The association between midlife lipid levels and late-life brain amyloid deposition.
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ABSTRACT:
SUBMITTER: Bennett EE
PROVIDER: S-EPMC7340169 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceMidlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood.ObjectiveTo determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET).Design, setting, and participantsThe Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015.ExposuresVascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level.Main outcomes and measuresStandardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable.ResultsAmong 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69).Conclusions and relevanceAn increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.
| S-EPMC5921896 | biostudies-literature
Project description:Background and objectivesTo evaluate the association between midlife plasma amyloid-β (Aβ1-42, Aβ1-40, Aβ42:Aβ40) and risk of mild cognitive impairment (MCI) and dementia.MethodsPlasma Aβ42 and Aβ40 were retrospectively measured with a fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ42, Aβ40, and Aβ42:Aβ40 ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011-2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, APOE, hypertension, diabetes, and body mass index.ResultsA total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ42:Aβ40 was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval [CI] 0.46-0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ42 (10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77-0.98), whereas every 1-SD increase in plasma Aβ40 (67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01-1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ42 and Aβ40 increased from midlife to late life, but changes were not associated with cognitive outcomes.DiscussionMidlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.
| S-EPMC8456355 | biostudies-literature
Project description:BackgroundAlthough inflammation has been implicated in the pathogenesis of Alzheimer's disease, the effects of systemic inflammation on brain amyloid deposition remain unclear.ObjectiveWe examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) - PET Study.Methods339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome.ResultsOur primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13-2.42), and among white (OR 1.33, 95% CI: 1.02-1.75), but not African American, participants (p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91).ConclusionsAlthough our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.
| S-EPMC6263742 | biostudies-literature
Project description:BackgroundLimited information exists regarding the association between midlife lipid levels and late-life total and regional brain volumes.MethodsWe studied 1872 participants in the longitudinal community-based Atherosclerosis Risk in Communities Neurocognitive Study. Serum lipid levels were measured in 1987-1989 (mean age, 53 ± 5 years). Participants underwent 3T brain MRI scans in 2011-2013. Brain volumes were measured using FreeSurfer image analysis software. Linear regression models were used to assess the associations between serum lipids and brain volumes modeled in standard deviation (SD) units, adjusting for potential confounders.ResultsIn adjusted analyses, one SD higher low-density lipoprotein cholesterol (LDL) levels were associated with larger total brain volumes (β 0.033, 95% CI 0.006-0.060) as well as larger volumes of the temporal (β 0.038, 95% CI 0.003-0.074) and parietal lobes (β 0.044, 95% CI 0.009-0.07) and Alzheimer disease-related region (β 0.048, 95% CI 0.048-0.085). Higher triglyceride levels were associated with smaller total brain volumes (β -0.033, 95% CI -0.060, -0.007). The associations between LDL levels and brain volumes were modified by age (P for interaction <0.001), with higher LDL levels associated with larger total and regional brain volumes only among adults >53 years at baseline, and were attenuated after application of weights to account for informative attrition, although associations with the parietal and Alzheimer's disease-related region remained significant. High-density lipoprotein cholesterol was not associated with brain volumes.ConclusionHigher LDL levels in late midlife were associated with larger brain volumes later in life, while higher triglyceride levels were associated with smaller brain volumes. These associations were driven by adults >53 years at baseline.
| S-EPMC9006082 | biostudies-literature
Project description:Late-life depression (LLD) is associated with an increased risk of all-cause dementia and may involve Alzheimer's disease pathology. Twenty-one LLD patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for a current major depressive episode and 21 healthy controls underwent clinical and neuropsychological assessments, magnetic resonance imaging to measure gray matter volumes, and high-resolution positron emission tomography to measure beta-amyloid (Aβ) deposition. Clinical and neuropsychological assessments were repeated after 10-12 weeks of Citalopram or Sertraline treatment (LLD patients only). LLD patients did not differ from healthy controls in baseline neuropsychological function, although patients improved in both depressive symptoms and visual-spatial memory during treatment. Greater Aβ in the left parietal cortex was observed in LLD patients compared with controls. Greater Aβ was correlated with greater depressive symptoms and poorer visual-spatial memory, but not with improvement with treatment. The study of LLD patients with prospective measurements of mood and cognitive responses to antidepressant treatment is an opportunity to understand early neurobiological mechanisms underlying the association between depression and subsequent cognitive decline.
| S-EPMC8730327 | biostudies-literature
Project description:ObjectiveMajor depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.MethodsWe performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately.ResultsWe found epigenome-wide significant associations between brain tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p value = 2.55 × 10-11; cg03899372, p value = 3.12 × 10-09; cg12796440, p value = 1.51 × 10-08, cg23982678, p value = 7.94 × 10-08). Analysis of differentially methylated regions (p value = 5.06 × 10-10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p value = 1.75 × 10-08), FNDC3B (cg20367479, p value = 4.97 × 10-08) and SLIT2 (cg10946669, p value = 8.01 × 10-08). Notably, brain tissue-based methylation levels were strongly associated with late-life MDD in men more than in women.ConclusionsWe identified altered methylation in the YOD1, UGT8, FNDC3B, and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.
| S-EPMC7393126 | biostudies-literature
Project description:BackgroundInsulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD.MethodsAsymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal).ResultsIn participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloid deposition.ConclusionsThis is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD.
| S-EPMC4297592 | biostudies-literature
Project description:This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of 33 individuals with amnestic MCI (mean age, 75.6 years) underwent 11C-Pittsburgh compound B positron emission tomography (PiB-PET), 18F-fluorodeoxyglucose positron emission tomography, magnetic resonance imaging or computed tomography, and CSF analysis. PET uptake of the frontal and temporoparietal lobes and posterior cingulate gyrus was assessed using the cerebellar cortex as the reference region. WMLs were assessed by the Fazekas scale. CSF levels of MMPs and TIMPs were measured with bead-based multiplex assays. After adjusting for covariates, multiple linear regression analysis showed that CSF levels of MMP-2 were negatively correlated with global PiB uptake (p = 0.035), especially in the parietotemporal lobe and posterior cingulate gyrus (p = 0.016 and p = 0.041, respectively). Moreover, CSF levels of MMP-7 were positively correlated with the severity of WMLs (p = 0.033). CSF levels of MMP-2 and MMP-7 are associated with brain amyloid deposition and severity of WMLs, respectively. These findings provide valuable insights into the role of MMPs in amyloid β catabolism and blood-brain barrier integration at the MCI stage.
| S-EPMC8533797 | biostudies-literature
Project description:ImportanceHearing impairment (HI) in midlife (45-65 years of age) may be associated with longitudinal neurodegeneration of temporal lobe structures, a biomarker of early Alzheimer disease.ObjectiveTo evaluate the association of midlife HI with brain volume trajectories in later life (≥65 years of age).Design, setting, and participantsThis prospective cohort study used data from the Baltimore Longitudinal Study of Aging to evaluate hearing from November 5, 1990, to October 3, 1994, and late-life volume change from July 10, 2008, to January 29, 2015, using magnetic resonance imaging (MRI) (mean follow-up time, 19.3 years). Data analysis was performed from September 22, 2017, to August 27, 2018. A total of 194 community-dwelling older adults who had midlife measures of peripheral hearing at a mean age of 54.5 years and late-life volume change of up to 6 years between the first and most recent MRI assessment were studied. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and bipolar disorder.ExposuresHearing as measured with pure tone audiometry in each ear from November 5, 1990, to October 3, 1994, and late-life temporal lobe volume change measured by MRI.Main outcomes and measuresLinear mixed-effects models with random intercepts were used to examine the association of midlife hearing (pure tone average of 0.5-4 kHz tones in the better ear and each ear separately) with longitudinal late-life MRI-based measures of temporal lobe structures (hippocampus, entorhinal cortex, parahippocampal gyrus, and superior, middle, and inferior temporal gyri) in the left and right hemispheres, in addition to global and lobar regions, adjusting for baseline demographic characteristics (age, sex, subsequent cognitive impairment status, and educational level) and intracranial volume.ResultsA total of 194 patients (mean [SD] age at hearing assessment, 54.5 [10.0] years; 106 [54.6%] female; 169 [87.1%] white) participated in the study. After Bonferroni correction, poorer midlife hearing in the better ear was associated with steeper late-life volumetric declines in the right temporal gray matter (β = -0.113; 95% CI, -0.182 to -0.044), right hippocampus (β = -0.008; 95% CI, -0.012 to -0.004), and left entorhinal cortex (β = -0.009; 95% CI, -0.015 to -0.003). Poorer midlife hearing in the right ear was associated with steeper late-life volumetric declines in the right temporal gray matter (β = -0.136; 95% CI, -0.197 to -0.075), right hippocampus (β = -0.008; 95% CI, -0.012 to -0.004), and left entorhinal cortex (β = -0.009; 95% CI, -0.015 to -0.003), whereas there were no associations between poorer midlife hearing in the left ear with late-life volume loss.Conclusions and relevanceThe findings suggest that midlife HI is a risk factor for temporal lobe volume loss. Poorer midlife hearing, particularly in the right ear, was associated with declines in hippocampus and entorhinal cortex.
| S-EPMC6613307 | biostudies-literature
Project description:ImportanceThe association between late-life blood pressure (BP) and cognition may depend on the presence and chronicity of past hypertension. Late-life declines in blood pressure following prolonged hypertension may be associated with poor cognitive outcomes.ObjectiveTo examine the association of midlife to late-life BP patterns with subsequent dementia, mild cognitive impairment, and cognitive decline.Design, setting, and participantsThe Atherosclerosis Risk in Communities prospective population-based cohort study enrolled 4761 participants during midlife (visit 1, 1987-1989) and followed-up over 6 visits through 2016-2017 (visit 6). BP was examined over 24 years at 5 in-person visits between visits 1 and 5 (2011-2013). During visits 5 and 6, participants underwent detailed neurocognitive evaluation. The setting was 4 US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Follow-up ended on December 31, 2017.ExposuresFive groups based on longitudinal patterns of normotension, hypertension (>140/90 mm Hg), and hypotension (<90/60 mm Hg) at visits 1 to 5.Main outcomes and measuresPrimary outcome was dementia onset after visit 5, based on Ascertain Dementia-8 informant questionnaires, Six-Item Screener telephone assessments, hospital discharge and death certificate codes, and the visit 6 neurocognitive evaluation. Secondary outcome was mild cognitive impairment at visit 6, based on the neurocognitive evaluation.ResultsAmong 4761 participants (2821 [59%] women; 979 [21%] black race; visit 5 mean [SD] age, 75 [5] years; visit 1 mean age range, 44-66 years; visit 5 mean age range, 66-90 years), there were 516 (11%) incident dementia cases between visits 5 and 6. The dementia incidence rate for participants with normotension in midlife (n = 833) and late life was 1.31 (95% CI, 1.00-1.72 per 100 person-years); for midlife normotension and late-life hypertension (n = 1559), 1.99 (95% CI, 1.69-2.32 per 100 person-years); for midlife and late-life hypertension (n = 1030), 2.83 (95% CI, 2.40-3.35 per 100 person-years); for midlife normotension and late-life hypotension (n = 927), 2.07 (95% CI, 1.68-2.54 per 100 person-years); and for midlife hypertension and late-life hypotension (n = 389), 4.26 (95% CI, 3.40-5.32 per 100 person-years). Participants in the midlife and late-life hypertension group (hazard ratio [HR], 1.49 [95% CI, 1.06-2.08]) and in the midlife hypertension and late-life hypotension group (HR, 1.62 [95% CI, 1.11-2.37]) had significantly increased risk of subsequent dementia compared with those who remained normotensive. Irrespective of late-life BP, sustained hypertension in midlife was associated with dementia risk (HR, 1.41 [95% CI, 1.17-1.71]). Compared with those who were normotensive in midlife and late life, only participants with midlife hypertension and late-life hypotension had higher risk of mild cognitive impairment (37 affected individuals (odds ratio, 1.65 [95% CI, 1.01-2.69]). There was no significant association of BP patterns with late-life cognitive change.Conclusions and relevanceIn this community-based cohort with long-term follow-up, sustained hypertension in midlife to late life and a pattern of midlife hypertension and late-life hypotension, compared with midlife and late-life normal BP, were associated with increased risk for subsequent dementia.
| S-EPMC6692677 | biostudies-literature