome 22-derived marker with a greatly elongated short arm containing 2 well-separated nucleolus organizer regions. Eleven of 24 of their biological relatives were also found to have the marker. In the sisters' generation and in the previous generation, 7 persons with Alzheimer disease had died. The average age at onset of dementia was 65.8 years and the average age at death, 74.9 years.

MAPPING

Wheelan and Race (1959) studied a family in which the mother and 5 of 10 children were affected. Possible linkage with the MNS locus was found.

In the large kindred reported by Weitkamp et al. (1983) studied the transmission of HLA and Gm types and concluded that 'genes in the HLA region of chromosome 6 and perhaps also in the Gm region of chromosome 14 are determinants of susceptibility.' The association between immunoglobulins and the amyloid in the senile plaque of AD was thought to be significant in this connection. The peak lod score with Gm was 1.37 (at theta = 0.05).

Nee et al. (1983) reported the most extensively affected kindred, with 51 affected persons in 8 generations. No preponderance of affected females and no increased incidence of Down syndrome or hematologic malignancy were found.

Nerl et al. (1984) reported an increase in the frequency of the C4B allele C4B2 in patients with Alzheimer disease, but Eikelenboom et al. (1988) failed to find a significant association between C4B2 allelic frequency and AD.

Kang et al. (1987) showed by somatic cell hybrids that the gene for A4 peptide is localized to chromosome 21. They commented on the fact that this protein shows similarities to the prion protein (PRNP; 176640) found in the amyloid of transmissible spongiform encephalopathies (Oesch et al., 1985). Membrane-spanning domains of both proteins may share an amyloid-forming or amyloid-inducing potential.

St. George-Hyslop et al. (1987) studied 4 extensive kindreds with many members affected with familial Alzheimer disease (FAD). They found linkage to DNA markers on chromosome 21. The markers in band 21q22, critical to the development of Down syndrome, showed negative lod scores. Notably, the marker B21S58, which is tightly linked to SOD1 (147450), was not tightly linked. The linked markers were found to lie on the centromere side of q22 in the region 21q11.2-21q21. Using a RFLP of SOD1 in the study of a large family with Alzheimer disease, David et al. (1988) concluded that SOD1 and AD are not closely linked. Goldgaber et al. (1987) used the first 20 of the 28 amino acids in the sequence to prepare an oligonucleotide probe for isolation of cDNA. They found that a 3.5-kb mRNA was detectable in mammalian brains and human thymus. The gene was found to be highly conserved in evolution and was mapped to chromosome 21 by somatic cell hybridization.

The type of Alzheimer disease coded by chromosome 21 may be an early-onset type; families with late onset are said not to show linkage to chromosome 21 markers (HGM9) (Cheng et al., 1988).

Using a RFLP of the A4-amyloid gene, Van Broeckhoven et al. (1987) found recombinants in 2 Alzheimer disease families. Two of their families were of early onset: one with 36 cases in 6 generations of which 10 had been histopathologically confirmed (mean age of onset, 33 years), and the second with 22 cases in 5 generations of which 4 had been histopathologically confirmed (mean age of onset, 34 years). All lod scores were negative in these 2 families. In 1 of 5 families of late onset, positive lod scores were observed. These data demonstrated that the gene for plaque core A4-amyloid cannot be the locus of the defect causing Alzheimer disease in these families. Tanzi et al. (1987) also found recombination between Alzheimer disease and the amyloid protein and came to the same conclusion.

Haines et al. (1987), who studied 4 large families with FAD, found linkage with 2 DNA markers on chromosome 21 that had previously been shown to be linked to each other at a distance of 8 cM. However, the pair-wise linkage analysis showed a lod score of 2.37 at theta = 0.08 for one and 2.32 at theta = 0.00 for the other. The use of multipoint analysis provided stronger evidence for linkage with a peak score of 4.25.

Bird et al. (1988) described 7 families with autopsy-confirmed AD, all being descendants of a group of immigrants known as the Volga Germans, who came to the United States between 1870 and 1920. Their ancestors had moved from Germany to the southern Volga region of Russia in the 1760s. All 5 were descendants of persons who originally lived in 2 small adjacent Volga German villages and shared several surnames known to have been present in the census records of those villages. There are more than 300,000 American descendants of the Volga Germans. In a further study of the 7 Volga German kindreds and in 8 other kindreds, all with autopsy-proven AD (except for 1 of the German Volga families), Schellenberg et al. (1988) could demonstrate no linkage to chromosome 21 markers. Other researchers have been unable to demonstrate linkage between late-onset Alzheimer disease and chromosome 21 markers, but the disorder in the families studied by Schellenberg et al. (1988) was of the early-onset type. The families studied by St. George-Hyslop et al. (1987) in which linkage with chromosome 21 markers was found had the early-onset type. The data strongly suggest that there is at least 1 other genetically distinct form of Alzheimer disease. (Rogaev et al. (1995) demonstrated that the mutation in the Volga Germans is located in the presenilin-2 gene encoded by chromosome 1 (600759.0001).)

By the study of linkage to DNA markers, Van Broeckhoven et al. (1988) concluded that the gene for early-onset familial Alzheimer disease is located close to the centromere of chromosome 21. Pulst et al. (1989) used a panel of aneuploid cell lines containing various regions of human chromosome 21 to map the physical order of DNA probes linked to the FAD locus. Van Camp et al. (1989) described the isolation of 35 chromosome 21 specific DNA probes for analysis in Alzheimer disease and Down syndrome. Ross et al. (1989) described the isolation of cDNAs from brain and spinal cord, mapping to chromosome 21, for investigation in Alzheimer disease. Pericak-Vance et al. (1988) found no linkage to chromosome 21 specific probes in studies of 13 families with FAD. The same group (Pericak-Vance et al., 1989, 1990) presented evidence for linkage to 2 markers on chromosome 19. When analysis was limited to the affecteds only, a lod score of 2.5 at theta = 0 was obtained for linkage with BCL3 (109560). Pericak-Vance et al. (1991) found evidence of both chromosome 19 linkage in their late-onset FAD families and chromosome 21 linkage in their early-onset FAD families. When only affected persons were used in the analysis, a high lod score was obtained also with ATP1A3 (182350), which maps to 19q12-q13.2. Haines (1991) gave a review.

Using the exclusion mapping method of Edwards (1987) and the affected-pedigree-member method (APM) of Weeks and Lange (1988), Roses et al. (1989) found some suggestion of implication of chromosome 19; predominantly late-onset families were studied.

Van Broeckhoven et al. (1989) described linkage analysis of 2 families with Alzheimer disease by use of chromosome 21 DNA markers. With probe D21S13, they found a lod score of 1.52 at theta = 0.09 in 1 family. Further studies analyzing D21S13 with D21S16 and D21S1/S11, 2 markers that had previously been linked to Alzheimer disease, found D21S13 to be tightly linked to D21S16 with a peak lod score of 6.24 at theta = 0. Pulsed field gel electrophoresis confirmed that the loci are separated by a distance of approximately 400 kb.

Using pulsed field gel electrophoresis to construct a physical map of the region of chromosome 21 around the FAD locus, Owen et al. (1989) suggested the following order: cen--D21S16--D21S48--D21S13--D21S46--(D21S52, D21S4)--(D21S1, D21S11). Using genetic linkage analysis, Goate et al. (1989) found a peak lod score of 3.3 between the FAD locus and locus D21S16.

Pulst et al. (1991) excluded the proximal portion of the long arm of chromosome 21 as the site of the AD gene in 1 large kindred.

Because of the conflicting findings concerning linkage to chromosome 21, St. George-Hyslop and many other members of the FAD collaborative study group undertook a study of 5 polymorphic chromosome 21 markers in a large unselected series of pedigrees with FAD. The results seemed to indicate that, in many families at least, early-onset Alzheimer disease is indeed due to a mutation on chromosome 21, whereas the late-onset form has other causes. From the work of Goate et al. (1991), it seems clear that 1 form of early-onset AD is caused by mutation in the gene for amyloid precursor protein (104760.0002). The families with Alzheimer disease mapping to chromosome 21 represent this form. Other families with early-onset AD and probably all families with late-onset AD have mutations on chromosomes other than chromosome 21.

Lawrence et al. (1992) reviewed the reported data on multiplex Alzheimer pedigrees for which lod scores had been reported; the AD1 locus which mapped to the site of the APP locus (104760) on 21q accounted for 63 11% of these pedigrees. The AD1/APP locus was placed at approximately 27.7 Mb from pter, corresponding to genetic intervals of 10.9 cM in males and 33.9 cM in females, flanked proximally by D21S8 and distally by D21S111. Since a much smaller proportion of pedigrees than 63% have mutations in the cDNA for beta-amyloid, which corresponds to exons 16 and 17 of APP, it is likely that the AD1 locus spans controlling elements near those exons. There was no evidence in this analysis for a second locus on chromosome 21.

MOLECULAR GENETICS

Delabar et al. (1986) analyzed DNA from 4 patients with Alzheimer disease and estimated the state of markers on chromosome 21. In all 4 cases, duplication of the ETS2 locus (164740) was found, whereas SOD1 (147450) was normal. These studies were undertaken because the patients had a phenotype of trisomy 21 but were found to have a normal karyotype; by chemical investigations and DNA analyses, they showed partial trisomy due to duplication of a short segment of chromosome 21, located at the interface between 21q21 and 21q22.1 and carrying the SOD1 and ETS2 genes.

Blanquet et al. (1987) found by molecular genetic methods that the Alzheimer amyloid protein gene and the ETS2 oncogene are distally located in the normal individual; surprisingly, 2 hybridization peaks were observed for ETS2 in the Alzheimer patient, 1 at the normal site of the oncogene and 1 at the site of the amyloid protein. Blanquet et al. (1987) interpreted these results as indicating that Alzheimer disease is associated with a complex rearrangement within chromosome 21, by which 2 distantly related genes come to lie in the vicinity of each other.

Overexpression of the gene in brain tissue from fetuses with Down syndrome is explained by dosage effect since the locus encoding the beta protein maps to chromosome 21. Regional localization of the gene by somatic cell hybridization and with linkage to DNA markers placed it in the vicinity of the genetic defect causing the inherited form of Alzheimer disease. This was done with somatic cell hybridization and with linkage to DNA markers (Tanzi et al., 1987). The 28-amino acid sequence has a variation at position 11: glutamine in the case of the cerebral vascular amyloid of Alzheimer disease, but glutamic acid in the case of cerebral vascular amyloid of Down syndrome and the amyloid plaque core of both disorders (Tanzi et al., 1987).

St. George-Hyslop et al. (1987), Podlisny et al. (1987) could demonstrate no evidence of duplication of chromosome 21 genes, and the amyloid beta protein gene specifically, in patients with either familial or sporadic Alzheimer disease; thus, some other mechanism for the brain-specific deposition of the amyloid beta protein must be sought. Murdoch et al. (1988) likewise found no duplication of the gene in autopsy-proved cases of Alzheimer disease.

ANIMAL MODEL

Selkoe et al. (1987) used a panel of antibodies against amyloid fibrils and their constituent vascular amyloid in 5 other species of aged mammals, including monkey, orangutan, polar bear, and dog. Antibodies to the 28-amino acid peptide recognized the cortical and microvascular amyloid of all the aged mammals examined (Selkoe et al., 1987).

Cheng et al. (1988) described the comparative mapping of DNA markers in the region of familial Alzheimer disease on human chromosome 21 and mouse chromosome 16. The linkage group shared by mouse chromosome 16 and human chromosome 21 includes both the Alzheimer amyloid beta precursor protein and markers linked to familial Alzheimer disease. The linkage group of 6 loci extends from anonymous DNA marker D21S52 to ETS2, and spans 39% recombination in man but only 6.4% recombination in the mouse. A break in synteny occurs distal to ETS2, and the homolog of human marker D21S56 maps to mouse chromosome 17.

To test whether the amyloid beta peptide in Alzheimer disease is neurotoxic, LaFerla et al. (1995) introduced a transgene, which included 1.8 kb of 5-prime flanking DNA from the mouse neurofilament-light (NF-L) gene, into mice to restrict expression of the peptide coding region of the APP gene to neuronal cells. In situ hybridization and immunostaining with amyloid beta antibodies detected extensive transgene expression and peptide in cerebral cortex and hippocampus, and limited expression in other areas of the brains of the transgenic mice. (Both the cerebral cortex and hippocampus are severely affected in Alzheimer disease.) The study showed that expression of amyloid beta is sufficient to induce a progressive series of changes within the brains of transgenic mice, initiating with neurodegeneration and apoptosis, followed by the activation of secondary events such as astrogliosis, and ultimately ending with spongiosis. Accompanying the cell death was the appearance of clinical features including seizures and premature death, both of which have been described in Alzheimer disease.