Effect of Neurotoxin Exposure on Blood Biomarkers of Neurodegeneration and Alzheimer Disease.

AIM: To determine whether exposure to neurotoxins in midlife is associated with changes in blood-based biomarkers of neurodegeneration and Alzheimer disease pathology. METHODS: Blood cadmium, lead, neurofilament light (NfL) chain, total tau (TTau), and amyloid beta (Aß) 40 and Aß42 concentrations were measured in 1516 participants in the Beaver Dam Offspring Study. Linear mixed-effect models were used to determine associations between baseline cadmium and lead levels and baseline NfL, TTau, and Aß42/Aß40, and 10-year change in concentrations using repeated measures of these biomarkers as the outcome. RESULTS: In women, higher cadmium and lead levels were associated with higher baseline TTau concentrations. A higher baseline cadmium level was associated with lower baseline Aß42/Aß40 in both men and women. In age-sex-adjusted models, a doubling in baseline cadmium level was associated with a 0.2% (95% CI: 0.0, 0.3) higher increase per year in NfL concentrations. In men, a doubling of baseline lead level was associated with a 0.9% (95% CI: 0.1, 1.7) higher increase per year in TTau concentration. CONCLUSIONS: Participants with relatively higher levels of cadmium and lead had blood biomarker concentrations consistent with more neuronal damage and Alzheimer disease pathology. Environmental exposure to neurotoxins may contribute to neurodegeneration.

Inflammation, metabolic dysregulation and environmental neurotoxins and risk of cognitive decline and impairment in midlife.

BACKGROUND: Age-related declines in cognitive function may begin in midlife. PURPOSE: To determine whether blood-based biomarkers of inflammation, metabolic dysregulation and neurotoxins are associated with risk of cognitive decline and impairment. METHODS: Baseline blood samples from the longitudinal Beaver Dam Offspring Study (2005-2008) were assayed for markers of inflammation, metabolic dysregulation, and environmental neurotoxins. Cognitive function was measured at baseline, 5-year (2010-2013) and 10-year (2015-2017) examinations. Participants without cognitive impairment at baseline and with cognitive data from at least one follow-up were included. Cox proportional hazards models were used to evaluate associations between baseline blood biomarkers and the 10-year cumulative incidence of cognitive impairment. Poisson models were used to estimate the relative risk (RR) of 5-year decline in cognitive function by baseline blood biomarkers. Models were adjusted for age, sex, education, and cardiovascular related risk factors. RESULTS: Participants (N = 2421) were a mean age of 49 years and 55% were women. Soluble vascular cell adhesion molecule-1 (sVCAM-1Tertile(T)3 vs T1-2 hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.05,2.82) and hemoglobin A1C (HR = 1.75, 95% CI = 1.18,2.59, per 1% in women) were associated with the 10-year cumulative incidence of cognitive impairment. sVCAM-1 (RRT3 vs T1-2 = 1.45, 95% CI = 1.06,1.99) and white blood cell count (RR = 1.10, 95% CI = 1.02,1.19, per 103/µL) were associated with 5-year cognitive decline. CONCLUSIONS: Biomarkers related to inflammation and metabolic dysregulation were associated with an increased risk of developing cognitive decline and impairment. These results extend previous research in cognitive aging to early markers of cognitive decline in midlife, a time when intervention methods may be more efficacious.

The pupil constriction to light is associated with cognitive measures in middle-aged and older adults.

AIMS: The evidence relating the pupil light reflex (PLR) and cognition have been inconsistent. In this cross-sectional study, we evaluated the association between the PLR and cognition in community-dwelling middle-aged and older individuals. METHODS: Pupil reactivity was recorded in a subgroup of 403 participants (mean age 60.7 years, 57.3% females) in an epidemiologic study of aging. Ten pupil parameters were calculated to describe pupil constriction to light stimuli. A principal component analysis (PCA) score was used to calculate an overall performance over four cognitive testings. Linear regression was used to assess the association between pupil parameters and PCA scores, adjusting for age, sex, education, medications, health-related quality of life questionnaire, and systemic and ocular comorbidities. RESULTS: The PCA scores decreased by 0.039 [95% CI (- 0.050, - 0.028)] per year increase in age and were lower in males than females by 0.76 [95% CI (- 0.96, - 0.55)] (p < 0.001). Pupil constriction amplitude in millimeters and the duration from stimulus onset to maximal constriction velocity were significantly associated with cognition after adjusting for (1) age and sex and (2) age, sex, and multiple covariates (p < 0.05). CONCLUSIONS: In this study, we provided moderate evidence suggesting the association between PLR and neuropsychological cognitive measures. The findings suggest the potential of pupil reactivity to serve as a biomarker of brain aging and warrant further longitudinal study to assess if changes in the PLR can predict cognitive decline over time.

Factors Associated with the Macular Ganglion Cell-Inner Plexiform Layer Thickness in a Cohort of Middle-aged U.S. Adults.

SIGNIFICANCE: The macular ganglion cell-inner plexiform layer (mGCIPL) may serve as a quick and easily obtained measure of generalized neurodegeneration. Investigating factors associated with this thickness could help to understand neurodegenerative processes. PURPOSE: This study aimed to characterize and identify associated factors of the mGCIPL thickness in a Beaver Dam Offspring Study cohort of middle-aged U.S. adults. METHODS: Baseline examinations occurred from 2005 to 2008, with follow-up examinations every 5 years. Included participants had baseline data and measured mGCIPL at 10-year follow-up (N = 1848). The mGCIPL was measured using the Cirrus 5000 HD-OCT Macular Cube Scan. Associations between mean mGCIPL thickness and thin mGCIPL, defined as 1 standard deviation (SD) below the population mean, and baseline risk factors were investigated using generalized estimating equations. RESULTS: Participants (mean [SD] baseline age, 48.9 [9.3] years; 54.4% women) had mean (SD) mGCIPL thicknesses of 78.4 (8.1) µm in the right eye and 78.1 (8.5) µm in the left (correlation coefficient = 0.76). In multivariable models, age (-1.07 µm per 5 years; 95% confidence interval [CI], -1.28 to -0.86 µm), high alcohol consumption (-1.44 µm; 95% CI, -2.72 to -0.16 µm), higher interleukin 6 levels (50% increase in level: -0.23 µm; 95% CI, -0.45 to 0.00 µm), myopia (-2.55 µm; 95% CI, -3.17 to -1.94 µm), and glaucoma (-1.74 µm; 95% CI, -2.77 to -0.70 µm) were associated with thinner mGCIPL. Age (per 5 years: odds ratio [OR], 1.38; 95% CI, 1.24 to 1.53), diabetes (OR, 1.89, 95% CI, 1.09 to 3.27), myopia (OR, 2.11; 95% CI, 1.63 to 2.73), and increasing and long-term high C-reactive protein (ORs, 1.46 [95% CI, 1.01 to 2.11] and 1.74 [95% CI, 1.14 to 2.65], respectively) were associated with increased odds of thin mGCIPL. CONCLUSIONS: Factors associated cross-sectionally with mGCIPL thickness, older age, high alcohol consumption, inflammation, diabetes, myopia, and glaucoma may be important to neural retina structure and health and neuronal health system-wide.

Neuroprotective Biomarkers and Cognitive Function in a Long-Term Prospective Population-based Study of Aging US Adults.

BACKGROUND: Relationships between brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), aldosterone, and cognition in aging were evaluated in the population-based Epidemiology of Hearing Loss Study (1993 to present). METHODS: Beginning in 1998 to 2000, cognitive impairment was assessed by report of physician diagnoses and the Mini-Mental State Examination. In 2009 to 2010 and 2013 to 2016, information was collected on diagnosis of mild cognitive impairment/dementia. Decline in cognitive function was assessed by principal component analysis from additional tests administered during 2009 to 2010 and 2013 to 2016. BDNF, IGF-1, and aldosterone were measured in serum collected in 1998 to 2000. RESULTS: There were 1970 participants (mean age=66.9 y; 59.1% female) without cognitive impairment at baseline. Among women, low BDNF was associated with 16-year incident cognitive impairment [hazard ratio=1.76; 95% confidence interval (CI)=1.04, 2.98]. Among men, increasing IGF-1 was associated with decreased risk [per SD: relative risk (RR)=0.57; 95% CI=0.35, 0.92], whereas increasing aldosterone levels were associated with increased risk (per SD: RR=1.28; 95% CI=1.01, 1.62) for 5-year incident mild cognitive impairment/dementia. Overall, low BDNF was associated with increased risk (RR=1.52; 95% CI=1.02, 2.26) for 5-year cognitive decline. CONCLUSION: Low levels of serum BDNF and IGF-1 were associated with poorer cognition during aging. There may be differential biomarker effects by sex.

NSAID Use and Incident Cognitive Impairment in a Population-based Cohort.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent dementia, but previous studies have yielded conflicting results. This study estimated the association of prior NSAID use with incident cognitive impairment in the population-based Epidemiology of Hearing Loss Study (EHLS, n=2422 without cognitive impairment in 1998-2000). Prospectively collected medication data from 1988-1990, 1993-1995, and 1998-2000 were used to categorize NSAID use history at the cognitive baseline (1998-2000). Aspirin use and nonaspirin NSAID use were separately examined. Cox regression models were used to estimate the associations between NSAID use history at baseline and incident cognitive impairment in 2003-2005 or 2009-2010. Logistic regression analyses were used to estimate associations with a second outcome, mild cognitive impairment/dementia, available in 2009-2010. Participants using aspirin at baseline but not 5 years prior were more likely to develop cognitive impairment (adjusted hazard ratio=1.77; 95% confidence interval=1.11, 2.82; model 2), with nonsignificant associations for longer term use. Nonaspirin NSAID use was not associated with incident cognitive impairment or mild cognitive impairment/dementia odds. These results provided no evidence to support a potential protective effect of NSAIDs against dementia.

The ethnic gap in mental health: A population-based study of Russian, Somali and Kurdish origin migrants in Finland.

AIMS: Research demonstrates that migrants are more vulnerable to poor mental health than general populations, but population-based studies with distinct migrant groups are scarce. We aim to (1) assess the prevalence of mental health symptoms in Russian, Somali and Kurdish origin migrants in Finland; (2) compare the prevalence of mental health symptoms in these migrant groups to the Finnish population; (3) determine which socio-demographic factors are associated with mental health symptoms. METHODS: We used data from the Finnish Migrant Health and Wellbeing Study and Health 2011 Survey. Depressive and anxiety symptoms were measured using the Hopkins Symptom Checklist-25 (HSCL-25), and 1.75 was used as cut-off for clinically significant symptoms. Somatization was measured using the Symptom Checklist-90 (SCL-90) somatization scale. The age-adjusted prevalence of mental health symptoms in the studied groups was calculated by gender using predicted margins. Logistic regression analysis was used to determine which socio-demographic factors are associated with mental health symptoms in the studied population groups. RESULTS: The prevalence of depressive and anxiety symptoms was higher in Russian women (24%) and Kurdish men (23%) and women (49%) than in the Finnish population (9-10%). These differences were statistically significant (p<.001). Socioeconomic disadvantage (e.g. unemployment and poor economic situation) and migration-related factors (e.g. poor language proficiency and short time since migration) significantly increased the odds for depressive and anxiety symptoms. CONCLUSIONS: Mental health symptoms are highly prevalent particularly in Kurdish migrants in Finland. Holistic interventions and co-operation between integration and mental health services are acutely needed.

Inflammatory and vascular markers and olfactory impairment in older adults.

BACKGROUND: the incidence of olfactory impairment increases sharply in the eighth and ninth decades of life but the aetiology of age-related olfactory decline is not well understood. Inflammation and atherosclerosis are associated with many age-related conditions and atherosclerosis has been associated with olfactory decline in middle-aged adults. OBJECTIVE: to determine if inflammatory markers and atherosclerosis are associated with the development of olfactory impairment in older adults. DESIGN: longitudinal, population-based study. SETTING/PARTICIPANTS: a total of 1,611 participants, aged 53-97 years in the Epidemiology of Hearing Loss Study without olfactory impairment at the 1998-2000 examination and with follow-up at a subsequent examination 5 and/or 10 years later. METHODS: the San Diego Odor Identification Test was used to measure olfaction. High sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α were measured in serum and carotid ultrasound images were obtained for the measurement of carotid intima media thickness (IMT) and plaque assessment. Medical history, behavioural and lifestyle information were obtained by interview. RESULTS: inflammatory markers, IMT and plaque were not associated with the 10-year cumulative incidence of olfactory impairment in adjusted Cox proportional hazard models. Among those <60 years, the mean IMT [hazard ratio (HR) = 4.35, 95% confidence interval (CI) = 1.69-11.21, tertile 3 versus tertile 1] and the number of sites with plaque (HR = 1.56, 95% CI = 1.17-2.08, per site) were associated with an increased risk of developing an olfactory impairment at follow-up. CONCLUSION: subclinical atherosclerosis at a younger age may be a risk factor for the development of olfactory impairment.

Pulse wave velocity and cognitive function in older adults.

Arterial stiffness may be associated with cognitive function. In this study, pulse wave velocity (PWV) was measured from the carotid to femoral (CF-PWV) and from the carotid to radial (CR-PWV) with the Complior SP System. Cognitive function was measured by 6 tests of executive function, psychomotor speed, memory, and language fluency. A total of 1433 participants were included (mean age 75 y, 43% men). Adjusting for age, sex, education, pulse rate, hemoglobin A1C, high-density lipoprotein cholesterol, hypertension, cardiovascular disease history, smoking, drinking, and depression symptoms, a CF-PWV>12 m/s was associated with a lower Mini-Mental State Examination score (coefficient: -0.31, SE: 0.11, P=0.005), fewer words recalled on Auditory Verbal Learning Test (coefficient: -1.10, SE: 0.43, P=0.01), and lower score on the composite cognition score (coefficient: -0.10, SE: 0.05, P=0.04) and marginally significantly associated with longer time to complete Trail Making Test-part B (coefficient: 6.30, SE: 3.41, P=0.06), CF-PWV was not associated with Trail Making Test-part A, Digit Symbol Substation Test, or Verbal Fluency Test. No associations were found between CR-PWV and cognitive performance measures. Higher large artery stiffness was associated with worse cognitive function, and longitudinal studies are needed to confirm these associations.

Midlife sensory and motor functions improve long-term predictions of cognitive decline and incidence of cognitive impairment.

INTRODUCTION: We aimed to assess whether midlife sensory and motor functions improve risk prediction of 10-year cognitive decline and impairment when added to risk prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS). METHODS: Longitudinal data of N = 1529 (mean age 49 years; 54% women) Beaver Dam Offspring Study (BOSS) participants from baseline, 5 and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function improves CAIDE or FRS risk predictions of 10-year cognitive decline or cognitive impairment incidence using logistic regressions. RESULTS: Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved areas under the curve for cognitive decline and impairment models. DISCUSSION: Including midlife sensory and motor function improved risk predictions of long-term cognitive decline and impairment in middle-aged to older adults. Sensory and motor assessments could contribute to cost-effective and non-invasive screening tools that identify high-risk individuals earlier to target intervention and prevention strategies. Highlights: Sensory and motor measures improve risk prediction models of cognitive decline.Sensory and motor measures improve risk prediction models of cognitive impairment.Prediction improvements were strongest in midlife (adults < 55 years of age).Sensory and motor changes may help identify high-risk individuals early.

Midlife sensory and motor functions improve prediction of blood-based measures of neurodegeneration and Alzheimer's disease in late middle-age.

INTRODUCTION: We assessed whether midlife sensory and motor functions added to prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS) improve risk predictions of 10-year changes in biomarkers of neurodegeneration and Alzheimer's disease. METHODS: Longitudinal data of N = 1529 (mean age 49years) Beaver Dam Offspring Study participants from baseline, 5-year, and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function measures improves CAIDE or FRS risk predictions of 10-year incidence of biomarker positivity of serum-based neurofilament light chain (NfL) and amyloid beta (Aß)42/Aß40 using logistic regression. RESULTS: Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved NfL and Aß42/Aß40 positivity predictions in adults above the age of 55. DISCUSSION: Including midlife sensory and motor function improved long-term biomarker positivity predictions. Non-invasive sensory and motor assessments could contribute to cost-effective screening tools that identify individuals at risk for neurodegeneration early to target interventions and preventions. Highlights: Sensory and motor measures improve risk prediction models of neurodegenerative biomarkersSensory and motor measures improve risk prediction models of AD biomarkersPrediction improvements were strongest in late midlife (adults >55 years of age)Sensory and motor assessments may help identify high-risk individuals early.

The relationship of atherosclerosis to the 10-year cumulative incidence of age-related macular degeneration: the Beaver Dam studies.

OBJECTIVE: To describe the relationships of intima-media thickness (IMT), plaque in the carotid artery, angina, myocardial infarction (MI), and stroke to the 10-year cumulative incidence of early and late age-related macular degeneration (AMD) and progression of AMD. DESIGN: Cohort study. PARTICIPANTS: A total of 1700 persons aged 53 to 96 years who participated in both the Epidemiology of Hearing Loss Study and the Beaver Dam Eye Study in 1998-2000, with photographs gradable for AMD at 5-year (2003-2005) and 10-year (2008-2010) follow-up examinations. METHODS: The IMT and presence of plaque were assessed using B-mode ultrasonography of the carotid artery. Presence of angina, MI, and stroke were defined on the basis of a self-reported history of physician diagnosis. The presence and severity of AMD were determined by systematic grading of stereoscopic color fundus photographs. MAIN OUTCOME MEASURES: Age-related macular degeneration. RESULTS: The 10-year cumulative incidence of early AMD was 15.7%, and the 10-year cumulative incidence of late AMD was 4.0%. After adjusting for age, sex, body mass index, smoking status, age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) genotypes, and other factors, mean IMT was associated with the 10-year incidence of early AMD (odds ratio [OR] per 0.1 mm IMT, 1.11; 95% confidence interval [CI], 1.00-1.21; P = 0.03) and late AMD (OR per 0.1 mm IMT, 1.27; CI, 1.10-1.47; P = 0.001). Mean IMT was associated with the 10-year incidence of pure geographic atrophy (OR per 0.1 mm IMT, 1.31; CI, 1.05-1.64; P = 0.02) but not exudative AMD (OR per 0.1 mm IMT, 1.14; CI, 0.97-1.34; P = 0.11). Similar associations were found for maximum IMT. The number of sites with plaque was related to the incidence of late AMD (OR per 0.1 mm IMT, 2.79 for 4-6 sites vs. none; CI, 1.06-7.37; P = 0.04) but not to early AMD. A history of angina, MI, or stroke was not related to any incident AMD outcome. CONCLUSIONS: In these population-based data, carotid artery IMT and carotid plaques had a weak relationship to the incidence of late AMD that was independent of systemic and genetic risk factors. Angina, MI, and stroke were not related to AMD. It is unclear whether the carotid IMT is a risk indicator of processes affecting Bruch's membrane and the retinal pigment epithelium, or a measure of atherosclerosis affecting susceptibility to AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Factors related to fungiform papillae density: the beaver dam offspring study.

The distribution of fungiform papillae density and associated factors were examined in the Beaver Dam Offspring Study. Data were from 2371 participants (mean age = 48.8 years, range = 21-84 years) with 1108 males and 1263 females. Fungiform papillae were highlighted with blue food coloring and the number of fungiform papillae within a standard 6-mm circle was counted. Whole mouth suprathreshold taste intensity was measured. The mean fungiform papillae density was 103.5 papillae/cm(2) (range = 0-212.2 papillae/cm(2)). For each 5-year increase in age, the mean fungiform papillae density was 2.8 papillae/cm(2) lower and the mean density for males was 10.2 papillae/cm(2) lower than for females. Smokers had significantly lower mean densities (former smokers: -5.1 papillae/cm(2); current smokers: -9.3 papillae/cm(2)) than nonsmokers, and heavy alcohol drinkers had a mean density that was 4.7 papillae/cm(2) lower than nonheavy drinkers. Solvent exposure was related to a significantly higher density (+6.8 papillae/cm(2)). The heritability estimate for fungiform papillae density was 40.2%. Propylthiouracil taster status, TAS2R38 haplotype, and perceived taste intensity were not related to density. In summary, wide variability in fungiform papillae density was observed and a number of related factors were found including the modifiable factors of smoking and alcohol consumption.

Lifestyle and factors of vascular and metabolic health and inflammation are associated with sensorineural-neurocognitive aging in older adults.

This study's aim was to identify risk factors associated with sensorineural and neurocognitive function (brain aging) in older adults. In N = 1,478 Epidemiology of Hearing Loss Study participants (aged 64-100 years, 59% women), we conducted sensorineural and cognitive tests, which were combined into a summary measure using Principal Component Analysis (PCA). Participants with a PCA score <-1 standard deviation (SD) were considered to have brain aging. Incident brain aging was defined as PCA score <-1 SD at 5-year follow-up among participants who had a PCA score ≥-1 SD at baseline. Logistic regression and Poisson models were used to estimate associations between baseline risk factors of lifestyle, vascular and metabolic health, and inflammation and prevalent or incident brain aging, respectively. In an age-sex adjusted multivariable model, not consuming alcohol (odds ratio(OR) = 1.77, 95% confidence Interval (CI) = 1.18,2.66), higher interleukin-6 levels (OR = 1.30, 95% CI = 1.03,1.64), and depressive symptoms (OR = 2.44, 95% CI = 1.63,3.67) were associated with a higher odds of having brain aging, while higher education had protective effects (OR = 0.55, 95% CI = 0.33,0.94). A history of stroke, arterial stiffness, and obesity were associated with an increased risk of developing brain aging during the five years of follow-up. Lifestyle, vascular, metabolic and inflammatory factors were associated with brain aging in older adults, which adds to the evidence of shared pathways for sensorineural and neurocognitive declines in aging. Targeting these shared central processing etiological factors with interventions may lead to retention of better neurological function, benefiting multiple systems, i.e., hearing, smell, and cognition, ultimately helping older adults retain independence and higher quality of life longer.

Association of Central Retinal Arteriolar and Venular Equivalents with Brain-aging and Macular Ganglion Cell-inner Plexiform Layer Thickness.

INTRODUCTION: Neurodegeneration and cognitive decline in aging are growing public health concerns. This study investigates associations between central retinal arteriolar and venular equivalents (CRAE, CRVE) and brain-aging, a sensory and cognitive test composite measure, and macular ganglion cell-inner plexiform layer (mGCIPL) thickness, a biomarker of neurodegeneration. METHODS: Beaver Dam Offspring Study (BOSS) participants are adult children (baseline (2005-2008) age 21-84 years) of the population-based Epidemiology of Hearing Loss Study participants. Follow-up occurred every 5 years. In 2010-2013, fundus photographs were used to measure retinal vessels. A brain-aging score was constructed by principal component analysis using sensorineural and cognitive data. Associations between incident brain-aging and vessel measures were investigated using logistic regression. Associations between CRAE and CRVE and mGCIPL thickness, measured in 2015-2017, were also investigated. RESULTS: Participants (N = 2381; mean age: 53.9 years (SD = 9.8); 54% women) had a mean CRAE and CRVE of 148.8 µm (SD = 14.5) and 221.7 µm (SD = 20.7), respectively. Among those without ocular conditions, wider CRAE was associated with decreased 5-year brain-aging risk (33% per SD CRAE increase). Both vessel measures were independently associated with mGCIPL thickness. The mGCIPL thickness increased by approximately 1.7 µm and 2.0 µm per SD increase in CRAE and CRVE, respectively. DISCUSSION: The association of CRAE with incident brain-aging indicates its potential use as a screening tool among those without eye disease. The associations between CRAE and CRVE and mGCIPL thickness indicate narrower vasculature could affect neuronal health. These associations point to potential usefulness of retinal vessel measurements to identify people at higher risk of sensorineural declines and neurodegeneration.

Associations of Midlife Lifestyle and Health Factors with Long-Term Changes in Blood-Based Biomarkers of Alzheimer's Disease and Neurodegeneration.

BACKGROUND: Pathological biomarkers of Alzheimer's disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life. OBJECTIVE: We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aß)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)). METHODS: In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age 49 years, standard deviation (SD) = 9; 54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes. RESULTS: We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aß42/Aß40. TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels. CONCLUSION: Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD.

Associations of Hearing Loss and Hearing Aid Use With Cognition, Health-Related Quality of Life, and Depressive Symptoms.

ObjectivesDetermine associations of hearing loss (HL) and hearing aid (HA) use with cognition, health-related quality of life (HRQoL), and depressive symptoms. Methods: Participants were from the Epidemiology of Hearing Loss Study or Beaver Dam Offspring Study. HL was defined as pure-tone average (.5-4.0 kHz) > 25 dB. A principal component analysis of 5 cognitive tasks measured cognition. The SF-12 measured mental and physical HRQoL. The Centers for Epidemiological Studies Depression Scale measured depressive symptoms (score ≥ 16). Regression models returned beta (B) coefficients or odds ratios (OR) with 95% confidence intervals. Results: This study included 3574 participants. HL (vs. none) was associated with poorer cognition (B-.12 [-.18, -.06]), mental (B-.99 [-1.65, -.33]) and physical (B-.76 [-1.50, -.03]) HRQoL, and increased odds of depressive symptoms (OR 1.49 [1.16, 1.91]). HA users had better cognition than non-users. Discussion: HL likely impacts cognition and well-being. HA use may have cognitive benefits.

Olfactory impairment in an adult population: the Beaver Dam Offspring Study.

The objective of this study was to determine the prevalence of olfactory impairment and associated risk factors and the effects of olfactory impairment on dietary choices and quality of life. Odor identification was measured in 2838 participants aged 21-84 years (mean 49 years) in the Beaver Dam Offspring Study. The overall prevalence of olfactory impairment was 3.8%, increased with age (from 0.6% in those<35 years to 13.9% among those≥65 years) and was more common in men than women. In a multivariate model age (odds ratio [OR]=1.48, 95% confidence interval [CI]=1.33, 1.64 for every 5-year increase), nasal polyps or deviated septum (OR=2.69, 95% CI=1.62, 4.48), ankle-brachial index<0.9 (OR=3.62, 95% CI=1.45, 9.01), and smoking (women only) (OR=2.43, 95% CI=1.19, 4.98 ever smoked vs. never) were associated with an increased odds of olfactory impairment, whereas higher household income, ≥$50,000 versus <$50,000 per year, was associated with a decreased odds of olfactory impairment (OR=0.48, 95% CI=0.31, 0.73). Participants with olfactory impairment were less likely to report that food tasted as good as it used to, or that they experienced food flavors the same. There was no association between olfactory impairment and general health-related quality of life, depressive symptoms, or dietary choices. The prevalence of olfactory impairment was low in this largely middle-aged cohort, and some factors associated with olfactory impairment are potentially modifiable.

Better cognitive function in younger generations - Insights from two cohort studies of middle-aged to older adults in Wisconsin.

BACKGROUND: Understanding generational trends in dementia and cognitive decline is essential to quantify future healthcare needs and may help identify interventions and preventions. We aimed to determine whether individuals from more recent generations showed better neurocognitive function. METHODS: This cross-sectional study combined data from 4439 participants (mean age 64 years (SD = 13); 57% were women) from the Epidemiology of Hearing Loss Study and Beaver Dam Offspring Study. We assessed participants' birth cohort (1901-1924, Greatest Generation; 1925-1945, Silent Generation; 1946-1964, Baby Boom Generation; 1965-1984, Generation X) and neurocognition (Trail-Making Tests A and B, Digit Symbol Substitution Test, Auditory Verbal Learning Test, Verbal Fluency Test). Multivariable linear regression models were utilized. RESULTS: Adjusted for age, sex, education, and known risk factors for cognitive decline, more recent generations showed better processing speed, executive function, attention, and verbal fluency than the Greatest Generation. Largest benefits were found in the Baby Boom Generation. Compared with the Greatest Generation, individuals from the Baby Boom Generation performed better on Trail-Making Tests A (-0.21 ln(time in s); 95% confidence interval (CI) -0.29, -0.13) and B (-0.31 ln(time in s); 95% CI -0.40, -0.22), Digit Symbol Substitution Test (6.07 numbers correct; 95% CI 3.61, 8.52) and Verbal Fluency Test (8.75 numbers correct; 95% CI 5.07, 12.42 in women; 5.28 numbers correct; 95% CI 0.79, 9.78 in men), with effect sizes similar to effects of 11-15 years of less aging. CONCLUSIONS: This indicates that some benefits of younger generations might be related to yet unknown and potentially modifiable environmental, health-related or lifestyle factors and motivates research of such underlying factors to promote healthy cognitive aging.

Effect of Long-Term Storage on the Reliability of Blood Biomarkers for Alzheimer's Disease and Neurodegeneration.

BACKGROUND: Stored blood samples from longitudinal cohort studies may be useful for studying biomarkers of preclinical Alzheimer's disease. OBJECTIVE: This study aimed to determine the reliability of amyloid-ß40 and amyloid-ß42 (Aß40, Aß42), total tau (TTau), and neurofilament light (NfL) concentrations measured in blood samples stored long-term at -80°C. METHODS: Aß40, Aß42, TTau, and NfL were measured in serum and plasma samples from two longitudinal cohort studies. Serum samples had been stored at -80°C for 5 (n = 24), 14 (n = 24), and 20 years (N = 78) and plasma samples had been stored for 16 years (N = 78). Biomarker concentrations were measured in duplicate using a single molecule array assay (Simoa; Quanterix, Billerica, MA). Replicate samples for each sample type and storage length were included. RESULTS: The concentrations of Aß40, Aß42, TTau, and NfL were within expected ranges. Some serum TTau concentrations were below the limit of detection. The average intra-assay coefficients of variation (CV) for duplicate measures were 2-7% for all assays except for serum TTau, which were higher (CVs 13% and 17%). Mean differences in original replicate pair Aß40, Aß42, and NfL concentrations were slightly greater in samples stored for longer versus shorter time periods. CONCLUSION: Aß40, Aß42, TTau, and NfL can be measured in serum and plasma samples that have been stored up to 20 years at -80°C. Long-term storage may be associated with small increases in the variability of concentrations in samples stored 14 or more years.