Decreased Risk Of Alzheimer's Disease Research Articles

Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer's Disease Risk: A Retrospective Cohort Proof-of-Concept Study.

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted.

The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Carriers of one copy of the apolipoprotein E gene (APOE) ε4 allele have a 4-fold increased AD risk, while APOE ε4/ε4-carriers have a 12-fold increased risk of developing AD in comparison with the APOE ε3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene may affect tau- and amyloid-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significantly associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotide sites of APOE.

Causal relationship between Alzheimer's disease and cardiovascular disease: a bidirectional Mendelian randomization analysis.

Observational studies suggest that cardiovascular disease (CVD) increases the risk of developing Alzheimer's disease (AD). However, the causal relationship between the two is not clear. This study applied a two-sample bidirectional Mendelian randomization method to explore the causal relationship between CVD and AD. Genome-wide association study (GWAS) data from 46 datasets of European populations (21,982 cases of AD and 41,944 controls) were utilized to obtain genetic instrumental variables for AD. In addition, genetic instrumental variables for atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), coronary heart disease (CHD), angina pectoris (AP), and ischemic stroke (IS) (including large-artery atherosclerotic stroke [LAS] and cardioembolic stroke [CES]) were selected from GWAS data of European populations (P < 5E-8). The inverse variance weighting method was employed as the major Mendelian randomization analysis method. Genetically predicted AD odds ratios (OR) (1.06) (95% CI: 1.02-1.10, P = 0.003) were linked to higher AP analysis. A higher genetically predicted OR for CES (0.9) (95% CI 0.82-0.99, P = 0.02) was linked to a decreased AD risk. This Mendelian randomized study identified AD as a risk factor for AP. In addition, CES was related to a reduced incidence of AD. Therefore, these modifiable risk factors are crucial targets for preventing and treating AD.

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach. An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R2 <0.001) and a p-value threshold of 5×10-8 . An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32-0.88; p-value: 0.01; false discovery rate [FDR] p-value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38-0.85; p-value: 0.01; FDR p-value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46-1.02; p-value: 0.06; FDR p-value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power. A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis. Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD). The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis. Among women, genetically determined effects of sex hormones were limited or null. Among men, a higher concentration of androgens decreased AD risk. This study suggests a causal relationship between androgens and AD among men.

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. To determine whether rare missense variants on APOE are associated with AD risk. Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Midlife lipid and glucose levels are associated with Alzheimer's disease.

It is unknown whether vascular and metabolic diseases assessed in early adulthood are associated with Alzheimer's disease (AD) later in life. Association of AD with lipid fractions, glucose, blood pressure, body mass index (BMI), and smoking obtained prospectively from 4932 Framingham Heart Study (FHS) participants across nine quadrennial examinations was evaluated using Cox proportional hazard and Kaplan-Meier models. Age-, sex-, and education-adjusted models were tested for each factor measured at each exam and within three adult age groups (early=35-50, middle=51-60, and late=61-70). A 15mg/dL increase in high density lipoprotein (HDL) cholesterol was associated with decreased AD risk during early (15.4%, P=0.041) and middle (17.9%, P=0.014) adulthood. A 15mg/dL increase in glucose measured during middle adulthood was associated with 14.5% increased AD risk (P=0.00029). These findings remained significant after adjusting for treatment. Our findings suggest that careful management of cholesterol and glucose beginning in early adulthood can lower AD risk.

Alcohol consumption and risk of Alzheimer's disease: A dose-response meta-analysis.

This study aimed to investigate the association between alcohol consumption and the risk of Alzheimer's disease (AD). PubMed and Web of Science databases were systematically searched as of 1 September 2019. Relative risk and 95% CI were used to evaluate the association between alcohol consumption and AD risk. Subgroup analyses based on the type of alcohol, ethnicity, study design and sex were carried out. An alcohol dose-response meta-analysis was carried out. A total of 13 studies were included in the quantitative synthesis, and six were used in the dose-response meta-analysis. Compared with non-drinkers, individuals who drank had a lower risk of AD (relative risk 0.68, 95% CI 0.53-0.87; I2 = 87.9%, P < 0.001). In subgroup analyses, drinking wine was found to reduce the occurrence of AD (relative risk 0.71, 95% CI 0.51-0.96). When stratified by ethnicity, sex and study design, no association was seen between AD risk and alcohol use. There was an overall non-linear, but not significant, association between alcohol intake dose and AD risk. A significant non-linear association was observed between excess AD risk and alcohol intake dose in men (overall P=0.023; P for non-linearity=0.025) starting from 14.8 drinks per week. Women's alcohol intake dose <16.9 drinks per week showed a significant non-linear association with decreased AD risk (overall P=0.002; P for non-linearity=0.019). Drinking alcohol could reduce the risk of AD. Alcohol dose had a non-linear, but non-significant, relationship with the development of AD. The amount of alcohol consumption showed significant sex-specific effects on AD. Geriatr Gerontol Int 2022; 22: 278-285.

Genome‐wide association for protective variants in Alzheimer’s disease in the Midwestern Amish

Alzheimer's disease (AD) is a progressive neurological disease that leads to atrophy of the brain and cognitive decline. There are many factors that play a role in the risk of AD, such as age, smoking, gender, and genetics. the genetic influence on AD is strong, with heritability estimates between 40-60%. Identifying genetic factors that either increase or decrease AD risk are critical in the understanding of this disease. Here, we studied a homogeneous, isolated population - the Ohio and Indiana Amish - to identify protective genetic factors for AD. Our previous studies in the Amish documented numerous individuals who are cognitively normal at advanced ages.Here, we have completed a genome wide association study (GWAS) on Amish individuals who are at high risk for AD (i.e., have an affected sibling and are over 76 years of age), but are cognitively normal. We have genotypes on 2096 individuals, 921 of which are being analyzed for association, in which we have a complex 5,000-person, 13-generation pedigree to help inform our results. MEGAex and GSA chips were used for genotyping. Both KING and GENESIS software were used for quality control and association analyses since they control for both population structure and kinship in evaluating association via a generalized linear mixed model (GLMM).We included 601 cognitively normal (CN), 320 cognitively impaired (CI) individuals. Association analysis was done on a total of 921 individuals, with 256,978 SNPs. We had a total of four SNPs reach a significance threshold of p ≤ 5 x 10-5 to also include suggestive association loci in our examination. (Nearest genes: DISC1, IQGAP2, and LOC401478 on chromosomes 1, 5 and 8. One SNP on chromosome 13, rs1556774, has no gene association currently known, and no known gene within 80kb.) These loci are currently under further examination.We studied cognitively resilient individuals from a founder population to identify potential protective genetic variants for AD. We identified four SNPs associated with CN in at-risk adults over 75. These loci might influence cognitive resilience. Here we have shed some light on possible genetic factors that may contribute to protection from cognitive decline.

Multiple viruses detected in human DNA are associated with Alzheimer disease risk.

Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer disease (AD) by independent lines of evidence. We quantified DNA sequence reads that align to viral and bacterial reference sequences present in whole exome (WES, N= 15,125) and whole genome (WGS, N= 4,443) sequences measured in blood (N=17,817) and brain (N=1,751) tissue from non-Hispanic white, African American and Caribbean Hispanic participants of the AD Sequencing Project including 9,380 AD cases and 10,188 controls. We tested the association of individual and cumulative normalized viral read counts with AD using logistic and LASSO regression models adjusting for tissue source, sequencing site, sex, APOE genotype, and population. Additional models were tested in subsets stratified by WES/WGS and tissue source. We used PathSeq, a software tool that performs subtraction on high-throughput sequencing data, to identify inserted microbial DNA and tested those species for association with AD. We detected sequences from 175 unique species of human viruses and 17,219 bacteria. Many individual and the cumulative viral read counts varied significantly by sequence center, tissue source, sex, and ancestry. Cumulative normalized human viral read count was associated with AD in every subset of the data (ORmeta = 1.05 per 100,000 units, Pmeta < 7.81x10-12 ). In the WES dataset, the presence of inserted herpes virus 6A sequence measured by PathSeq was protective against AD (OR=0.41, P=0.0007). We also found significant associations using LASSO. In the WES dataset, Hepatitis C was associated with increased AD risk. Herpes 6B was associated with decreased AD risk in both the WES and WGS datasets. In brain samples, herpes 4 and 6B were negatively associated with AD in both WES and WGS datasets, whereas herpes 8 was positively associated with AD and human herpes 3 was negatively associated in the WES dataset. No bacterial species were significantly associated with AD. These results are consistent with the hypothesis that viral infections contribute to AD pathogenesis and highlight the utility of next generation sequencing to detect microbial agents in multiple tissues. Contrary to previous results, except for human herpes 8, herpes viral DNA species are protective against AD.

Sleep/wake cycle alterations as a cause of neurodegenerative diseases: A Mendelian randomization study

Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N=17,996), AD (N=21,235) and ALS (N=40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p=8.47×10-09 and 95%CI:-7.28 to -4.44, p=5.87×10-16, respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p=0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p=0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS.

Chemotherapy and the Risk of Alzheimer's Disease in Colorectal Cancer Survivors: Evidence From the Medicare System.

Evidence on the nature of the relationship between patients receiving chemotherapy as an essential part of guideline-concordant cancer care and the onset of Alzheimer's Disease (AD) and other adverse cognitive outcomes has been mixed. Biological mechanisms were proposed to support both a potentially beneficial and an adverse role. To explore the relationship between chemotherapy and onset of AD and other neurocognitive disorders (ND) in colorectal cancer survivors. We conducted a retrospective cohort study of 135,834 individuals older than 65 years diagnosed with colorectal cancer between 1998 and 2007, using SEER-Medicare data. A proportional hazards model was used before and after the use of inverse probability weighting to account for populational differences between the chemotherapy and nonchemotherapy groups. Weights were normalized to the total sample size. After inverse probability weighting, chemotherapy was associated with decreased AD risk (hazard ratio [HR]: 0.791; 95% CI: 0.758 to 0.824) and lower risk for the majority of other ND including AD-related diseases (HR: 0.823; CI: 0.802 to 0.844), dementia (permanent mental disorder) (HR: 0.807; CI: 0.782 to 0.832), and dementia (senile) (HR: 0.772; CI: 0.745 to 0.801). The only adverse effect to remain significant was cerebral degeneration (excluding AD) (HR: 1.067; CI: 1.033 to 1.102). The effects for AD remained after treatment was stratified by chemotherapy agent type and remained significant for up to 6 years past diagnosis. Chemotherapy use in colorectal cancer survivors demonstrated an association with reduced risk for AD and other ND.

Reader response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.

I read with interest the Null Hypothesis article by Meyer et al.1 In 2001, Weggen et al.2 suggested that flurbiprofen and ibuprofen had an effect on gamma secretase not shared by other cyclooxygenase inhibitors. This finding, along with several other failed studies of anti-inflammatory mechanisms in Alzheimer disease (AD), suggests that the widely replicated epidemiologic findings of nonsteroidal anti-inflammatory drug (NSAID) benefit for decreasing AD risk could be related to the effect on gamma-secretase, not inflammation. A flurbiprofen study failed to show a benefit for patients with AD,3 but a considerable number of studies suggest that the NSAID-related benefit requires years of treatment before dementia develops, which the study by Meyer et al.1 was appropriately targeting. However, the question remains as to whether ibuprofen is the drug to test, not naproxen.

Association of PICALM Gene Polymorphisms with Alzheimer's Disease: Evidence from an Updated Meta-Analysis

Previous studies have examined the roles of three polymorphisms (rs3851179, rs541458, and rs592297) of the PICALM gene in susceptibility to Alzheimer's disease (AD) with inconclusive findings. We performed a meta-analysis to explore whether these three polymorphisms in the PICALM gene were associated with susceptibility to AD. Bibliographical searches were conducted in the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. Summary Odds Ratios (ORs) with 95% Confidence Intervals (CIs) were used to assess the strength of association in a random effects model. Potential sources of heterogeneity were identified by subgroup and meta-regression analyses. Twenty studies (9,017 cases and 15,448 controls) on rs3851179, 12 studies (8,077 cases and 12,022 controls) on rs541458, and 4 studies (2,106 cases and 2,234 controls) on rs592297 were considered eligible for meta-analyses. For both rs3851179 and rs541458, the overall ORs were significant under all genetic models with mild heterogeneity. Compared with G carriers, A carriers of rs3851179 were associated with a decreased risk of AD (OR = 0.88; 95% CI 0.84, 0.91, P for Z-test <0.001, I2 = 0.0%). Compared with T carriers, C carriers of rs541458 were inversely associated with AD risk (OR = 0.86; 95% CI 0.81, 0.92, P for Z-test <0.001, I2 = 39.5%). No association was observed for rs592297. Subgroup and meta-regression analyses indicated that the protective effect of the rs541458 C allele was observed only among Caucasians, not among Asians (P for interaction: 0.021~<0.001). rs3851179 and rs541458 appear to be associated with decreased AD risk. The null associations for rs592297 with AD risk need further confirmation with a larger number of participants.

Impact of Social Frailty on Alzheimer's Disease Onset: A 53-Month Longitudinal Cohort Study.

We investigated the association between social frailty and Alzheimer's disease (AD) incidence among community-dwelling older adults in Japan. A 53-month follow-up cohort study was conducted in Obu City, Japan. Participants comprised 3,720 community-dwelling older adults (mean age, 71.7 years; 48.4% men). The operational definition of social frailty comprised five items: going out infrequently, rarely visiting friends, feeling unhelpful to friends or family, living alone, and not always talking with someone each day. During follow-up, the cumulative AD incidence risk between socially robust, pre-frail, and frail groups was 4.1%, 5.5%, and 10.7%, respectively. In both crude (HR 2.72, 95% CI 1.90-3.89, p < 0.001) and adjusted Cox proportional hazards models (HR 1.53, 95% CI 1.03-2.28, p = 0.035), social frailty was associated with a significantly higher AD incidence risk. The present study revealed that social frailty is strongly associated with AD incidence among Japanese older adults. Further research should elucidate whether social frailty prevention is effective for decreasing AD risk.

Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis.

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

A Meta-Analysis on the Relationship of the PON Genes and Alzheimer Disease.

This study aimed to evaluate the association of the paraoxonase (PON) gene variants and Alzheimer disease (AD) using meta-analysis. Relevant studies were identified by searching English and Chinese databases extensively. Allele and genotype frequencies for each included study were extracted. Newcastle-Ottawa Scale (NOS) was employed to assess the quality of included studies. The odds ratio (OR) with 95% confidence interval (95% CI) was calculated using a random-effects or fixed-effects model. A Q statistic was used to evaluate homogeneity, and Egger test and funnel plot were used to assess publication bias. A total of 15 studies (involving 5 polymorphisms) were included and identified for the current meta-analysis. The NOS scores ranged from 7 to 8, meaning good quality of studies. It was found that the SS genotype of PON2 S311C polymorphism had an significant association with AD in the studied population (OR = 0.82, 95% CI: 0.68-0.99, P = .04), and the A allele of PON1 rs705379 polymorphism was positively related to AD in Caucasian population (OR = 1.21, 95% CI: 1.05-1.39, P = .009) as well as the GG genotype decreased AD risk significantly in Caucasians (OR = 0.7, 95% CI: 0.56-0.88, P = .002). However, there was no significant relationship between other 3 genetic variants of PON genes (L55 M, Q192 R, and -161C/T of PON1 gene) and AD. Existing evidence indicates that the S311C polymorphism (SS genotype) and the rs705379 (the A allele and GG genotype) are associated with risk of AD in studied population. Future studies with larger sample sizes will be necessary to confirm the present results.

EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease

Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared with APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE. The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-β (Aβ) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h-APOE genotypes for identifying mechanisms underlying APOE-modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions.

Association of cancer and Alzheimer's disease risk in a national cohort of veterans

IntroductionTo examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. MethodsRetrospective cohort of 3,499,378 mostly male US veterans aged ≥65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. ResultsSurvivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. DiscussionSurvivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD.

LESS CONVERSION TO AD AND FEWER NEUROFIBRILLARY TANGLES IN MCI PATIENTS TAKING CERTAIN ANTIHYPERTENSIVES

With the projected increase in Alzheimer's disease (AD) prevalence, repurposing existing drugs generally recognized as safe, and show promise in AD studies, shortens the time to provide urgently needed treatment options. The renin-angiotensin system (RAS) regulates blood pressure, fluid homeostasis, and has been implicated in memory consolidation. Research suggests that antihypertensives that act via the RAS, may decrease AD risk, possibly via Aβ and/or tau. We previously reported that individuals taking RAS acting medications (ACE-Is or A2RBs), particularly those that are centrally acting, show slower cognitive decline and are less likely to progress from mild cognitive impairment (MCI) to AD over three years. However, the potential mechanism was unclear, due to the absence of neuropathological findings on these individuals. Here we test the hypothesis that individuals taking RAS acting antihypertensives may exhibit slower clinical disease progression and less AD related neuropathology than individuals taking non-RAS acting antihypertensives. Participants were older (M=83.1 years), 32% male, well educated (M=15.7 years) and 9.2% identified as Black. Males comprised a larger proportion of RAS users vs non-users (45% vs 20% for RAS users vs. non-RAS users, respectively). Groups did not differ in percent of ApoE4 positive individuals (28%) or Baseline MMSE score (M=26). While there were no group differences in blood pressure (M=138/72 mmHg), HDL (M=59mg/dL) or LDL (M=101 mg/dL), RAS users were more likely to be diabetic than non-RAS users (p=.01). Participants with MCI at Baseline who were taking a RAS medication were less likely to progress to AD than non-RAS users (p=.02). There were no group differences in brain weight, amyloid level, diffuse plaques, or NIA Reagan, Braak or CERAD scores. However, individuals taking RAS acting medications exhibited significantly fewer neurofibrillary tangles (NFT) than non-RAS users in brain regions including the hippocampal CA1 region (p<.01), entorhinal cortex (p=.04), and the average of tangles in the angular gyrus, inferior temporal, mid-frontal cortex and superior frontal (p=.03). Results suggest that prevention or clearance of NFTs via abnormal tau hyperphosphorylation represents a plausible mechanism by which RAS acting medications aid in slowing the progression from MCI to AD.

Influence of four polymorphisms in ABCA1 and PTGS2 genes on risk of Alzheimer's disease: a meta-analysis.

We preformed this meta-analysis to investigate the influence of ABCA1 (ATP-binding cassette sub-family A member 1) rs2422493 (C-477T), rs1800977 (C-14T), rs2066718 (V771M), and PTGS2 (Prostaglandin-endoperoxide synthase 2) rs20417 (G-765C) polymorphisms on the risk of Alzheimer's disease (AD). Seventeen eligible case-control studies were acquired from PubMed, Embase, Alzgene, Chinese National Knowledge Infrastructure and Wanfang databases. The pooled odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated to evaluate the association under five genetic models. Combined data indicated that ABCA1 rs2422493 polymorphism was statistically significant associated with increasing AD risk in three genetic models (allelic T vs C: OR=1.12, 95% CI: 1.01-1.24; homozygous TT vs CC: OR=1.26, 95% CI: 1.03-1.55; and recessive TT vs TC+CC: OR=1.33, 95% CI: 1.12-1.58) while no association was found between two other ABCA1 polymorphisms and AD susceptibility. Nevertheless, a further risk-stratification analysis showed that ApoE-ε4 carriers with any ABCA1 polymorphism suffered a much higher probability to be AD patients. Meanwhile, PTGS2 rs20417 polymorphism was linked to decreasing AD risk with a P<0.0001 in five genetic models (e.g., allelic C vs G: OR=0.59, 95% CI: 0.50-0.70; homozygous CC vs GG: OR=0.31, 95% CI: 0.18-0.52; and heterozygous CG vs GG: OR=0.64, 95% CI: 0.52-0.78). In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2 rs20417 variant showed a protective effect on AD risk. In addition, ABCA1 rs2066718 and rs1800977 polymorphisms might not contribute to AD susceptibility in general population, but they should play a role on AD development when interacted with ApoE-ε4.