Jie-Qiong Li

Meta-analysis of modifiable risk factors for Alzheimer's disease

Background The aetiology of Alzheimers disease (AD) is believed to involve environmental exposure and genetic susceptibility. The aim of our present systematic review and meta-analysis was to roundly evaluate the association between AD and its modifiable risk factors. Methods We systematically searched PubMed and the Cochrane Database of Systematic Reviews from inception to July 2014, and the references of retrieved relevant articles. We included prospective cohort studies and retrospective case–control studies. Results 16 906 articles were identified of which 323 with 93 factors met the inclusion criteria for meta-analysis. Among factors with relatively strong evidence (pooled population >5000) in our meta-analysis, we found grade I evidence for 4 medical exposures (oestrogen, statin, antihypertensive medications and non-steroidal anti-inflammatory drugs therapy) as well as 4 dietary exposures (folate, vitamin E/C and coffee) as protective factors of AD. We found grade I evidence showing that one biochemical exposure (hyperhomocysteine) and one psychological condition (depression) significantly increase risk of developing AD. We also found grade I evidence indicative of complex roles of pre-existing disease (frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population) increasing risk whereas history of arthritis, heart disease, metabolic syndrome and cancer decreasing risk) and lifestyle (low education, high body mass index (BMI) in mid-life and low BMI increasing the risk whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high BMI in late-life decreasing the risk) in influencing AD risk. We identified no evidence suggestive of significant association with occupational exposures. Conclusions Effective interventions in diet, medications, biochemical exposures, psychological condition, pre-existing disease and lifestyle may decrease new incidence of AD.

The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis

BACKGROUND Neuropsychiatric symptoms (NPS) are being increasingly recognized as common serious problems in Alzheimers disease (AD). However, published data on the prevalence of NPS in persons with AD are conflicting. This meta-analysis aimed to estimate the prevalence of NPS in persons with AD. METHODS Studies published from 1964 to September 30, 2014, were identified from PubMed and Embase database, reference lists and conference abstracts. We calculated prevalence rates and conducted meta-regression analysis with random-effects model, according to study characteristics, population demographics or condition information. RESULTS We identified 48 eligible articles, which provided data for 12 NPS reported in Neuropsychiatric Inventory (NPI). The most frequent NPS was apathy, with an overall prevalence of 49% (95% CI 41-57%), followed by depression, aggression, anxiety and sleep disorder, the pooled prevalence estimates of which were 42% (95% CI 37-46%), 40% (95% CI 33-46%), 39% (95% CI 32-46%) and 39% (95% CI 30-47%), respectively. The less prevalent NPS were irritability (36%, 31-41%), appetite disorder (34%, 27-41%), aberrant motor behavior (32%, 25-38%), delusion (31%, 27-35%), disinhibition (17%, 12-21%) and hallucination (16%, 13-18%). Least common was euphoria, with an overall prevalence of 7% (95% CI 5-9%). LIMITATIONS Several aspects, such as the quality of included studies were not always optimal and there was significant heterogeneity of prevalence estimate across studies. CONCLUSIONS NPS were observed to be highly prevalent in AD patients. Disease duration, age, education level, population origin and the severity of cognitive impairment had influence on the prevalence of some NPS.

The role of the LRRK2 gene in Parkinsonism

Parkinson’s disease (PD), like many common age-related conditions, has been recognized to have a substantial genetic component. Multiple lines of evidence suggest that Leucine-rich repeat kinase 2 (LRRK2) is a crucial factor to understanding the etiology of PD. LRRK2 is a large, widely expressed, multi-domain and multifunctional protein. LRRK2 mutations are the major cause to inherited and sporadic PD. In this review, we discuss the pathology and clinical features which show diversity and variability of LRRK2-associated PD. In addition, we do a thorough literature review and provide theoretical data for gene counseling. Further, we present the evidence linking LRRK2 to various possible pathogenic mechanism of PD such as α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction as well as autophagy-lysosomal system. Based on the above work, we investigate activities both within GTPase and outside enzymatic regions in order to obtain a potential therapeutic approach to solve the LRRK2 problem.

Risk factors for predicting progression from mild cognitive impairment to Alzheimer’s disease: a systematic review and meta-analysis of cohort studies

Objective We sought to identify the risk factors for predicting the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Methods We searched 6 electronic databases for cohort studies published from January 1966 to March 2015. Eligible studies were required to be relevant to the subject and provide sufficient data for our needs. Results 60 cohort studies with 14 821 participants from 16 countries were included in the meta-analysis. The strongest positive associations between risk factors and the progression from MCI to AD were found for abnormal cerebrospinal fluid (CSF), phosphorylated τ (p-τ) (relative risk (RR)=2.43, 95% CI=1.70 to 3.48), abnormal CSF τ/Aβ1–42 (RR=3.77, 95% CI=2.34 to 6.09), hippocampal atrophy (RR=2.59, 95% CI=1.95 to 3.44), medial temporal lobe atrophy (RR=2.11, 95% CI=1.70 to 2.63) and entorhinal atrophy (RR=2.03, 95% CI=1.57 to 2.62). Further positive associations were found for the presence of apolipoprotein E (APOE)ε4ε4 and at least 1 APOEε4 allele, CSF total-τ (t-τ), white matter hyperintensity volume, depression, diabetes, hypertension, older age, female gender, lower mini-mental state examination (MMSE) score and higher AD assessment scale cognitive subscale (ADAS-cog) score. Negative associations were found for high body mass index (RR=0.85, 95% CI=0.76 to 0.96) and higher auditory verbal learning test delay score (RR=0.86, 95% CI=0.77 to 0.96). Conclusions Patients with MCI with APOEε4, abnormal CSF τ level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hypertension, older age, female gender, lower MMSE score and higher ADAS-cog score, had a high risk for the progression to AD.

Endoplasmic Reticulum Dysfunction in Alzheimer’s Disease

The endoplasmic reticulum (ER) serves many crucial cellular functions. However, when misfolded or unfolded proteins accumulated in the ER, the stress of ER will be induced. Meanwhile, the intracellular signaling network, which is called unfolded protein response, will also be activated to cope with. Those unfolded proteins can be recognized by three kinds of stress sensors which are IRE1, PERK, and ATF6. Based on lots of medical reports, ER stress in postmortem brains from Alzheimer’s disease (AD) patients, animals, and vitro models have indicated that ER dysfunction might work as an important part in causing AD. In this review, we demonstrated that the effect of ER stress contributed to the pathogenesis of AD. ER stress associates almost the whole brain pathology processes which can be observed in AD, such as gene mutation of presenilin1, the abnormal clipped mRNA of presenilin2, β-amyloid production, tau phosphorylation, and cell death. The status of ER stress and unfolded protein response in the pathogenesis of AD also suggests they can be used as potential therapeutic agents.

Genetics of Vascular Dementia: Systematic Review and Meta-Analysis

BACKGROUND Vascular dementia (VaD) is the second most common type of dementia. So far, little is known about the contribution of genetic polymorphisms to the risk of VaD. Many candidate genetic polymorphisms have been examined in a large number of studies. However, due to the conflicting results, the genetics of VaD is still behind the shadow. OBJECTIVE We conducted a comprehensive meta-analysis on associations between genetic polymorphisms of any gene and VaD to investigate the genetics of VaD. METHOD We sought the published studies of associations between any genetic polymorphism and VaD and critically appraised them. We assessed the effects of genetic models by calculating pooled odds ratios (ORs), investigating the origin of heterogeneity by subgroup analysis, and testing the robustness by random effect model and sensitivity analysis. RESULTS 69 studies with 4,462 cases and 11,583 controls were included. We identified APOE ɛ2/ɛ3/ɛ4 and additional four genetic polymorphisms including MTHFR C677T, PON1 L55M, TGF-β1 +29C/T, and TNF-α -850C/T associated with VaD. Tested by random effect model and sensitivity analysis, the pooled results show nice robustness. CONCLUSIONS Our comprehensive meta-analysis highlighted the genetic contribution to sporadic VaD. Because of the small amount of data on associations between genetic polymorphisms, except for APOE, and VaD, more studies are needed to test the existing genetic polymorphisms and detect other related genetic variants.

GWAS-Linked Loci and Neuroimaging Measures in Alzheimer's Disease.

Recently, 19 susceptibility loci for Alzheimer’s disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and β-amyloid (Aβ) deposition on neuroimaging in a large cohort from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Aβ deposition. APOE ε4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE ε4) have been detected to be associated with one or a few established AD-related neuroimaging measures.

Genome-wide association study identifies two loci influencing plasma neurofilament light levels

BackgroundPlasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD.MethodsThis study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model.ResultsThe minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10− 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10− 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018–2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234).ConclusionGWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.

Genome-wide association study identified ATP6V1H locus influencing cerebrospinal fluid BACE activity

BackgroundThe activity of cerebrospinal fluid (CSF) β-site APP cleaving enzyme (BACE) is a potential diagnostic biomarker for Alzheimer disease (AD).MethodsA total of 340 non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI) database were included in this study with quality-controlled CSF BACE and genotype data. Association of CSF BACE with the genetic variants of single nucleotide polymorphisms (SNPs) was assessed using PLINK under the additive genetic model. The P values of all SNPs for CSF BACE were adjusted for multiple comparisons.ResultsOne SNP (rs1481950) in the ATP6V1H gene reached genome-wide significance for associations with CSF BACE (P = 4.88 × 10− 9). The minor allele (G) of rs1481950 was associated with higher CSF BACE activity. Although seven SNPs in SNX31, RORA, CDH23, RGS20, LRRC4C, MAPK6PS1 and LOC105378355 did not reach genome-wide significance (P < 10− 8), they were identified as suggestive loci (P < 10− 5).ConclusionThis study identified rs1481950 within ATP6V1H influencing human CSF BACE activity, which indicated that ATP6V1H gene may play some roles in the pathogenesis of neurodegenerative diseases such as AD.