Prevalence of Alzheimer's disease in very elderly people: a prospective neuropathological study.

BACKGROUND: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. OBJECTIVE: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. METHODS: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. RESULTS: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE epsilon4 allele and AD: Sixty-three percent of APOE epsilon4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. CONCLUSIONS: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.

Relation of collagen type I alpha 1 (COLIA 1) and vitamin D receptor genotypes to bone mass, turnover, and fractures in early postmenopausal women and to hip fractures in elderly people.

Background: In a previous study, we showed an association between the vitamin D receptor (VDR) gene BsmI restriction fragment polymorphism and peak bone mass in young Finnish adults. Design: The previous finding prompted us to study the relationship of the same polymorphism, as well as of the polymorphism in the Sp1 binding site of the collagen type I alpha 1 (COLIA 1) gene, to bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry and adjusted for age, weight, height, and lifestyle factors. Also studied was the relationship of VDR and COLIA 1 genotypes to markers of bone turnover [serum osteocalcin, type I procollagen carboxy- (PICP), and aminoterminal (PINP) propeptide, and type I collagen carboxyterminal telopeptide (ICTP)] and bone fractures in 513 early postmenopausal women (1-5 years postmenopausal), as well as hip fractures in 172 very old people. Results: The BB, Bb, and bb genotypes of the VDR gene, as well as the SS, Ss, and ss genotypes of the COLIA 1 gene, were distributed similarly among 402 early postmenopausal women with osteopenia in the lumbar spine and among 111 women with normal BMD (P=0.12 for VDR, P=0.53 for COLIA 1). There was no relation between the VDR and COLIA 1 genotypes and lumbar spine BMD among osteopenic women, among normal women, or in the combined study population. Among the women with vertebral osteopenia, the femoral neck BMD did not associate significantly with the VDR or COLIA 1 polymorphisms. The frequencies of the different VDR and COLIA 1 genotypes were similar among women with or without a history of a low-energy fracture. There was a borderline association between the VDR genotype and serum osteocalcin concentrations, with the Bb genotype associated with the highest median level (P=0.037). In a population-based sample of very old individuals (>85 years), the frequencies of the different VDR and COLIA 1 genotypes were similar among those with (n=64) and without (n=108) a history of hip fracture. Conclusion: The present data suggest that, in the Finnish population, the VDR and COLIA 1 genotypes do not determine the bone mass of early postmenopausal women or their bone turnover rate. The polymorphisms are not associated with risk of hip fractures in elderly people or with low-energy fractures in early postmenopausal women.

Does apolipoprotein E influence learning and memory in the nondemented oldest old?

The objective of this study was to analyze the relationship of the apolipoprotein E (apoE) epsilon4 and epsilon2 alleles to learning and memory performances in the nondemented oldest old. Forty-six nondemented persons aged 85 years or over from a randomly selected group of 128 subjects in Vantaa, Finland, were studied. ApoE genotyping was performed using the minisequencing technique. A structured clinical examination and interview were carried out. The test variables studied were learning and memory scores (from the Fuld Object-Memory Evaluation), verbal fluency, and conceptualization (the Similarities subtest of the WAIS-R). We compared apoE-epsilon4 carriers to noncarriers and apoE-epsilon2 carriers to noncarriers. No statistically significant differences were found in any of the test variables. The results failed to confirm the hypotheses that poor cognitive performance is associated with the apoE-epsilon4 allele and good performance with the apoE-epsilon2 allele in the oldest old. This suggests that the apoE alleles do not have a detectable relationship to learning and memory in nondemented very elderly people.

Apolipoprotein E, cognitive function, and dementia in a general population aged 85 years and over.

We examined 510 subjects representing 83.2% of all citizens of a Finnish city aged 85 years or over. Mini-Mental State Examination (MMSE) scores, diagnosis of dementia by DSM-III-R criteria, and Apo-E genotype were determined. The prevalence of dementia was 38.6%. The odds ratio (OR) of the Apo-E epsilon4 carriers (with the reference population of people with the genotype epsilon3/epsilon3) for dementia was 2.36 (95% CI 1.58 - 3.53). There was a significant sex difference: The OR in women was 3.23 (95% CI 2.02 - 5.17) whereas among men it was insignificant. The mean MMSE score (+/- SD) among the Apo-E epsilon4 carriers (15.0 +/- 10.0) and noncarriers (18.7 8.6) (p < .001) differed among the whole population, but not within the demented or nondemented subjects analyzed separately. This study does not support the hypothesis that the Apo-E epsilon4 allele impairs cognitive functions of nondemented elderly, at least in those surviving to very old age.

Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings.

OBJECTIVES: To review, on a genome-wide scale, a linkage result obtained in an earlier candidate gene analysis in this same study sample, and to look for other possible contributing genetic loci predisposing to hypertension in this population. DESIGN: An affected sibpair linkage study with highly polymorphic genetic markers spanning the genome at an average intermarker density of 10 cM. PARTICIPANTS: A total of 47 families with two affected siblings (mostly dizygotic twins) and all available additional family members from the genetic isolate of Finland. The families were identified through the Finnish Twin Cohort Study, the total number of this follow-up cohort being 13,888. The study sample was selected on the basis of early-onset hypertension with minimal presence of other phenotypic risk factors such as obesity. RESULTS: The AT1 locus stood out as the most significant locus in this population (maximum likelihood score 4.04). Some evidence for linkage was also detected with markers on chromosomes 2q (maximum likelihood score 2.96), 22q (2.07), and Xp (2.41). CONCLUSIONS: Our results establish the role of the AT1 locus, on a genome-wide scale, as a major contributing locus to essential hypertension in this study sample.

APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old.

OBJECTIVE: To examine the effect of the epsilon 4 allele on cognitive decline in the oldest old. METHODS: We studied all 601 citizens of the city of Vantaa age 85 years and older in 1991. A total of 553 subjects (92%) took part in the study, which used the Mini-Mental State Examination (MMSE) and assessment of dementia according to the Diagnostic and Statistical Manual of Mental Disorders, third ed., revised (DSM-III-R) criteria. The survivors were re-examined 3 years later. APOE genotype was determined in 510 subjects, representing 83.2% of the original population. RESULTS: Approximately one-half of the subjects (n = 250) died before the follow-up, and 253 subjects (97.3% of the survivors) were re-examined. The occurrence of the APOE epsilon 4 allele did not have any significant effect on survival. Of the 187 previously nondemented subjects, 58 (31%) had developed dementia. The OR for the epsilon 4 carriers to develop dementia was not significant: OR = 1.78; 95% CI = 0.88 to 3.60. In individuals with a follow-up MMSE score (n = 222), the mean decline in the score was 3.1 points. APOE epsilon 4 carrier status did not have a significant effect on the mean MMSE change except in the previously demented subjects, among whom the drop was larger in the APOE epsilon 4 carriers. CONCLUSIONS: The lack of association between APOE epsilon 4 carrier status and mortality, or development of dementia, or cognitive decline in these very elderly people, whether analyzed in the whole population or among the nondemented subjects only, suggests that the APOE epsilon 4 effect in younger subjects is age-dependent, and that it is no longer present in very old age.

New source for electroweak baryogenesis in the minimal supersymmetric standard model.

One of the most experimentally testable explanations for the origin of the baryon asymmetry of the Universe is that it was created during the electroweak phase transition, in the minimal supersymmetric standard model. Previous efforts have focused on the current for the difference of the two Higgsino fields, H1-H2, as the source of biasing sphalerons to create the baryon asymmetry. We point out that the current for the orthogonal linear combination, H1+H2, is larger by several orders of magnitude. Although this increases the efficiency of electroweak baryogenesis, we nevertheless find that large CP-violating angles > or = 0.15 are required to get a large enough baryon asymmetry.

Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.

OBJECTIVES: The purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder. BACKGROUND: An inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families. METHODS: Two unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus. RESULTS: Of the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood. CONCLUSIONS: A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.

Angiotensin converting enzyme gene insertion/deletion polymorphism, angiotensinogen gene polymorphisms, family history of hypertension, and childhood blood pressure.

Earlier epidemiologic studies have yielded inconsistent results on the extent and timing of the blood pressure (BP) increase in offspring of hypertensive parents. We hypothesized that a familial influence on the BP of the offspring exists from birth on, but becomes significant only later in childhood. We studied the influence of familial occurrence of hypertension on the BP of 3596 children aged 6 to 18 years during a 6-year follow-up. In addition, we examined the possible associations of BP variations with polymorphisms of two candidate genes for hypertension, ie, those coding for the angiotensin converting enzyme (ACE) and those coding for angiotensinogen. A positive family history of hypertension was reflected as the occurrence of higher systolic BP values from the age of 9 years and upward among the females and from the age of 12 years and upward among the males. The mean differences in BP varied from 3.2 to 5.8 mm Hg (systolic) and 2.1 to 5.9 mm Hg (diastolic) between the female offspring of normotensive and hypertensive parents and grandparents. The systolic BP values were significantly higher among females with a hypertensive history in two generations in comparison with females from normotensive families. Among the male offspring of hypertensive and normotensive families, the BP differences were inconsistent. The deletion/deletion males had higher systolic BP values than those with other ACE genotypes. In contrast, variation at the angiotensinogen gene locus was not significantly associated with BP. We conclude that parental history of hypertension is a risk factor for high blood pressure among the offspring from the ages of 9 to 12 years and upward, and hypertension within two generations may enhance this effect. Although the common genetic variation of ACE may influence blood pressure in male children and adolescents, our data do not suggest a role for the common variation of the angiotensinogen gene as a BP regulator during childhood.

Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes.

OBJECTIVES: We studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin-angiotensin system. BACKGROUND: Adaptive left ventricular hypertrophy is a feature of the athlete's heart. However, similarly training athletes develop left ventricular mass to a different extent, suggesting that genetic factors may modulate heart size. METHODS: We measured left ventricular mass by echocardiography in 50 male and 30 female elite endurance athletes aged 25 +/- 4 (mean +/- SD) years. Deoxyribonucleic acid samples were prepared for genotyping of angiotensinogen (AGT) gene M235T polymorphism, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and angiotensin II type 1 receptor (AT1) gene A1166C polymorphism. RESULTS: The AGT gene M235T genotypes were significantly associated with left ventricular mass independently of blood pressure in both genders (p = 0.0036 for pooled data). TT homozygotes had greater mass compared with MM homozygotes in both men (147 +/- 12 g/m vs. 132 +/- 15 g/m, p = 0.032) and women (121 +/- 12 g/m vs. 101 +/- 13 g/m, p = 0.019). There was a gender difference in the relation between myocardial mass and AGT genotype, MT heterozygotes resembling MM homozygotes among women and TT homozygotes among men. The other studied gene polymorphisms were not associated with left ventricular mass. CONCLUSIONS: Angiotensinogen gene M235T polymorphism is associated with the variability in left ventricular hypertrophy induced by endurance training, with athletes homozygous for the T allele having the largest hearts. We found no association between ACE gene I/D or AT1 gene A1166C polymorphisms and left ventricular mass.

Testing of human homologues of murine obesity genes as candidate regions in Finnish obese sib pairs.

The human homologues of recently discovered murine obesity genes provide relevant candidates to study the genetic component of obesity in humans. We analysed the human counterparts to murine obesity genes ob, db, agouti, tub, melanocortin 4-receptor (MC4-R) and mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3), as well as two other chromosomal regions reported to be linked to obesity-related phenotypes in restricted populations. We found no significant evidence for linkage to any analysed loci in our total study material of 105 affected sib pairs collected from the genetically homogenous population of Finland. However, several markers on 14 cM chromosomal region flanking the MC4-R gene showed sharing of alleles identical-by-descent (IBD) more frequently than expected. A selected subset of non-diabetic obese sib pairs strengthened the P values down to 0.003 in this particular region. The smallest P value (P = 0.001) was obtained with a marker D18S487 in a subgroup containing only sib pairs with one lean and one obese parent. We therefore screened seven obese subjects included in our sib pair material for sequence changes in their MC4-R gene, but no mutations of apparent causal relationship were found. In conclusion, we could not find evidence for significant contribution of the chromosomal loci corresponding to the murine single gene obesity genes for human morbid obesity, but additional studies are still needed to clarify whether DNA alterations within or adjacent to the MC4-R gene play some role.

Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension.

Components of the renin-angiotensin system play an important role in the normal regulation of blood pressure. We carried out a comprehensive genetic linkage study of the genes involved in the renin-angiotensin cascade in Finnish hypertensive twins and their affected siblings. We found no evidence for linkage between essential hypertension and the genes coding for renin, angiotensinogen, angiotensin-converting enzyme, or kallikrein 1 in the 329 hypertensive individuals of 142 families studied. In contrast, two intragenic markers for the type 1 angiotensin II receptor (AT1) showed some evidence for linkage in the total sample. A closer examination of this gene locus was carried out using subgroups of nonobese sibpairs with early onset of hypertension and uniform geographical origin. These stratifications yielded suggestive evidence for linkage of hypertension to the genetic area containing the AT1 gene, with a maximal multipoint logarithm of the odds (LOD) score of 2.9. A genetic association study carried out in an independent series of 50 hypertensive cases and 122 normotensive controls showed an increase in the frequency of the A1166-->C allele of the AT1 gene in the hypertensive individuals. In a novel variant of model-free multipoint linkage analysis allowing linkage disequilibrium in the calculations, an LOD score of 5.13 was obtained. Sequence analyses of the entire coding region and 848 bp of promoter region in the DNA sample on 8 index samples did not reveal previously unpublished sequence variations. The data provide evidence that a common genetic variant of the AT1 gene locus influences the risk of essential hypertension in the Finnish population.

Molecular genetics of the long QT syndrome: two novel mutations of the KVLQT1 gene and phenotypic expression of the mutant gene in a large kindred.

At least three different gene loci were recently shown to account for the long QT syndrome (LQTS), a monogenic disorder with altered myocardial repolarization and occurrence of life-threatening cardiac arrhythmias. We screened 44 unrelated probands for mutations of the gene encoding the cardiac potassium channel KVLQT1 using single-strand conformational polymorphism (SSCP) and subsequent DNA sequencing. Two different mutations, T182I and D188N, were identified in two separate pedigrees. Cosegregation of the mutation with the disease phenotype was evident in both families. No mutations were identified at codon 212, previously suggested to represent a mutational hot spot of the KVLQT1 channel, in any of the 44 probands. The large pedigree with the D188N mutation (30 affected and 43 nonaffected individuals) permitted an analysis of expression of the mutant gene in its documented carriers. Although the mean (+/-SD) QTc interval was markedly longer in affected (484+/-38 ms) than in nonaffected individuals (406+/-27 ms, P < 0.001), there was a marked overlapping of individual values in these two groups. QTc values in symptomatic and asymptomatic carriers of the mutant gene were not significantly different. In conclusion, we have identified two novel mutations of the KVLQT1 component of a cardiac potassium channel. Our data support the functional significance of the pore-S6 domain of this membrane protein and emphasize the diagnostic usefulness of DNA analyses in families with LQTS.

Novel polymorphism of the human ob gene promoter in lean and morbidly obese subjects.

OBJECTIVE: Leptin, the circulating product of the human ob gene, may play role in control of appetite and metabolic rate. We screened the proximal promoter area of the ob gene for mutations and common polymorphisms in order to find out whether genetic variation in the regulatory area of this gene plays a role in human obesity. DESIGN: The technique of single-strand-conformation polymorphism (SSCP) was applied to screen for the promoter area of the ob gene for genetic alterations in morbidly obese patients. SUBJECTS: A total of 249 morbidity obese (present or past body mass index [BMI] > or = 40 kg/m2) and 141 lean (BMI < or = 25 kg/m2) subjects. MEASUREMENTS: DNA analysis was carried out using a single-strand conformation polymorphism (SSCP) technique and PCR followed by digestion with the restriction enzyme BssHll. Leptin was determined by radioimmunoassay in obese subjects. Serum lipids, glucose and insulin concentrations in the obese subjects were also determined. RESULTS: A new polymorphism C(-188)A was identified in the promoter region of the ob gene. This polymorphism was detected with allelic frequencies of 0.06 in morbidly obese subjects and 0.09 in lean controls (P = 0.28). Initial studies failed to show an association of this polymorphism with serum leptin, response to treatment for obesity, history and extent of weight gain, or serum insulin, glucose of lipid concentrations. CONCLUSIONS: We have identified a common polymorphism in the promoter area of the human ob gene which appears to be very useful for genetic association and linkage studies. Further studies are needed to elucidate its potential role in the regulation of the human ob gene and in human metabolic disorders.

Markers for the gene ob and serum leptin levels in human morbid obesity.

Leptin, the product of the ob gene, reduces body fat in genetically obese animals and circulates in elevated concentrations in the blood of obese patients. Polymorphic markers situated in the proximity of the human ob gene have recently been suggested to be linked to morbid obesity. We have studied the possible association between the microsatellite markers near the ob gene and morbid obesity in 252 morbidly obese patients with a mean body mass index (BMI) of 43 +/- 7 kg/m2, and 151 lean controls with a mean BMI of 22 +/- 2 kg/m2, and searched for linkage of these gene markers to obesity in 76 affected sib-pairs (BMI > or = 32). No significant association was observed between any of the eight microsatellite markers and morbid obesity, and affected-sib-pair analysis failed to show linkage of three selected ob gene markers to obesity in the sibships. There was a strong positive correlation between serum leptin levels and BMI in morbidly obese patients; a carrier status for either of the two most prevalent alleles of the microsatellite marker D7S530 in the vicinity of the ob gene was associated with serum leptin levels in the obese subjects. Two of the markers (D7S2519, D7S649) showed a significant relation to the weight-losing response to a 16-week very-low-calorie dietary intervention. We have thus been able to confirm a tight relationship between serum leptin and body mass but have found no evidence for genetic linkage of the ob gene markers to morbid obesity in a population considered to represent a genetic isolate and to be an ideal model for studies of complex disorders.

Polymorphism of the beta 3-adrenergic receptor gene in morbid obesity.

OBJECTIVE: The Trp64-->Arg allele of the beta 3-adrenergic receptor gene was recently proposed to be associated with an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM), features of insulin resistance and a tendency to gain weight. We investigated whether the Arg64 allele predisposes to severe obesity. DESIGN AND SUBJECTS: A genetic association study of 254 subjects with morbid obesity [body-mass index (BMI) > or = 40; mean 42.8 +/- 7.0] and 151 lean healthy control subjects [BMI < or = 25; mean BMI 22.3 +/- 1.9]. MEASUREMENTS: beta 3-adrenergic receptor genotyping was carried out with a solid-phase minisequencing technique. Serum lipids, glucose and insulin levels in the obese subjects were also determined. RESULTS: The frequency of the Arg64 did not significantly differ in the morbidly obese patients (9.1%) and lean controls (8.9%), nor was there any statistically significant association between the mean BMI values and the beta 3-adrenergic receptor genotype. However, obese subjects carrying the Arg64 allele developed obesity more often before the age of 15 y than those without it (P < 0.05, adjusted for multiple comparisons). The frequency of the Arg64 allele was similar in nondiabetic and diabetic patients; the mean age at the onset of NIDDM did not differ according to the beta 3-adrenergic receptor genotype. There was no significant association between the receptor genotype and the level of the serum cholesterol, HDL-cholesterol, triglyceride, glucose or insulin, nor was this polymorphism associated with the behavioural or psychopathological characteristics of the morbidly obese subjects. Response to a 16 w treatment program including a very-low calorie diet (VLCD) regimen, dietary and exercise counseling, as well as behavioural modifications, did not differ according to the genotype. CONCLUSION: Our data do not support a significant role for the codon 64 polymorphism of the beta 3-adrenergic receptor as a genetic marker of morbid obesity. Although there was an association between the Arg64 allele and an earlier onset of obesity in individuals subsequently developing morbid obesity, this allele was not associated with the actual BMI gained or response to weight-loss therapy on a hypocaloric diet.