The relationships between multidimensional sleep health and work productivity in individuals with neurological conditions.

Numerous studies have reported the negative impacts of poor sleep on work productivity in the general population. However, despite the known sleep issues that individuals living with neurological conditions experience, no study has explored its impact on their work productivity. Sleep health is a concept that includes multiple domains of sleep, measured with a combination of objective and subjective measures. Therefore, this study aimed to ascertain the associations between sleep health and its domains and work productivity in individuals with neurological conditions. Sleep health domains were determined through actigraphy data collected over 1 week and sleep questionnaires. Work productivity was assessed via the Work Productivity and Activity Impairment Questionnaire. A comparison of sleep health scores between demographic variables was performed using Mann-Whitney U and Kruskal-Wallis tests. Associations between the sleep health domains and work productivity were performed using linear regression models. There were no significant differences in sleep health scores between sex, smoking status, education level, employment status or any work productivity domain. Individuals with non-optimal sleep timing had greater absenteeism (22.99%) than the optimal group. Individuals with non-optimal sleep quality had an increase in presenteeism (30.85%), work productivity loss (26.44%) and activity impairment (25.81%) compared to those in the optimal group. The findings from this study highlight that self-reported sleep quality has the largest impact on work productivity. Improving individuals' sleep quality through triage for potential sleep disorders or improving their sleep hygiene (sleep behaviour and environment) may positively impact work productivity.

A Potential Role for Sirtuin-1 in Alzheimer's Disease: Reviewing the Biological and Environmental Evidence.

Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer's disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-ß and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia.

Utility of DNA Methylation as a Biomarker in Aging and Alzheimer's Disease.

Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual's biological age based on an algorithmically defined set of CpGs. A number of studies have found associations between disease and/or disease risk with increased biological age, adding weight to the theory of increased biological age being linked with disease processes. Hence, this review takes a closer look at the utility of DNA methylation as a biomarker in aging and disease, with a particular focus on Alzheimer's disease.

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aß) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; ß = 0.35, SE = 0.01, P = 6.2 × 10-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; ß = 0.07, SE = 0.01, P = 9.2 × 10-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; ß = 0.1, SE = 0.02, P = 2.4 × 10-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; ß = 0.16, SE = 0.03, P = 1.1 × 10-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, ß = 0.79, SE = 0.14, P = 1.4 × 10-08, MAF = 0.006, sex-interaction P = 9.8 × 10-07) and chr11p.15.2 (rs192346166, ß = 0.94, SE = 0.17, P = 3.7 × 10-08, MAF = 0.004, sex-interaction P = 1.3 × 10-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Impaired muscle function, including its decline, is related to greater long-term late-life dementia risk in older women.

BACKGROUND: Impaired muscle function has been identified as a risk factor for declining cognitive function and cardiovascular health, both of which are risk factors for late-life dementia (after 80 years of age). We examined whether hand grip strength and timed-up-and-go (TUG) performance, including their change over 5 years, were associated with late-life dementia events in older women and whether any associations provided independent information to Apolipoprotein E ℇ 4 (APOE ℇ 4) genotype. METHODS: Grip strength and TUG were assessed in community-dwelling older women (mean ± SD; age 75.0 ± 2.6 years) at baseline (n = 1225) and 5 years (n = 1052). Incident 14.5-year late-life dementia events (dementia-related hospitalization/death) were obtained from linked health records. Cardiovascular risk factors (Framingham Risk Score), APOE genotyping, prevalent atherosclerotic vascular disease and cardiovascular-related medications were evaluated at baseline. These were included in multivariable-adjusted Cox-proportional hazards models assessing the relationship between muscle function measures and late-life-dementia events. RESULTS: Over follow-up, 207 (16.9%) women had a late-life dementia event. Compared with women with the highest grip strength (Quartile [Q] 4, 25.8 kg), those with the lowest grip strength (Q1, 16.0 kg) had greater hazard for a late-life dementia event (HR 2.27 95% CI 1.54-3.35, P < 0.001). For TUG, the slowest women (Q4, 12.4 vs. Q1, 7.4 s) also recorded a greater hazard for a late-life dementia event (HR 2.10 95% CI 1.42-3.10, P = 002). Weak hand grip (<22 kg) or slow TUG (>10.2 s) provided independent information to the presence of an APOE ℇ 4 allele (n = 280, 22.9%). Compared with women with no weakness and no APOE ℇ 4 allele, those with weakness and APOE ℇ 4 allele had a greater hazard (HR 3.19 95% CI 2.09-4.88, P < 0.001) for a late-life dementia event. Women presenting with slowness and the APOE ℇ 4 allele also recorded a greater hazard for a late-life dementia event (HR 2.59 95% CI 1.64-4.09, P < 0.001). For 5-year muscle function changes, compared with women with the lowest performance decrement (Q1), those with the largest decrement (Q4) had higher hazards for a late-life dementia event (grip strength HR 1.94 95% CI 1.22-3.08, P = 0.006; TUG HR 2.52 95% CI 1.59-3.98, P < 0.001) over the next 9.5 years. CONCLUSIONS: Weaker grip strength and slower TUG, and a greater decline over 5 years, were significant risk factors for a late-life-dementia event in community-dwelling older women, independent of lifestyle and genetic risk factors. Incorporating muscle function measures as part of dementia screening appears useful to identify high-risk individuals who might benefit from primary prevention programmes.

Genomics of Alzheimer's disease implicates the innate and adaptive immune systems.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterised by cognitive impairment, behavioural alteration, and functional decline. Over 130 AD-associated susceptibility loci have been identified by genome-wide association studies (GWAS), while whole genome sequencing (WGS) and whole exome sequencing (WES) studies have identified AD-associated rare variants. These variants are enriched in APOE, TREM2, CR1, CD33, CLU, BIN1, CD2AP, PILRA, SCIMP, PICALM, SORL1, SPI1, RIN3, and more genes. Given that aging is the single largest risk factor for late-onset AD (LOAD), the accumulation of somatic mutations in the brain and blood of AD patients have also been explored. Collectively, these genetic findings implicate the role of innate and adaptive immunity in LOAD pathogenesis and suggest that a systemic failure of cell-mediated amyloid-ß (Aß) clearance contributes to AD onset and progression. AD-associated variants are particularly enriched in myeloid-specific regulatory regions, implying that AD risk variants are likely to perturbate the expression of myeloid-specific AD-associated genes to interfere Aß clearance. Defective phagocytosis, endocytosis, and autophagy may drive Aß accumulation, which may be related to naturally-occurring antibodies to Aß (Nabs-Aß) produced by adaptive responses. Passive immunisation is providing efficiency in clearing Aß and slowing cognitive decline, such as aducanumab, donanemab, and lecanemab (ban2401). Causation of AD by impairment of the innate immunity and treatment using the tools of adaptive immunity is emerging as a new paradigm for AD, but immunotherapy that boosts the innate immune functions of myeloid cells is highly expected to modulate disease progression at asymptomatic stage.

TNF-Block Genotypes Influence Susceptibility to HIV-Associated Sensory Neuropathy in Indonesians and South Africans.

HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning TNF and seven neighboring genes (the TNF-block) in Indonesians (n = 202; 34/168 cases) and South Africans (n = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of BAT1 (alternatively DDX39B) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and >500 copies of HIV RNA/mL (model p = 0.0011, Pseudo R2 = 0.09). rs4947324*T (between NFKBIL1 and LTA) independently associated with reduced risk of HIV-SN and African haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: p = 0.0003, Pseudo R2 = 0.23). These results confirm TNF-block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use.

Twelve weeks of resistance training does not influence peripheral levels of neurotrophic growth factors or homocysteine in healthy adults: a randomized-controlled trial.

INTRODUCTION: There is growing evidence for a preventative effect of resistance training on cognitive decline through physiological mechanisms; yet, the effect of resistance training on resting growth factors and homocysteine levels is incompletely understood. This study aimed to investigate the effect of intense resistance training, for 12 weeks, on changes in peripheral growth factors and homocysteine in late middle-aged adults. METHODS: 45 healthy adults were enrolled into the single-site parallel groups' randomized-controlled trial conducted at the Department of Exercise Science, Strength and Conditioning Laboratory, Murdoch University. Participants were allocated to the following conditions: (1) high-load resistance training (n = 14), or (2) moderate-load resistance training (n = 15) twice per week for 12 weeks; or (3) non-exercising control group (n = 16). Data were collected from September 2016 to December 2017. Fasted blood samples were collected at baseline and within 7 days of trial completion for the analysis of resting serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1, vascular endothelial growth factor, and plasma homocysteine levels. RESULTS: No differences in baseline to post-intervention change in serum growth factors or plasma homocysteine levels were observed between groups. A medium effect was calculated for BDNF change within the high-load condition alone (+ 12.9%, g = 0.54). CONCLUSIONS: High-load or moderate-load resistance training twice per week for 12 weeks has no effect on peripheral growth factors or homocysteine in healthy late middle-aged adults. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12616000690459.

Mediterranean diet adherence and rate of cerebral Aß-amyloid accumulation: Data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing.

Accumulating research has linked Mediterranean diet (MeDi) adherence with slower cognitive decline and reduced Alzheimer's disease (AD) risk. However, no study to-date has examined the relationship between MeDi adherence and accumulation of cerebral Aß-amyloid (Aß; a pathological hallmark of AD) in older adults. Cognitively normal healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing completed the Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to construct a MeDi score for each participant (score range 0-9; higher score indicating higher adherence). Cerebral Aß load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months: Only individuals categorised as "Aß accumulators", and thus considered to be on the AD pathway, were included in the analysis (N = 77). The relationship between MeDi adherence, MeDi components, and change in cerebral Aß load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aß accumulation in our cohort (ß = -0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aß (ß = -0.04 ± 0.01, p = 0.00036). Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.

The Effects of Latrepirdine on Amyloid-ß Aggregation and Toxicity.

Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-ß (Aß) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aß:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aß42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aß aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aß aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aß aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis.

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.

Is cholesterol and amyloid-ß stress induced CD147 expression a protective response? Evidence that extracellular cyclophilin a mediated neuroprotection is reliant on CD147.

The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-ß (Aß), the neurotoxic peptide implicated in neuronal degeneration in Alzheimer's disease (AD). Given that high fat/cholesterol is linked to amyloid deposition in AD, we investigated if cholesterol and/or Aß can alter CD147 expression in rat cortical neuronal cultures. Water-soluble cholesterol and Aß42 dose-dependently increased CD147 protein expression, but reduced FL-AßPP protein expression. Cholesterol and Aß42 treatment also increased lactate dehydrogenase release but to varying degrees. Upregulation of CD147 expression was probably mediated by oxidative stress, as H2O2 (3 µM) also induced CD147 protein expression in neuronal cultures. In light of these findings, we investigated if CD147 induction was cytoprotective, a compensatory response to injury, or alternatively, a cell death signal. To this end, we used recombinant adenovirus to overexpress human CD147 (in SH-SY5Y cells and primary cortical neurons), and pre-treated cultures with or without recombinant cyclophilin A (rCYPA) protein, prior to Aß42 exposure. We showed that increased CD147 expression protected against Aß42, only when rCYPA protein was added to neuronal cultures. Together, our findings reveal potentially important relationships between cholesterol loading, CD147 expression, Aß toxicity, and the putative involvement of CYPA protein in neuroprotection in AD.

Blood-based protein biomarkers for diagnosis of Alzheimer disease.

OBJECTIVE: To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD). DESIGN: Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data. SETTING: General community-based, prospective, longitudinal study of aging. PARTICIPANTS: A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study (AIBL) cohort with identified biomarkers that were validated in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. RESULTS: A biomarker panel was identified that included markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, ß(2) microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine) and decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin) in AD. Cross-validated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0) for the area under the receiver operating characteristic curve. A second validation using the ADNI cohort attained accuracy measures of 80% (3.0%) for sensitivity and specificity and 85% (3.0) for area under the receiver operating characteristic curve. CONCLUSIONS: This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis.

Functional effects of genetic polymorphism in inflammatory genes in subjective memory complainers.

A number of genetic risk factors have been identified for Alzheimer's disease (AD) including genes involved in the inflammatory response (interleukin 1A, [IL-1α (-889)], interleukin 1B (IL-1ß [+3953]), and tumor necrosis factor (TNF [-308 and -850]). We investigated the prevalence and functional consequences (baseline cognitive performance, plasma cytokine levels) of possession of these putative genetic risk factors within a group of subjective memory complainers (SMC, n = 226) and age and sex matched noncomplainers (NMC, n = 167). We observed no effect of any of the genetic factors investigated on cognitive performance. Further, there was no difference in the frequency of the disease-associated alleles, or cytokine levels between subjective memory complainers and noncomplainer participants. There was no relationship between TNF polymorphisms and TNF levels. There was a significant increase in plasma IL-1ß levels in those homozygous for the disease-associated allele (i.e., IL-1ß +3953 TT). Follow-up longitudinal assessments on this cohort will provide insight as to how these polymorphisms may affect the risk of cognitive decline over time.

No association of common VCP variants with sporadic frontotemporal dementia.

Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.

Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease.

BACKGROUND: Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases. METHODS: Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE epsilon4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases. RESULTS: APOE epsilon4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE epsilon4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases. CONCLUSION: These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.

Gonadotropins and cognition in older women.

Recent research studies associate elevated gonadotropin levels with dementia. Specifically, an age associated increase in levels of luteinizing hormone has been linked to an increased risk of Alzheimer's disease. The objective of this study was to investigate the association between gonadotropin levels and cognition in older, healthy postmenopausal women. Cognitive functioning was compared with plasma levels of estradiol, luteinizing hormone, follicle stimulating hormone, Abeta40 and APOE genetic status in 649 community-dwelling, non-demented older women residing in Western Australia. High endogenous luteinizing hormone levels were associated with a lower cognitive score, especially in older women and in those women that were depressed. Unexpectedly, disproportionately well preserved cognitive functioning was found for the oldest women who had high endogenous levels of follicle stimulating hormone. The findings indicate that gonadotropins can impact upon cognitive functioning in older postmenopausal women, and that luteinizing hormone and follicle stimulating hormone may exert contrasting effects. Taken together, the findings have important implications for the development of possible preventive strategies for dementia.

TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels.

Alzheimer disease (AD), vascular dementia, and stroke are all associated with inflammation though their respective initiating factors differ. Recently a polymorphism in the proinflammatory cytokine tumor necrosis factor (TNF), in association with apolipoprotein E (APOE), was reported to increase AD risk. Two SNPs, rs1799724 (-850C>T; NT_007592.14:g.22400733C>T) and rs1800629 (-308G>A; [NT_007592.14:g.22401282G>A]), and the APOE polymorphism were genotyped in 506 patients with sporadic AD and in 277 cognitively healthy controls. In a subset of 90 individuals we also investigated whether these SNPs exerted any functional effects on cerebrospinal fluid (CSF) beta-amyloid (Abeta) levels. The frequency of the rs1799724 genotypes and the rs1799724-T allele were significantly different in AD individuals (P=0.009; odds ratio [OR], 1.63; 95% confidence interval [CI], 1.13-2.34), while the rs1800629 SNP was not associated with AD. Significant interaction was observed between the rs1799724-T and APOE epsilon4 alleles in that the rs1799724-T allele significantly modified risk associated with possession of the epsilon4 allele only (epsilon4 in absence of rs1799724-T: OR, 2.92; 95% CI, 2.00-4.27; epsilon4 in presence of rs1799724-T: OR, 6.65; 95% CI, 3.26-13.55; P=0.03). Haplotyping analysis revealed a significant overrepresentation of an rs1799724-T/rs1800629-G haplotype in AD (P=0.012; OR, 1.60; 95% CI, 1.11-2.29), although to a lesser degree than rs1799724-T alone. Further, the rs1799724-T allele was found to be associated with lower levels of CSF Abeta42 (P=0.023), thus corroborating the genetic findings. Inheritance of the rs1799724-T allele appears to synergistically increase the risk of AD in APOEepsilon4 carriers and is associated with altered CSF Abeta42 levels. Further investigations are warranted to assess the significance of these novel findings.

Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription.

Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (> 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The epsilon4 allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the epsilon 4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOE epsilon4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the epsilon2/epsilon3/epsilon4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the epsilon2/epsilon3/epsilon4 locus.