Family history aggregation unit-based tests to detect rare genetic variant associations with application to the Framingham Heart Study.

A challenge in standard genetic studies is maintaining good power to detect associations, especially for low prevalent diseases and rare variants. The traditional methods are most powerful when evaluating the association between variants in balanced study designs. Without accounting for family correlation and unbalanced case-control ratio, these analyses could result in inflated type I error. One cost-effective solution to increase statistical power is exploitation of available family history (FH) that contains valuable information about disease heritability. Here, we develop methods to address the aforementioned type I error issues while providing optimal power to analyze aggregates of rare variants by incorporating additional information from FH. With enhanced power in these methods exploiting FH and accounting for relatedness and unbalanced designs, we successfully detect genes with suggestive associations with Alzheimer disease, dementia, and type 2 diabetes by using the exome chip data from the Framingham Heart Study.

Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer.

SNPs associated with human stroke risk have been identified in the intergenic region between Forkhead family transcription factors FOXF2 and FOXQ1, but we lack a mechanism for the association. FoxF2 is expressed in vascular mural pericytes and is important for maintaining pericyte number and stabilizing small vessels in zebrafish. The stroke-associated SNPs are located in a previously unknown transcriptional enhancer for FOXF2, functional in human cells and zebrafish. We identify critical enhancer regions for FOXF2 gene expression, including binding sites occupied by transcription factors ETS1, RBPJ, and CTCF. rs74564934, a stroke-associated SNP adjacent to the ETS1 binding site, decreases enhancer function, as does mutation of RPBJ sites. rs74564934 is significantly associated with the increased risk of any stroke, ischemic stroke, small vessel stroke, and elevated white matter hyperintensity burden in humans. Foxf2 has a conserved function cross-species and is expressed in vascular mural pericytes of the vessel wall. Thus, stroke-associated SNPs modulate enhancer activity and expression of a regulator of vascular stabilization, FOXF2, thereby modulating stroke risk.

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Impaired Kidney Function, Cerebral Small Vessel Disease and Cognitive Disorders: The Framingham Heart Study.

BACKGROUND AND HYPOTHESIS: It remains unclear if the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD) and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. METHODS: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain MRI late in life (exam cycles 7-9), cognitive outcome data and available interim hypertension and blood pressure assessments. We related CKD (estimated glomerular filtration rate < 60 ml/min/1.73m2) and albuminuria (urine albumin-to-creatinine ratio ≥ 30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses. RESULTS: Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD and 9% albuminuria), albuminuria was independently associated with covert infarcts (adjusted OR, 1.55 [1.00-2.38]; P = 0.049) and incident MCI and dementia (adjusted HR, 1.68 [1.18-2.41]; P = 0.005 and 1.71, [1.11-2.64]; P = 0.015, respectively). CKD was not associated with CSVD markers but was associated with higher risk of incident dementia (HR, 1.53 [1.02-2.29]; P = 0.041), While albuminuria was predictive of the Alzheimer's disease subtype (Adjusted HR = 1.68, [1.03-2.74]; P = 0.04), CKD was predictive of vascular dementia (Adjusted HR, 2.78, [1.16-6.68]; P = 0.023). CONCLUSIONS: Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond blood pressure related injury.

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration.

BACKGROUND AND PURPOSE: Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. METHODS: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. RESULTS: In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (ß = -3.5, 95% confidence interval [CI] = -5.4 to -1.7), total gray matter (ß = -1.9, 95% CI = -3.4 to -0.3), and total cortical gray matter (ß = -1.9, 95% CI = -3.7 to -0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (ß = -7.3, 95% CI = -11.1 to -3.5). Heterogeneity between studies was low. CONCLUSIONS: NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

The association between levels of brain-derived neurotrophic factor and comorbid depression in patients with cardiovascular disease: The Framingham Heart Study.

AIM: The current study aims to investigate the association of serum brain-derived neurotrophic factor (BDNF) levels with symptoms of depression in adults with and without prevalent cardiovascular disease (CVD), an often burdensome comorbidity. METHODS: This cross-sectional study included participants from FHS (Framingham Heart Study) who had available serum BDNF levels. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression Scale (CES-D) with a score ≥16 indicating mild to moderate and ≥21 severe depression. Participants taking antidepressant medications were excluded from the study. RESULTS: Altogether 3716 FHS participants were included in the final analysis (mean age, 64.3 ± 11.5 years; 55% women). After adjusting for potential confounders, greater BDNF levels were associated with reduced severe depression risk (odds ratio [OR], 0.78 [95% CI, 0.64-0.96]; P = 0.016). Among participants with CVD, greater BDNF levels were related to lower risk of depressive symptoms (CES-D ≥ 16 OR, 0.63 [95% CI, 0.45-0.89], P = 0.008; CES-D ≥ 21 OR, 0.49 [95% CI, 0.31-0.76], P = 0.002). The inverse relationship between BDNF and depressive symptom risk was present in women with CVD (CES-D ≥ 16 OR, 0.63 [95% CI, 0.40-0.99], P = 0.047; CES-D ≥ 21 OR, 0.38 [95% CI, 0.21-0.70], P = 0.002) but not in men. CONCLUSION: Lower serum BDNF levels are associated with a higher risk of depressive symptoms in CVD, particularly among women. These findings implicate BDNF in the complex biological mechanisms that underlie prior associations observed between CVD and depression. To reduce the burden of depression in the large proportion of midlife and older adults with CVD, a better understanding of how BDNF may modify these pathways is merited.

A novel neuroimaging signature for ADRD risk stratification in the community.

INTRODUCTION: Early risk stratification for clinical dementia could lead to preventive therapies. We identified and validated a magnetic resonance imaging (MRI) signature for Alzheimer's disease (AD) and related dementias (ARDR). METHODS: An MRI ADRD signature was derived from cortical thickness maps in Framingham Heart Study (FHS) participants with AD dementia and matched controls. The signature was related to the risk of ADRD and cognitive function in FHS. Results were replicated in the University of California Davis Alzheimer's Disease Research Center (UCD-ADRC) cohort. RESULTS: Participants in the bottom quartile of the signature had more than three times increased risk for ADRD compared to those in the upper three quartiles (P < 0.001). Greater thickness in the signature was related to better general cognition (P < 0.01) and episodic memory (P = 0.01). Results replicated in UCD-ADRC. DISCUSSION: We identified a robust neuroimaging biomarker for persons at increased risk of ADRD. Other cohorts will further test the validity of this biomarker.

Concurrent nutrient deficiencies are associated with dementia incidence.

INTRODUCTION: While observational research suggests a protective role for nutrition in brain aging, intervention studies remain inconclusive. This failing translation from observational to interventional research may result from overlooking nutrient interactions. METHODS: We developed a nutrient status index capturing the number of suboptimal statuses of omega-3 fatty acids, homocysteine, and vitamin D (range 0 to 3). We associated this index with dementia incidence in a subsample (age ≥ 50 years) of the Framingham Heart Study Offspring cohort. RESULTS: Among 968 participants, 79 developed dementia over 15.5 years (median follow-up). Each point increase in nutrient status index was associated with a 50% higher risk of dementia (hazard ratio [HR] = 1.50; 95% confidence interval [CI] = 1.16, 1.96). Participants with three high-risk statuses had a four-fold increased risk of dementia compared to participants without high-risk status (HR = 4.68; 95% CI = 1.69, 12.94). DISCUSSION: Concurrent nutrient deficiencies are associated with the risk of dementia. The potential of optimizing nutritional status to lower dementia risk warrants further study. HIGHLIGHTS: Nutrition and dementia research calls for multiple-nutrient approaches. We studied combined suboptimal statuses of omega-3 polyunsaturated fatty acids, homocysteine, and vitamin D. Suboptimal status of the three nutrients was associated with dementia risk. The risk estimate was larger than for other factors (ie, diabetes, apolipoprotein E Îµ4 carrier). Future studies should assess the effect of improving nutrient status on dementia risk.

Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos.

INTRODUCTION: We conducted admixture mapping and fine-mapping analyses to identify ancestry-of-origin loci influencing cognitive abilities. METHODS: We estimated the association of local ancestry intervals across the genome with five neurocognitive measures in 7140 diverse Hispanic and Latino adults (mean age 55 years). We prioritized genetic variants in associated loci and tested them for replication in four independent cohorts. RESULTS: We identified nine local ancestry-associated regions for the five neurocognitive measures. There was strong biological support for the observed associations to cognitive function at all loci and there was statistical evidence of independent replication at 4q12, 9p22.1, and 13q12.13. DISCUSSION: Our study identified multiple novel loci harboring genes implicated in cognitive functioning and dementia, and uncovered ancestry-relevant genetic variants. It adds to our understanding of the genetic architecture of cognitive function in Hispanic and Latino adults and demonstrates the power of admixture mapping to discover unique haplotypes influencing cognitive function, complementing genome-wide association studies. HIGHLIGHTS: We identified nine ancestry-of-origin chromosomal regions associated with five neurocognitive traits. In each associated region, we identified single nucleotide polymorphisms (SNPs) that explained, at least in part, the admixture signal and were tested for replication in independent samples of Black, non-Hispanic White, and Hispanic/Latino adults with the same or similar neurocognitive tests. Statistical evidence of independent replication of the prioritized SNPs was observed for three of the nine associations, at chr4q12, chr9p22.1, and chr13q12.13. At all loci, there was strong biological support for the observed associations to cognitive function and dementia, prioritizing genes such as KIT, implicated in autophagic clearance of neurotoxic proteins and on mast cell and microglial-mediated inflammation; SLC24A2, implicated in synaptic plasticity associated with learning and memory; and MTMR6, implicated in phosphoinositide lipids metabolism.

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data.

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study.

BACKGROUND: The remaining lifetime risk (RLR) is the probability of developing an outcome over the remainder of one's lifespan at any given age. The RLR for atherosclerotic cardiovascular disease (ASCVD) in three 20-year periods were assessed using data from a single community-based cohort study of predominantly White participants. METHODS: Longitudinal data from the Framingham study in 3 epochs (epoch 1, 1960-1979; epoch 2, 1980-1999; epoch 3, 2000-2018) were evaluated. The RLR of a first ASCVD event (myocardial infarction, coronary heart disease death, or stroke) from 45 years of age (adjusting for competing risk of death) in the 3 epochs were compared overall, and according to the following strata: sex, body mass index, blood pressure and cholesterol categories, diabetes, smoking, and Framingham risk score groups. RESULTS: There were 317 849 person-years of observations during the 3 epochs (56% women; 94% White) and 4855 deaths occurred. Life expectancy rose by 10.1 years (men) to 11.9 years (women) across the 3 epochs. There were 1085 ASCVD events over the course of 91 330 person-years in epoch 1, 1330 ASCVD events over the course of 107 450 person-years in epoch 2, and 775 ASCVD events over the course of 119 069 person-years in epoch 3. The mean age at onset of first ASCVD event was greater in the third epoch by 8.1 years (men) to 10.3 years (women) compared with the first epoch. The RLR of ASCVD from 45 years of age declined from 43.7% in epoch 1 to 28.1% in epoch 3 (P<0.0001), a finding that was consistent in both sexes (RLR [epoch 1 versus epoch 3], 36.3% versus 26.5% [women]; 52.5% versus 30.1% [men]; P<0.001 for both). The lower RLR of ASCVD in the last 2 epochs was observed consistently across body mass index, blood pressure, cholesterol, diabetes, smoking, and Framingham risk score strata (P<0.001 for all). The RLR of coronary heart disease events and stroke declined in both sexes (P<0.001). CONCLUSIONS: Over the past 6 decades, mean life expectancy increased and the RLR of ASCVD decreased in the community-based, predominantly White Framingham study. The residual burden of ASCVD underscores the importance of continued and effective primary prevention efforts with better screening for risk factors and their effective treatment.

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Deep neural network heatmaps capture Alzheimer's disease patterns reported in a large meta-analysis of neuroimaging studies.

Deep neural networks currently provide the most advanced and accurate machine learning models to distinguish between structural MRI scans of subjects with Alzheimer's disease and healthy controls. Unfortunately, the subtle brain alterations captured by these models are difficult to interpret because of the complexity of these multi-layer and non-linear models. Several heatmap methods have been proposed to address this issue and analyze the imaging patterns extracted from the deep neural networks, but no quantitative comparison between these methods has been carried out so far. In this work, we explore these questions by deriving heatmaps from Convolutional Neural Networks (CNN) trained using T1 MRI scans of the ADNI data set and by comparing these heatmaps with brain maps corresponding to Support Vector Machine (SVM) activation patterns. Three prominent heatmap methods are studied: Layer-wise Relevance Propagation (LRP), Integrated Gradients (IG), and Guided Grad-CAM (GGC). Contrary to prior studies where the quality of heatmaps was visually or qualitatively assessed, we obtained precise quantitative measures by computing overlap with a ground-truth map from a large meta-analysis that combined 77 voxel-based morphometry (VBM) studies independently from ADNI. Our results indicate that all three heatmap methods were able to capture brain regions covering the meta-analysis map and achieved better results than SVM activation patterns. Among them, IG produced the heatmaps with the best overlap with the independent meta-analysis.

Association of Apolipoprotein E ɛ4 Allele with Enlarged Perivascular Spaces.

OBJECTIVE: Enlarged perivascular spaces have emerged as markers of cerebral small vessel disease and are linked to perivascular drainage dysfunction. The apolipoprotein E-ɛ4 (APOE-ɛ4) allele is the strongest genetic risk factor for cerebral amyloid angiopathy and Alzheimer's neuropathology, but the underlying mechanisms remain unclear. We studied the relationship between APOE-ɛ4 and the topography and burden of enlarged perivascular spaces to elucidate underlying mechanisms between APOE-ɛ4 and adverse clinical outcomes. METHODS: We included 3,564 Framingham Heart Study participants with available genotypes and magnetic resonance imaging. Enlarged perivascular spaces in the basal ganglia and centrum semiovale were rated using a validated scale. We related APOE-ɛ4 allele presence to high burden of enlarged perivascular spaces in each region and a mixed score reflecting high burden in both regions using multivariable logistic regression. Exploratory analyses incorporated presence of cerebral microbleeds and assessed effect modification by hypertension. RESULTS: Mean age was 60.7 years (SD = 14.6), 1,644 (46.1%) were men, 1,486 (41.8%) were hypertensive, and 836 (23.5%) participants were APOE-ɛ4 carriers. APOE-ɛ4 was associated with high burden of enlarged perivascular spaces in the centrum semiovale (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.16, 1.81) and mixed regions (OR = 1.37, 95% CI = 1.11, 1.68). Associations were slightly stronger in hypertensive subjects. INTERPRETATION: The APOE-ɛ4 allele plays a modest role in the burden of enlarged perivascular spaces in the centrum semiovale. Further studies are needed to clarify the underlying small vessel disease type in community-dwelling individuals with predominant centrum semiovale enlarged perivascular spaces, which may be hypertensive angiopathy in our sample. ANN NEUROL 2022;92:23-31.

Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study.

OBJECTIVE: Women have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults. METHODS: 328 CN participants from the Framingham Study (mean age = 57 years (±10 years), 161 women, of whom, 104 were post-menopausal) underwent tau and ß-amyloid (Aß)-PET neuroimaging. We examined global Aß-PET, and tau-PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aß and APOEε4 genotype. RESULTS: Women exhibited higher tau-PET signal (p < 0.002), and global Aß-PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age-matched men, post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions (p < 0.0001). By contrast, no differences in tau-PET signal existed between pre-menopausal women and men. Aß-PET was not associated with menopausal status or age. Neither Aß-PET nor APOEε4 status moderated sex or menopause associations with tau-PET. INTERPRETATION: Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aß and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aß burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways. ANN NEUROL 2022;92:11-22.

Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study.

INTRODUCTION: We investigated associations of obesity with the expression of Alzheimer's disease (AD)-related genes in a large community-based cohort. METHODS: The sample consisted of 5619 participants from the Framingham Heart Study. Obesity metrics included body mass index (BMI) and waist-to-hip ratio (WHR). Gene expression was measured for a set of 74 AD-related genes, derived by integrating genome-wide association study results with functional genomics data. RESULTS: Obesity metrics were associated with the expression of 21 AD-related genes. The strongest associations were observed with CLU, CD2AP, KLC3, and FCER1G. Unique associations were noted with TSPAN14, SLC24A4 for BMI, and ZSCAN21, BCKDK for WHR. After adjustment for cardiovascular risk factors, 13 associations remained significant for BMI and 8 for WHR. Dichotomous obesity metrics exhibited unique associations with EPHX2 for BMI, and with TSPAN14 for WHR. DISCUSSION: Obesity was associated with AD-related gene expression; these findings shed light on the molecular pathways linking obesity to AD.

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort.

INTRODUCTION: We investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort. METHODS: A total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI). RESULTS: Higher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P < .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures. DISCUSSION: Our findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

INTRODUCTION: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). METHODS: We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. RESULTS: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DISCUSSION: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.