Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

Pathways linking car transport for young adults and the public health in Northern Ireland: a qualitative study to inform the evaluation of graduated driver licensing.

BACKGROUND: Novice drivers are at relatively high risk of road traffic injury. There is good evidence that Graduated Driving Licensing (GDL) schemes reduce collisions rates, by reducing exposure to risk and by extending learning periods. Legislation for a proposed scheme in Northern Ireland was passed in 2016, providing an opportunity for future evaluation of the full public health impacts of a scheme in a European context within a natural experiment. This qualitative study was designed to inform the logic model for such an evaluation, and provide baseline qualitative data on the role of private cars in health and wellbeing. METHODS: Nine group interviews with young people aged 16-23 (N = 43) and two group interviews with parents of young people (N = 8) were conducted in a range of settings in Northern Ireland in 2015. Data were analysed using thematic content analysis. RESULTS: Informal car-pooling within and beyond households led to routine expectations of lift provision and uptake. Experiences of risky driving situations were widespread. In rural areas, extensive use of farm vehicles for transport needs meant many learner drivers had both early driving experience and expectations that legislation may have to be locally adapted to meet social needs. Cars were used as a site for socialising, as well as essential means of transport. Alternative modes (public transport, walking and cycling) were held in low esteem, even where available. Recall of other transport-related public health messages and parents' existing use of GDL-type restrictions suggested GDL schemes were acceptable in principle. There was growing awareness and use of in-car technologies (telematics) used by insurance companies to reward good driving. CONCLUSIONS: Key issues to consider in evaluating the broader public health impact of GDL will include: changes in injury rates for licensed car occupants and other populations and modes; changes in exposure to risk in the licensed and general population; and impact on transport exclusion. We suggest an important pathway will be change in social norms around offering and accepting lifts and to risk-taking. The growing adoption of in-car telematics will have implications for future GDL programmes and for evaluation.

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.

Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.

A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene.

Although mutations in the beta-amyloid precursor protein gene (APP) on chromosome 21 cause some cases of early-onset Alzheimer's disease (AD), most cases evidently do not have mutations in APP. We analysed ten early-onset families for linkage to APP and markers elsewhere in the genome. One family (F172) was consistent with linkage to chromosome 21 and was subsequently found to have an APP Val to Ile mutation. Of the others, all but one were consistent with linkage to markers in the middle long arm of chromosome 14. However, no family showed independent evidence of linkage with two point analysis and only one showed independent evidence of linkage on multipoint analysis. Therefore, we cannot rule out heterogeneity at these loci although tests for heterogeneity were not significant.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms.

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K. brevis in seawater and carried inland within marine aerosol. Exposure to K. brevis occurs during residential, recreational, and occupational activities and has been associated with upper respiratory tract (URT) symptoms in healthy and medically vulnerable individuals. Additionally, ingestion of brevetoxin-contaminated seafood causes neurotoxic shellfish poisoning (NSP), and severe headaches prompting emergency department visits which occur in excess during K. brevis blooms. The current study examined a dose-response relationship between K. brevis in coastal waters and URT and NSP-like symptoms and headaches among southwest Florida residents. Data on past medical history (PMH) and medical symptoms were collected from the participants (n = 258) in five southwest Florida counties between June 2019 to August 2021. A dose-response relationship was observed between K. brevis blooms and reporting of URT and NSP-like symptoms and headaches. Reporting of NSP-like symptoms was higher among participants with a PMH of migraines, chronic fatigue syndrome (CFS) and mild memory loss, while the association of headaches with K. brevis blooms was accentuated among individuals with a PMH of migraines. These results suggest further investigations into the threshold of aerosolized brevetoxin dose required to elicit URT, headaches and/or NSP-like symptoms. These symptoms ultimately cause significant public health safety concerns, primarily among vulnerable populations with preexisting neurological conditions.

Demonstration of safety in Alzheimer's patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study.

BACKGROUND: Nilvadipine may lower rates of conversion from mild-cognitive impairment to Alzheimer's disease (AD), in hypertensive patients. However, it remains to be determined whether treatment with nilvadipine is safe in AD patients, given the higher incidence of orthostatic hypotension (OH) in this population, who may be more likely to suffer from symptoms associated with the further exaggeration of a drop in BP. OBJECTIVE: The aim of this study was to investigate the safety and tolerability of nilvadipine in AD patients. METHODS: AD patients in the intervention group (n = 56) received nilvadipine 8 mg daily over 6-weeks, compared to the control group (n = 30) who received no intervention. Differences in systolic (SBP) and diastolic (DBP) blood pressure, before and after intervention, was assessed using automated sphygmomanometer readings and ambulatory BP monitors (ABP), and change in OH using a finometer. Reporting of adverse events was monitored throughout the study. RESULTS: There was a significant reduction in the SBP of treated patients compared to non-treated patients but no significant change in DBP. Individuals with higher initial blood pressure (BP) had greater reduction in BP but individuals with normal BP did not experience much change in their BP. While OH was present in 84% of the patients, there was no further drop in BP recorded on active stand studies. There were no significant differences in adverse event reporting between groups. CONCLUSION: Nilvadipine was well tolerated by patients with AD. This study supports further investigation of its efficacy as a potential treatment for AD.

Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation.

Alzheimer's disease (AD) has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. CD40 expression was increased on cultured microglia treated with freshly solublized amyloid-beta (Abeta, 500 nanomolar) and on microglia from a transgenic murine model of AD (Tg APPsw). Increased tumor necrosis factor alpha production and induction of neuronal injury occurred when Abeta-stimulated microglia were treated with CD40 ligand (CD40L). Microglia from Tg APPsw mice deficient for CD40L demonstrated reduction in activation, suggesting that the CD40-CD40L interaction is necessary for Abeta-induced microglial activation. Finally, abnormal tau phosphorylation was reduced in Tg APPsw animals deficient for CD40L, suggesting that the CD40-CD40L interaction is an early event in AD pathogenesis.

Genetic and molecular advances in Alzheimer's disease.

The abnormal deposition of amyloid beta protein (A beta) in the brain is the major neuropathological characteristic of Alzheimer's disease (AD). The disease in some early-onset familial cases develops as a result of mutations in the gene coding for the beta-amyloid precursor protein (beta APP) and in the majority of the rest appears to be caused by an unidentified gene on chromosome 14. Only one of the beta APP gene mutations has been associated with aberrant beta APP processing, resulting in an excess production of A beta in vitro, a result suggesting that there might be excessive A beta cleavage from beta APP in AD in vivo. By contrast with the beta APP mutants, no particular allele of the apolipoprotein E (APOE) gene predicts the disease completely but one allele is associated with the disease suggesting APOE is a risk locus for AD. This discovery has been linked to increased deposition of A beta in those cases carrying the risk allele. However, the genetic evidence is currently not sufficient to indicate whether beta APP mismetabolism, direct or indirect A beta neurotoxicity or dysfunction of beta APP (or its derivatives) are central to the AD process.

Molecular genetic studies of manic-depression and schizophrenia.

The application of molecular genetics to the study of mental disorders has begun in earnest. Most of the initial interest has focused on the functional psychoses as these common and debilitating disorders have long been known to have a significant genetic component. A number of groups have now reported data from RFLP linkage studies of both schizophrenia and bipolar affective disorder (manic-depression). Unfortunately the results are already conflicting with early findings of linkage unconfirmed by subsequent studies.

CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase.

Reactive microglia have been suggested to play a role in the Alzheimer's disease (AD) process, and previous studies have shown that expression of CD45, a membrane-bound protein-tyrosine phosphatase (PTP), is elevated in microglia in AD brain compared with controls. To investigate the possible role of CD45 in microglial responsiveness to beta-amyloid (Abeta) peptides, we first co-treated primary cultured microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 micrometer] and freshly solubilized Abeta peptides (1000 nm). Data show synergistic induction of microglial activation as evidenced by tumor necrosis factor alpha (TNF-alpha) production and nitric oxide (NO) release, both of which we show to be dependent on activation of p44/42 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with phen and Abeta peptides results in microglia-induced neuronal cell injury. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibits these effects via inhibition of p44/42 MAPK, suggesting that CD45 is a negative regulator of microglial activation. Accordingly, primary cultured microglia from CD45-deficient mice demonstrate hyper-responsiveness to Abeta, as evidenced by TNF-alpha release, NO production, and neuronal injury after stimulation with Abeta peptides. As a validation of these findings in vivo, brains from a transgenic mouse model of AD [transgenic Swedish APP-overexpressing (Tg APP(sw)) mice] deficient for CD45 demonstrate markedly increased production of TNF-alpha compared with Tg APP(sw) mice. Taken together, these results suggest that therapeutic agents that stimulate the CD45 PTP signaling pathway may be effective in suppressing microglial activation associated with AD.

Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice.

Mounting evidence suggests that cholesterol may contribute to the pathogenesis of Alzheimer disease (AD). We examined whether cholesterol might be present in senile plaques, a hallmark neuropathological feature of AD. We employed 2 different fluorometric-staining techniques (filipin staining and an enzymatic technique) for the determination of cholesterol in brains of postmortem confirmed AD patients and in nondemented, age-matched histopathologically normal controls. AD patient brains showed abnormal accumulation of cholesterol in congophilic/birefringent dense cores of senile plaques that was essentially absent in histopathologically normal controls. To determine whether increased senile plaque-associated cholesterol occurred generally in all plaques or was restricted to a specific subset, quantitative analysis was performed. Data indicate abnormal accumulation of cholesterol in cores of mature plaques but not in diffuse or immature plaques. Additionally, transgenic mice that overexpress the "Swedish" amyloid precursor protein (Tg APP(SW), line 2576) exhibited a similar pattern of abnormal cholesterol accumulation in mature, congophilic amyloid plaques at 24 months of age that was absent in their control littermates or in 8-month-old Tg APP(SW) mice (an age prior to amyloid deposition). Taken together, our results imply a link between cholesterol and AD pathogenesis and suggest that cholesterol plays an important role in the formation and/or progression of senile plaques.

Soluble beta-amyloid peptides mediate vasoactivity via activation of a pro-inflammatory pathway.

Freshly solubilized beta-amyloid (Abeta) peptides display vasoactive properties, increasing both the magnitude and the duration of endothelin-1-induced vasoconstriction. We show that Abeta vasoactivity is mediated by the stimulation of a pro-inflammatory pathway involving activation of secretory phospholipase A(2) (PLA(2)), mitogen activated protein kinase (MAPK) kinase (MEK1/2), p38 MAPK, cytosolic PLA(2), and the release of arachidonic acid. Ultimately, arachidonic acid is metabolized into proinflammatory eicosanoids via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of which we show to be required for A beta vasoactivity. Accordingly, p38 MAPK activity is higher in the brains of transgenic mice that overproduce A beta, and COX-2 immunoreactivity is increased in the cerebrovasculature of these transgenic animals. Taken together, our data show that freshly solubilized A beta peptides can trigger a pro-inflammatory reaction in the vasculature that can be blocked by inhibiting specific target molecules, providing the basis for novel therapeutic intervention.

Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val-->Ile mutation in the amyloid precursor protein gene.

Alzheimer's disease (AD) is the most common cause of dementia (32). Although the majority of cases of AD are sporadic, the most consistent risk factor detected in several epidemiological studies has been a positive family history of the disease (14,21). In addition, many large pedigrees have been described in which AD appears to be inherited as an autosomal dominant disorder. In one such pedigree (F23) a point mutation within the beta-amyloid precursor protein (APP) gene at codon 717 was identified and hypothesized to be pathogenic (10). The mutation results in a valine to isoleucine change in APP (APP717 Val-->Ile). Subsequent screening has revealed four other pedigrees, detailed in this study, in which this mutation co-segregates with AD (13,26,37). In addition, one other pedigree (Tor3) with this mutation has been described (15) and detailed clinical, neuropsychological, and neuropathological data are reported. Tor3 is discussed below in comparison to the findings in the families in this study. The five families we report with the mutation were identified in Britain (1 family), the United States (1 family), and Japan (3 families). The mutation has not been reported in the general population of any of these countries (3,13,26,33). On this basis alone it seems this mutation is pathogenic. Other APP codon 717 mutations have been identified which co-segregate with the disease (4,25). Also, a double mutation in APP at codons 670/671 has been shown to cosegregate with the disease in two large Swedish pedigrees (22). In all cases, there is complete co-segregation of the APP mutation with early onset AD, providing overwhelming statistical evidence that these mutations are pathogenic. We present the clinical features and limited neuropathology of AD in these families with the APP 717 Val-->Ile mutation.

Modelling the occurrence and pathology of Alzheimer's disease.

Our work has confirmed that of St. George-Hyslop and colleagues, suggesting FAD linkage to the short arm of chromosome 21 in outbred families with a presenile onset of the disease. Future genetic studies should help clarify the current apparent discrepancies between certain laboratories and ultimately lead to a better understanding of the variables which predispose individuals to the disease.

The molecular genetics of Alzheimer's disease.

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of beta-amyloid peptide (A beta) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for beta-amyloid precursor protein (beta APP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the beta APP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the beta APP mutations cause the disease and discuss recent advances in beta APP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of the APOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of beta APP and its derivatives.

Alzheimer's beta-amyloid vasoactivity: identification of a novel beta-amyloid conformational intermediate.

The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-1 induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity. To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis--Dutch type (A beta(22Q)(1-40)). The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40). However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure. The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta. This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them.

Is APOE--epsilon4 a risk factor for cognitive impairment in normal aging?

OBJECTIVES: To examine the relationship between APOE genotype and cognitive functioning in normal aging, and to determine whether this relationship was moderated by age or the presence of a number of disease conditions, including cardiovascular disease and diabetes. METHODS: The sample was drawn from the Charlotte County Healthy Aging Study, a community-based, cross-sectional study of randomly selected older adults in Charlotte County, FL. A total of 413 older adults (mean age = 72.90 years) were examined in the current study. Participants completed tasks that indexed a variety of dimensions of cognitive functioning, including episodic memory, implicit memory, psychomotor speed, and attention. In addition, participants provided self-reported and objective indices of health status and were genotyped for APOE. RESULTS: Mean-level results indicated that groups with and without the APOE-epsilon4 allele performed similarly on all domains of cognitive functioning. Significant age group differences were observed in episodic memory, psychomotor speed, and attention but not implicit memory. Significant gender differences were present for episodic memory and the Stroop test. Analyses also indicated that participants' age did not exert an impact on the relationship between APOE-epsilon4 and cognitive functioning. Further, the presence of cardiovascular disease or diabetes did little to moderate the relationship between APOE-epsilon4 and cognition. CONCLUSIONS: The authors found no evidence for a relationship between presence of the APOE-epsilon4 allele and cognitive functioning. Further, age or the presence of a number of chronic conditions did not significantly moderate the effect of APOE genotype on cognitive performance. These results indicate that the presence of the epsilon4 allele is not a risk factor for cognitive impairment in normal aging.

A cross-ethnic analysis of risk factors for AD in white Hispanics and white non-Hispanics.

BACKGROUND: The prevalence of AD appears to vary widely in different ethnic groups. Certain risk factors for AD are well established for the general population, but there is little information regarding the relevance of these risk factors in specific ethnic groups. OBJECTIVE: The authors examined the risk of AD associated with the APOE-epsilon4 allele, the APOE-epsilon2 allele, smoking, alcohol consumption, history of hypertension, low educational level, estrogen replacement therapy, and history of head trauma with loss of consciousness among samples of white non-Hispanics (WNH) (392 AD patients, 202 normal subjects) and white Hispanics (WHIS) (188 AD patients, 84 normal controls). DESIGN: This was a case-control study of patients evaluated at an outpatient memory disorders clinic and control subjects recruited from a free memory screening offered to the community. RESULTS: Increased risk for AD was associated with the APOE-epsilon4 allele after controlling for age, education, and gender among WNH (OR = 3.5; 95% CI = 2.3 to 5.5) and WHIS (OR = 3.1; 95% CI = 1.7 to 5.8). No protective effect was conferred by the APOE-epsilon2 allele, although this relationship approached significance among WNH (p = 0.02). Low levels of education increased the risk for AD among WNH (OR = 3.1; 95% CI = 1.8 to 5.9) but not WHIS. Alcohol use and hypertension approached significance as risk factors in WNH (p < 0.05) but not WHIS. Estrogen replacement treatment approached significance as a protective factor in both ethnic groups (p < 0.05). CONCLUSIONS: Although the APOE-epsilon4 allele is a risk factor for AD among WHIS and WNH, other risk factors such as low education and hypertension appear to be important only for WNH. Risk factors for AD reported or suggested previously that were not confirmed by this study include smoking and head trauma with loss of consciousness.

Transmission and age-at-onset patterns in familial Alzheimer's disease: evidence for heterogeneity.

We evaluated age at onset and lifetime risk for Alzheimer's disease (AD) in 70 kindreds with familial AD (designated FAD) composed of 541 affected and 1,066 unaffected offspring of demented parents who were identified retrospectively. Using a survival analysis method which takes into account affected persons with unknown onset ages and unaffected persons with unknown censoring ages, we found lifetime risk of AD among at-risk offspring by age 87 to be 64%. Analysis of age at onset among kindreds showed evidence for a bimodal distribution: in this sample, families with a mean onset age of less than 58 years were designated as having early-onset, while late-onset families had a mean onset age greater than 58 years. At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, which is significantly less than the risk of 86% that was estimated for offspring in late-onset families. Men and women in early-onset families had equivalent risk of dementia. In late-onset families, the risk to female offspring was somewhat higher than to male offspring but this difference was marginally significant. Lifetime risk of dementia in early-onset FAD kindreds is consistent with an autosomal dominant inheritance model. Our results may suggest that late-onset FAD has at least 2 etiologies; AD in some families may be transmitted as a dominant trait, whereas a proportion of cases in these and other late-onset families may be caused by other genetic or shared environmental factors.

APOE genotype influences acquisition and recall following traumatic brain injury.

APOE has been demonstrated to influence traumatic brain injury (TBI) outcome. The relationship between APOE genotype and memory following TBI was examined in 110 participants in the Defense and Veterans' Head Injury Program. Memory performance was worse in those who had an APOE epsilon 4 allele (n = 30) than those who did not (n = 80), whereas genotype groups did not differ on demographic or injury variables or on measures of executive functioning. These data support a specific role for the APOE protein in memory outcome following TBI, and suggest an APOE isoform-specific effect on neuronal repair processes.