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.

Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970.

Importance: Human brain development and maintenance is under both genetic and environmental influences that likely affect later-life dementia risk. Objective: To examine environmental influences by testing whether time-dependent secular differences occurred in cranial and brain volumes and cortical thickness over birth decades spanning 1930 to 1970. Design, Setting, and Participants: This cross-sectional study used data from the community-based Framingham Heart Study cohort for participants born in the decades 1930 to 1970. Participants did not have dementia or history of stroke and had magnetic resonance imaging (MRI) obtained from March 18, 1999, to November 15, 2019. The final analysis dataset was created in October 2023. Exposure: Years of birth ranging from 1925 to 1968. Main Measures: Cross-sectional analysis of intracranial, cortical gray matter, white matter, and hippocampal volumes as well as cortical surface area and cortical thickness. The secular measure was the decade in which the participant was born. Covariates included age at MRI and sex. Results: The main study cohort consisted of 3226 participants with a mean (SD) age of 57.7 (7.8) years at the time of their MRI. A total of 1706 participants were female (53%) and 1520 (47%) were male. The birth decades ranged from the 1930s to 1970s. Significant trends for larger intracranial, hippocampal, and white matter volumes and cortical surface area were associated with progressive birth decades. Comparing the 1930s birth decade to the 1970s accounted for a 6.6% greater volume (1234 mL; 95% CI, 1220-1248, vs 1321 mL; 95% CI, 1301-1341) for ICV, 7.7% greater volume (441.9 mL; 95% CI, 435.2-448.5, vs 476.3 mL; 95% CI, 467.0-485.7) for white matter, 5.7% greater value (6.51 mL; 95% CI, 6.42-6.60, vs 6.89 mL; 95% CI, 6.77-7.02) for hippocampal volume, and a 14.9% greater value (1933 cm2; 95% CI, 1908-1959, vs 2222 cm2; 95% CI, 2186-2259) for cortical surface area. Repeat analysis applied to a subgroup of 1145 individuals of similar age range born in the 1940s (mean [SD] age, 60.0 [2.8] years) and 1950s (mean [SD] age, 59.0 [2.8] years) resulted in similar findings. Conclusion and Relevance: In this study, secular trends for larger brain volumes suggested improved brain development among individuals born between 1930 and 1970. Early life environmental influences may explain these results and contribute to the declining dementia incidence previously reported in the Framingham Heart Study cohort.

Association of Neurotrophic Factors at Midlife With In Vivo Measures of ß-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults.

BACKGROUND AND OBJECTIVES: Neurotrophic factors (NTFs) play an important role in Alzheimer disease (AD) pathophysiology. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are important NTFs. However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-ß (Aß) and tau burden remains to be elucidated. We explored the relationship of BDNF and VEGF serum levels with future brain Aß and tau pathology in a cohort of cognitively healthy, predominantly middle-aged adults and tested for possible effect modifications by sex and menopausal status. METHODS: This cross-sectional analysis was conducted using data from the Framingham Heart Study (FHS), a community-based cohort study. The study sample included cognitively healthy participants from the FHS Offspring and Third-generation cohorts. BDNF and VEGF were measured in the third-generation cohort during examination cycles 2 (2005-2008) and 1 (2002-2005), respectively, and in the offspring cohort during examination cycle 7 (1998-2001). Participants underwent 11C-Pittsburgh compound B amyloid and 18F-Flortaucipir tau-PET imaging (2015-2021). Linear regression models were used to assess the relationship of serum BDNF and VEGF levels with regional tau and global Aß, adjusting for potential confounders. Interactions with sex and menopausal status were additionally tested. RESULTS: The sample included 414 individuals (mean age = 41 ± 9 years; 51% female). Continuous measures of BDNF and VEGF were associated with tau signal in the rhinal region after adjustment for potential confounders (ß = -0.15 ± 0.06, p = 0.018 and ß = -0.19 ± 0.09, p = 0.043, respectively). High BDNF (≥32,450 pg/mL) and VEGF (≥488 pg/mL) levels were significantly related to lower rhinal tau (ß = -0.27 ± 0.11, p = 0.016 and ß = -0.40 ± 0.14, p = 0.004, respectively) and inferior temporal tau (ß = -0.24 ± 0.11, p = 0.028 and ß = -0.26 ± 0.13, p = 0.049, respectively). The BDNF-rhinal tau association was observed only among male individuals. Overall, BDNF and VEGF were not associated with global amyloid; however, high VEGF levels were associated with lower amyloid burden in postmenopausal women (ß = -1.96 ± 0.70, p = 0.013, per 1 pg/mL). DISCUSSION: This study demonstrates a robust association between BDNF and VEGF serum levels with in vivo measures of tau almost 2 decades later. These findings add to mounting evidence from preclinical studies suggesting a role of NTFs as valuable blood biomarkers for AD risk prediction.

Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology.

BACKGROUND AND OBJECTIVES: Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease. METHODS: Two Framingham Heart Study overlapping samples were studied: participants who underwent 11C-Pittsburg Compound B amyloid and 18F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics. RESULTS: The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average ß [SE] 0.0062 [0.0024], p = 0.009; short to long ß [SE] 0.0164 [0.0076], p = 0.031; average to long ß [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (ß [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (ß [SE] -0.43 [0.20], p = 0.028; ß [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, ß [SE] 0.12 [0.04], p = 0.003; ß [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; ß [SE] 0.24 [0.10], p = 0.019; ß [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes. DISCUSSION: Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. RESULTS: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (ß = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (ß = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. DISCUSSION: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Hypertension Trends and White Matter Brain Injury in the Offspring Framingham Heart Study Cohort.

BACKGROUND: Hypertension is the most potent stroke risk factor and is also related to cerebral small vessel disease. We studied the relation between mid-to-late-life hypertension trends and cerebral white matter injury in community-dwelling individuals from the FHS (Framingham Heart Study). METHODS: FHS Offspring cohort participants with available mid-life and late-life blood pressure measurements and brain magnetic resonance imaging were included. Multiple regression analyses were used to relate hypertension trends (normotension-normotension [reference], normotension-hypertension, and hypertension-hypertension) to white matter injury metrics on diffusion tensor imaging (free water, fractional anisotropy, and peak skeletonized mean diffusivity) and Fluid Attenuated Inversion Recovery (white matter hyperintensity volume) by different blood pressure cutoffs (130/80, 140/90, and 150/90 mm Hg). RESULTS: We included 1018 participants (mean age 47.3±7.4 years at mid-life and 73.2±7.3 at late-life). At the 140/90 mm Hg cutoff, the hypertension-hypertension trend was associated with higher free water (ß, 0.16 [95% CI, 0.03-0.30]; P=0.021) and peak skeletonized mean diffusivity (ß, 0.15 [95% CI, 0.01-0.29]; P=0.033). At a 130/80 mm Hg cutoff, the hypertension-hypertension trend had significantly higher free water (ß, 0.16 [95% CI, 0.01-0.30]; P=0.035); and the normotension-hypertension (ß, 0.24 [95% CI, 0.03-0.44]; P=0.027) and hypertension-hypertension (ß, 0.22 [95% CI, 0.04-0.41]; P=0.022) trends had significantly increased white matter hyperintensity volume. Exploratory stratified analysis showed effect modifications by APOE ɛ4 allele and age. CONCLUSIONS: Mid-to-late-life hypertension exposure is significantly associated with microstructural and to a lesser extent, visible white matter injury; the effects are observed at both conventional and lower blood pressure cutoffs and are associated with longer duration of hypertension.

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.

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.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Association Between Slow-Wave Sleep Loss and Incident Dementia.

Importance: Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal. Objective: To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss. Design, Setting, and Participants: This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023. Exposure: Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years). Main Outcome: Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG. Results: From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P < .001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE ε4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P = .01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE ε4 allele) but not hippocampal volumes measured proximal to the first PSG. Conclusions and Relevance: This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.

The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury.

BACKGROUND: Preclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex. METHODS: This exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer's disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined. RESULTS: Participants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (ß ± SE = - 0.12 ± 0.06, p = 0.034 and ß ± SE = 0.08 ± 0.04, p = 0.026, respectively). CONCLUSIONS: Circulating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer's disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.

Association of MRI Visible Perivascular Spaces and Neurofilament Light Chain: The Framingham Heart Study.

BACKGROUND: Neurofilament light chain (NfL) is a marker of neuronal injury. Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) represent cerebral small vessel disease (CSVD) but their role as markers of neuronal injury needs further clarification. OBJECTIVE: To relate PVS burden according to brain topography and plasma NfL. METHODS: Framingham Heart Study (FHS) participants with brain MRI and NfL measurements were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) using validated methods and categorized based on counts. A mixed region variable representing high burden PVS in either BG or CSO was assessed. Multivariable linear regression analyses were used to relate PVS burden to log-transformed NfL levels in models adjusted for age, sex, FHS cohort, time between MRI and clinic exam, and image view (model 1), vascular risk factors (model 2), and white matter hyperintensity volume, covert brain infarcts, and cerebral microbleeds (model 3). RESULTS: Among 1,457 participants (68.1±8.5 years, 45% males), NfL levels increased with higher PVS burden. Multivariable analysis showed an association of high PVS burden strictly in BG with NfL (ß= 0.117, 95% CI 0.014-0.221; p = 0.027), but attenuated in model 3. The associations were mainly in participants≥65 years (ß= 0.122, 95% CI 0.015-0.229, p = 0.026), women (ß= 0.156, 95% CI 0.024-0.288, p = 0.021), and APOE ɛ4 non-carriers (ß= 0.140, 95% CI 0.017-0.263, p = 0.026). CONCLUSIONS: The association of strictly BG high PVS burden with NfL suggests a role for PVS as markers of neuroaxonal injury, but our results are hypothesis generating and require further replication.

Association of Physical Inactivity with MRI Markers of Brain Aging: Assessing Mediation by Cardiometabolic and Epigenetic Factors.

INTRODUCTION: Cardiometabolic risk factors and epigenetic patterns, increased in physically inactive individuals, are associated with an accelerated brain aging process. OBJECTIVE: To determine whether cardiometabolic risk factors and epigenetic patterns mediate the association of physical inactivity with unfavorable brain morphology. METHODS: We included dementia and stroke free participants from the Framingham Heart Study Third Generation and Offspring cohorts who had accelerometery and brain MRI data (n = 2,507, 53.9% women, mean age 53.9 years). We examined mediation by the 2017-revised Framingham Stroke Risk Profile (FSRP, using weights for age, cardiovascular disease, atrial fibrillation, diabetes and smoking status, antihypertension medications, and systolic blood pressure) and the homeostatic model of insulin resistance (HOMA-IR) in models of the association of physical inactivity with brain aging, adjusting for age, age-squared, sex, accelerometer wear time, cohort, time from exam-to-MRI, and season. We similarly assessed mediation by an epigenetic age-prediction algorithm, GrimAge, in a smaller sample of participants who had DNA methylation data (n = 1,418). RESULTS: FSRP and HOMA-IR explained 8.3-20.5% of associations of higher moderate-to-vigorous physical activity (MVPA), higher steps, and lower sedentary time with higher brain volume. Additionally, FSRP and GrimAge explained 10.3-22.0% of associations of physical inactivity with lower white matter diffusivity and FSRP explained 19.7% of the association of MVPA with lower free water accumulation. CONCLUSION: Our results suggest that cardiometabolic risk factors and epigenetic patterns partially mediate the associations of physical inactivity with lower brain volume, higher white matter diffusivity, and aggregation of free water in the extracellular compartments of the brain.

Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors.

Importance: Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain. Objective: To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline. Design, Setting, and Participants: Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023. Exposures: Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels. Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Results: A total of 1120 eligible dementia-free individuals with incident stroke were identified; 982 (87.7%) had available covariate data and 138 (12.3%) were excluded for missing covariate data. Of the 982, 480 (48.9%) were female individuals, and 289 (29.4%) were Black individuals. The median age at incident stroke was 74.6 (IQR, 69.1-79.8; range, 44.1-96.4) years. Cumulative mean poststroke SBP and LDL cholesterol levels were not associated with any cognitive outcome. However, after accounting for cumulative mean poststroke SBP and LDL cholesterol levels, higher cumulative mean poststroke glucose level was associated with faster decline in global cognition (-0.04 points/y faster per each 10-mg/dL increase [95% CI, -0.08 to -0.001 points/y]; P = .046) but not executive function or memory. After restricting to 798 participants with apolipoprotein E4 (APOE4) data and controlling for APOE4 and APOE4 × time, higher cumulative mean poststroke glucose level was associated with a faster decline in global cognition in models without and with adjustment for cumulative mean poststroke SBP and LDL cholesterol levels (-0.05 points/y faster per 10-mg/dL increase [95% CI, -0.09 to -0.01 points/y]; P = .01; -0.07 points/y faster per 10-mg/dL increase [95% CI, -0.11 to -0.03 points/y]; P = .002) but not executive function or memory declines. Conclusions and Relevance: In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aß) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; ß = 0.35, SE = 0.01, P = 6.2 × 10-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; ß = 0.07, SE = 0.01, P = 9.2 × 10-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; ß = 0.1, SE = 0.02, P = 2.4 × 10-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; ß = 0.16, SE = 0.03, P = 1.1 × 10-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, ß = 0.79, SE = 0.14, P = 1.4 × 10-08, MAF = 0.006, sex-interaction P = 9.8 × 10-07) and chr11p.15.2 (rs192346166, ß = 0.94, SE = 0.17, P = 3.7 × 10-08, MAF = 0.004, sex-interaction P = 1.3 × 10-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Inflammatory biomarkers and MRI visible perivascular spaces: The Framingham Heart Study.

We studied the association between inflammatory biomarkers and magnetic resonance imaging (MRI) visible perivascular spaces (PVS) in Framingham Heart Study participants free of stroke and dementia. PVS in the basal ganglia (BG) and centrum semiovale (CSO) were rated with validated methods and categorized based on counts. A mixed score of high PVS burden in neither, one or both regions was also evaluated. We related biomarkers representing various inflammatory mechanisms to PVS burden using multivariable ordinal logistic regression analysis accounting for vascular risk factors and other MRI markers of cerebral small vessel disease. Among 3604 participants (mean age 58±13 years, 47% males), significant associations were observed for intercellular adhesion molecule1, fibrinogen, osteoprotegerin, and P-selectin in relation to BG PVS, P-selectin for CSO PVS, and tumor necrosis factor receptor 2, osteoprotegerin and cluster of differentiation 40 ligand for mixed topography PVS. Therefore, inflammation may have a role in the pathogenesis of cerebral small vessel disease and perivascular drainage dysfunction represented by PVS, with different and shared inflammatory biomarkers depending on PVS topography.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (ß = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

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.

Association of Accelerometer-Measured Physical Activity and Sedentary Time with Epigenetic Markers of Aging.

INTRODUCTION/PURPOSE: Physical activity may influence chronic disease risk, in part, through epigenetic mechanisms. Previous studies have demonstrated that an acute bout of physical activity can influence DNA methylation status. Few studies have explored the relationship between habitual, accelerometer-measured physical activity or sedentary time with epigenetic markers of aging. METHODS: We used linear regression to examine cross-sectional associations of accelerometer-measured physical activity and sedentary time with extrinsic and intrinsic epigenetic age acceleration (EEAA and IEAA) models and GrimAge measured from blood samples from Framingham Heart Study participants with accelerometry and DNA methylation data ( n = 2435; mean age, 54.9 ± 14.3; 46.0% men). Residuals of Hannum-, Horvath-, and GrimAge-predicted epigenetic age were calculated by regressing epigenetic age on chronological age. We took into account blood cell composition for EEAA, IEAA, and AdjGrimAge. Moderate to vigorous physical activity was log-transformed to normalize its distribution. Adjustment models accounted for family structure, age, sex, smoking status, cohort-laboratory indicator, and accelerometer wear time. We additionally explored adjustment for body mass index (BMI). RESULTS: Walking 1500 more steps per day or spending 3 fewer hours sedentary was associated with >10 months lower GrimAge biological age (or ~1 month lower AdjGrimAge, after adjusting for blood cells, P < 0.05). Every 5 min·d -1 more moderate to vigorous physical activity was associated with 19-79 d of lower GrimAge (4-23 d lower using EEAA or AdjGrimAge, P < 0.01). Adjusting for BMI attenuated these results, but all statistically significant associations with AdjGrimAge remained. CONCLUSIONS: Greater habitual physical activity and lower sedentary time were associated with lower epigenetic age, which was partially explained by BMI. Further research should explore whether changes in physical activity influence methylation status and whether those modifications influence chronic disease risk.