Higher Risk Of Alzheimer's Disease Research Articles

Systematic identification of risk factors and drug repurposing options for Alzheimer's disease.

IntroductionSeveral Mendelian randomization studies have been conducted that identified multiple risk factors for Alzheimer's disease (AD). However, they typically focus on a few pre‐selected risk factors.MethodsA two‐sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1037 risk factors/medical conditions and 31 drugs with the risk of late‐onset AD. To correct for multiple comparisons, the false discovery rate was set at < 0.05.ResultsThere was strong evidence of a causal association between glioma risk, reduced trunk fat‐free mass, lower education levels, lower intelligence and a higher risk of AD. For 31 investigated treatments (such as antihypertensive drugs), we found limited evidence for their associations.DiscussionMR found robust evidence of causal associations between glioma, trunk fat‐free, and AD. Our study also confirms that higher educational attainment and higher intelligence are associated with a reduced risk of AD.

Plasma antioxidants and risk of dementia in older adults.

IntroductionPlant‐based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.MethodsWe measured antioxidants in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow‐up. We measured baseline plasma levels of retinol, α‐, and γ‐tocopherol; zeaxanthin and lutein (combined); beta‐cryptoxanthin; cis‐lycopene; trans‐lycopene; α‐carotene; and trans‐β‐carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist‐adjudicated risks of all‐cause dementia and AD.ResultsPlasma retinol, α‐, and γ‐tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β‐carotene, or vitamin E supplements. Higher trans‐β‐carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans‐β‐carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α‐carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α‐carotene: 1.15; 95% CI: 1.02, 1.29).DiscussionPlasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

Long-term trajectories and current BMI are associated with poorer cognitive functioning in middle-aged adults at high Alzheimer's disease risk.

IntroductionWe examined relationships of body mass index (BMI) with cognition in middle‐aged adults at Alzheimer's disease (AD) risk due to parental family history.MethodsParticipants are offspring of AD patients from the Israel Registry of Alzheimer's Prevention (N = 271). Linear regressions assessed associations of BMI and cognition, and whether associations differed by maternal/paternal history. Analyses of covariance examined associations of long‐term trajectories of BMI with cognition.ResultsHigher BMI was associated with worse language (P = .045). Interactions of BMI with parental history were significant for episodic memory (P = .023), language (p = .027), working memory (P = .006), global cognition (P = .008); associations were stronger among participants with maternal history. Interactions of BMI trajectories with parental history were significant for episodic memory (P = .017), language (P = .013), working memory (P = .001), global cognition (P = .005), with stronger associations for maternal history.DiscussionHigher BMI and overweight/obese trajectories were associated with poorer cognition in adults with maternal history of AD, but not those with paternal history.

The IMI‐EU H2020 project MOPEAD: Outcome of different screening methods to identify MCI/early AD

AbstractBackgroundThe MOPEAD project (Rodríguez‐Gómez O et al, Alzheimers Dement 2019) aims to explore different ways to stimulate early diagnosis of Alzheimer Disease (AD). Four innovative pre‐screening strategies are pursued to identify individuals at high risk for mild cognitive impairment (MCI) or early AD. We aimed to validate positive results from these pre‐screening strategies by performing a full clinical evaluation of the patients at specialized memory clinics.MethodIndividuals with a positive pre‐screening result were referred to one of the five participating memory clinics in Ljubljana (Slovenia), Barcelona (Spain), Stockholm (Sweden), Amsterdam (Netherlands), and Cologne (Germany). A harmonized clinical evaluation including physical, neurological, neuropsychological and functionality assessment was performed in these centers as well as MRI neuroimaging and optional cerebral spinal fluid sampling. Based on the result of this evaluation, we estimated the positive predictive value (PPV) of the different pre‐screening strategies, as the proportion of patients with MCI or AD among all referred individuals.ResultA total of 402 individuals with a positive pre‐screening result were evaluated: 91 from a web‐based pre‐screening tool, 161 from an open house initiative, 94 patients from a primary care‐based pre‐screening, and 56 patients identified at diabetes clinics. The number confirmed cases of MCI/AD and PPV were 49(53.8%), 82(50.9%), 58(61.7%), and 47(83.9%) respectively. Within pre‐screening strategy, the results varied greatly between participating countries. Thus, PPV for the web‐based tool was 0% in Germany, and over 70% in Spain and Sweden. Similarly, PPV for the open house initiative was 3% in the Netherlands, but over 95% in Spain. Germany and the Netherlands showed the lowest PPVs (20% and 17% respectively) for the primary care‐based strategy, whereas the all remaining countries had PPVs well over 70%. Country‐specific PPVs estimates in the diabetes clinic strategy were not very reliable due to the small number of patients evaluated.ConclusionWe were able to confirm more than half of patients with a positive result in all four pre‐screening strategies being evaluated. However, our results suggest that despite the harmonization efforts, PPVs of these innovative pre‐screening strategies are highly dependent on the study site.

HAPPCAP‐AD (Human‐Application Combined Approach for Prevention of Alzheimer's Disease): A novel feasibility study of a personalized midlife intervention to prevent AD

AbstractBackgroundDeveloping efficient Alzheimer's disease (AD) prevention strategies is imperative as AD has no cure. Physical inactivity, obesity, type 2 diabetes [T2D], hypertension, smoking, depression, and low educational attainment, are the seven major potentially modifiable risk factors showing consistent association with AD. We have launched a novel, "real‐life", feasibility study of personalized 18‐months intervention for prevention of cognitive decline in middle‐aged individuals at high AD risk due to a parental family history. Our study implements an innovative approach combining a smartphone application (app) with study team guidance through phone‐calls. Our aims are to investigate: 1) The feasibility of our novel intervention and factors associated with adherence to it; 2) Whether our intervention improves AD risk factors and whether greater adherence is associated with larger improvement; and 3) Whether our intervention improves cognition and cerebral blood flow.MethodWe will recruit one hundred 40‐65 years old AD patients' offspring, to two groups (67 at the intervention group and 33 at the passive control). All participants will have at least two risk factors of the seven major modifiable AD risk factors. The 18‐months intervention will include advice for risk factors improvement, interactive follow‐up using a smartphone app and dynamic feedback on risk factors management for its modification, through both the app and the study team.ResultRecruitment has recently begun, through publishing an online eligibility questionnaire. Thus far, 200 individuals have completed the questionnaire, with 113 fulfilling eligibility criteria‐ among them 86% with physical inactivity, 87% with obesity, 38% with T2D, 17% with hypertension, 13% smoking, and 32% with depression. Thus far 33 participants have been recruited‐ Among them, 10 participants have completed the baseline evaluation, and have been randomized to the study's arms (8 of them had started the active intervention, with an average app‐adherence of 83%). additional 23 participants have completed partial base‐line evaluation.ConclusionResults of this study will provide feasibility data on the adherence to the human‐app approach, characteristics of those who adhere, on whether the approach improves risk factors, and will provide initial data on intervention effects on cognition. At AAIC, interim results will be presented.

Younger patients have an increased risk for dementia after coronary artery bypass grafting, a population-based cohort study from the SWEDEHEART registry

Abstract Background Previous studies investigating the association between coronary artery bypass grafting (CABG) and risk for dementia show conflicting results. Purpose To compare the long-term risk for dementia in CABG patients to matched individuals in the general population, and to identify independent predictors for developing dementia after CABG. Methods Data from the SWEDEHEART registry and three other mandatory national registries were merged to compare all patients who underwent isolated CABG in Sweden from 1992 to 2015 (n=111.335) with an age- and sex-matched control individuals from the general population (n=222.396). Cumulative incidence adjusted for the competing risk for death and Cox regression models with Hazard Ratio (HR) and 95% confidence interval (CI) adjusted for age, gender, co-morbidity and socioeconomic variables, were used to calculate the risk of dementia. Median follow-up was 10.1 years (IQR 2.5–14.7) among CABG patients and 10.7 years (5.6–15.7) among the controls. Identified interactions of the excess risk for dementia with sex and age categories (&amp;lt;65, 65-&amp;lt;75, ≥75 years) resulted in analyses being stratified on those sub-cohorts. Results The overall cumulative incidence at 20 years follow up of all-cause dementia was 9.6% (95% CI 9.4–9.9) among CABG patients and 9.0 (8.8–9.2) among individuals in the general population. The adjusted relative risk for all-cause dementia was increased among CABG patients &amp;lt;65 years and 65–75 years, (HR 1.29 (95% CI 1.17–1.41) and HR 1.06 (1.01–1.11), respectively (fig 1). The risk for all-cause dementia was higher in CABG women than in CABG men (HR 1.62 (1.30–2.03) vs HR 1.22 (1.10–1.35)). In the oldest age group (75 years and older) the risk for all cause dementia, vascular dementia and Alzheimer's disease was lower for CABG patients compared to controls (HR 0.73 (0.69–0.78). Female CABG patients &amp;lt;65 years had an increased risk for Alzheimer's disease (HR 1.83 (1.06–3.15). Hypertension, diabetes, preoperative stroke, renal failure, heart failure, atrial fibrillation, depression and low income were independent predictors for all-cause dementia in CABG patients. Conclusion CABG patients younger than 75 years at the time of surgery have an increased risk of all-cause dementia compared to an age- and sex-matched population. Women younger than 65 years that underwent CABG had also a markedly higher risk for Alzheimer disease. Increased awareness of the higher risk for dementia in younger CABG patients is warranted to avoid delay of diagnosis and treatment. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Swedish Heart and Lung Foundation, Swedish State

Higher Plasma Amyloid-β Levels Are Associated with a Higher Risk of Cancer: A Population-Based Prospective Cohort Study

Various studies show an inverse relation between Alzheimer disease and cancer, but findings are likely to be biased by surveillance and survival bias. Plasma amyloid-β (Aβ) is defined as a preclinical feature of Alzheimer disease, with lower levels of Aβ42 being associated with a higher risk of Alzheimer disease. To get more insight into the biological link between Alzheimer disease and cancer, we investigated plasma Aβ levels in relation to the risk of cancer. Between 2002 and 2005, we measured plasma Aβ40 and Aβ42 levels in 3,949 participants from the population-based Rotterdam Study. These participants were followed until the onset of cancer, all-cause dementia, death, loss to follow-up, or January 1, 2014, whichever came first. We used Cox proportional hazards models to investigate the association between plasma Aβ40 and Aβ42 levels, and the risk of cancer. Analyses were stratified by cancer site. During a median (interquartile range) follow-up of 9.0 years (6.9-10.1), 560 participants were diagnosed with cancer. Higher levels of log2 plasma Aβ40 and Aβ42 were associated with a higher risk of cancer [hazard ratio per standard deviation increase for Aβ40 = 1.12 (95% confidence interval, CI = 1.02-1.23) and Aβ42 = 1.12 (95% CI = 1.03-1.23)]. These effect estimates were most pronounced for hematologic cancers, urinary tract cancers, and cancers of unknown primary origin. We found that higher levels of both plasma Aβ40 and Aβ42 were associated with a higher risk of cancer. Our study suggests a potential biological link between Alzheimer disease and cancer. The pathophysiologic role of Aβ in cancer and its causality warrant further investigation.

Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study.

ObjectiveTo explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD).MethodsWe conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance–weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization–Egger for sensitivity analyses to test for pleiotropic effects.ResultsWe found that higher risk of AD was significantly associated with being a “morning person” (odds ratio [OR] 1.01, p = 0.001), shorter sleep duration (self-reported: β = −0.006, p = 1.9 × 10−4; accelerometer based: β = −0.015, p = 6.9 × 10−5), less likely to report long sleep (β = −0.003, p = 7.3 × 10−7), earlier timing of the least active 5 hours (β = −0.024, p = 1.7 × 10−13), and a smaller number of sleep episodes (β = −0.025, p = 5.7 × 10−14) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, p = 7 × 10−13). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD.ConclusionWe found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.

Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention.

A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer disease (AD). By investigating human DS frontal cortices, we found early and sustained PERK activation associated with the induction of eIF2α and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects are repressed in a mechanism implicating the transcription repressor Bach1. The pharmacological inhibition of PERK in DS mice reduced eIF2α-related translational repression and promoted Nrf2 nuclear translocation, favoring the rescue of Nrf2/Bach1 imbalance. The further analysis of peripheral cells from living DS individuals provided strong support of the pathological link between PERK and trisomy 21. Our results suggest that failure to regulate the PERK pathway is a peculiar characteristic of DS pathology and it may represent an essential step to promote cellular dysfunction, which actively contributes in the brain to the early development of AD.

Does parity matter in women\u2019s risk of dementia? A COSMIC collaboration cohort study

BackgroundDementia shows sex difference in its epidemiology. Childbirth, a distinctive experience of women, is associated with the risk for various diseases. However, its association with the risk of dementia in women has rarely been studied.MethodsWe harmonized and pooled baseline data from 11 population-based cohorts from 11 countries over 3 continents, including 14,792 women aged 60 years or older. We investigated the association between parity and the risk of dementia using logistic regression models that adjusted for age, educational level, hypertension, diabetes mellitus, and cohort, with additional analyses by region and dementia subtype.ResultsAcross all cohorts, grand multiparous (5 or more childbirths) women had a 47% greater risk of dementia than primiparous (1 childbirth) women (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.10–1.94), while nulliparous (no childbirth) women and women with 2 to 4 childbirths showed a comparable dementia risk to primiparous women. However, there were differences associated with region and dementia subtype. Compared to women with 1 to 4 childbirths, grand multiparous women showed a higher risk of dementia in Europe (OR = 2.99, 95% CI = 1.38–6.47) and Latin America (OR = 1.49, 95% CI = 1.04–2.12), while nulliparous women showed a higher dementia risk in Asia (OR = 2.15, 95% CI = 1.33–3.47). Grand multiparity was associated with 6.9-fold higher risk of vascular dementia in Europe (OR = 6.86, 95% CI = 1.81–26.08), whereas nulliparity was associated with a higher risk of Alzheimer disease (OR = 1.91, 95% CI 1.07–3.39) and non-Alzheimer non-vascular dementia (OR = 3.47, 95% CI = 1.44–8.35) in Asia.ConclusionParity is associated with women’s risk of dementia, though this is not uniform across regions and dementia subtypes.

Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials.

The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.

Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models.

Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2-/- mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aβ42 in Trem2-/- or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD.

Medial Temporal Atrophy Alone is Insufficient to Predict Underlying Alzheimer's Disease Pathology.

BackgroundThe medial temporal region is the earliest affected structure in patients with Alzheimer’s disease (AD), and its atrophy is known as the hallmark of AD. This study aimed to investigate the value of medial temporal atrophy (MTA) for detecting 18F-florbetaben positron emission tomography (PET)-proven AD pathology.MethodsWe retrospectively enrolled 265 subjects complaining of cognitive decline at a dementia outpatient clinic from March 2015 to December 2017. All subjects underwent brain magnetic resonance imaging, 18F-fluorodeoxyglucose PET, and 18F-florbetaben PET at baseline. We performed multivariable logistic regression analyses on variables including age, sex, years of education, white matter hyperintensities, apolipoprotein E (APOE) genotype, and memory composite scores in various combinations to investigate whether MTA was indicative of underlying AD pathology.ResultsOur sample population of 265 patients comprised 121 with AD-related cognitive impairment, 42 with Lewy bodies-related cognitive impairment, 32 with vascular cognitive impairment, and 70 with other or undetermined pathologies. In the multivariable logistic regression analyses, MTA was not an independent predictor of underlying AD pathology (P>0.200). The predictive power of underlying AD-related cognitive impairment significantly increased when multiple variables including APOE genotype and memory composite scores were considered together (area under the curve >0.750).ConclusionOur results suggest that MTA alone may be insufficient to accurately predict the presence of AD pathology. It is necessary to comprehensively consider various other factors such as APOE genotype and a detailed memory function to determine whether the patient is at high risk of AD.

Genetic Risk for Alzheimer's Disease Moderates the Association Between Medial Temporal Lobe Volume and Episodic Memory Performance Among Older Adults.

A complex set of interactions between biological, genetic, and environmental factors likely underlies the development of Alzheimer's disease (AD). Identifying which of these factors is most associated with AD is important for early diagnosis and treatment. We sought to examine genetic risk and structural brain volume on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD. 686 adults (55-91 years old) completed a 3T MRI scan, baseline cognitive assessments, and biospecimen collection through the Alzheimer's Disease Neuroimaging Initiative. Hierarchical linear regression analyses examined main and interaction effects of medial temporal lobe (MTL) volume and polygenic hazard score (PHS), indicating genetic risk for AD, on a validated episodic memory composite score. Genetic risk moderated the relationship between MTL volume and memory, such that individuals with high PHS and lower hippocampal and entorhinal volume had lower memory composite scores [ΔF (1,677) = 4.057, p = 0.044, ΔR2 = 0.002]. Further analyses showed this effect was driven by the left hippocampus [ΔF(1,677) = 5.256, p = 0.022, ΔR2 = 0.003] and right entorhinal cortex [ΔF (1,677) = 6.078, p = 0.014, ΔR2 = 0.003]. Among those with high genetic risk for AD, lower volume was associated with poorer memory. Results suggest that the interaction between AD genetic risk and MTL volume increases the likelihood for memory impairment among older adults. Results from this study suggest that genetic risk and brain volume should be considered key factors in tracking cognitive decline.

Associations of Infectious Agents with Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The role of infectious agents in the development of Alzheimer's disease (AD) has long been debated, however, uncertainties still persist. We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81-10.67; I2 = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04-7.75; I2 = 0%, Epstein-Barr virus (OR:1.45, 95% CI = 1.00-2.08; I2 = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02-1.75; I2 = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15-1.74; I2 = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future.

“Choosing Wisely”: Apolipoprotein E Genetic Testing for the Diagnosis of Alzheimer’s Disease in Dementia Clinics

Apolipoprotein E (APOE) ɛ4 allele carriers have an increased risk of late-onset Alzheimer's disease (AD). However, in the "Choosing Wisely" campaign for avoiding unnecessary medical tests, treatments, and procedures, APOE genetic testing is not recommended as a predictive test for AD. The aim of this study was to investigate the potential value of APOE genetic testing in a specific clinical context. Subjects with poor performance in the Korean version of the Mini-Mental Status Examination for dementia screening (MMSE-DS) with a Z-score of less than -1.5 were recruited from the public health centers. All participants underwent APOE genetic testing. Family history of dementia (FHx) was confirmed if one or more first-degree relatives had dementia. Among 349 subjects, 162 (46.4%) were diagnosed with AD. APOEɛ4 allele carriers had a much higher risk of AD in the group with FHx than in the group without FHx (OR = 15.81, 95% CI = 2.74-91.21 versus OR = 1.82, 95% CI = 1.00-3.27, z = 2.293, p = 0.011). The sensitivity, specificity, positive predictive value, and negative predictive value for the APOEɛ4 allele were 47.7%, 90.9%, 91.3%, and 46.5% in the group with FHx. It would be a wise choice to perform the APOE genetic testing for the diagnosis of AD in subjects with poor performance in a screening test and a family history of dementia.

Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.

Approximately two-thirds of those suffering with Alzheimer's disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD.

Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer's disease in patients with rheumatoid arthritis and psoriasis.

This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer's disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn's disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.

Mixed evidence for the relationship between periodontitis and Alzheimer's disease: A bidirectional Mendelian randomization study.

Recent experimental studies indicated that a periodontitis-causing bacterium might be a causal factor for Alzheimer's disease (AD). We applied a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD bidirectionally in the population of European ancestry. We used publicly available data of genome-wide association studies (GWAS) on periodontitis and AD. Five single-nucleotide polymorphisms (SNPs) were used as instrumental variables for periodontitis. For the MR analysis of periodontitis on risk of AD, the causal odds ratio (OR) and 95% confidence interval (CI) were derived from the GWAS of periodontitis (4,924 cases vs. 7,301 controls) and from the GWAS of AD (21,982 cases vs. 41,944 controls). Seven non-overlapping SNPs from another latest GWAS of periodontitis was used to validate the above association. Twenty SNPs were used as instrumental variables for AD. For the MR analysis of liability to AD on risk of periodontitis, the causal OR was derived from the GWAS of AD including 30,344 cases and 52,427 controls and from the GWAS of periodontitis consisted of 12,289 cases and 22,326 controls. We employed multiple methods of MR. Using the five SNPs as instruments of periodontitis, there was suggestive evidence of genetically predicted periodontitis being associated with a higher risk of AD (OR 1.10, 95% CI 1.02 to 1.19, P = 0.02). However, this association was not verified using the seven independent SNPs (OR 0.97, 95% CI 0.87 to 1.08, P = 0.59). There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00, 95% CI 0.96 to 1.04, P = 0.85). In summary, we did not find convincing evidence to support periodontitis being a causal factor for the development of AD. There was also limited evidence to suggest genetic liability to AD being associated with the risk of periodontitis.

Research progresses in the genetic susceptibility of late-onset Alzheimer's disease

Alzheimer's disease (AD) is a common chronic neurodegenerative disease in the central nervous system. Its pathogenesis and mechanism have not been identified. Studies indicate that an individual carrying certain genotypes of susceptibility gene has a higher risk of AD. With the completion of the Human Genome Project and the development of genome-wide association studies(GWAS), a series of susceptibility genes associated with late-onset AD (LOAD) have been discovered. In this paper, the development of susceptibility genes associated with LOAD is reviewed, so as to provide readers with current research progress and clues for future research. Key words: Alzheimer's disease; Susceptibility gene; Neurodegenerative diseases