APOE Genotype Research Articles

Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease

BackgroundLate-onset Alzheimer’s disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined.MethodsIn-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted.ResultsThe relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-β binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia.ConclusionThis study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development.

Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.

Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study

BackgroundApolipoprotein-E (APOE) genetic testing for Alzheimer’s disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one’s genetic risk for Alzheimer’s disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment.MethodsAn online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran’s Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios.ResultsMost participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77–89%), would participate in medication trials (79–88%), and would make long-term arrangements, e.g. retirement, health care, will (69–82%), with larger proportions for scenarios with higher hypothetical genetic risk.ConclusionsOur findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.

Linking alcohol use to Alzheimer’s disease: Interactions with aging and APOE along immune pathways

Although it is known that APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), AD development is a multifactorial process. Alcohol use is a contributor to the epidemic of AD and related dementias in the US and globally, yet mechanisms are not fully understood. Carriers of the APOE ε4 allele show elevated risk of dementia in relation to several lifestyle factors, including alcohol use. In this review, we describe how alcohol interacts with APOE genotype and aging with potential implications for AD promotion. Age-related immune senescence and “inflammaging” (i.e., low-grade inflammation associated with aging) are increasingly recognized as contributors to age-related disease. We focus on three immune pathways that are likely contributors to AD development, centering on alcohol and APOE genotype interactions, specifically: 1) microbial translocation and immune activation, 2) the senescence associated secretory phenotype (SASP), and 3) neuroinflammation. First, microbial translocation, the unphysiological movement of gut products into systemic circulation, elicits a proinflammatory response and increases with aging, with proposed links to AD. Second, the SASP is a set of intercellular signaling factors, e.g., proinflammatory cytokines and chemokines, growth regulators, and proteases, that drives cellular aging when senescent cells remain metabolically active. The SASP can drive development of aging-diseases such as AD. Third, neuroinflammation occurs via numerous mechanisms such as microglial activation and is gaining recognition as an etiological factor in the development of AD. This review focuses on interactions of alcohol with APOE genotype and aging along these three pathways that may promote AD. Further research on these processes may inform development of strategies to prevent onset and progression of AD and to delay associated cognitive decline.

Low serum HDL-cholesterol is associated with increased risk of the subcortical small vessel type of dementia

BackgroundThere are conflicting results whether serum lipid pattern is related to the amount of white matter hyperintensities (WMHs) on magnetic resonance imaging. Little is known of the associations between lipid concentrations and the subsequent risk of the subcortical small vessel type of dementia (SSVD), in which WMHs are a prominent manifestation. Here, we determined whether lipid levels are associated with the risk of SSVD, Alzheimer's disease (AD), or mixed dementia (combined AD and SSVD). MethodsThis was a longitudinal, prospective study of 329 patients with subjective or objective mild cognitive impairment at baseline. The statistical analyses included Cox proportional hazards regression with adjustments for age, gender, education, body mass index, current smoking, hypertension, diabetes mellitus, and APOE ε4 genotype. ResultsDuring the follow-up (mean 4.1 years), 80 patients converted to dementia [SSVD, n = 15 (5 %); AD, n = 39 (12 %); and mixed dementia, n = 26 (8 %)]. Serum high-density lipoprotein cholesterol (HDL, per SD increase) was inversely associated with the risk of SSVD, whereas triglycerides (TG), low-density lipoprotein cholesterol (LDL)/HDL ratio, and TG/HDL ratio were positively associated with SSVD risk. Furthermore, the lowest HDL tertile was associated with a sevenfold, and the highest tertile of TG/HDL ratio with a threefold, increase in SSVD risk. There were no associations with the risk of AD or mixed dementia after adjustment for covariates. ConclusionIn a memory clinic population, low HDL and high TG/HDL ratio were independent risk factors of SSVD, but not of AD or mixed dementia.

Does Physical Exercise Modify the Pathophysiology of Alzheimer's Disease in Older Persons?

Physical exercise is well known for its benefits on brain health. However, the mechanisms through which these benefits occur remain discussed, especially in the context of cognitive conditions such as Alzheimer's disease. The present short review summarizes the findings of interventional studies that examined the effects of exercise training on the specific and non-specific biomarkers of Alzheimer's disease. Controlled exercise intervention studies published in the English language were selected if they assessed the effects of a physical exercise intervention of at least 2 weeks in middle-aged or older adults on one of the following biomarkers measured either in the brain, the cerebrospinal fluid or the blood: beta-amyloid, tau, neurofilament light chain, and glial fibrillary acidic protein. Overall, there was no strong evidence of significant effects of exercise interventions on any of the selected biomarkers. However, in specific populations, such as women with obesity, pre-diabetes, or depression, favorable changes in blood beta-amyloid concentrations were reported. Further benefits on cerebrospinal fluid beta-amyloid were also demonstrated in APOE-ε4 allele carriers with Alzheimer's disease. In conclusion, the current evidence suggests that physical exercise does not modulate the pathophysiology of Alzheimer's disease in the overall population of middle-aged and older adults. Nonetheless, some specific populations, such as women with metabolic disorders and Alzheimer's disease patients with APOE-ε4 genotype, seem to be favorably affected. Further studies, including long follow-ups, large sample sizes, and concomitantly assessing the effects of other factors such as sedentary behavior and diet, are required to bring further evidence to the field.

Effect of matcha green tea on cognitive functions and sleep quality in older adults with cognitive decline: A randomized controlled study over 12 months.

Lifestyle habits after middle age significantly impact the maintenance of cognitive function in older adults. Nutritional intake is closely related to lifestyle habits; therefore, nutrition is a pivotal factor in the prevention of dementia in the preclinical stages. Matcha green tea powder (matcha), which contains epigallocatechin gallate, theanine, and caffeine, has beneficial effects on cognitive function and mood. We conducted a randomized, double-blind, placebo-controlled clinical study over 12 months to examine the effect of matcha on cognitive function and sleep quality. Ninety-nine participants, including 64 with subjective cognitive decline and 35 with mild cognitive impairment were randomized, with 49 receiving 2 g of matcha and 50 receiving a placebo daily. Participants were stratified based on two factors: age at baseline and APOE genotype. Changes in cognitive function and sleep quality were analyzed using a mixed-effects model. Matcha consumption led to significant improvements in social acuity score (difference; -1.39, 95% confidence interval; -2.78, 0.002) (P = 0.028) as evaluated by the perception of facial emotions in cognitive function. The primary outcomes, that is, Montreal Cognitive Assessment and Alzheimer's Disease Cooperative Study Activity of Daily Living scores, showed no significant changes with matcha intervention. Meanwhile, Pittsburgh Sleep Quality Index scores indicated a trend toward improvement with a difference of 0.86 (95% confidence interval; -0.002, 1.71) (P = 0.088) between the groups in changes from baseline to 12 months. The present study suggests regular consumption of matcha could improve emotional perception and sleep quality in older adults with mild cognitive decline. Given the widespread availability and cultural acceptance of matcha green tea, incorporating it into the daily routine may offer a simple yet effective strategy for cognitive enhancement and dementia prevention.

Traffic-related air pollution and dementia incidence in the Adult Changes in Thought Study

BackgroundWhile epidemiologic evidence links higher levels of exposure to fine particulate matter (PM2.5) to decreased cognitive function, fewer studies have investigated links with traffic-related air pollution (TRAP), and none have examined ultrafine particles (UFP, ≤100 nm) and late-life dementia incidence. ObjectiveTo evaluate associations between TRAP exposures (UFP, black carbon [BC], and nitrogen dioxide [NO2]) and late-life dementia incidence. MethodsWe ascertained dementia incidence in the Seattle-based Adult Changes in Thought (ACT) prospective cohort study (beginning in 1994) and assessed ten-year average TRAP exposures for each participant based on prediction models derived from an extensive mobile monitoring campaign. We applied Cox proportional hazards models to investigate TRAP exposure and dementia incidence using age as the time axis and further adjusting for sex, self-reported race, calendar year, education, socioeconomic status, PM2.5, and APOE genotype. We ran sensitivity analyses where we did not adjust for PM2.5 and other sensitivity and secondary analyses where we adjusted for multiple pollutants, applied alternative exposure models (including total and size-specific UFP), modified the adjustment covariates, used calendar year as the time axis, assessed different exposure periods, dementia subtypes, and others. ResultsWe identified 1,041 incident all-cause dementia cases in 4,283 participants over 37,102 person-years of follow-up. We did not find evidence of a greater hazard of late-life dementia incidence with elevated levels of long-term TRAP exposures. The estimated hazard ratio of all-cause dementia was 0.98 (95 % CI: 0.92–1.05) for every 2000 pt/cm3 increment in UFP, 0.95 (0.89–1.01) for every 100 ng/m3 increment in BC, and 0.96 (0.91–1.02) for every 2 ppb increment in NO2. These findings were consistent across sensitivity and secondary analyses. DiscussionWe did not find evidence of a greater hazard of late-life dementia risk with elevated long-term TRAP exposures in this population-based prospective cohort study.

The association between APO-E genotype and inflammation and the risk of premature CHD in smokers versus non-smokers

The association between APO-E genotype and inflammation and the risk of premature CHD in smokers versus non-smokers

APOE 5'UTR Methylation Pattern Analysis in Blood and Brain Tissue from Alzheimer's Disease Affected Patients.

APOE ε4 allele is the major genetic risk factor for Alzheimer's Disease (AD). Furthermore, APOE methylation pattern has been described to be associated with the disease and to follow a bimodal pattern, with a hypermethylated CpG island and a hypomethylated promoter region. However, little is known about the methylation levels in the APOE 5'UTR region. Here, the methylation of two regions (R1 and R2) within APOE 5'UTR was investigated in both peripheral blood mononuclear cells (PBMCs) and hippocampus (HIC) samples to identify differentially methylated CpG sites and to associate clinical, genetic features and cerebrospinal fluid (CSF) biomarkers levels. DNA was extracted from PBMCs of 20 AD and 20 healthy controls (HC) and from 6 AD and 3 HC HIC samples. The methylation analysis was carried out by means of pyrosequencing. In AD PBMCs we found that R1 region displayed a higher methylation level, while the opposite trend was observed in R2. The presence of ε4 allele highlighted a marked increase in R1 methylation level and a decrease in R2. In AD PBMCs and HIC, age progression resulted to be associated with an increase in the methylation level of R1. Lastly, the methylation of a CpG site in R2 was found to be related to CSF biomarkers. Despite the lack of a statistical significance, the outcome from this exploratory analysis highlighted the presence of a difference in methylation in APOE 5'UTR in PBMCs of AD patients which seemed to be associated also with APOE genotype, age and CSF biomarkers level.

Predicting the apolipoprotein E ε4 allele carrier status based on gray matter volumes and cognitive function.

Apolipoprotein E (ApoE) ε4 carriers have a higher risk of developing Alzheimer's disease (AD) and show brain atrophy and cognitive decline even before diagnosis. To predict ApoE ε4 status using gray matter volume (GMV) obtained from magnetic resonance imaging images and demographic data with machine learning (ML) methods. We recruited 74 participants (25 probable AD, 24 amnestic mild cognitive impairment, and 25 cognitively normalolder people) with known ApoE genotype (22 ApoE ε4 carriers and 52 noncarriers) and scanned them with three-dimensional (3D) T1-weighted (T1W) and 3D double inversion recovery (DIR) sequences. We extracted GMV from regions of interestrelated to AD pathology and used them as features along with age and mini-mental state examination (MMSE) scores to train different ML models. We performed both receiver operating characteristiccurve analysis and the prediction analysis of the ApoE ε4 carrier with different ML models. The best model of ML analyses was a cubic support vector machine (SVM3) that used age, the MMSE score, and DIR GMVs at the amygdala, hippocampus, and precuneus as features (AUC=.88). This model outperformed models using T1W GMV or demographic data alone. Our results suggest that brain atrophy with DIR GMV and cognitive decline with aging can be useful biomarkers for predicting ApoE ε4 status and identifying individuals at risk of AD progression.

Modulation of Bone Mineral Density and Its Response to Menopausal Hormone Therapy according to the Apolipoprotein E Genotype in Postmenopausal Korean Women.

Genetic factors are a major cause of osteoporosis. The present study evaluated the association of the apolipoprotein E (ApoE) genotype with bone mineral density (BMD) and its response to menopausal hormone therapy (MHT) in postmenopausal Korean women. This retrospective cohort study included 172 postmenopausal women with no endocrine diseases, medications, or lifestyles that would affect bone metabolism and who were continuously treated with MHT for at least 2 years. BMDs were measured at baseline and periodically. Linear regression analysis demonstrated similar baseline BMDs at the lumbar spine, but significantly lower at the femur neck and total hip in the ApoE ε4 carrier than in the noncarrier group, after controlling for age, body mass index, and history of MHT usage. Overall, the Wilcoxon signed rank test demonstrated that MHT increased the BMD percentage change at all three regions, and the Generalized Estimating Equation (GEE) demonstrated significant time trends at the lumbar spine and femur neck. ApoE ε4 noncarriers exhibited a significant time trend in BMD changes at the femur neck, whereas ε4 carriers exhibited a time trend at the lumbar spine. However, BMD changes at each time point were comparable at all regions between the groups. Notably, GEE adjusted for baseline characteristics and BMD revealed a significant interaction effect of time and ApoE ε4 allele in BMD changes at the femur neck. Postmenopausal Korean women carrying the ApoE ε4 allele demonstrated a lower hip BMD compared with ε4 noncarriers. Furthermore, the ε4 allele may modulate hip BMD responses to MHT.

Specific vegetable types are associated with lower long-term risk for late-life dementia: the Perth Longitudinal Study of Aging Women.

This study examined the relationship between total vegetable intake, including specific vegetable types with long-term late-life dementia (LLD) risk in older Australian women. 1206 community-dwelling older women aged ≥70 years were included. Consumption of total vegetable intake and vegetable types (yellow/orange/red [YOR], cruciferous, allium, green leafy vegetables [GLV], and legumes) were estimated using a validated food frequency questionnaire at baseline (1998). LLD was considered any form of dementia occurring after 80 years of age. LLD events (comprising hospitalisation and/or death) were obtained from linked health records. Associations were examined using restricted cubic splines within multivariable-adjusted (including APOE4 genotype) Cox proportional hazard models. Over 14.5 years of follow-up (∼15 134 person-years) there were 207 (17.2%) LLD events, 183 (15.25%) with LLD hospitalisations and 83 (6.9%) with LLD deaths. Compared to women in the lowest Quartile (Q1) of total vegetable intake, those with higher intakes (Q3, but not Q4) had 39% lower hazard for a LLD death. Compared to Q1, women in the highest quartile of YOR intake (Q4) consistently recorded lower hazards for a LLD event (47%), hospitalisation (46%), and death (50%). Similarly, women with the highest allium intake (Q4), had lower hazards for LLD events (36%) and deaths (49%), compared to Q1. Women with the highest GLV intake (Q4) also recorded 45% lower hazards for a LLD death. Whilst total vegetable intake may be important, allium, GLV and especially YOR vegetables may be most beneficial when considering LLD risk. These results require further validation in other cohorts, including men. The clinical trial registry numbers are https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368778&isReview=true, CAIFOS: ACTRN12615000750583, and https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372818&showOriginal=true&isReview=true, PLSAW: ACTRN12617000640303.

Effects of the ApoE genotype on cognitive function in aging mice fed with a high-fat diet and the protective potential of n-3 polyunsaturated fatty acids.

The ApoE4 allele is the strongest genetic determinant for Alzheimer's disease (AD), while obesity is a strong environmental risk for AD. The modulatory effect of the ApoE genotype on aging-related cognitive function in tandem with a high-fat diet (HFD) remains uncertain. This study aimed to elucidate the effects of ApoE3/ApoE4 genotypes in aged mice exposed to a HFD, and the benefits of n-3 polyunsaturated fatty acids (PUFAs) from fish oil. Remarkably, the HFD led to weight gain and lipid accumulation, more pronounced in ApoE3 mice, while ApoE4 mice experienced exacerbated cerebral insulin resistance, neuroinflammation, and oxidative stress. Critically, n-3 PUFAs modulated the cerebral insulin signaling via the IRS-1/AKT/GLUT4 pathway, mitigated microglial hyperactivity, and reduced IL-6 and MDA levels, thereby counteracting cognitive deficits. These findings highlight the contrasting impacts of ApoE genotypes on aging mice exposed to a HFD, supporting n-3 PUFAs as a strategic nutritional intervention for brain health, especially for ApoE4 carriers.

Design and Rationale of a Two-Armed Randomized Controlled Trial on Yoga/Brisk Walking-Based Lifestyle Modification on Dementia Risk Reduction, and Influence of ApoE Genotypes on the Intervention.

Though considered a late-onset disease, the 2020 report of the Lancet Commission emphasizes the necessity of conducting primary prevention trials with an approach of never too early in the life course for dementia prevention. Driven by the same notion, we hereby aim to compare the dementia risk reduction potential of two potential interventions, 48 weeks (12 months) of yoga and brisk walking, in middle-aged high-risk subjects. A randomized controlled trial. Community in India. In total, 323 at-risk dementia subjects will be recruited from community settings through health awareness camps and door-to-door surveys across Delhi, India. Participants will be randomized into yoga or brisk-walking groups (1:1). The yoga intervention group will receive 60 contact yoga sessions per 60-min/day at the community parks, followed by continued tele-supervised home practice, further followed by at-home self-practice, and will be tested at 3-time points (baseline, 24-week and 48-week, post-randomization) to test the efficacy of the intervention. The control group will be asked to do brisk walking daily for 45 minutes at their convenience, followed by weekly telephone follow-ups. Applying the intention-to-treat principle, the primary endpoint will be the change from baseline at the 12th month in the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) Scores. Secondary outcomes will include the composite scores derived from a comprehensive neuropsychology battery, comprising the Trail Making Test, Digit Span Test, N Back, Color Trail, Animal Fluency Test, COWA (Controlled Oral Word Association Test), and Digit Symbol Substitution. The primary outcome will be analyzed using mixed-effect models for repeated measures, adjusted for covariates as fixed effects. The study has been prospectively registered (CTRI/2023/02/049746) on February 15, 2023. The protocol was conceptualized in 2021 and approved by the Institutional Ethics Committee of SVYASA. Recruitment began in February 2023 and is underway with patient enrollment. To our knowledge, this is the first controlled trial to investigate the longitudinal effects of a yoga-based intervention on dementia risk reduction using the CAIDE risk score. The findings of this trial will also provide insight into a better understanding of genotype-dependent responses to yoga intervention and open up avenues for understanding the implications of gene-intervention interactions for precision prevention using yoga.

An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains

The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.

Plasma neurofilament light chain associated with impaired regional cerebral blood flow in healthy individuals.

Background: Recent findings suggest that the plasma axonal structural protein, neurofilament light (NFL) chain, may serve as a potential blood biomarker for early signs of neurodegenerative diseases, such as Alzheimer's disease (AD). Given the need for early detection of neurodegenerative disorders, the current study investigated the associations between regional cerebral blood flow (rCBF) in brain regions associated with neurodegenerative disorders and memory function with plasma NFL in AD, mild cognitive impairment (MCI), and healthy controls (HCs). Methods: We recruited 29 AD, 76 MCI, and 39 HCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database in the current cross-sectional study. We used Pearson's correlation models adjusted for the effect of age, sex, and APOE genotype to investigate the association between plasma NFL and rCBF. Results: We found non-significant differences in age (F(2, 141) = 1.304; P = 0.275) and years of education (F(2, 141) = 0.013; P = 0.987). Additionally, we found significant differences between groups in terms of MMSE scores (F(2, 141) = 100.953; P < 0.001). Despite the observation of significantly reduced rCBF in AD and MCI groups versus HCs, we did not detect significant differences in plasma NFL between these groups. We found significant negative associations between plasma NFL and rCBF in various AD-related regions, these findings were only observed after analyses in all participants, and were observed in HCs alone and no significant associations were observed in the AD or MCI groups. Conclusion: These outcomes add to our current understanding surrounding the use of rCBF and plasma NFL biomarkers as tools for early detection and diagnosis of neurodegenerative diseases. A conclusion might be that the association between NFL and impaired rCBF exists before the clinical symptoms appear. Further longitudinal studies with a large sample size should be performed to examine the correlation between plasma NFL and rCBF in order to understand these complex relationships.

A Genome-Wide Interaction Study of Erythrocyte ω-3 Polyunsaturated Fatty Acid Species and Memory in the Framingham Heart Study Offspring Cohort

BackgroundCognitive decline, and more specifically Alzheimer’s disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized in the diagnosis of cognitive decline that assess executive function, short- and long-term memory, cognitive flexibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids. ObjectivesWe aimed to examine the potential moderating effect of main species of ω-3 polyunsaturated fatty acids (PUFAs) on an individual’s genetically conferred risk of cognitive decline. MethodsThe Offspring cohort from the Framingham Heart Study was cross-sectionally analyzed in this genome-wide interaction study (GWIS). Our sample included all individuals with red blood cell ω-3 PUFA, genetic, cognitive testing (via Trail Making Tests [TMTs]), and covariate data (N = 1620). We used linear mixed effects models to predict each of the 3 cognitive measures (TMT A, TMT B, and TMT D) by each ω-3 PUFA, single nucleotide polymorphism (SNP) (0, 1, or 2 minor alleles), ω-3 PUFA by SNP interaction term, and adjusting for sex, age, education, APOE ε4 genotype status, and kinship (relatedness). ResultsOur analysis identified 31 unique SNPs from 24 genes reaching an exploratory significance threshold of 1×10-5. Fourteen of the 24 genes have been previously associated with the brain/cognition, and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identified, DAB1, SORCS2, SERINC5, OSBPL3, CPA6, DLG2, MUC19, and RGMA, have been associated with both cognition and circulating lipids. We identified 22 unique SNPs for which individuals with the minor alleles benefit substantially from increased ω-3 fatty acid concentrations and 9 unique SNPs for which the common homozygote benefits. ConclusionsIn this GWIS of ω-3 PUFA species on cognitive outcomes, we identified 8 unique genes with plausible biology suggesting individuals with specific polymorphisms may have greater potential to benefit from increased ω-3 PUFA intake. Additional replication in prospective settings with more diverse samples is needed.

Genetic epidemiology of monogenic dyslipidemia and statin-associated adverse drug phenotypes in Indian population from whole-genomes of 1029 self-declared healthy individuals

BackgroundMonogenic dyslipidemia is a group of inherited genetic disorders characterized by abnormal levels of lipids and lipoproteins in blood, contributing to a significant risk for coronary artery diseases (CAD) and stroke. There is a paucity of prevalence estimates and genetic epidemiology of monogenic dyslipidemia in South Asian populations. The availability of population-scale genome sequencing datasets could potentially enable a better understanding of the genetic epidemiology of the disease. MethodsWe analyzed whole-genome sequence data of 1029 healthy individuals from India to identify pathogenic variants in 24 genes associated with 26 primary monogenic dyslipidemias. The American College of Medical Genetics and Genomics (ACMG) guidelines was used to classify the variants. We also inferred statin-associated adverse drug phenotypes from SLCO1B1, ABCG2, and CYP2C9 genotypes/haplotypes. ResultsOur analysis identified 12 pathogenic (P) and 9 likely pathogenic (LP) variants in 10 different genes. Autosomal dominant monogenic dyslipidemia prevalence ranged from 0.1% to 0.9%, while autosomal recessive disorder ranged from 0.000005% and 0.0005%. An infrequent ε4/ε4 APOE genotype associated with hypercholesterolemia was found in 1% of samples. Our pharmacogenomic analysis revealed that 10% may require reduced dosage for most statins including atorvastatin, and 1.5% may require reduced dosage for rosuvastatin. ConclusionOur study emphasizes the need for population-scale screening to enable early diagnosis and appropriate treatment of monogenic dyslipidemia in India. By identifying variants and estimating prevalence, our findings can inform healthcare providers in developing targeted prevention and management strategies to reduce cardiovascular disease risk.

SUBJECTIVE COGNITIVE CONCERNS AND 5-YEAR NEUROPSYCHOLOGICAL TRAJECTORIES IN PARKINSON’S DISEASE

Abstract Subjective cognitive concerns (SCC) are often associated with Alzheimer’s disease (AD)-related cognitive declines in cognitively unimpaired (CU) individuals. However, it is unknown whether the same is true for CU individuals with Parkinson’s disease (PD). Therefore, this study examined relationships between SCC and 5-year neuropsychological trajectories in CU individuals with newly-diagnosed PD (mean age=60.45 years; 35.2% female) in the Parkinson’s Progression Markers Initiative (PPMI) cohort. Participants were classified as having SCC (n=52) or no SCC (n=204) based on participant or caregiver report for item 1 on the Unified Parkinson’s Disease Rating Scale, part 1. First, baseline cerebrospinal fluid (CSF) biomarkers were examined by SCC group. Next, linear mixed effects models, adjusting for age, education, sex/gender, APOE genotype, psychiatric factors, and motor symptoms examined 5-year trajectories of individual neuropsychological measures by SCC status. Relative to participants without SCC, those with SCC had worse levels of CSF tau (p=.011), p-tau (p=.016), and p-tau/amyloid ratio (p=.003), but not amyloid or alpha synuclein. SCC was associated with faster rates of decline in learning (β=-.059, p=.018), memory (β=-.050, p=.035), and processing speed (β=-.052, p=.031), but not in semantic fluency, visuoperceptual abilities, working memory, or on a global cognition screening measure. Overall, SCC was associated with learning/memory and processing speed declines, but not other measures that may be more PD-specific (e.g., working memory, visuoperceptual). Given the elevated AD biomarkers, SCC may be particularly related to early changes due to co-occurring AD and PD pathology. Future work should investigate longitudinal AD and PD-related biomarker trajectories by SCC status.