Genome scan on Swedish Alzheimer's disease families.

Alzheimer's disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes were identified, which directly cause the disease (APP, PSEN1 and PSEN2) or greatly increase the risk of disease development (APOE), it has proved exceedingly difficult to identify additional genes involved in the pathogenesis. However, several linkage and association studies have repeatedly supported the presence of susceptibility genes on chromosomes (chrms) 9, 10 and 12. The study populations have, however, mostly been of great genetic heterogeneity, and this may have contributed to the meagre successes in identifying the disease associated genetic variants. In this study, we have performed a genome wide linkage study on 71 AD families from the relatively genetically homogeneous Swedish population where it is also possible to study the genetic ancestry in public databases. We have performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE varepsilon4. Our results suggest that the families included in this study are tightly linked to the APOE region, but do not show evidence of linkage to the previously reported linkages on chrms 9, 10 and 12. Instead, we observed the next highest LOD score on chromosome 5q35 in the total material. Further, the data suggest that the major fraction of families linked to this region is APOE varepsilon4 positive.

Conversion from preclinical to dinical stage of Alzheimer's disease as shown by decline of cognitive function in carriers of the Swedish APP-mutation.

The characterisation of the borderline syndrome between normal cognitive function and Alzheimer's disease (AD), often mentioned as Mild Cognitive Impairment (MCI) has been a goal for recent research. However, a variety of definitions of MCI-like syndromes and the uncertainty about the final diagnosis have hampered progress. To overcome these problems, the present study will describe cognitive function in two healthy mutation carriers and two matched non-carriers of the Swedish double mutation family, during the time period when carriers convert to a symptomatic stage, i.e., true preclinical AD, and finally into the stage when a clinical diagnosis of AD is first possible. The findings question the generality of common MCI concepts and the commonly held beliefs about cognitive features in late preclinical stage of AD.

The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.

Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.

Investigations of a CA repeat in the oestrogen receptor beta gene in patients with Alzheimer's disease.

Several studies have shown that oestrogen treatment after menopause decreases the risk for Alzheimer's disease (AD). It is also known that oestrogen stimulates the outgrowth of nerve cells and that apolipoprotein E (Apo E) synthesis and amyloid precursor protein (APP) metabolism are regulated by oestrogen. Recently a new oestrogen receptor was identified, oestrogen receptor beta (ERbeta), located at chromosome 14q22-24. Several genes close to this chromosomal region have been implicated in AD, but the results are conflicting. Our hypothesis was that variations in the ERbeta gene could be the underlying cause to the positive findings in these genes and we have therefore investigated a CA repeat(1) in intron 5 of the ERbeta gene. Three hundred and thirty-six AD cases and 110 healthy age-matched controls were included in this study. Fourteen different alleles were found with frequencies between 0.1 and 37%. There was no significant difference between AD cases and controls when all alleles were compared. However, allele 5 was seen in 13.6% of the controls but only in 8.0% of AD cases (P=0.014; odds ratio (OR)=0.55). No AD patient homozygous for this allele was seen but three controls were homozygous. In conclusion, our findings suggest the ERbeta allele 5 to be a protective factor. However, this has to be confirmed in a larger population.

Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women.

Estrogens may be implicated in the development of Alzheimer's disease (AD). Most of their effects are mediated via receptors whose function and expression may be modified by DNA polymorphisms. Here the estrogen receptor 1 gene (ESR1) polymorphisms XbaI and PvuII were analyzed in 214 AD patients and 290 controls. In logistic regression analysis, a significantly increased risk of familial AD due to interaction between the ESR1 xx genotype and the apolipoprotein E epsilon4 allele was observed in women in a Swedish clinic-based sample, taking subjects who had neither the xx genotype nor epsilon4 as reference (OR 11.3, 95% CI 2.9-43.8). The risk of AD was more pronounced in early-onset (OR 22.0, 95% CI 3. 7-132.7) than in late-onset (OR 6.0, 95% CI 1.2-29.7) female patients. For women carrying the pp genotype together with epsilon4 the risk of AD was similarly elevated. Likewise in a Swedish community-based set of women, an increased risk of familial AD was observed in subjects who had either the ESR1 xx or pp genotype together with epsilon4. Furthermore, the Pp genotype frequency was found to be significantly increased in Finnish women with sporadic AD. We, thus, conclude that the ESR1 gene may have a role in the development of AD in females.

A follow-up study of the family with the Swedish APP 670/671 Alzheimer's disease mutation.

OBJECTIVE: To study the progression of Alzheimer's disease (AD) at a very early stage and to evaluate clinical markers of presymptomatic AD. SETTING: Longitudinal study at a university hospital. SUBJECTS: A Swedish family harboring a double mutation at codons 670/671 of the APP gene on chromosome 21 was followed longitudinally for 3 years. Both mutation carriers and noncarriers participated. OUTCOME MEASUREMENTS: Results from clinical investigations, electroencephalography, neuropsychological and neuroradiological examinations including magnetic resonance imaging, single-photon emission computed tomography and positron emission tomography were assessed and compared on two or more occasions. MAIN OUTCOME: During follow-up, 1 initially asymptomatic mutation carrier who was near the expected age of onset for this family, developed cognitive symptoms, and at the end of the follow-up fulfilled the diagnostic criteria for AD. One mutation carrier with cognitive symptoms at the first examination showed clinical deterioration and was diagnosed with AD. One demented mutation carrier died and was shown to have typical AD neuropathology at autopsy. The two remaining asymptomatic mutation carriers, as well as all the noncarriers were asymptomatic. These mutation carriers who were near the expected age of onset of AD but without clinical signs of the disease, did not show changes in either electrophysiological parameters or volumes of the temporal lobes. However, in these 2 individuals the blood flow in the temporal lobe showed intermediate values between the symptomatic mutation carriers and healthy noncarriers. Two neuropsychological tests showed a deterioration that paralleled clinical symptoms in 1 of the mutation carriers who was close to the expected age of onset and who at the end of the follow-up had clinical signs of AD. In the same subject, brain glucose metabolism was pathologically reduced in the temporal lobes before other clinical symptoms were obvious. CONCLUSION: In this familial form of AD a reduced temporal lobe glucose metabolism was indicative of AD before the expected clinical onset. Reduced glucose metabolism even preceded the development of subjective or objective cognitive dysfunction and might therefore serve as a clinical marker for AD before the onset of clinical symptoms. Reduced cerebral blood flow in the temporal lobes and cognitive deterioration paralleled the clinical decline in the early stage of the disease. Copyrightz1999S.KargerAG,Basel

Apolipoprotein E and alpha1-antichymotrypsin genotypes and age of onset of familial Alzheimer's disease.

Apolipoprotein E (APOE) and alpha1-antichymotrypsin (ACT) genotype and allele frequency distribution were investigated in 113 familial Alzheimer's disease (AD) cases. A significantly higher sigma4 frequency was observed in patients with an age of onset between 55-64 and 65-74 years compared to individuals with later or earlier onset. No difference in ACT A allele frequency was seen in any onset group, nor was any influence of ACT genotypes on the age of onset observed. However, the mean age of onset was lowered by the presence of the ACT/AA and ACT/TT genotypes among APOE sigma3/3 bearers. Possible APOE effects on age of onset were evaluated in 78 affected sib pairs. An earlier age of onset was observed in siblings with an sigma4 allele compared to siblings without an sigma4 allele. This supports the notion that the sigma4 allele promotes an earlier age of onset. However, in siblings with the same APOE genotype, a wide range of onset was seen, indicating that unknown genetic or environmental factors affect the expression of AD.

Tau gene polymorphisms and apolipoprotein E epsilon4 may interact to increase risk for Alzheimer's disease.

In an effort to analyze the genetic role of tau in Alzheimer's disease (AD), 17 polymorphisms were identified. Eleven of these polymorphisms were in complete linkage disequilibrium and segregated as two haplotypes, A and B. The A and B haplotypes were investigated in 269 AD cases and 238 controls from two different sources, a clinic-based group (mean age of onset 65+/-9 years), and a population-based group (mean age of onset 80+/-5 years). A synergistic effect between the common tau genotype AA and apolipoprotein E (APOE epsilon4) was found in the clinic-based AD group. Our study suggests that the common tau genotype AA may interact with APOE epsilon4 in increasing the risk of AD in a subgroup of the AD population.

Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene.

OBJECTIVES: To describe clinical and genealogical data of a Swedish family with a His163Tyr mutation in the presenilin-1 gene (PS1) and to study the Alzheimer disease (AD) penetrance in this family. DESIGN: Interviews with relatives, studies of medical records, analysis of pedigree, physician examination of the affected individuals, and comparison with other families affected by AD with PS1 mutations. SETTING: Large university-affiliated hospital. PATIENTS AND OTHER PARTICIPANTS: Individuals with a His163Tyr mutation in PS1 and their relatives. RESULTS: A study of this family with a history of very early AD onset (mean age, 47 years) has been previously published, but an investigation of the extended family revealed a new pattern of onset, with a mean age at onset of 54 years (range, 44-65 years). In general, families with AD show a tight cluster of age at onset with high penetrance of the disease. However, in this family, an individual whose child carries the PS1 mutation died at age 67 years free from cognitive symptoms, indicating a very late age at onset or nonpenetration of the disease. No association between age at onset and disease duration was found. Furthermore, the disease duration did not differ between those having an early onset compared with those having a late onset. The earliest clinical manifestations were deficits in memory function and disorientation in time and place. Myoclonic jerks and epileptic seizures were common symptoms later in the disease. CONCLUSION: The large range in age at onset in this family with a uniform genetic basis for the disease, a His163Tyr mutation in PS1, supports the existence of other unknown genetic or environmental factors of importance for the expression of the AD phenotype.

A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease.

Several mutations causing early-onset familial Alzheimer's disease (AD) have been detected in the presenilin 1 (PS-1) gene. Pathogenic mutations have also been described in an homologous gene, presenilin 2 (PS-2). In order to screen for mutations in these genes, cDNA samples from early-onset AD cases were analysed, using single strand conformation polymorphism (SSCP) and direct cDNA sequencing. Two missense mutations in the PS-1 gene were detected, a previously unidentified amino acid substitution Leu262Phe and an earlier reported amino acid substitution Glu318Gly. No disease-related mutations were found in the PS-2 gene.

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at theta = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of -2.79, and -2.27 at theta = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease.

Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.

OBJECTIVE: To describe symptoms, signs, neuroimaging results, and neuropathologic findings in patients from a family with chromosome 17q21-linked autosomal dominant frontotemporal dementia. DESIGN: Multiple case report with genetic investigations. SUBJECTS: The disease was observed in a Swedish family and documented in 3 generations. Four siblings are described in this article. RESULTS: A rapidly progressive dementia with genetic linkage to chromosome 17q21 was observed. The mean age of onset was 51 years and the average duration of disease to death was 3 years. Two patients started with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia and akinesia and muscular rigidity, and in 1 patient reckless driving was the first symptom. Loss of spontaneous speech developed later in all patients and emotional bluntness in 3 of the patients. Cerebral perfusion was decreased in the frontal areas in all patients. In the person with apraxia as the onset symptom, the cerebral blood flow was also diminished in the left hemisphere, where a slight atrophy was detected on magnetic resonance imaging scans. At the postmortem examination, slight gliosis of the parietal lobes was observed in this patient. In all patients there was a frontocentral degeneration of the cortex with discrete microvacuolation and gliosis. CONCLUSION: Clinical features of frontotemporal dementia, parkinsonism, an early age of onset, a rapid disease progression, and variable onset symptoms were seen in these patients. Two other clinically distinct diseases, dementia with pallido-ponto-nigral degeneration and a disinhibition-dementia-parkinsonism-amyotrophy complex, have recently been mapped to chromosome 17q21. In the family described in this article, genetic linkage was detected to the same region, suggesting the possibility that these diseases may originate from pathogenic mutations in the same gene.

Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families.

An association between the epsilon 4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset Ad families. We found an association of familial AD to the APOE epsilon 4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE epsilon 4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis.

Apolipoprotein epsilon 4 allele in Swedish twins and siblings with Alzheimer disease.

Allelic frequencies of apolipoprotein epsilon 4 were compared in 13 dizygotic twin pairs and 13 sibling pairs in which at least one member has Alzheimer disease (AD). Among discordant pairs of twins and siblings, frequencies were significantly greater in affected than intact partners. There was no significant difference in allelic frequencies between twins with a positive family history and twins with a negative family history. The epsilon 4 allele was more common in the sibling sample selected for family aggregation of AD than the twin sample. Several lines of evidence indicate that while the epsilon 4 allele appears to be one risk factor for AD, other etiological factors must be considered as well.

A large Swedish family with Alzheimer's disease with a codon 670/671 amyloid precursor protein mutation. A clinical and genealogical investigation.

OBJECTIVE: To describe clinical and genealogic features in a Swedish family with Alzheimer's disease with a double mutation of the amyloid precursor protein gene at codon 670/671 and to study the effects of anticipation and imprinting. DESIGN: Interviews with relatives, clinical investigations of the diseased, pedigree analysis, studies of medical records, and comparison with other families affected by Alzheimer's disease with amyloid precursor protein mutations. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge (Sweden) University Hospital. PATIENTS AND OTHER PARTICIPANTS: Individuals with the amyloid precursor protein codon 670/671 mutation and their relatives (N = 66). RESULTS: The trait was traced through eight generations, and an autosomal dominant inheritance with very high penetrance was observed. Onset occurred between 44 and 61 years of age (mean, 53 years). The mean duration of disease was 8.5 years (range, 3 to 13 years). The earliest clinical manifestations were deficits in memory function and abstract reasoning. Myoclonic jerks and seizures were common symptoms late in the disease. Anticipation and imprinting effects were not found in this family. CONCLUSIONS: The disease in this family has a single origin--a double mutation in the amyloid precursor protein gene at codon 670/671 transmitted as an autosomal dominant trait. The wide range in age at onset and the clinical symptoms in this pedigree give a characteristic phenotype similar to that seen in some of the other pedigrees with amyloid precursor protein mutations.

Amyloid precursor protein mutation causes Alzheimer's disease in a Swedish family.

Since the report of a double mutation at codons 670 and 671 of the amyloid precursor protein (APP) gene identified in two Swedish families with clinically diagnosed Alzheimer's disease (AD), a carrier with dementia has died. Neuropathology confirmed the clinical diagnosis of AD. Genealogical investigations have confirmed that the two families are related to common founders. Two-point linkage analysis of the mutation versus the disease in the revised pedigree now gives a lod score of 7.62.

Low frequency of the APP 670/671 mutation in familial Alzheimer's disease in Sweden.

Molecular genetic studies have identified disease-causing mutations at codon 717 of the amyloid protein precursor gene in families with early-onset Alzheimer's disease. Recently, we reported a new mutation at codon 670/671 in a large Swedish family with Alzheimer's disease. The mutation results in two amino acid changes at the N-terminal of the beta-amyloid region. In the present study, we screened for the APP 670/671 mutation in sufferers from 31 other Swedish families with Alzheimer's disease using PCR and restriction enzyme digestion. The mutation was found only in the family previously reported and not in any other family. It is concluded that this mutation is a rare cause of familial Alzheimer's disease in Sweden.