Erratum to "Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome" [Neurobiol. Aging 35 (2014) 1513.e1-1513.e5].
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ABSTRACT:
SUBMITTER: Mok KY
PROVIDER: S-EPMC5617740 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
Publications
Erratum to "Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome" [Neurobiol. Aging 35 (2014) 1513.e1-1513.e5].
Mok Kin Y KY Jones Emma L EL Hanney Marisa M Harold Denise D Sims Rebecca R Williams Julie J Ballard Clive C Hardy John J
Neurobiology of aging 20140906 12
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Project description:It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.
| S-EPMC3969241 | biostudies-literature
Project description:ImportanceThis work quantifies the fatal burden of dementia associated with Alzheimer disease in individuals with Down syndrome (DS).ObjectiveTo explore the association of dementia associated with Alzheimer disease with mortality and examine factors associated with dementia in adults with DS.Design, settings and participantsProspective longitudinal study in a community setting in England. Data collection began March 29, 2012. Cases were censored on December 13, 2017. The potential sample consisted of all adults 36 years and older from the London Down Syndrome Consortium cohort with 2 data times and dementia status recorded (N = 300); 6 withdrew from study, 28 were lost to follow-up, and 55 had a single data collection point at time of analysis. The final sample consisted of 211 participants, with 503.92 person-years' follow-up.ExposuresDementia status, age, sex, APOE genotype, level of intellectual disability, health variables, and living situation.Main outcomes and measuresCrude mortality rates, time to death, and time to dementia diagnosis with proportional hazards of predictors.ResultsOf the 211 participants, 96 were women (45.5%) and 66 (31.3%) had a clinical dementia diagnosis. Twenty-seven participants (11 female; mean age at death, 56.74 years) died during the study period. Seventy percent had dementia. Crude mortality rates for individuals with dementia (1191.85 deaths per 10 000 person-years; 95% CI, 1168.49-1215.21) were 5 times higher than for those without (232.22 deaths per 10 000 person-years; 95% CI, 227.67-236.77). For those with dementia, APOE ε4 carriers had a 7-fold increased risk of death (hazard ratio [HR], 6.91; 95% CI, 1.756-27.195). For those without dementia, epilepsy with onset after age 36 years was associated with mortality (HR, 9.66; 95% CI, 1.59-58.56). APOE ε4 carriers (HR, 4.91; 95% CI, 2.53-9.56), adults with early-onset epilepsy (HR, 3.61; 95% CI, 1.12-11.60), multiple health comorbidities (HR, 1.956; 95% CI, 1.087-3.519), and those living with family (HR, 2.14; 95% CI, 1.08-4.20) received significantly earlier dementia diagnoses.Conclusions and relevanceDementia was associated with mortality in 70% of older adults with DS. APOE ε4 carriers and/or people with multiple comorbid health conditions were at increased risk of dementia and death, highlighting the need for good health care. For those who died without a dementia diagnosis, late-onset epilepsy was the only significant factor associated with death, raising questions about potentially undiagnosed dementia cases in this group.
| S-EPMC6439956 | biostudies-literature
Project description:BackgroundInfection with high-risk human papillomavirus (HR-HPV) genotypes, mainly HPV16 and HPV18, is a major risk factor for cervical cancer and responsible for its progression. While the transforming role of the HPV E6 and E7 proteins is more characterized, the molecular mechanisms of the oncogenic activity of the E5 product are still only partially understood, but appear to involve deregulation of growth factor receptor expression. Since the signaling of the transforming growth factor beta (TGFbeta) is known to play crucial roles in the epithelial carcinogenesis, aim of this study was to investigate if HPV16 E5 would modulate the TGF-BRII expression and TGFbeta/Smad signaling.FindingsThe HPV16 E5 mRNA expression pattern was variable in low-grade squamous intraepithelial lesions (LSIL), while homogeneously reduced in high-grade lesions (HSIL). Parallel analysis of TGFBRII mRNA showed that the receptor transcript levels were also variable in LSILs and inversely related to those of the viral protein. In vitro quantitation of the TGFBRII mRNA and protein in human keratinocytes expressing 16E5 in a dose-dependent and time-dependent manner showed a progressive down-modulation of the receptor. Phosphorylation of Smad2 and nuclear translocation of Smad4 were also decreased in E5-expressing cells stimulated with TGFbeta1.ConclusionsTaken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis.
| S-EPMC3661392 | biostudies-literature
Project description:It is known that individuals with Down syndrome develop Alzheimer's disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer's disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer's disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer's disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer's disease in Down syndrome.
| S-EPMC3898582 | biostudies-literature
Project description:Amyloid-β protein (Aβ) is the main component of neuritic plaques, the pathological hallmark of Alzheimer's disease (AD). β-site APP cleaving enzyme 1 (BACE1) is a major β-secretase contributing to Aβ generation. β-site APP cleaving enzyme 2 (BACE2), the homolog of BACE1, is not only a θ-secretase but also a conditional β-secretase. Previous studies showed that regulator of calcineurin 1 (RCAN1) is markedly increased by AD and promotes BACE1 expression. However, the role of RCAN1 in BACE2 regulation remains elusive. Here, we showed that RCAN1 increases BACE2 protein levels. Moreover, RCAN1 inhibits the turnover of BACE2 protein. Furthermore, RCAN1 attenuates proteasome-mediated BACE2 degradation, but not lysosome-mediated BACE2 degradation. Taken together, our work indicates that RCAN1 inhibits BACE2 turnover by attenuating proteasome-mediated BACE2 degradation. It advances our understanding of BACE2 regulation and provides a potential mechanism of BACE2 dysregulation in AD.
| S-EPMC7293731 | biostudies-literature
Project description:People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt(5-8), in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt(5-8) and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD.
| S-EPMC3010675 | biostudies-literature
Project description:ImportanceWith the advancement in administrative data as a research tool and the reliance on public health insurance for individuals with Down syndrome, population-level trends in Alzheimer dementia in this population are beginning to be understood.ObjectiveTo comprehensively describe the epidemiology of Alzheimer dementia in adults with Down syndrome in a full US Medicare and Medicaid sample.Design, setting, and participantsThis cohort study included 132 720 adults aged 18 years or older with Medicaid and/or Medicare claims data with an International Statistical Classification of Diseases and Related Health Problems code for Down syndrome. Data were collected from January 1, 2011, to December 31, 2019, and analyzed from August 2023 to May 2024.Main outcomes and measuresThe main outcome was prevalence of Alzheimer dementia in each calendar year and during the 9-year period. Alzheimer dementia incidence rates by calendar year and age and stratified for race or ethnicity as well as time to death after Alzheimer dementia diagnosis were also assessed.ResultsThere were 132 720 unique adults with Down syndrome from 2011 to 2019: 79 578 (53.2%) were male, 17 090 (11.7%) were non-Hispanic Black, 20 777 (15.7%) were Hispanic, 101 120 (68.8%) were non-Hispanic White, and 47 692 (23.3%) had ever had an Alzheimer dementia diagnosis. Incidence was 22.4 cases per 1000 person-years. The probability of an incident Alzheimer dementia diagnosis over 8 years was 0.63 (95% CI, 0.62-0.64) for those entering the study between ages 55 to 64 years. Mean (SD) age at incident diagnosis was 54.5 (7.4) years and median (IQR) age was 54.6 (9.3) years. Mean (SD) age at death among those with Alzheimer dementia was 59.2 (6.9) years (median [IQR], 59.0 [8.0] years). The mean (SD) age at onset for the Hispanic group was 54.2 (9.2) years, 52.4 (7.8) years for the American Indian or Alaska Native group, and 52.8 (8.2) years for the mixed race groups compared with 55.0 (7.8) years for the White non-Hispanic group. For age at death, there were no differences by sex. The mean (SD) age at death was later for the White non-Hispanic group (59.3 [6.8] years) compared with the Hispanic group (58.5 [7.8] years), Native American group (57.8 [7.1] years), and mixed race group (58.2 [7.0] years).Conclusions and relevanceIn this cohort study of adults with Down syndrome who were enrolled in Medicaid and Medicare, Alzheimer dementia occurred at high rates. Consistency with clinical studies of dementia in Down syndrome supports the use of administrative data in Down syndrome-Alzheimer dementia research.
| S-EPMC11420697 | biostudies-literature
Project description:ImportanceEarly-onset dementia, presenting in individuals younger than 65 years, is a diagnosis with significant social and financial implications. The early-onset form of dementia with Lewy bodies (DLB) is poorly understood.ObjectiveTo investigate clinical features that distinguish early-onset DLB (onset and diagnosis at age <65 years) from late-onset DLB (onset at age ≥65 years) and from early-onset Alzheimer disease (AD) dementia.Design, setting, and participantsThis is a retrospective case-control study on patients with pathologically confirmed DLB or AD enrolled in the National Alzheimer's Coordinating Center database from January 2005 to July 2017. The National Alzheimer's Coordinating Center Uniform Data Set comprised deidentified data collected by Alzheimer disease centers in the United States. Of patients fulfilling criteria for all-cause dementia at enrollment (n = 1152), those who at post mortem received a pathological diagnosis of either AD (n = 848) or Lewy body disease (n = 218) were selected. Excluding 52 patients owing to missing data and 12 diagnosed with Parkinson disease dementia, remaining patients were classified by age of symptom onset into early-onset AD, early-onset DLB, and late-onset DLB subgroups. Data were analyzed from June to December 2018 and from November to December 2021.ExposuresDemographics, cognitive, behavioral, and motor features recorded at first clinic visit and neuropathological characteristics at autopsy were analyzed by disease subgroup.Main outcomes and measuresConcordance between initial etiologic diagnosis of dementia and final pathological diagnosis was assessed, as was time to death.ResultsA total of 542 individuals were categorized as having early-onset AD (n = 363; mean [SD] age, 53.0 [5.8] years; 208 [57.3%] male), early-onset DLB (n = 32; mean [SD] age, 57.9 [3.2] years; 23 [71.9%] male), and late-onset DLB (n = 147; mean [SD] age, 73.5 [5.5] years; 103 [70.1%] male). Early-onset DLB was clinically misdiagnosed in 16 individuals (50%). Features that predicted a diagnosis of early-onset DLB over early-onset AD included visual hallucinations (15 [46.9%] vs 42 [11.6%]), slowness (23 [71.9%] vs 95 [26.2%]), apathy (23 [71.9%] vs 189 [52.1%]), and motor deterioration that preceded cognitive and behavioral symptoms (7 [21.9%] vs 6 [1.7%]). Late-onset DLB had more amnestic features, but this was accounted for by a higher proportion of neocortical neuritic plaques and diffuse plaques (frequent in 79 [53.7%] vs 8 [25%]) than seen in early-onset DLB.Conclusions and relevanceThis study found that early-onset DLB has clinical features that distinguish it from early-onset AD, whereas features of late-onset DLB are associated with a higher burden of AD copathology.
| S-EPMC9127709 | biostudies-literature
Project description:ObjectivesThis study examined whether late-onset (versus early-onset) suicidal behavior is associated with worse cognition.MethodsParticipants included 278 adults aged 50+ years (56 nonpsychiatric comparison group; 67 nonsuicidal depressed older adults; 63 depressed suicide ideators; and 44 late-onset (55+ years) and 48 early-onset suicide attempters (<55 years). Using a case-control design, this study examined group differences in global cognition, episodic memory, information processing speed, and executive functioning, assessed using the Repeatable Battery of Neuropsychological Status and the Trail Making Test from the Delis-Kaplan Executive Function System. Linear regression was used for data analyses.ResultsBoth attempter groups displayed worse executive functioning than nonsuicidal depressed older adults. Late-onset attempters additionally displayed poorer global cognition and processing speed than nonsuicidal depressed older adults and poorer memory than early-onset attempters.ConclusionsLate-onset suicidal behavior is associated with worse performance in a broad range of cognitive domains, possibly reflective of a dementia prodrome.
| S-EPMC8187470 | biostudies-literature
Project description:BACKGROUND:Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to the pathogenesis of cerebral ischemias and AD. Memantine acts as an antagonist of N-methyl-D-aspartate (NMDA) type receptors, which is thought to reduce abnormal activation of glutamate neurotransmission. It binds with a low affinity to the NMDA receptor and so should not prevent learning and the formation of memory. Memantine can improve cognitive function and slow the decline of AD in the general population over time, and is the subject of this review. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population. OBJECTIVES:To determine the effectiveness and safety of memantine for people with DS who develop AD. SEARCH STRATEGY:CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of memantine, as well as experts in the field, to ask about reports of unpublished or ongoing trials. SELECTION CRITERIA:Randomised controlled trials of participants with DS and AD in which treatment with memantine was administered compared with a placebo group. DATA COLLECTION AND ANALYSIS:No study was identified which met the inclusion criteria for this review. MAIN RESULTS:No study was identified which met inclusion criteria for this review, however there is an on-going randomised controlled study being conducted in the UK and data are expected in 2009. AUTHORS' CONCLUSIONS:As there are no included trials, recommendations cannot be made about memantine for AD in DS. Well-designed, adequately powered studies are required.
| S-EPMC7197456 | biostudies-literature