Reduced Risk Of Alzheimer's Disease Research Articles

Unexpected Low Rate of Amyloid-β Pathology in Multiple Sclerosis Patients.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-β plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-β pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024.

Understanding Health Beliefs and Health Behaviors in Older Adults at Risk for Alzheimer's Disease.

There are significant public health benefits to delaying the onset of Alzheimer's disease (AD) in individuals at risk. However, adherence to brain healthy behaviors is low. The Health Belief Model proposes that specific beliefs are mediators of behavior change. To characterize health belief measures from the Science of Behavior Change Research Network (SBCRN) in an older adult population and associations between health beliefs, AD risk, and current health behaviors. A total of 172 individuals from the Rhode Island AD Prevention Registry participated. SBCRN health belief measures included assessments of future time perspective, self-efficacy, deferment of gratification, and consideration of future consequences. Outcome measures included individual AD risk index score, dementia risk awareness, and lifestyle behaviors including physical, cognitive, and social activity. Participants who were older had higher scores for AD risk, lower future time perspective, and lower generalized self-efficacy (all at p < 0.001). Higher generalized self-efficacy was related to increased physical activity (p < 0.010). Higher future time perspective (p < 0.001) and generalized self-efficacy (p = 0.48) were associated with lower AD risk score. Subjective cognitive decline (SCD) was associated with lower self-efficacy, ability to delay gratification, and a less expansive future time perspective. Greater self-efficacy and perceived future time remaining were associated with lower AD risk and greater engagement in physical activity. SCD was associated with health beliefs that may negatively affect engagement in positive brain health behaviors. Assessment of and psychoeducation about these intrapersonal health belief constructs may be important targets for behavioral interventions to reduce AD risk.

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer's disease in the Framingham Heart Study.

Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

Genome‐wide association study for Alzheimer disease in APOE ɛ4/ɛ4 carriers

AbstractBackgroundThe APOE ɛ4/ɛ4 genotype has the greatest risk for late‐onset Alzheimer disease (AD). However, modifying effects of other genes on AD risk in APOE ɛ4 homozygotes are not fully understood.MethodsWe conducted a genome‐wide association study (GWAS) for AD among 1,223 non‐Hispanic White APOE ɛ4/ɛ4 carriers assembled by the Alzheimer’s Disease Genetics Consortium (ADGC). Expression of genes within 50 kb of suggestively associated single nucleotide polymorphisms (SNPs, P&lt;10−6) were compared between AD and control brains from 576 Religious Orders Study and Memory and Aging Project (ROSMAP) subjects. We conducted survival analysis between carriers and non‐carriers of AD risk alleles for the suggestive SNPs in 4,287 Framingham Heart Study (FHS) participants. We compared expression of the top‐ranked genes between ɛ2/ɛ2 (APOE2) and ɛ4/ɛ4 (APOE4) human induced pluripotent stem cells (iPSC)‐derived neurons (iNeurons) and astrocytes (iAstrocytes) in a co‐culture system (Jun et al, 2022) and separately evaluated associations of their expression levels with neuropathological traits from 208 brains from FHS participants.ResultsWe identified association of AD with 11 SNPs at the suggestive level of which four near TRIB2, CTNNA2, ZNF443, and KLHL29 were genome‐wide significant (P&lt;5×10−8). Rs75983775 near TRIB2, the most significant finding (P = 9.4×10−11), was associated with decreased risk of AD in ADGC APOE ɛ4 homozygotes (odds ratio = 0.12) and increased TRIB2 expression in ROSMAP ɛ4‐carrier brains (P = 0.02). TRIB2 expression was increased in APOE2 compared to APOE4 iAstrocytes (log2 fold change (log2FC) = 0.41, adjusted P (adjP) = 0.03) and iNeurons (log2FC = 0.31, adjP = 0.002) and elevated the Iba1 level in FHS brains (P = 0.03). Association with TENM3 SNP rs56035906 was suggestively associated with reduced AD risk in ADGC APOE ɛ4 homozygotes (odds ratio = 0.30, P = 4.3×10−7) and with lower incidence of AD among FHS ɛ4 carriers (P = 0.03). TENM3 expression was decreased in APOE2 compared to APOE4 iNeurons (log2FC = 0.59, adjP = 2.4×10−4) and associated with increasing phosphorylated tau 181 (P = 0.007) and C4a protein expression (P = 9.6×10−4) in FHS brains.ConclusionWe identified variants that may protect against AD risk among APOE ɛ4/ɛ4 carriers, delay disease onset, modulate expression of nearby genes in iAstrocytes and iNeurons, and are associated with measures of tau and neuroinflammation in autopsied brains.

Skipping of FCER1G Exon 2 Is Common in Human Brain But Not Associated with the Alzheimer's Disease Genetic Risk Factor rs2070902.

Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer's disease (AD) may provide insights into treatments that could reduce AD risk. Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2. AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR. The protein encoded by FCER1G, FcRγ, is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon 2 (D2-FCER1G) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype. In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902.

Loop diuretics association with Alzheimer's disease risk.

Objectives: To investigate whether exposure history to two common loop diuretics, bumetanide and furosemide, affects the risk of developing Alzheimer's disease (AD) after accounting for socioeconomic status and congestive heart failure. Methods: Individuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the de-identified Observational Medical Outcomes Partnership platform. We matched the AD case cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, and hypertension, and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases and 1,705 controls) were exposed to bumetanide. Results: After adjusting for socioeconomic status and other confounders, the exposure of bumetanide and furosemide was significantly associated with reduced AD risk (respectively, bumetanide odds ratio [OR] = 0.23; 95% confidence interval [CI], 0.15-0.36; p = 4.0 × 10-11; furosemide OR = 0.42; 95% CI, 0.38-0.47; p < 2.0 × 10-16). Discussion: Our study replicates in an independent sample that a history of bumetanide exposure is associated with reduced AD risk while also highlighting an association of the most common loop diuretic (furosemide) with reduced AD risk. These associations need to be additionally replicated, and the mechanism of action remains to be investigated.

Association of Lifelong Cognitive Reserve with Dementia and Mild Cognitive Impairment among Older Adults with Limited Formal Education: A Population-Based Cohort Study

Introduction: Early-life educational attainment contributes to cognitive reserve (CR). We investigated the associations of lifelong CR with dementia and mild cognitive impairment (MCI) among older people with limited formal education. Methods: This population-based cohort study included 2,127 dementia-free participants (≥60 years; 59.4% women; 81.5% with no or elementary school) who were examined at baseline (August-December 2014) and follow-up (March-September 2018). Lifelong CR score at baseline was generated from six lifespan intellectual factors. Dementia, MCI, and their subtypes were defined according to the international criteria. Data were analyzed using Cox proportional-hazards models. Results: During the total of 8,330.6 person-years of follow-up, 101 persons were diagnosed with dementia, including 74 with Alzheimer's disease (AD) and 26 with vascular dementia (VaD). The high (vs. low) tertile of lifelong CR score was associated with multivariable-adjusted hazards ratios (95% confidence interval) of 0.28 (0.14–0.55) for dementia and 0.18 (0.07–0.48) for AD. The association between higher CR and reduced AD risk was significant in people aged 60–74 but not in those aged ≥75 years (p for interaction = 0.011). Similarly, among MCI-free people at baseline (n = 1,635), the high (vs. low) tertile of lifelong CR score was associated with multivariable-adjusted hazard ratios of 0.51 (0.38–0.69) for MCI and 0.46 (0.33–0.64) for amnestic MCI. Lifelong CR was not related to VaD or non-amnestic MCI. Discussion: High lifelong CR is associated with reduced risks of dementia and MCI, especially AD and amnestic MCI. It highlights the importance of lifelong CR in maintaining late-life cognitive health even among people with no or limited education.

Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer

Alzheimer disease (AD) and cancer have been reported to be inversely correlated in incidence, but the mechanism remains elusive. A case-control study was conducted, based on the SEER (Surveillance, Epidemiology, and End Results) Research Plus data, to evaluate 12 factors in patients with cancer. Severe pain was related to reduced AD risk, while older age at cancer diagnosis, female, longer survival years after tumor diagnosis, more benign/borderline tumors, less cancer-directed surgery, and more chemotherapy were associated with higher AD risk. In addition, patients of different races or with different cancer sites were associated with different risks of getting AD. Cases had a higher prevalence of severe pain than controls in all race and cancer site subgroups, except for in digestive cancer, where the result was the opposite. This study indicated pain as a novel protective factor for AD in patients with cancer. The mechanism behind it may provide new perspective on AD pathogenesis and AD-cancer association, which we discussed in our own hypothesis of the mechanism of pain action. In addition, digestive cancer pain had an opposite impact on AD risk from other cancer pains, which suggests the uniqueness of digestive system in interacting with the central nervous system.

Sex differences in risk for Alzheimer’s disease with extended maternal and paternal family history and vascular risk factors. The Cache County Study.

AbstractBackgroundAge, family history (FH), APOE status, and vascular factors are known risk factors for Alzheimer’s disease (AD). Sex differences in AD risk have been reported for some but not all of these factors. We examined sex differences in the association between FH and AD risk, studying the role of maternal/paternal lineage, parental longevity, and vascular factors in a population‐based cohort.Methods3677 participants (59% female) of the Cache County Memory Study [mean(SD) age = 75.75(7.11) years] were studied. FH of AD and health information were obtained from self‐report or Medicare claims and death certificates via data linkage through the Utah Population Database. AD cases were determined via clinical examination and Medicare claims and non‐cases via clinical examination or negative cognitive screenings.ResultsMultivariate logistic regression models (covarying age, education, and APOE) found that individuals with a first‐ degree relative with AD was associated with a 58% and 66% increased risk of AD in males and females, respectively. In males, APOE Ɛ4 carriers with a history of exceptional maternal longevity (survival age 87+) had 3‐times the risk of AD than males with neither risk factor (OR = 3.15, p interaction p = .020). Males with both exceptional maternal and paternal longevity (survival age 87+) had an 11% reduced risk of AD (OR = 0.894, interaction p = .041). A history of both maternal and paternal lineages of AD was associated with a 46% lower risk (OR = 0.544) at trend level significance (interaction p = .054). In females, maternal lineage of AD was associated with a 56% increased risk of AD (OR = 1.56; p = .005). Females with a history of congestive heart failure and paternal lineage of AD had twice the AD‐risk (OR = 2.26, interaction p = .013) compared to females with neither risk factor. Parental exceptional longevity was not associated with AD risk in females.ConclusionRisk for AD associated with family history varies by sex, maternal and paternal lineage of AD and exceptional parental longevity. Elucidating mechanisms and modifiable lifestyle factors underlying sex differences may facilitate developing primary AD prevention strategies.

Link of BIN1, CLU, and IDE Gene Polymorphisms with the Susceptibility of Alzheimer's Disease: Evidence from a Meta-analysis.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder. The association of BIN1, CLU, and IDE genetic polymorphisms with AD risk have been evaluated overtimes that produced conflicting outcomes. We performed this meta-analysis to investigate the contribution of BIN1 (rs744373 and rs7561528), CLU (rs11136000 and rs9331888), and IDE (rs1887922) polymorphisms to AD risk. From a systemic literature search up to July 15, 2021, we included 25 studies with rs744373, 16 studies with rs7561528, 37 studies with rs11136000, 16 studies with rs9331888, and 4 studies with rs1887922. To analyze the correlation, we constructed seven genetic models that used odds ratio and 95% confidence intervals. We used RevMan 5.4 for meta-analysis. Our study suggests that BIN1 rs744373 is associated with a significantly increased risk of AD in five genetic models (OR>1). Again, CLU rs11136000 showed reduced association in all genetic models (OR<1). CLU rs9331888 revealed an increased association in two models (OR>1). The IDE rs1887922 showed significantly increased risk in four models (OR>1). From subgroup analysis, a significantly increased risk of AD was observed in Caucasians and Asians for BIN1 rs744373. Again, BIN1 rs7561528 showed a significantly enhanced risk of AD only in Caucasians. CLU rs11136000 showed significantly reduced risk in Caucasians but rs9331888 showed increased risk in the same ethnicity. Our meta-analysis confirms the association of BIN1 rs744373, CLU rs9331888, and IDE rs1887922 polymorphisms with an increased risk of AD, especially in Caucasians. Again, CLU rs11136000 is associated with reduced AD risk in the overall population and Caucasians.

Pathways explaining racial/ethnic disparities in incident all-cause and Alzheimer's disease dementia among older US men and women.

IntroductionRacial disparities in Alzheimer's disease (AD) and all‐cause dementia (DEMENTIA) incidence may exist differentially among men and women, with unknown mechanisms.MethodsA retrospective cohort study examining all‐cause and AD dementia incidence was conducted linking Third National Health and Nutrition Examination Survey (NHANES III) to Centers for Medicare & Medicaid Services Medicare data over ≤26 years of follow‐up (1988 to 2014). Cox regression and generalized structural equation models (GSEMs) were constructed among men and women ≥60 years of age at baseline (N = 4592). Outcomes included onset ages of all‐cause and AD dementia, whereas the main exposures were race/ethnicity contrasts (RACE_ETHN). Potential mediators) included socio‐economic status (SES), lifestyle factors (dietary quality [DIET] nutritional biomarkers [NUTR], physical activity [PA], social support [SS], alcohol [ALCOHOL], poor health [or HEALTH], poor cognitive performance [or COGN]. In addition to RACE_ETHN, the following were exogenous covariates in the GSEM and potential confounders in Cox models: age, sex, urban‐rural, household size, and marital status.ResultsNon‐Hispanic Black (NHB) women had a higher risk of DEMENTIA versus non‐Hispanic White (NHW) women in GSEM, consistent with Cox models (age‐adjusted model: hazard ratio [HR] = 1.34, 95% confidence interval [CI]: 1.10 to 1.61). The total effect of this RACE_ETHN contrast in women was explained by four main pathways: (1) RACE_ETHN→ poor cognitive performance (COGN, +) → DEMENTIA (+); (2) RACE_ETHN → SES (−) → COGN (−) → DEMENTIA (+); (3) RACE_ETHN → SES (−) → physical activity (PA, +) → COGN (−) → DEMENTIA (+); and (4) RACE_ETHN → SES (−) → DIET (+) → COGN (−) → DEMENTIA (+). A reduced AD risk in Mexican American (MA) women versus NHW women upon adjustment for SES and downstream factors (HR = 0.53, 95% CI: 0.35 to 0.80). For the non‐White versus NHW contrast in incident DEMENTIA, pathways involved lower SES, directly increasing cognitive deficits (or indirectly through lifestyle factors), which then directly increases DEMENTIA .DiscussionSocioeconomic and lifestyle factors explaining disparities between NHB and NHW in dementia onset among women are important to consider for future observational and intervention studies.

Multi-omics approaches reveal a link between the MS4A gene loci, TREM2, and microglia function.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We recently identified common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region that were associated with CSF sTREM2 concentrations. One variant (rs1582763) was associated with increased CSF sTREM2 and reduced AD risk, while a second variant (rs6591561) was associated with reduced CSF sTREM2 and increased AD risk. Using human induced pluripotent stem cell-derived microglia, we found that MS4A4A and TREM2 colocalize on lipid rafts at the plasma membrane. Here, we sought to define the molecular mechanism by which variants in the MS4A gene region impact sTREM2, microglia function and AD risk. To define the functional effects of MS4A variants, we used genotype and bulk RNAseq data from 579 human brain samples. We then evaluated microglia specific effects using single nuclei RNAseq data obtained from 64 human brains. Leveraging genotypic and transcriptomic data in human brain tissue, we found that rs1582763 and rs6591561 alter distinct molecular pathways. Rs1582763, which confers AD resilience, impacts pathways associated with cholesterol metabolism, while rs6591561, which confers AD risk, impacts pathways associated with chemokine regulation. Using single nuclei RNAseq data in human brain tissue, we found that these variants are associated with MS4A4A expression within microglia. Additionally, these variants modify cellular proportions of a functionally distinct microglia population. Together, these findings begin to provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

Diet and APOE as moderators of the relationship between trimethylamine N‐oxide and biomarkers of Alzheimer's disease and glial activation

Dietary patterns appear to impact cognitive trajectories in aging, and gut microbiota have been implicated in Alzheimer's disease (AD) pathogenesis, potentially as modulators of neuroinflammation early in the disease. Diets featuring low meat and dairy consumption have been linked to reduced AD risk, and recently, the gut microbial metabolite trimethylamine N-oxide (TMAO) was found in cerebrospinal fluid (CSF) and linked to CSF biomarkers of AD. Because TMAO is largely derived from dietary sources of choline, carnitine, and betaine, we examined whether these precursors drive the association between TMAO and sTREM2, a marker for glial activation. Additionally, TMAO has been found to inhibit cholesterol metabolism, a strong risk factor for AD, which is further dysregulated by the APOE4 allele. Therefore, we aimed to determine whether TMAO-glial activation relationships are moderated by APOE4 carrier status.Participants from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center provided CSF samples (n=570, Table 1). sTREM2 and YKL-40 biomarkers were measured with the exploratory Roche NeuroToolKit assays, a panel of robust prototype immunoassays (Roche Diagnostics International Ltd). TMAO, carnitine, choline, and betaine relative abundance were obtained using Metabolon's UHPLC-MS/MS metabolomics platform. A subset of participants (n=159) completed the MIND diet questionnaire. Metabolite and biomarker levels were log-transformed for analysis; models were adjusted for age, sex, and APOE4 carrier status. Linear regression tested associations between intake of TMAO precursor-containing foods (red meat, butter, cheese, fish) and CSF levels of each TMAO precursor. Path analysis with Satorra-Bentler adjustments tested whether TMAO mediated precursor-biomarker relationships. Linear regression tested whether APOE4 carrier status moderated TMAO-biomarker relationships.Red meat and cheese consumption predicted levels of CSF carnitine (βs=0.009, -0.017; ps=0.0609, 0.0007; Figure 1 A, B; respectively). TMAO mediated the relationship between carnitine and sTREM2, although effects were marginal; several individual relationships throughout both path models showed strong associations (Tables 2, 3; Figures 2, 3). APOE4 carrier status did not significantly moderate TMAO-glial activation relationships.This study suggests that CSF carnitine reflects dietary intake, and may drive the TMAO-sTREM2 association previously identified. Future studies in animal models are required to confirm these results mechanistically.

Exploring the Mechanisms of Anti‐Aβ42 Aggregation Activity of Walnut‐derived Peptides using Transcriptomics and Proteomics in vitro

Inhibiting β‐amyloid (Aβ) aggregation is of significance in finding potential candidates for Alzheimer's disease (AD) treatment. Accumulating evidence suggests that nutrition is important for improving cognition and reducing AD risk. Walnut has been widely used as a functional food for brain health; however the underlying mechanisms remain unknown. Here, we investigated the molecular level alteration in Arctic mutant Aβ42 induced aggregation cell model by RNA‐seq and iTRAQ approaches after walnut‐derived peptides Pro‐Pro‐Lys‐Asn‐Trp (PW5) and Trp‐Pro‐Pro‐Lys‐Asn (WN5) interventions. PW5 or WN5 could significantly decrease abnormal Aβ42 aggregates. However, resultant alterations in transcriptome (substantially unchanged) were inconsistent with proteomic data (marked change). Proteomic analysis revealed 184 and 194 differentially expressed proteins unique to PW5 and WN5 treatment, respectively, for inhibiting Aβ42 protein production or increasing protein degradation via the mismatch repair pathways. Our study provides new insights into the effectiveness of food‐derived peptides for anti‐Aβ42 aggregation in AD.

Preventing Alzheimer's disease within reach by 2025: Targeted-risk-AD-prevention (TRAP) strategy.

IntroductionAlzheimer's disease (AD) is a progressive neurodegenerative disease that currently affects 6.2 million people in the United States and is projected to impact 12.7 million worldwide in 2050 with no effective disease‐modifying therapeutic or cure. In 2011 as part of the National Alzheimer's Project Act, the National Plan to Address Alzheimer's Disease was signed into law which proposed to effectively prevent AD by 2025, which is rapidly approaching. The preclinical phase of AD can begin 20 years prior to diagnosis, which provides an extended window for preventive measures that would exert a transformative impact on incidence and prevalence of AD.MethodsA novel combination of text‐mining and natural language processing strategies to identify (1) AD risk factors, (2) therapeutics that can target risk factor pathways, and (3) studies supporting therapeutics in the PubMed database was conducted. To classify the literature relevant to AD preventive strategies, a relevance score (RS) based on STRING (search tool for the retrieval of interacting genes/proteins) score for protein–protein interactions and a confidence score (CS) on Bayesian inference were developed. To address mechanism of action, network analysis of protein targets for effective drugs was conducted. Collectively, the analytic approach, referred to as a targeted‐risk‐AD‐prevention (TRAP) strategy, led to a ranked list of candidate therapeutics to reduce AD risk.ResultsBased on TRAP mining of 9625 publications, 364 AD risk factors were identified. Based on risk factor indications, 629 Food and Drug Administration‐approved drugs were identified. Computation of ranking scores enabled identification of 46 relevant high confidence (RS & CS > 0.7) drugs associated with reduced AD risk. Within these candidate therapeutics, 16 had more than one clinical study supporting AD risk reduction. Top‐ranked therapeutics with high confidence emerged within lipid‐lowering, anti‐inflammatory, hormone, and metabolic‐related drug classes.DiscussionOutcomes of our novel bioinformatic strategy support therapeutic targeting of biological mechanisms and pathways underlying relevant AD risk factors with high confidence. Early interventions that target pathways associated with increased risk of AD have the potential to support the goal of effectively preventing AD by 2025.

Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.

Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. To develop effective therapies, we should establish the causal link between serum calcium levels and AD. Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.

Education Research: Online Alzheimer education for high school and college students: A randomized controlled trial.

Alzheimer disease (AD) risk factors are present throughout the lifespan. This randomized controlled trial evaluated the effectiveness of various online education strategies concerning AD risk reduction and brain health in younger populations. High school and college students were recruited via social media (Facebook and Instagram) to join AlzU.org, an evidence-based education portal, and were randomized to 1 of 4 courses: highly interactive webinar lessons narrated by actor Seth Rogen (celebrity webinar) or a physician (doctor webinar), minimally interactive video lessons with Seth Rogen (celebrity video), or minimally interactive video lessons (control). Surveys were administered at baseline and postcourse. The primary outcome was change in knowledge of AD risk reduction assessed by pre vs post lesson quiz scores. Secondary outcomes included change in awareness of AD research, hopefulness about AD, interest in pursuing health care, willingness to volunteer, and likelihood of recommending AlzU.org. A total of 721 participants joined. A total of 281 (38.9%) completed the course. Among college students, quiz score improvements were greater in celebrity webinar and celebrity video vs doctor webinar and control. Among high school students, no differences were found in quiz scores. In both groups, celebrity webinar, celebrity video, and doctor webinar resulted in greater improvements in awareness that nutrition and exercise may reduce AD risk vs controls. Among college students, celebrity webinar and celebrity video group participants felt more hopeful about the future of AD and more likely to recommend AlzU.org vs doctor webinar and control participants. Among college students, celebrity webinar, celebrity video, and doctor webinar participants were more willing to volunteer for AD causes and pursue health care careers vs controls. Online education involving a celebrity may be an effective strategy for educating college students about AD risk reduction strategies. Further studies are warranted in high school students.

Repetitive negative thinking is associated with amyloid, tau, and cognitive decline.

The Cognitive Debt hypothesis proposes that repetitive negative thinking (RNT), a modifiable process common to many psychological risk factors for Alzheimer's disease (AD) may itself increase risk. We sought to empirically examine relationships between RNT and markers of AD, compared with anxiety and depression symptoms. Two hundred and ninety-two older adults with longitudinal cognitive assessments, including 113 with amyloid-positron emission tomography (PET) and tau-PET scans, from the PREVENT-AD cohort and 68 adults with amyloid-PET scans from the IMAP+ cohort were included. All participants completed RNT, anxiety, and depression questionnaires. RNT was associated with decline in global cognition (P = .02); immediate (P = .03) and delayed memory (P = .04); and global amyloid (PREVENT-AD: P = .01; IMAP+: P = .03)and entorhinal tau (P = .02) deposition. Relationships remained after adjusting for potential confounders. RNT was associated with decline in cognitive domains affected early in AD and with neuroimaging AD biomarkers. Future research could investigate whether modifying RNT reduces AD risk.

Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4

Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear. To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4. This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019. The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling. Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04). The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults

Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear. To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism. This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses. Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes. Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms. The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk. ClinicalTrials.gov Identifier: NCT02977819.