Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD. OBJECTIVES: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance. DESIGN: A phase 3, double-blind, placebo-controlled, randomized clinical trial. SETTING: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. PARTICIPANTS: Cognitively normal older adults aged 65 to 83. INTERVENTION: Pioglitazone tablet. MEASUREMENTS: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes. RESULTS: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. CONCLUSIONS: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.

Diabetes, Edentulism, and Cognitive Decline: A 12-Year Prospective Analysis.

Diabetes mellitus (DM) is a recognized risk factor for dementia, and increasing evidence shows that tooth loss is associated with cognitive impairment and dementia. However, the effect of the co-occurrence of DM and edentulism on cognitive decline is understudied. This 12-y cohort study aimed to assess the effect of the co-occurrence of DM and edentulism on cognitive decline and examine whether the effect differs by age group. Data were drawn from the 2006 to 2018 Health and Retirement Study. The study sample included 5,440 older adults aged 65 to 74 y, 3,300 aged 75 to 84 y, and 1,208 aged 85 y or older. Linear mixed-effect regression was employed to model the rates of cognitive decline stratified by age cohorts. Compared with their counterparts with neither DM nor edentulism at baseline, older adults aged 65 to 74 y (ß = -1.12; 95% confidence interval [CI], -1.56 to -0.65; P < 0.001) and those aged 75 to 84 y with both conditions (ß = -1.35; 95% CI, -2.09 to -0.61; P < 0.001) had a worse cognitive function. For the rate of cognitive decline, compared to those with neither condition from the same age cohort, older adults aged 65 to 74 y with both conditions declined at a higher rate (ß = -0.15; 95% CI, -0.20 to -0.10; P < 0.001). Having DM alone led to an accelerated cognitive decline in older adults aged 65 to 74 y (ß = -0.09; 95% CI, -0.13 to -0.05; P < 0.001); having edentulism alone led to an accelerated decline in older adults aged 65 to 74 y (ß = -0.13; 95% CI, -0.17 to -0.08; P < 0.001) and older adults aged 75 to 84 (ß = -0.10; 95% CI, -0.17 to -0.03; P < 0.01). Our study finds the co-occurrence of DM and edentulism led to a worse cognitive function and a faster cognitive decline in older adults aged 65 to 74 y.

Twin pairs discordant for neuropathologically confirmed Lewy body dementia.

AIM: Little is known about the concordance rate in twins for dementia with Lewy bodies (DLB). The rate of agreement between clinical and pathological diagnoses for DLB is typically low, necessitating confirmation of the diagnosis neuropathologically. METHODS: Participants were 17 twin pairs enrolled in the Duke Twins Study of Memory in Aging in which at least one member of the pair had an autopsy confirmed diagnosis of DLB, Alzheimer's disease (AD) with Lewy bodies or frontotemporal dementia with Lewy bodies. The characteristics of those with dementia were assessed and rates of concordance for pathological confirmed dementia were examined. RESULTS: Four monozygotic twin pairs had a proband with neuropathologically confirmed pure DLB; all remained discordant for dementia for periods up to 16 years or more. Five of 13 pairs in which the proband had AD plus DLB were concordant for dementia but only one pair was concordant for AD plus DLB, while the co-twins in the other four pairs had other types of dementia. CONCLUSIONS: The present study indicates that even among twins, a diagnosis of DLB in one twin does not predict the same diagnosis in the other twin. Neuropathological discordance in type of dementia among monozygotic pairs hints at environmental or epigenetic factors playing a role in Lewy body pathology.

Prevalence of dementia in the United States: the aging, demographics, and memory study.

AIM: To estimate the prevalence of Alzheimer's disease (AD) and other dementias in the USA using a nationally representative sample. METHODS: The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. RESULTS: The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71-79 years to 37.4% of those aged 90 and older. CONCLUSIONS: Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.

Prevalence of depression and its treatment in an elderly population: the Cache County study.

BACKGROUND: Previous estimates of the prevalence of geriatric depression have varied. There are few large population-based studies; most of these focused on individuals younger than 80 years. No US studies have been published since the advent of the newer antidepressant agents. METHODS: In 1995 through 1996, as part of a large population study, we examined the current and lifetime prevalence of depressive disorders in 4,559 nondemented individuals aged 65 to 100 years. This sample represented 90% of the elderly population of Cache County, Utah. Using a modified version of the Diagnostic Interview Schedule, we ascertained past and present DSM-IV major depression, dysthymia, and subclinical depressive disorders. Medication use was determined through a structured interview and a "medicine chest inventory." RESULTS: Point prevalence of major depression was estimated at 4.4% in women and 2.7% in men (P= .003). Other depressive syndromes were surprisingly uncommon (combined point prevalence, 1.6%). Among subjects with current major depression, 35.7% were taking an antidepressant (mostly selective serotonin reuptake inhibitors) and 27.4% a sedative/hypnotic. The current prevalence of major depression did not change appreciably with age. Estimated lifetime prevalence of major depression was 20.4% in women and 9.6% in men (P<.001), decreasing with age. CONCLUSIONS: These estimates for prevalence of major depression are higher than those reported previously in North American studies. Treatment with antidepressants was more common than reported previously, but was still lacking in most individuals with major depression. The prevalence of subsyndromal depressive symptoms was low, possibly because of unusual characteristics of the population.

A twin study of late-onset depression and apolipoprotein E epsilon 4 as risk factors for Alzheimer's disease.

A prior history of depression and the epsilon 4 allele of apolipoprotein E (APOE) have each been associated with development of Alzheimer's disease (AD). In a sample of 142 elderly twins from a large study of dementia, we examined the relation of major depression, APOE genotype and AD using time-dependent proportional hazards models. Compared against the risk for AD with no history of depression and no epsilon 4 allele, the risk ratio for AD with two epsilon 4 alleles was 2.87 (C.I. = 1.56-5.28), with one epsilon 4 allele, 1.82 (C.I. = 1.09-3.04) and with late-onset depression and no epsilon 4 allele, 2.95 (C.I. = 1.55-5.62). There was no suggestion of an interaction between prior depression and APOE genotype in their effects on AD risk. Results were similar when the sample was stratified by twin pair, so that a single genetic marker is unlikely to explain the relation among depression, APOE, and dementia. Risk ratios declined substantially with increasing intervals between the onset of depression and AD. Thus, for many individuals, the association of depression and AD may reflect the occurrence of prodromal depressive symptoms rather than a true risk relationship.

Alzheimer's disease in the National Academy of Sciences-National Research Council Registry of Aging Twin Veterans. III. Detection of cases, longitudinal results, and observations on twin concordance.

OBJECTIVES: To detect cases of Alzheimer's disease (AD) in a large population of twins living throughout the United States and to examine concordance for AD in twins as a function of age and genotype for apolipoprotein E (APOE). SETTING: Nationwide survey. DESIGN: Multistage screening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological measures, physician examination, and diagnostic consensus among experts. PARTICIPANTS: Membership in 1990-1991 of intact pairs in the National Academy of Sciences--National Research Council Registry of veteran twins, then aged 62 to 73 years. MAIN OUTCOME MEASURES: Completeness of case detection was examined in collateral studies. Zygosity and APOE genotypes were determined by restriction mapping. Concordance was calculated by the proband method. RESULTS: Ninety subjects who screened positively for AD were studied in person, and 60 whose differential diagnoses included AD were followed up, as were their co-twins. Sensitivity of screening was estimated at greater than 99%, but 24% of subjects refused participation after initial screening. Seven of 38 diagnoses of AD have been confirmed at autopsy, and 31 other subjects eventually met criteria for probable or possible AD (prevalence estimate, 0.42%, 95% confidence interval, 0.29% to 0.56%), with good interrater reliability (intraclass r = .86). Excluding one discordant pair with unknown zygosity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/18) for dizygotic probands. Concordance was 50% for twins sharing the epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-twins of 15 probands with onset before age 70 years, no epsilon 4 allele, and no family history of AD. The mean (SD) period of discordance in the latter pairs was 11.3 (3.3) years. CONCLUSIONS: The multistage case-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial screening. Genetic influences in AD at this age are limited, except among homozygotes for allele epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental cause of AD.

Intelligence and education as predictors of cognitive state in late life: a 50-year follow-up.

We evaluated the relation of education and intelligence in early adult life to cognitive function in a group of elderly male twins. The Army General Classification Test (AGCT) was administered to US armed forces inductees in the early 1940s. Fifty years later, as part of a study of dementia in twins, we tested the cognitive status of 930 of these men using the modified Telephone Interview for Cognitive Status (TICS-m). TICS-m scores obtained in later life were correlated with AGCT scores (r = 0.457) and with years of education (r = 0.408). Thus, in univariate analyses, the AGCT score accounted for 20.6% and education accounted for 16.7% of variance in cognitive status. However, these two effects were not fully independent. A multivariable model using AGCT score, education, and the interaction of the two variables as predictors of the TICS-m score explained 24.8% of the variance, a slightly but significantly greater proportion than was explained by either factor alone. In a separate analysis based on 604 pairs of twins who took the AGCT, heritability of intelligence (estimated by AGCT score) was 0.503. Although this study does not address the issue of education and premorbid IQ as risk factors for dementia, the findings suggest that basic cognitive abilities in late life are related to cognitive performance measures from early adult life (ie, education and IQ).

APOE and AD concordance in twin pairs as predictors of AD in first-degree relatives.

OBJECTIVE: To examine the independent effects of the APOE genotype (APOE) and concordance for AD in twin pairs on the occurrence of AD in first-degree relatives. BACKGROUND: Studies of twins have been undertaken to investigate the influence of genes in a variety of conditions, including AD. A previous study, performed before reports linking APOE to AD, demonstrated an increase in AD among first-degree relatives of twins concordant for AD compared with relatives of discordant twins. METHODS: In a sample of 94 twin pairs the authors examined the association between concordance for AD within the twin pair and family history of AD among first-degree relatives of twins. They then examined the extent to which the presence of the APOE epsilon4 allele in the twin pair explains the association between concordance for AD within the twin pair and family history of AD. RESULTS: Concordance among twins was associated with increased risk of AD among relatives (logrank test, chi2 = 12.558; p = 0.0004), and the presence of at least one APOE epsilon4 allele in each member of the twin pair is also associated with increased risk of AD among family members (logrank test, chi2 = 7.712; p = 0.0055). CONCLUSIONS: APOE genotype explains much but not all of the association between concordance among twins and increased familial risk of AD.

Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study.

We conducted a co-twin control study among 50 elderly twin pairs with onsets of Alzheimer's disease (AD) separated by 3 or more years. Twenty-three male pairs (46%) were screened from the (U.S.) National Academy of Sciences-National Research Council Registry (NAS-NRC Registry) of World War II veteran twins; others (mostly women) had responded to advertisements or were referred from AD clinics. Twenty-six pairs (52%) were monozygous. The onset of AD was inversely associated with prior use of corticosteroids or ACTH (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.06 to 0.95; p = 0.04). Similar but weaker trends were present among pairs discordant for history of arthritis or for prior daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. The association was strongest when we combined use of steroids/ACTH or NSAIDs post hoc into a single variable of anti-inflammatory drugs (AIs) (OR, 0.24; CI, 0.07 to 0.74; p = 0.01). The inverse relation was strong in female (volunteer) twin pairs but was not present in the younger men from the NAS-NRC Registry. AIs had typically been taken for arthritis or related conditions, but a similar result was apparent after controlling statistically for the arthritis variable (OR, 0.08; CI, 0.01 to 0.69; p = 0.02). AIs have been proposed as a means of retarding the progression of AD symptoms, and these data suggest that AIs may also prevent or delay the initial onset of AD symptoms. Because of limitations in the case-control method, our results require corroboration with hypothesis-driven research designed to control bias and confounding.

Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition.

We examined the relation of APOE-epsilon 4, hippocampal volume, and cognitive performance in ten pairs of cognitively normal twins who had a mean age of 62.5 years (SD = 7.8). There were no significant differences in neuropsychological measures of the groups categorized by the presence of an epsilon 4 allele. However, the mean normalized right and left hippocampal volumes were smaller in the epsilon 4 groups compared to the group without epsilon 4. Combined with prior reports, these findings suggest that epsilon 4 is associated with differences in brain morphology that may be evident when no symptoms of dementia are present.

Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study.

OBJECTIVE: To examine the association between postmenopausal hormone replacement therapy (HRT) and the trajectory of global cognitive change with age. METHODS: The Modified Mini-Mental State Examination (MMSE) was administered to a population sample of 2,073 nondemented, community-dwelling female residents of Cache County, UT, aged 65 and older. Current and past HRT and other medications at a baseline interview and at follow-up 3 years later were assessed. Between interviews, a telephone Women's Health Questionnaire was administered to assess initial exposure, duration, and recency of HRT. Generalized estimating equation marginal models were used to evaluate the cross-sectional and longitudinal relations of HRT and modified MMSE score. Also assessed were effects with multivitamins and calcium supplements as exposures likely to reflect a "healthy lifestyle" among HRT users. Model covariates included the presence of APOE epsilon4 alleles, age, education, concurrent depression, several chronic diseases, and self-perceived general health. RESULTS: Age, lower education, depression, and APOE epsilon4 were all associated with lower baseline modified MMSE scores. With these covariates in the model, lifetime HRT use was associated with better baseline modified MMSE scores and a slower rate of decline. Stratification by APOE genotype did not alter these effects. Apparent benefits with HRT were attenuated but remained significant after elimination of scores from participants with incident dementia. A significant interaction between age and HRT indicated the strongest effects in women aged 85 and older. Measures of age at initial use of HRT, duration, and recency of exposure did not improve the models. No effects were seen with the "healthy lifestyle" control exposures. CONCLUSIONS: In a population cohort of older women, lifetime HRT exposure was associated with improved global cognition and attenuated decline over a 3-year interval. Improvements were greatest in the oldest old.

APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study.

OBJECTIVE: To examine the prevalence of Alzheimer's disease (AD) and other dementias in relation to age, education, sex, and genotype at APOE. Recent studies suggest age heterogeneity in the risk of AD associated with the APOE genotype and a possible interaction between APOE-epsilon4 and female sex as risk factors. We studied these topics in the 5,677 elderly residents of Cache County, Utah, a population known for long life expectancy and high participation rates. METHODS: We screened for dementia with a brief cognitive test and structured telephone Dementia Questionnaire, then examined all individuals with apparent cognitive symptoms and a sample of others. We estimated age-specific prevalence of AD and other dementias and used multiple logistic regression models to describe relation of AD prevalence to age, sex, education, and APOE genotype. RESULTS: We found 335 demented individuals, 230 (69%) with definite, probable, or possible AD (positive predictive value versus autopsy confirmation 85%). The adjusted prevalence estimate for AD was 6.5% and for all dementias 9.6%. After age 90, the adjusted prevalence estimate for AD was 28% and for all dementias 38%. Regression models showed strong variation in AD prevalence with age, sex, education, and number of epsilon4 alleles (effect of epsilon2 not significant). Models were improved by a term for age-squared (negative coefficient) and by separate terms for interaction of age with presence of one or two epsilon4 alleles. An association of AD with female sex was ascribable entirely to individuals with epsilon4. CONCLUSIONS: In participants with no epsilon4 alleles, the age-specific prevalence of AD reached a maximum and then declined after age 95. In epsilon4 heterozygotes a similar maximum was noted earlier at age 87, in homozygotes at age 73. Female sex was a risk factor for AD only in those with epsilon4. The epsilon4 allele accounted for 70% of the population attributable risk for AD.

Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias.

BACKGROUND: The association between antecedent head injury and AD is inconsistent. OBJECTIVE: To examine the association between early adult head injury, as documented by military hospital records, and dementia in late life; and to evaluate the interaction between head injury and APOE epsilon4 as risk factors for dementia. METHODS: The study had a population-based prospective historical cohort design. It included men who were World War II Navy and Marine veterans, and were hospitalized during their military service with a diagnosis of either a nonpenetrating head injury or another unrelated condition. In 1996 to 1997, military medical records were abstracted to document the occurrence and details of closed head injury. The entire sample was then evaluated for dementia and AD using a multistage procedure. There were 548 veterans with head injury and 1228 without head injury who completed all assigned stages of the study. The authors estimated risk of dementia, specifically AD, using proportional hazards models. RESULTS: Both moderate head injury (hazard ratio [HR] = 2.32; CI = 1.04 to 5.17) and severe head injury (HR = 4.51; CI = 1.77 to 11.47) were associated with increased risk of AD. Results were similar for dementia in general. The results for mild head injury were inconclusive. When the authors stratified by the number of APOE epsilon4 alleles, they observed a nonsignificant trend toward a stronger association between AD and head injury in men with more epsilon4 alleles. CONCLUSIONS: Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.

Recent advances in the genetics of Alzheimer's disease and vascular dementia with an emphasis on gene-environment interactions.

OBJECTIVE: To review recent findings in the genetics of Alzheimer's disease (AD) and vascular dementia (VaD) with particular emphasis on gene-environment interactions. DESIGN: A survey and critique of recent literature on the genetic etiology of AD and VaD. CONCLUSIONS: Recent research has identified several genes associated with AD, including loci on chromosome 1, 14, 19, and 21. Two of these loci, encoding the beta-amyloid precursor protein and apolipoprotein E, have gene products that are well characterized and of evident significance in the pathogenesis of AD. The four genes together probably account for little more than 50% of all cases of AD, but other undiscovered loci are likely. Interaction of genetic effects with environmental influences may affect both onset and expression of AD. By contrast, only a small minority of VaD cases can be attributed to a pure genetic etiology. The majority of VaD is caused by both genetic and environmental factors. Many of the environmental antecedents also have genetic determinants (e.g., smoking). Knowledge of the gene-environment interactions for both AD and VaD will facilitate identification of early preclinical symptoms of disease, a stage of the disease process during which treatment may be most beneficial.

Enhanced cognitive performance with estrogen use in nondemented community-dwelling older women.

OBJECTIVE: To examine the association between history of postmenopausal estrogen use and cognitive function in a large sample of nondemented community-dwelling older women. SETTING: A community of older residents in Cache County, Utah. PARTICIPANTS: A total of 2338 nondemented women aged 65 and older. MEASUREMENTS: All subjects were administered the Modified Mini-Mental State Examination (3MSE). Self-reported information on current and past use of estrogen after menopause was also obtained using a structured interview. Estrogen use was trichotomized as: no use, past use, and current use. Apolipoprotein E (APOE) genotype was determined and was dichotomized by the presence of an epsilon4 allele. A series of variance/covariance models was conducted with the 3MSE score as the dependent variable, first considering estrogen use alone, then adding, sequentially as covariates, education, age, health status, APOE genotype, current depression status, and history of head injury. RESULTS: In the simplest bivariate model, the 3MSE means (and confidence intervals) were 92.1 (91.7-92.4), 93.5 (93.1-93.9), and 94.4 (94.0-94.7) for never-, past-, and current users, respectively. In the final model (R2 = 0.28), no use of estrogen replacement therapy (P = .006), lower education (P < .001), poorer perceived health status (P = .035), current depression (P = .014), and presence of at least one APOE epsilon4 allele (P < .001) each independently predicted lower 3MSE score. Both current and past estrogen users had significantly higher 3MSE scores than never-users (P = .0063 and P = .0096, respectively). CONCLUSIONS: In this large community study, women who had used estrogen after menopause scored higher on the 3MSE. This finding remained, even after controlling for the effects of age, education, APOE genotype, and other variables that may affect cognition. These data support studies reporting a beneficial role of estrogen on cognition in postmenopausal women, particularly among current estrogen users.

Perceptual cues used to reproduce an inspired lung volume.

The perceptual cues used to reproduce a specific lung volume were studied in five healthy males. Performance was examined under three conditions that were designed progressively to remove the reliability of cues that a subject might use to duplicate a specific lung volume. As judged by the mean errors (disregarding the sign of the error) and constant errors (including the sign of the error), there were no significant differences in the accuracy with which subjects reproduced a standard volume, even when they were required to perform the reproductions at various inspiratory rates and starting volumes. The best performance was in the final experimental session in which the mean error for the group, all conditions combined, was 133 ml. There was a difference between conditions on the just-noticeable differences (a measure of variability including the sign of the error); subject performance was significantly more variable when the inspiratory flow rate was altered. The group mean error for the final session for just-noticeable differences was 93.3 ml. Our results indicate that a specific lung volume can be achieved using cues other than those associated with the movement made to attain that lung volume. The specific afferents that provided these cues are not known, but we propose that they uniquely signal static position.

Abdominal muscle activity during speech production.

Abdominal muscle activity was investigated during resting tidal breathing and speech production in upright and supine body positions in five male and five female young adult subjects. Results showed that patterns of abdominal electromyographic (EMG) activity were highly dependent on body position. Data for resting tidal breathing resembled those of previous investigations and revealed one sex-related finding. Data for speech production indicated that the lateral region of the abdomen was highly active in the upright position and occasionally active in the supine position. In the upright position, lateral EMG levels during speech production were characterized by generally higher levels in the lower than upper lateral sites and were almost always higher than during resting tidal breathing. In the supine position, EMG levels during speech production occasionally exceeded those associated with resting tidal breathing but were substantially lower than those associated with upright speech production. Abdominal EMG activity was most prevalent during loud speech production and during speech produced at low lung volumes. Findings are discussed in relation to current knowledge of respiratory mechanics and neural control.

Maximal activation of the human diaphragm but not inspiratory intercostal muscles during static inspiratory efforts.

It is widely held that transdiaphragmatic pressure is a reliable index of the extent of central activation of the diaphragm but the maximal voluntary transdiaphragmatic pressure is lower during inspiratory than expulsive efforts. To determine whether the diaphragm is fully activated during the two manoeuvres supramaximal stimuli were delivered to both phrenic nerves during maximal efforts. No discernible twitch was evoked during 30-55% of attempted maximal efforts with either voluntary manoeuvre. Thus the difference in maximal transdiaphragmatic pressure between the manoeuvres must reflect changes in chest-wall geometry or mechanics rather than in the phrenic motor outflow. Inspiratory intercostal muscle activity was consistently submaximal during maximal inspiratory efforts.

The genetics of dementia in late life.

Recent advances in the genetics of AD and other late-life dementias have provided new insights but also have raised new queries and ethical issues. This review reflects the current state of knowledge in a rapidly evolving field. The complex relation of genes and environment to AD, VaD, and other late-life dementias suggests that the answers to these many issues will evolve through time. New issues undoubtedly will arise as additional genes are discovered and new data accrue that relate APOE and other genes to the mechanism and expression of dementing illness. The clinical relevance and applicability of such research findings will increase when effective treatments become available. Given this potential, we encourage readers to monitor new developments as they arise.