Association Between Overall and Mentholated Cigarette Smoking With Headache in a Nationally Representative Sample.

OBJECTIVE: The objective of this study was to determine associations between cigarette smoking and the existence of headache in a nationally representative sample, with attention to differences in effect estimates between mentholated and non-mentholated cigarettes smoking. METHODS: We examined cross-sectional associations between cigarette smoking and headache in 8,399 adults who participated in the National Health and Nutrition Examination Survey (NHANES) 1999-2004. The existence of headache was determined by an affirmative response to the question "During the past 3 months, did you have severe headaches or migraines?" Further refinement of headache diagnosis was not possible. We used logistic regression models to examine the association between cigarette smoking and headache. RESULTS: The current study included 8,399 participants aged 20 years and over, including 68% (n = 5491) never smokers and 32% (n = 2548) current smokers. Among the current smokers, 24% (n = 739) smoked menthol cigarettes, and 76% (n = 1719) smoked non-menthol cigarettes. Compared with never smokers, after adjustment for potential confounding factors, current smokers were more likely to have headache (OR: 1.38; 95% CI: 1.17-1.62; P < .001). With the increase of both the number of cigarettes smoked daily and pack-years of smoking, the likelihood of having headache was significantly increased compared with never smokers (P for linear trend < .001). Compared with non-mentholated smokers, mentholated smokers were not more likely to have headache (P = .302). CONCLUSIONS: Based on a nationally representative sample, we found that cigarette smoking was associated with headache in an exposure-response manner. Mentholated cigarette smokers were not more likely to have headache compared to non-mentholated cigarette smokers.

Soluble apoE/Aß complex: mechanism and therapeutic target for APOE4-induced AD risk.

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-ß (Aß), particularly in a soluble oligomeric form (oAß), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAß are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAß levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aß, namely apoE/Aß complex, modulate Aß levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aß complexes, resulting in reduced apoE4/Aß levels and increased accumulation, particularly of oAß. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.

Levels of soluble apolipoprotein E/amyloid-ß (Aß) complex are reduced and oligomeric Aß increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples.

Human apolipoprotein E (apoE) isoforms may differentially modulate amyloid-ß (Aß) levels. Evidence suggests physical interactions between apoE and Aß are partially responsible for these functional effects. However, the apoE/Aß complex is not a single static structure; rather, it is defined by detection methods. Thus, literature results are inconsistent and difficult to interpret. An ELISA was developed to measure soluble apoE/Aß in a single, quantitative method and was used to address the hypothesis that reduced levels of soluble apoE/Aß and an increase in soluble Aß, specifically oligomeric Aß (oAß), are associated with APOE4 and AD. Previously, soluble Aß42 and oAß levels were greater with APOE4 compared with APOE2/APOE3 in hippocampal homogenates from EFAD transgenic mice (expressing five familial AD mutations and human apoE isoforms). In this study, soluble apoE/Aß levels were lower in E4FAD mice compared with E2FAD and E3FAD mice, thus providing evidence that apoE/Aß levels isoform-specifically modulate soluble oAß clearance. Similar results were observed in soluble preparations of human cortical synaptosomes; apoE/Aß levels were lower in AD patients compared with controls and lower with APOE4 in the AD cohort. In human CSF, apoE/Aß levels were also lower in AD patients and with APOE4 in the AD cohort. Importantly, although total Aß42 levels decreased in AD patients compared with controls, oAß levels increased and were greater with APOE4 in the AD cohort. Overall, apoE isoform-specific formation of soluble apoE/Aß modulates oAß levels, suggesting a basis for APOE4-induced AD risk and a mechanistic approach to AD biomarkers.

APOE4-specific changes in Aß accumulation in a new transgenic mouse model of Alzheimer disease.

APOE4 is the greatest risk factor for Alzheimer disease (AD) and synergistic effects with amyloid-ß peptide (Aß) suggest interactions among apoE isoforms and different forms of Aß accumulation. However, it remains unclear how the APOE genotype affects plaque morphology, intraneuronal Aß, soluble Aß42, and oligomeric Aß (oAß), particularly in vivo. As the introduction of human APOE significantly delays amyloid deposition in transgenic mice expressing familial AD (FAD) mutations (FAD-Tg), 5xFAD-Tg mice, which exhibit amyloid deposition by age 2 months, were crossed with apoE-targeted replacement mice to produce the new EFAD-Tg mice. Compared with 5xFAD mice, Aß deposition was delayed by ∼4 months in the EFAD mice, allowing detection of early changes in Aß accumulation from 2-6 months. Although plaque deposition is generally greater in E4FAD mice, E2/E3FAD mice have significantly more diffuse and E4FAD more compact plaques. As a first report in FAD-Tg mice, the APOE genotypes had no effect on intraneuronal Aß accumulation in EFAD mice. In E4FAD mice, total apoE levels were lower and total Aß levels higher than in E2FAD and E3FAD mice. Profiles from sequential three-step extractions (TBS, detergent, and formic acid) demonstrated that the lower level of total apoE4 is reflected only in the detergent-soluble fraction, indicating that less apoE4 is lipoprotein-associated, and perhaps less lipidated, compared with apoE2 and apoE3. Soluble Aß42 and oAß levels were highest in E4FAD mice, although soluble apoE2, apoE3, and apoE4 levels were comparable, suggesting that the differences in soluble Aß42 and oAß result from functional differences among the apoE isoforms. Thus, APOE differentially regulates multiple aspects of Aß accumulation.

Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene.

Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case-control series. PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case-control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0-1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Abeta42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma--but not brain--Abeta42 as well as Abeta40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Abeta42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Abeta42, but additional biological experiments are required to show this definitively.