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PubMed1995

Characterization of subspecies of lipoprotein containing apolipoprotein A-I in heterozygotes for familial lecithin:cholesterol acyltransferase deficiency.

We characterized two species of lipoproteins containing apo A-I, one containing only apo A-I (LpA-I) and the other containing both apo A-I and apo A-II (LpA-I/A-II), in three heterozygotes for familial lecithin:cholesterol acyltransferase deficiency (LCAT). In these patients, particle size and the chemical composition of LpA-I differed from those in normal controls. Small particles < 8.8 nm in diameter were predominant, and protein content was higher in patients' LpA-I than that in normal LpA-I. Changes in LpA-I/A-II were mostly quantitative. Percent lipid and protein composition in LpA-I/A-II were similar to those in normal controls. Despite low LCAT mass and activity in the heterozygotes, the molar and fractional rate of cholesterol esterification in their LpA-I and LpA-I/A-II particles were similar to, or higher than, that of normal controls. We conclude that: (i) low LCAT mass and activity is the likely cause of the quantitative and qualitative differences in LpA-I in heterozygotes; and (ii) a deficiency of normal LpA-I particles 11.1 nm in diameter and the existence of small particles < 8.8 nm in diameter may be responsible for the normal, or higher than normal, cholesterol esterification rate of LpA-I and LpA-I/A-II in heterozygotes.

Adult↗
PubMed1990

Improved test to identify heterozygotes for congenital adrenal hyperplasia without index case examination.

In an attempt to improve detection of heterozygote carriers of the gene for congenital adrenal hyperplasia (21-hydroxylase deficiency; CAH) 64 families with at least 1 affected member (72 homozygotes and 191 clinically healthy subjects) were studied by HLA genotyping and by the single-dose corticotropin stimulation test. Plasma samples were drawn immediately before corticotropin and 60 min after its injection, and they were analysed simultaneously for eight adrenal steroids by radioimmunoassay after extraction and automated gel chromatography. Heterozygosity was defined as the presence of one HLA haplotype in common with the affected relative. Of the various basal and corticotropin-stimulated steroid levels and their ratios, the ratio of 17-hydroxyprogesterone to 11-deoxycorticosterone after corticotropin had the greatest power to discriminate between heterozygotes and normal relatives; that ratio was significantly higher in the heterozygotes (n = 116) than in the normal relatives (n = 75) and there was no overlap between the groups (range 12.2-214 vs 1.2-11.9). Thus, it is possible to detect all CAH heterozygotes without examining the index case by means of specific steroid analysis.

17-alpha-Hydroxyprogesterone↗
PubMed1989

Ultraviolet-induced chromosomal instability in cultured fibroblasts of heterozygote carriers for xeroderma pigmentosum.

Fibroblast cultures of seven patients with xeroderma pigmentosum (XP), 19 healthy sibs or parents of XP patients (XP-heterozygotes), and 24 healthy normal controls were studied for chromosome instability induced by ultraviolet rays (UV). We used a UV source that contained predominantly UV-A and UV-B at an intensity of 500 J/m2 and evaluated the induction of micronuclei (MN) and sister chromatid exchange (SCE). the XP homozygotes had a UV sensitivity that was clearly above that of all heterozygotes and normal controls. Heterozygotes had an increased rate of UV-induced MN (4.76 +/- 1.96 vs. 1.82 +/- 2.05, p less than 0.0001) and increased UV induction of SCE (13.21 +/- 3.49 vs. 9.01 +/- 1.25, p less than 0.001), as compared to normal controls. These data support epidemiologic findings that suggest that XP heterozygotes are particularly cancer prone. In addition, the determination of the UV sensitivity in vitro as described may be used for genetic counseling of asymptomatic relatives of XP patients.

Cells, Cultured↗
PubMedDate not supplied

Deceleration of age-specific mortality rates in chromosomal homozygotes and heterozygotes of Drosophila melanogaster.

Age-specific mortality trajectories were estimated in mixed-sex cohorts of D. melanogaster. We studied 22,000 flies that were either second-chromosome homozygotes or heterozygotes with a randomized genetic background. Broad-sense heritabilities for longevity were estimated to be 6% for males and 9% for females. Heterozygotes lived longer than homozygotes on average, but there were exceptions to the usual heterotic pattern; in several crosses parental homozygotes had average life spans as long as that of their F1 heterozygotes. Estimated age-specific mortality rates were found to decelerate at advanced ages in both homozygotes and heterozygotes. The mortality models that best fit the data are the logistic model and the two-stage Gompertz model, both of which produce mortality trajectories that level off at advanced ages. Old-age mortality deceleration is not peculiar to inbred Drosophila.

Animals↗
PubMed2006

Muscle protein analysis in the detection of heterozygotes for recessive limb girdle muscular dystrophy type 2B and 2E.

The diagnosis of isolated heterozygotes for recessive LGMD is quite difficult because no specific biochemical or protein assays are available, and the molecular analysis is not feasible due to the wide genetic heterogeneity. We investigated a series of definite heterozygotes for different forms of LGMD to determine whether the carrier status will result in a detectable protein defect in muscle biopsy. Definite heterozygotes from 4 families (3 LGMD2B and 1 LGMD2E) underwent quantitative immunoblot analysis of mutant protein in their muscle. While the quantity of beta-sarcoglycan was nearly normal in the LGMD2E carrier, the levels of dysferlin protein were reduced to 50% of controls in the carriers of LGMD2B. We have demonstrated the value of protein analysis in the identification of both familial and isolated LGMD2B heterozygotes, and suggested the use of dysferlin protein testing to select muscle biopsies from suspected carriers for a subsequent mutation analysis. Muscle protein analysis would be used to screen asymptomatic patients who underwent muscle biopsy because of unexplained hyperCKemia.

Adolescent↗
PubMed2001

Detection of mucopolysaccharidosis type I heterozygotes on the basis of the biochemical properties of plasma alpha-L-iduronidase.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a disease caused by deficiency of the enzyme alpha-L-iduronidase (IDUA). Since no treatment is currently available for this disorder, the detection of heterozygotes is very important for genetic counseling and prenatal diagnosis. The objective of the present study was to characterize plasma IDUA from MPS I heterozygotes in an attempt to distinguish it from that of normal individuals. METHODS: We determined the optimum pH, Km, Vmax and Calpha (Vmax/Km) of the reaction and the thermal stability of IDUA at 50 degrees C. RESULTS: MPS I heterozygotes can be separated from normal individuals on the basis of Km, Calpha and thermal stability of the enzyme. CONCLUSIONS: Taking into consideration the clinical status of the homozygous offspring, we were able to subdivide the MPS I heterozygotes into various subgroups (Hurler, Scheie or Hurler/Scheie compound), and verified that the Hurler subgroup had a lower optimum pH for IDUA activity than controls and other MPS I subgroups, and that all MPS I subgroups had higher Km and lower Calpha when compared to controls.

Enzyme Stability↗
PubMed1997

Rapid identification of Smith-Lemli-Opitz syndrome homozygotes and heterozygotes (carriers) by measurement of deficient 7-dehydrocholesterol-delta 7-reductase activity in fibroblasts.

To extend the enzyme deficiency in Smith-Lemli-Opitz syndrome (SLOS) to extrahepatic tissues, 7-dehydrocholesterol-delta 7-reductase activity was measured in fibroblasts from 10 controls, five SLOS homozygotes, and five obligate heterozygotes. In cells grown almost to confluence in cholesterol-containing medium (4 mg/dL), the conversion of [1,2-3H]7-dehydrocholesterol to cholesterol (7-dehydrocholesterol-delta 7-reductase activity) was 3.8 times higher in control than in homozygote cells and 2.2 times higher than in heterozygote cells. After 24 hours' exposure of the fibroblasts to cholesterol-deficient medium supplemented with lovastatin, 7-dehydrocholesterol-delta 7-reductase activity increased twofold in controls, but did not change significantly in either heterozygous or homozygous cells. In contrast, the activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lathosterol 5-dehydrogenase, two key enzymes that precede 7-dehydrocholesterol-delta 7-reductase in the cholesterol biosynthetic pathway, and low-density lipoprotein (LDL) receptor-mediated binding were equal in control, homozygote, and heterozygote fibroblasts. Further, HMG-CoA reductase activity and LDL receptor-mediated binding increased after exposure of the cells to cholesterol-deficient medium. Fibroblast cholesterol concentrations were approximately equal, although homozygote cells contained 30 times more 7-dehydrocholesterol. Thus, markedly reduced 7-dehydrocholesterol-delta 7-reductase activity that cannot be upregulated after exposure of the cells to cholesterol-deficient medium is diagnostic for the biochemical defect in SLOS. Significantly reduced enzyme activity between the levels in controls and homozygotes without accumulation of 7-dehydrocholesterol in fibroblasts identified heterozygotes.

Fibroblasts↗
PubMed2001

Radiation induced apoptosis in ataxia telangiectasia homozygote, heterozygote and normal cells.

Recent reports suggest that the radiation-induced, p53-dependent, apoptotic response is aberrant in ataxia telangiectasia (AT) cells. We investigated the possibility that an aberrant apoptotic response to ionizing radiation may also be the characteristic of AT heterozygotes and may facilitate in discriminating AT heterozygotes from the general population. Log phase, Epstein Barr virus (EBV) transformed lymphoblastoid cell lines and primary lymphocytes from three AT families were irradiated and the apoptotic response at 30h post radiation was measured by flow cytometry using TUNEL and hypodiploid methods. Our results show that the apoptotic response of AT homozygote (ATM-/-), AT heterozygote (ATM+/-) and normal cells (ATM+/+) to ionizing radiation, measured by the hypodiploid and TUNEL methods using flow cytometry, is dose and time dependent. Furthermore, this response is paradoxical in that ATM (-/-) lymphoblastoid cells were characterized by a reduced post radiation apoptotic response compared to their normal counterparts. Heterozygote (ATM+/-) lymphoblastoid cells displayed an intermediate response to ionizing radiation. In contrast, primary, non-transformed AT cells exhibited the same apoptotic response as their normal counterparts. Our results thus indicate that pre-radiation, EBV-transformed, lymphoblastoid cell lines from individual families may be useful in discriminating ATM status, but patient-derived, primary AT homozygous, heterozygous and normal primary cultured lymphocytes cannot be discriminated by this assay.

Apoptosis↗
PubMed1990

Abnormal movements in brindled mutant mouse heterozygotes: as related to the development of their offspring--biochemical and morphological studies.

As a possible preventive measure for brain dysfunction in Menkes disease, prenatal treatment by maternal administration of zinc, vitamin E and copper was examined in brindled mutant mice. During pregnancy and lactation, female heterozygous mice received 20 ppm zinc or 0.004% alpha-tocopherol acetate (vitamin E) throughout and 6 ppm copper from gestational day 13 in the drinking fluid, ad libitum. The maternal administration of zinc and vitamin E, as antioxidants, or copper resulted in decreased fetal and neonatal death of offspring, especially those of hemizygous males, as compared with the administration of water only. When offspring did not grow, maternal abnormal movements, which comprised rotatory movements of high speed with tremor and ataxia, were frequently observed. In the heterozygotes with abnormal movements, the level of lipid peroxidation in cerebrum and the concentration of copper in kidney were much higher than those in the heterozygotes with normal movement. Morphologically, in cerebellum of the heterozygotes with abnormal movements, the loss of Purkinje cells, abundance of lipofuscin granules and abnormal mitochondria or degenerative bodies of high electron density were frequently observed, as compared with heterozygotes with normal movement. These findings suggest that the development of hemizygous male mice may be influenced by both copper and oxygen radical metabolism.

Animals↗
PubMed2001

Silent cerebral infarcts in basal ganglia are advanced in congenital protein C-deficient heterozygotes with hypertension.

Congenital protein C deficiency is now widely recognized as a genetic risk for venous thrombosis. However, it remains uncertain whether this condition also confers risk for arterial thrombosis. We evaluated the association of congenital protein C deficiency with hypertension and silent cerebrovascular disease using brain magnetic resonance imaging (MRI) (T1- and T2-weighted and proton density images) in a large family pedigree of protein C deficiency diagnosed by gene analysis, compared with 46 non-pedigree related control subjects with normal protein C levels (> or = 75%) who were selected from among 55 asymptomatic hypertensive subjects matched for age and cardiovascular risk factors. Of the 58 living subjects in this pedigree, we measured plasma protein C levels in 45 subjects, and found 2 cerebral infarctions in the 24 heterozygotic subjects, whereas there was no stroke in the 21 normal homozygotic subjects. We performed brain MRI in 14 asymptomatic hypertensive subjects without any cardiovascular disease and in two patients with cerebral infarction, and found 28 cerebral infarcts (two corresponded to the patients' neurologic deficits and 26 were silent). All were lacunar infarcts < 10 cm in size. A total of 25 silent lacunar infarcts were found in nine heterozygotic subjects, whereas only one was found in the seven normal homozygotic subjects (2.8 v 0.14 lacunes per person, P = .002). No advanced white matter hyperintense lesions in T2-weighted images were found in either group. The prevalence of silent lacunar infarcts in the heterozygotic subjects was also significantly higher than that in normal control subjects (1.0 per person, P = .01). Concerning the distribution of silent infarcts, the number of lacunes located in the basal ganglia was higher in the heterozygotic subjects (2.3 per person, P < .001) than in the seven normal homozygotic subjects (0.14 per person) or in the control group (0.28 per person), whereas the number of lacunes in the white matter was not different among the groups. In conclusion, congenital protein C deficiency may accelerate the progression of silent cerebral infarct formation in hypertension, particularly in the basal ganglia, and may be a potential risk for stroke or vascularly induced dementia.

Aged↗
PubMed2003

Accurate mass measurement by electrospray ionization quadrupole mass spectrometry: detection of variants differing by <6 Da from normal in human hemoglobin heterozygotes.

Mass spectrometry has a basic limitation when human hemoglobin variants are analyzed, because it cannot resolve two globin chains that differ in mass by <6 Da. Several common beta-chain variants differ by 1 Da from normal and, hence, when present in heterozygotes, are not resolved from the normal beta-chain. Normal and variant chains appear together in the spectrum as a single entity, whose mass is the abundance weighted mean of the two chains. Here we show that such heterozygotes can be detected in 500-fold diluted blood by accurately measuring the mass of the beta-chain using an electrospray ionization quadrupole instrument and the alpha-chain for internal mass calibration. A statistical analysis of the normal beta-chain mass (n = 86) showed that the standard deviation (SD) of the mean was <+/-0.05 Da (<+/-3.2 ppm). Hence, at the 95% confidence level (+/-2 SD), an abnormal alpha- or beta-chain differing by 1 Da from normal should be detectable in a heterozygote provided its abundance is >10% of total alpha- or beta-chains, respectively. Variants whose masses lay between 1 and 4 Da from normal were detected in 19 heterozygotes. Moreover, the proportion of each variant estimated from the mass change correlated with the proportion determined by cation-exchange HPLC. Variants were assigned to the alpha- or beta-chain by combining the sign of the mass change with the polarity change inferred from electrophoretic data. This procedure could be used for screening clinically significant hemoglobin variants.

Calibration↗
PubMed1998

The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies.

The incidence of cystic fibrosis (CF) has previously been calculated from epidemiological surveys and from neonatal screening. With the cloning of the CF gene it has become possible to derive incidence figures from heterozygote frequencies, provided that the distribution of mutant alleles among healthy carriers is the same as among affected people. We have estimated the allele frequencies for four CF mutations, AF508, G551D, G542X and R117H, in 14360 unselected women undergoing antenatal heterozygote screening. The proportion of R117H, an allele of known mild effect, was much greater for heterozygotes than for homozygotes. The incidence of CF was therefore calculated from the heterozygote frequencies of AF508, G551D and G542X in a larger cohort of 27 161 successively screened women. The point estimate for the incidence of CF in the Scottish population was 1 in 1984, with 95% confidence intervals of 1 in 1692 to 1 in 2336.

Alleles↗
PubMed2002

Heterozygote deficiencies in small lacustrine populations of brook charr Salvelinus Fontinalis Mitchill (Pisces, Salmonidae): a test of alternative hypotheses.

Empirical studies of natural populations have commonly reported departures from Hardy-Weinberg expected proportions of heterozygote individuals. Recent advances in statistical population genetics now offer the potential to exploit individual multilocus genotypic information to test more rigorously for possible sources of heterozygote deficiencies. In a previous study in lacustrine brook charr (Salvelinus fontinalis), we reported stronger deficits in small than in large lakes. In the present paper, we propose a methodology for empirically testing alternative hypotheses to identify the cause of the deficits observed in three of the smallest lakes (85, 109 and 182 ha) analysed. First, as in several salmonid species, brook charr may exhibit a trophic polymorphism in north temperate lakes. If morphs are genetically divergent, indiscriminate sampling of both forms would result in less heterozygote individuals than expected in a randomly mating population (Wahlund effect). Using an individual-based method aiming at detecting cryptic population structure, we can reject this explanation as the sole source of deficits for all three lakes. Secondly, mating among relatives could also be frequent in small lakes and lead to heterozygote deficiencies. Significantly more fish than expected at random had low individual multilocus heterozygosity in two of the lakes, suggesting that inbred fish may have been present. Thirdly, sampling of genetically related fish would also lead to departures from Hardy-Weinberg proportions. In the same two lakes, the distribution of pairwise relatedness coefficients departed from its random expectation, suggesting that non-random sampling of kin may have occurred.

Animals↗
PubMed1998

Purine metabolism in female heterozygotes for hypoxanthine-guanine phosphoribosyltransferase deficiency.

BACKGROUND: Female carriers of the X-linked recessive disorder hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency show somatic cell mosaicism, and this may cause an increased synthesis of purines. We have examined whether urinary oxypurines could be useful for carrier diagnosis. METHODS: Carrier testing was performed in 35 women belonging to 16 unrelated Spanish families with at least one subject affected by the Lesch-Nyhan syndrome (11 families, 14 patients) or the Kelley-Seegmiller syndrome (five families, six patients) by means of HPRT and adenine phosphoribosyltransferase activities in hair follicles and/or molecular studies. Plasma and 24-h urinary concentrations of hypoxanthine, xanthine and uric acid were measured while subjects were on a purine-restricted diet. RESULTS: Mean plasma urate concentrations and 24-h urinary hypoxanthine, xanthine and uric acid excretion rates were significantly higher in 22 heterozygotes than in 13 non-carriers (P < 0.02). Daily urinary oxypurine excretion rates were also significantly higher in heterozygotes than in 12 normal women (P = 0.0011). Cumulative 5-day radioactivity excretion after [8-14C]-adenine infusion was markedly increased in 10 carrier women compared with five normal women (P = 0.0369). The sensitivity of 24-h urinary hypoxanthine and xanthine excretion rates was 86% and 77%, respectively, and the specificity 100% for both tests. CONCLUSION: Female heterozygotes for HPRT deficiency show an enhanced purine nucleotide degradation and purine overproduction. An elevated hypoxanthine and/or xanthine excretion rate differentiated most heterozygotes for HPRT deficiency from non-carrier women and thus could be useful for carrier diagnosis.

Adolescent↗
PubMed2000

Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes.

BACKGROUND: Hereditary haemochromatosis (HH) is a common autosomal recessive disease. Recently, HH heterozygosity has been identified as an independent risk factor for myocardial infarction and cardiovascular mortality. Iron may play an important role in atherogenesis by catalyzing peroxidation of low-density-lipoprotein (LDL), an essential step in atherogenesis. In iron overload conditions, non-transferrin-bound iron (NTBI) is found in serum, which can catalyze lipid peroxidation. We investigated whether sera of HH heterozygotes contain more NTBI than sera of normal controls. METHODS: In 27 treated HH homozygotes, 22 HH heterozygotes and 17 healthy control subjects, conventional parameters of iron status (serum iron, transferrin saturation, serum ferritin) were measured. NTBI was detected using HPLC after addition of nitrilotriacetic acid and pretreatment with cobalt. RESULTS: The conventional parameters of iron status were similar in the HH heterozygous group and the control group. NTBI was significantly higher in homozygotes compared to heterozygotes (1.79 micromol L-1 vs. 0.51 micromol L-1, 95% CI of the difference = 0.6-1.95, P < 0.001), and controls (1.79 micromol L-1 vs. - 0.3 micromol L-1, 95% CI of the difference = 1.36-2.81, P < 0.001). The difference in NTBI between the heterozygous subjects and control subjects was also significant (0.51 micromol L-1 vs. - 0. 3 micromol L-1, 95% CI of the difference = 0.05-1.57, P < 0.05). CONCLUSION: Phlebotomy treated HH homozygotes maintain a high and potentially harmful serum NTBI. HH heterozygotes have a higher serum NTBI than normal controls. The reported increased risk of cardiovascular events in heterozygous haemochromatosis may be explained by NTBI-catalyzed LDL peroxidation.

Cardiovascular Diseases↗
PubMed2003

Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice.

Clearance rates for serotonin (5-HT) in heterozygote (+/-) and homozygote (-/-) serotonin transporter (5-HTT) knockout (KO) mice have not been determined in vivo. Moreover, the effect of selective serotonin reuptake inhibitors (SSRIs) on 5-HT clearance in these mice has not been examined. In this study, the rate of clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus of anesthetized mice using high-speed chronoamperometry. Compared with wild-type mice, the maximal rate of 5-HT clearance from extracellular fluid (ECF) was decreased in heterozygotes and more markedly so in KO mice. Heterozygote mice were more sensitive to the 5-HT uptake inhibitor, fluvoxamine, resulting in longer clearance times for 5-HT than in wild-type mice; as expected, the KO mice were completely unresponsive to fluvoxamine. There were no associated changes in norepinephrine transporter density, nor was there an effect of the norepinephrine uptake inhibitor, desipramine, on 5-HT clearance in any genotype. Thus, adaptive changes in the norepinephrine transport system do not occur in the CA3 region of hippocampus as a consequence of 5-HTT KO. These data highlight the potential of the heterozygote 5-HTT mutant mice to model the dynamic in vivo consequences of the human 5-HTT polymorphism.

Adrenergic Uptake Inhibitors↗
PubMed2003

HFE genotype and parameters of iron metabolism in German first-time blood donors - evidence for an increased transferrin saturation in C282Y heterozygotes.

BACKGROUND: Hemochromatosis is usually inherited in an autosomal recessive mode and associated with missense mutations in the hemochromatosis gene (HFE), an HLA class 1 related gene. However the degree of penetrance is presently matter of debate. METHODS: To elucidate the frequency of HFE mutations in a German population and the relationship between genotype and phenotype, we determined the HFE C282Y and H63D genotypes in 500 first-time blood donors using an allele-specific ligase chain reaction (LCR). Ferritin and transferrin saturation (TS) of all donors found to have at least one mutation were compared to gender- and age-matched controls. RESULTS: The C282Y allele frequency was 46 in 1000 chromosomes (4.6 %). The allele frequency of H63D was 108 in 1000 (10.8 %) chromosomes. We found three persons homozygous for H63D, nine compound heterozygotes and none homozygous for C282Y. TS was elevated in C282Y heterozygotes (p = 0.002) and C282Y/H63D compound heterozygotes (p = 0.04) compared to wild-type controls. Serum ferritin tended to be elevated in compound heterozygotes (p = 0.053). Mean corpuscular volume (MCV) and hemoglobin (MCH) were not different from controls. CONCLUSION: The frequency of HFE mutations in the tested population was comparable to those of other northern European populations. The elevated TS in subjects carrying a single copy of the C282Y mutation suggests that C282Y heterozygosity is associated with an increased intestinal iron absorption and might therefore offer a selection advantage in conditions of iron depletion.

Alleles↗
PubMed2001

Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease.

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) epsilon4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal epsilon4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal epsilon4 heterozygotes and 15 epsilon4 noncarriers 50-63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The epsilon4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the epsilon4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal epsilon4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

Aged↗