Familial Alzheimer's Disease Pedigrees Research Articles

A Rare Variation in the 3' Untranslated Region of the Presenilin 2 Gene Is Linked to Alzheimer's Disease.

Rare variations in coding regions may alter the amino acid sequence and function of presenilins (PSENs), which results in the dysfunction of gamma-secretase, in turn contributing to the development of familial Alzheimer's disease (AD). However, whether rare variations in the 3' untranslated region (UTR) may change the expression level of PSEN2 leading to AD remains unclear. In a familial AD pedigree, DNA samples of the patients were screened for APP, PSEN1, and PSEN2 gene mutations using Sanger sequencing. Allele A of rs537889666, a rare variation located in the 3' UTR of PSEN2, was found in all AD patients, but not in the healthy control in the family. Cosegregation analysis (n = 5) revealed that allele A of rs537889666 may be a pathogenic rare variation. The dual-luciferase assay revealed that allele A suppressed the combination of miR-183-5p and the 3' UTR of PSEN2, which may block the miR-183-5p-mediated suppression of PSEN2 expression. Further study showed an elevated ratio of Aβ42/40 under overexpressed PSEN2 conditions. Measurements of the cerebrospinal fluid showed that PSEN2 levels were increased in both sporadic and AD in this family, suggesting that elevated PSEN2 was associated with the disease. In addition, the miR-183-5p inhibitor or mimic can increase or decrease Aβ42/40 ratios. In conclusion, the results indicate that allele A of rs537889666 upregulated PSEN2 levels, increasing the Aβ42/40 ratio and contributing to AD development.

PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease.

The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles. The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.

A Novel AβPP M722K Mutation Affects Amyloid-β Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals.

Mutations within exons 16 and 17 of the amyloid-β protein precursor (AβPP) gene were the first known causes of early-onset familial Alzheimer's disease (EOFAD). Since the first AβPP mutation was reported, 39 different AβPP variations have been discovered in EOFAD. We described a novel AβPP M722K mutation found in a Chinese familial Alzheimer's disease pedigree and confirmed its effects on amyloid-β (Aβ) secretion and tau phosphorylation. We performed direct sequencing of exons 16 and 17 of the AβPP gene and coding exons 3-12 of the PSEN1 and PSEN2 genes for genetic analysis. N2a cells were transfected with wild-type AβPP, AβPP constructs harboring the M722K mutation, or AβPP constructs harboring the Swedish mutation to demonstrate the effects of the AβPP M722K mutation on Aβ secretion and tau phosphorylation. Different phenotypes of patients carrying the AβPP M722K mutation maybe were related to different apolipoprotein E genotypes. The expression of AβPP M722K in mouse neuroblastoma N2a cells induced a 1.7-fold increased ratio of Aβ 42 to Aβ 40 without changes in sAβPPα and sAβPPβ. Tau phosphorylation at the AT8 sites was also increased. Maybe the AβPP M722K mutation contributed to the cause of EOFAD in this Chinese pedigree mediated by increased Aβ 42/Aβ 40. Further studies should be conducted to validate the pathogenicity of AβPP M722K and the interactions among γ-secretase, APOE, and AβPP.

Chinese Presenilin-1 V97L mutation enhanced Aβ42 levels in SH-SY5Y neuroblastoma cells

Presenilin-1 gene mutations have been proven to be associated with the majority of early-onset familial Alzheimer's disease (FAD). There have been, however, no systematic studies of Presenilin-1 gene mutation in FAD in China so far. We found a novel Val → Leu missense mutation at codon 97 (Val97Leu) of the Presenilin-1 gene in a Chinese FAD pedigree. To verify whether this mutation is pathologically functional, we established mutation type and wild type Presenilin-1 gene stably transfected cell lines (human neuroblastoma SH-SY5Y cells) to detect β-amyloid (Aβ) concentrations using ELISA and radioimmunity methods. We also examined levels of β-amyloid precursor protein cleaving enzyme (BACE) and amyloid precursor protein (APP) to explore their impact upon β-amyloid production. Our results showed that Aβ42 concentration was significantly enhanced at 48 h when compared to that at 24 h in the mutant type cells. At 48 h Aβ42 levels in the V97L mutants was also found to be elevated significantly, both intracellularly and extracellularly when compared to wild and mock transfected cells. The total Aβ in either group did not alter, consistent with unchanged BACE and APP expression levels. Our data reveal that the Presenilin-1 V97L variant can elevate Aβ42 levels both intracellularly and extracellularly, and was a potentially pathogenic mutation for this Chinese FAD pedigree. It also suggests that there are common mechanisms in the pathogenesis of FAD between Chinese and other ethnic populations, although their gene mutation sites are different.

Modeling Clinically Heterogeneous Presenilin Mutations with Transgenic Drosophila

To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years . PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity . Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease.

Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation.

Three affected individuals are described from a small English kindred with early-onset autosomal dominant familial Alzheimer disease (FAD) caused by a leucine-to-valine change at codon 153 (L153V) of the presenilin 1 (PSEN1) gene. Clinical information on the pedigree was collected directly from family members and from hospital records. Samples of DNA were screened by means of direct sequencing of all coding exons of PSEN1. One patient underwent neuropathological examination. Mean age at onset of symptoms was 35.3 years (95% confidence interval [CI], 34.6-36.0 years); at death, 44.0 years (95% CI, 39.1-48.9 years). Mean duration of illness was 8.3 years (95% CI, 4.7-11.9 years). Myoclonus was a late feature in 1 patient; seizures were not reported in any subjects. Spastic paraparesis and extrapyramidal signs were absent. The neuropsychometric profile of 1 patient showed relatively preserved naming skills in the setting of global cognitive deficits. Results of neuropathological examination demonstrated the signature lesions of Alzheimer disease and the presence of occasional cortical Lewy bodies. The PSEN1 L153V mutation lies in the main mutation cluster of PSEN1 in the second transmembrane domain. It causes early-onset FAD with clinical features similar to those of other reported FAD pedigrees.

A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy

A number of missense mutations associated with early-onset familial Alzheimer's disease have been reported in the presenilin-1 gene. The mutations were demonstrated to cluster in specific regions of the protein. We report here a novel missense mutation at the C-terminus of the third transmembrane domain in the presenilin-1 protein in a family of Japanese origin with early-onset Alzheimer's disease. This mutation is located at a site that is different from the sites at which mutations are known to cluster. Although the clinical phenotype is similar to those of pedigrees associated with other presenilin-1 mutations, postmortem examination of this pedigree revealed heavy amyloid deposits in the walls of small meningeal arteries as well as around small vessels within the brain parenchyma. These results indicate that a mutation at the C-terminus of the third transmembrane domain in the presenilin-1, which is a novel site for mutations, may play a key role in Alzheimer's pathogenesis.

Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal MRI study.

The hippocampal formation (HF) is known from pathological and MRI studies to be severely atrophied in established Alzheimer's disease. However, it is unclear when the earliest changes in the HF occur. We performed a longitudinal study of asymptomatic individuals at risk of autosomal dominant familial Alzheimer's disease in order to assess presymptomatic changes in the HF. Seven at risk members of a familial Alzheimer's disease pedigree associated with the amyloid precursor protein 717 valine to glycine mutation underwent serial MR scanning and neuropsychological assessments over 3 years. These assessments were compared with results from 38 normal controls. During the study three at risk subjects became clinically affected. Volumetric measurement of the HF showed that asymmetrical atrophy developed in these subjects before the appearance of symptoms. Verbal and visual memory measures declined in parallel with hippocampal loss. A loss of up to 8% per annum of the volume of the HF occurred in the 2 years over which symptoms first appeared. These findings may have implications for early diagnosis of Alzheimer's disease.

Clinical and neuroimaging features of familial Alzheimer's disease.

Subtle phenotypic differences between familial Alzheimer's disease (FAD) pedigrees can be identified which may reflect the genetic and allelic heterogeneity of the disease. Positron emission tomography (PET) of APP mutation and chromosome 14-linked FAD pedigree members reveals biparietal bitemporal hypometabolism. Scanning of asymptomatic at-risk individuals reveals a similar, but quantitatively less severe, pattern of hypometabolism.

The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families

Genetic linkage studies place a gene causing early onset familial Alzheimer's disease (FAD) on chromosome 14q24.3 (refs 1-4). Five mutations within the S182 (Presenilin 1: PS-1) gene, which maps to this region, have recently been reported in several early onset FAD kindreds. We have localized the PS-1 gene to a 75 kb region and present the structure of this gene, evidence for alternative splicing and describe six novel mutations in early onset FAD pedigrees all of which alter residues conserved in the STM2 (Presenilin 2: PS-2) gene.

Early onset Alzheimer's disease in a South American pedigree from Argentina

We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed β amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the β amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease.

Early onset Alzheimer's disease in a South American pedigree from Argentina.

We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed beta amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the beta amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease.

Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation.

The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer disease (AD), is secreted by cultured human cells during normal metabolism. In studies of cell lines transfected with beta-amyloid precursor protein (beta APP) cDNAs, the beta APP mutation K670N/M671L found in a Swedish familial AD (FAD) pedigree has previously been shown to cause a marked augmentation of A beta secretion. Here, we have conducted blinded analyses of beta APP metabolism in primary skin fibroblasts from affected members of the Swedish FAD pedigree and their unaffected siblings or spouses. These fibroblasts continuously secrete a homogenous population of A beta molecules starting at Asp-1 (D672 of beta APP). We found a consistent and significant approximately 3-fold elevation of A beta release from all biopsied skin fibroblasts bearing the FAD mutation. No significant alterations of other metabolic derivatives of beta APP were detected. The elevated A beta levels were found in cells from both patients with clinical AD and presymptomatic subjects. Thus, A beta overproduction in this FAD pedigree is not a secondary event but is consistent with a causal role in the development of the disease. Increased A beta secretion can begin many years prior to onset of symptoms, even in peripheral tissues, indicating that it does not require preexisting neural abnormalities.

Search for the genes responsible for familial Alzheimer's disease.

Inherited or Familial Alzheimer's Disease (FAD) has clearly been shown to be a genetically heterogeneous disorder. Mutations in the gene on chromosome 21 encoding the beta-amyloid protein precursor (APP) have been shown to be linked to 2-3% of FAD kindreds examined around the world. A late onset FAD locus has been mapped to a region of chromosome 19 in which a recently isolated APP-like gene, APLP1 has also been localized, making this gene a strong candidate to harbor a late-onset FAD defect. More recently, a major FAD locus has been mapped to the long arm of chromosome 14. The chromosome 14 locus appears to be mainly linked to the gene defect in early onset FAD pedigrees. Besides the FAD loci on chromosome 21, 19, and 14, at least two other loci must exist since the gene defect in some early- and late-onset FAD pedigrees do not appear to segregate with markers from any of these autosomes. As different gene defects responsible for various forms of FAD are discovered, perhaps, a common basis for the etiology of this devastating disorder can be discerned.

Alzheimer's disease families with amyloid precursor protein mutations.

Early onset Familial Alzheimer's Disease (FAD) is an autosomal dominant disease with apparent complete penetrance. It is genetically heterogeneous with some families carrying mutations in the amyloid precursor protein (APP) gene which segregate with the disease. In addition, there is allelic heterogeneity with four mutations associated with FAD. Three mutations have been reported at APP 717, just distal to the C-terminus of the beta-amyloid domain, APP 717 val-ile, APP 717 val-phe, and APP 717 val-gly, which are associated with autopsy-proven Alzheimer's disease (AD). APP 670/671 lies at the N terminus of the beta-amyloid domain and is associated with clinically diagnosed FAD in two Swedish families. FAD tends to have prominent myoclonus and this is shared by the cases with APP mutations. In two unrelated UK families with APP 717 val-ile mutations there was early prominent memory impairment with dyscalculia proceeding to generalized cognitive impairment with a lack of insight. There was a late development of a gait disturbance with extrapyramidal features in some members. Positron emission tomography (PET) with fluorodeoxyglucose demonstrated posterior bitemporal biparietal hypometabolism in one case. Magnetic resonance imaging (MRI) showed generalized cerebral atrophy particularly affecting the temporal lobes and hippocampus. At autopsy, a single case showed extensive beta-amyloid deposition with congophilic angiopathy and widespread senile plaques and neurofibrillary tangles. The cytoskeletal pathology associated with abnormally phosphorylated tau was similar to cases of sporadic AD. In addition, there were widespread cortical and subcortical Lewy bodies. A single family with the APP 717 val-gly mutation also showed prominent myoclonus, lack of insight, and seizures, PET, in a single case, showed classical biparietal bitemporal hypometabolism. Autopsy, in a single case, showed diffuse deposits of beta-amyloid throughout the cortex with frequent neuritic plaques and neurofibrillary tangles. No other inclusion bodies were seen. There was severe congophilic angiopathy. The age at onset of APP mutations is around 50 years of age by contrast to other early onset FAD pedigrees.

A novel but non-pathogenic mutation in exon 4 of the human amyloid precursor protein (APP) gene

Mutations in the β-amyloid precursor protein (APP) gene have been associated with both familial Alzheimer disease (FAD) and with hereditary cerebral haemorrhage. The polymerase chain reaction was used to both amplify and sequence exon 4 of the APP gene from genomic DNA of subjects with FAD and normal control subjects. A novel, rare, conservative DNA sequence variant was discovered at nucleotide 459 of codon 153 (valine) in exon 4 of the APP gene in an affected member of a large FAD pedigree. Segregation studies indicate that this mutation is likely to be non-pathogenic, but must be recognized and discriminated from pathogenic mutations during sequencing studies of the APP gene in patients with FAD.

The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene.

Amyloid beta-protein (AP) is a peptide of relative molecular mass (Mr) 42,000 found in the senile plaques, cerebrovascular amyloid deposits, and neurofibrillary tangles of patients with Alzheimer's disease and Down's syndrome (trisomy 21). Recent molecular genetic evidence has indicated that AP is encoded as part of a larger protein by a gene on chromosome 21 (refs 5-7). The defect in the inherited autosomal dominant form of Alzheimer's disease, familial Alzheimer's disease (FAD), has been mapped to the same approximate region of chromosome 21 by genetic linkage to anonymous DNA markers, raising the possibility that this gene product, which could be important in the pathogenesis of Alzheimer's disease, is also the site of the inherited defect in FAD (ref. 5). We have determined the pattern of segregation of the AP gene in FAD pedigrees using restriction fragment length polymorphisms. The detection of several recombination events with FAD suggests that the AP gene is not the site of the inherited defect underlying this disorder.

Chapter 18 DNA damage, DNA repair and the genetic basis of Alzheimer's disease

The high frequency of Alzheimer's disease (AD) is an important consideration in assessing possible genetic components. Conservative estimates placing the incidence of severe dementia at more than 5% among individuals over 65 years of age put this disease group in a high-incidence category. A number of studies have examined human leukocyte antigen (HLA) associations with AD to identify genetic markers, with reports of increased frequencies of HLA-B7, HLA-CW3, and DR4. Another study, involving 44 patients and 100 controls, suggested that the relative risk for individuals carrying HLA-AW30, B14, or B13 might be increased. Direct approaches to the genetic analysis of AD are now available. The use of restriction fragment length polymorphism analysis employing random or, potentially, specific chromosome DNA probes should yield marker information in familial AD pedigrees, just as it has for Huntington's disease. Both the scattered chromosome data and broad theories of aging have led to the studies concerned with the response of cells from AD patients to DNA-damaging agents. There is no doubt that increased sensitivity to DNA damaging agents, such as ionizing radiation, is associated with AD in a statistical sense. However, not all individuals with AD exhibit the considerable heterogeneity of the underlying mutations.