Midlife Risk Research Articles

Computer use and cardiovascular risk biomarkers in midlife and older adults

With increased computer usage amongst midlife and older adults, concerns are emerging with regards to the potential adverse health effects of computer use given the sedentary habits it may encourage. The current study aims to investigate the relationship between computer use and cardiovascular risk in midlife and older adults. From the National Survey of Midlife Development in the United States II: Biomarker Project (2004–2009) and the National Survey of Midlife Development in the United States (MIDUS II), 2004–2006, we examined five cardiovascular risk biomarkers—high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, interleukin-6, and C-reactive protein—in relation to self-reported general computer use frequency and computer use at work frequency. Our results show that general computer use frequency and computer use at work frequency were not significant predictors of any of the five cardiovascular risk biomarkers—HDL cholesterol, LDL cholesterol, triglycerides, interleukin-6, and C-reactive protein. However, our exploratory analysis showed that employment status significantly moderated the relationship between general computer use frequency and LDL cholesterol. Our study highlights the importance of a more nuanced approach to understanding the health implications of computer use and sedentary behaviour in general.

Spatiotemporal Gait Characteristics and Neuropsychological Performance in Midlife

Abstract Background Midlife risk factors such as Type 2 Diabetes Mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life, with executive function, memory and attention domains often affected first. Spatiotemporal gait characteristics are increasingly recognised as biomarkers of neurocognitive function and later dementia risk. Methods Using an automated walkway, 24 spatiotemporal gait parameters were examined across 5 domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions. Neurocognitive function was measured using a neuropsychological assessment battery. Linear regression was used assess the relationship between each gait parameter across the three walks and cognitive function. Results 102 middle-aged adults underwent assessment, 65 with uncomplicated T2DM (57.5 ± 8.0 years; 40% female) and 37 healthy controls (57.0 ± 8.3 years; 62.1% female). T2DM was associated with significant changes in gait phases and rhythm domains at usual-pace, and greater gait variability observed during maximal-pace and dual-task. In the overall cohort, both gait pace and rhythm domains were associated with memory and executive function during usual pace walking. At maximal-pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual-task, associations between gait variability and delayed memory and executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Conclusion This supports the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals. Discrete associations were seen between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms, in addition to single-task usual-pace gait, may be important in cognitively unimpaired populations with risk factors for later cognitive decline - with the aim of identifying individuals who may benefit most from potential preventative interventions.

Proteomic analyses reveal plasma EFEMP1 and CXCL12 as biomarkers and determinants of neurodegeneration.

Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes. We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n=815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk. Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization. Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration. Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration.

Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia

Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

While immune function is known to play a mechanistic role in Alzheimer’s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression – a central feature of AD – remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Discrete Relationships between Spatiotemporal Gait Characteristics and Domain-Specific Neuropsychological Performance in Midlife.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline-with the aim of identifying individuals who may benefit from potential preventative interventions.

Association of midlife air pollution exposures and residential road proximity with incident dementia: The Atherosclerosis Risk in Communities (ARIC) study

BackgroundIncreasing evidence links higher air pollution exposures to increased risk of cognitive impairment. While midlife risk factors are often most strongly linked to dementia risk, few studies have considered associations between midlife roadway proximity or ambient air pollution exposure and incident dementia decades later, in late life. ObjectivesOur objective was to determine if midlife exposures to ambient air pollution or roadway proximity are associated with increased risk of dementia in the Atherosclerosis Risk in Communities (ARIC) study over up to 29 years of follow-up. MethodsOur eligible sample included Black and White ARIC participants without dementia at Visit 2 (1990–1992). Participants were followed through Visit 7 (2018–2019), with dementia status and onset date defined based on formal dementia ascertainment at study visits, informant interviews, and surveillance efforts. We used adjusted Weibull survival models to assess the associations of midlife ambient air pollution and road proximity with incident dementia. ResultsThe median age at baseline (1990–1992, Visit 2) of the 12,700 eligible ARIC participants was 57.0 years; 56.0% were female, 24.2% were Black, and 78.9% had at least a high school education. Over up to 29 years of follow-up, 2511 (19.8%) persons developed dementia. No associations were found between ambient air pollutants and proximity to major roadways with risk of incident dementia. In exploratory analyses, living closer to roadways in midlife increased dementia risk in individuals younger at baseline and those without midlife hypertension, and there was evidence of increased risk of dementia with increased midlife exposure to NOx, several PM2.5 components, and trace metals among those with diabetes in midlife. ConclusionsMidlife exposure to ambient air pollution and midlife roadway proximity was not associated with dementia risk over decades of follow-up. Further investigation to explore potential for greater susceptibility among specific subgroups identified here is needed.

Forecasting the 20-Year Incidence of Dementia by Socioeconomic Status, Race/Ethnicity, and Region Based on Mid-Life Risk Factors in a U.S. Nationally Representative Sample.

Alzheimer's disease and related dementias (ADRD) incidence varies based on demographics, but mid-life risk factor contribution to this variability requires more research. The purpose of this study is to forecast the 20-year incidence of dementia in the U.S. overall and stratified by race/ethnicity, socioeconomic status (SES), and U.S. geographic region given prior mid-life risk factor prevalence and to examine the extent to which risk factor differences 20 years ago may explain current SES, race/ethnicity, or regional disparities in dementia incidence. We applied the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) prediction model to the 2006 wave of the Health and Retirement Study (HRS) in participants aged 45 to 64 to estimate the 20-year risk of incident ADRD. The 20-year risk of dementia among middle-aged Americans was 3.3% (95% CI: 3.2%, 3.4%). Dementia incidence was forecast to be 1.51 (95% CI: 1.32, 1.71) and 1.27 (95% CI: 1.14, 1.44) times that in Hispanic and Non-Hispanic Black individuals respectively compared statistically to Non-Hispanic White individuals given mid-life risk factors. There was a progressive increase in dementia risk from the lowest versus highest SES quintile. For geographic region, dementia incidence was forecast to be 1.17 (95% CI: 1.06, 1.30) and 1.27 (95% CI: 1.14, 1.43) times that in Midwestern and Southern individuals respectively compared statistically to Western individuals. Some disparities in dementia incidence could be explained by differences in mid-life risk factors and may point toward policy interventions designed to lessen the ADRD disease burden through early prevention.

Loss of neuronal lysosomal acid lipase drives amyloid pathology in Alzheimer's disease.

Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed Aβ localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal Aβ. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with Aβ1-42, and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of Aβ in neuronal lysosomes to drive AD amyloid pathology.

Concussion burden and later-life cardiovascular risk factors in former professional American-style football players.

Mid-life cardiovascular risk factors are associated with later cognitive decline. Whether repetitive head injury among professional athletes impacts cardiovascular risk is unknown. We investigated associations between concussion burden and postcareer hypertension, high cholesterol, and diabetes among former professional American-style football (ASF) players. In a cross-sectional study of 4080 professional ASF players conducted between January 2015 and March 2022, we used an mulitsymptom concussion symptom score (CSS) and the number of loss-of-consciousness (LOC) episodes as a single severe symptom to quantify football-related concussion exposure. Primary outcomes were hypertension, dyslipidemia, and diabetes, defined by current or recommended prescription medication use. The prevalence of hypertension, high cholesterol, and diabetes among former players (52 ± 14 years of age) was 37%, 34%, and 9%. Concussion burden was significantly associated with hypertension (lowest vs. highest CSS quartile, odds ratio (OR) = 1.99; 95%CI: 1.33-2.98; p < 0.01) and high cholesterol (lowest vs. moderate CSS, OR = 1.46, 95%CI, 1.11-1.91; p < 0.01), but not diabetes. In fully adjusted models, the prevalence of multiple CVD was associated with CSS. These results were driven by younger former players (≤ 40 year of age) in which the odds of hypertension were over three times higher in those in the highest CSS quartile (OR = 3.29, 95%CI: 1.39-7.61; p = 0.01). Results were similar for LOC analyses. Prior concussion burden is associated with postcareer atherogenic cardiovascular risk profiles among former professional American football players.

Modifiable risk factors and risk of myocardial infarction in offspring with parental disease.

Children of patients with early-onset myocardial infarction (MI) are at increased risk, but the importance of concordant versus discordant parent-offspring risk factor profiles on MI risk is largely unknown. We quantified the long-term absolute risk of MI according to shared risk factors in adulthood. We sampled data on familial predisposed offspring and their parents from the Framingham Heart Study. Early MI was defined as a history of parental MI onset before age 55 in men or 65 in women. Individuals were matched 3:1 with non-predisposed offspring. Cardiovascular risk factors included obesity, smoking, hypertension, high cholesterol, and diabetes. We estimated the absolute 20-year incidence of MI using the Aalen-Johansen estimator. At age 40, the 20-year risk of MI varied by cholesterol level (high cholesterol 25.7% [95% confidence interval 11.2%; 40.2%] vs. non-high cholesterol 3.4% [0.5; 6.4]) among predisposed individuals and this difference was greater than in controls (high cholesterol 9.3% [1.5; 17.0] vs. non-high cholesterol 2.5% [1.1; 3.8]). Similar results were observed for prevalent hypertension (26.7% [10.8; 42.5] vs. 4.0% [0.9; 7.1] in predisposed vs. 10.8% [3.2; 18.3] and 2.1% [0.8; 3.4] in controls). Among offspring without risk factors, parental risk factors carried a residual impact on 20-year MI risk in offspring (0% [0; 11.6] for 0-1 parental risk factors versus 3.3% [0; 9.8] for ≥2 parent risk factors at age 40, versus 2.9% [0; 8.4] and 8.5% [0; 19.8] at age 50 years). Children of patients with early-onset MI have low absolute risks of MI in the absence of midlife cardiovascular risk factors, especially if the parent also had a low risk factor burden prior to MI.

Women with a history of gestational diabetes mellitus present an accumulation of cardiovascular risk factors at age 46-A birth cohort study.

The incidence of gestational diabetes mellitus (GDM) is globally increasing, and it has been associated with later type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, long-term population-based studies investigating common CVD risk factors years after pregnancy are lacking. To evaluate the future mortality and morbidity in cardiovascular and metabolic diseases, we conducted a thorough investigation of midlife risk factors in women with and without previous GDM. A prospective population-based cohort study was conducted of 3173 parous women from the Northern Finland Birth Cohort, 1966. Study participants were obtained from the national register or patient records. Those with a GDM diagnosis formed the GDM cohort (n = 271), and those without a previous GDM diagnosis formed the control cohort (n = 2902). Clinical examinations were performed on participants at the age of 46 and included anthropometric measurements, oral glucose tolerance test (OGTT), biochemical measurements, and cardiovascular assessment. At the age of 46, women in the GDM cohort had a higher body mass index (BMI, 29.0 kg/m2 vs 26.3 kg/m2, p < 0.001) and greater waist circumference (94.1 cm vs 86.5 cm, p < 0.001) than the control cohort. In the GDM cohort, a higher incidence of impaired glucose tolerance (12.6% vs 7.3%, p = 0.002), more previously diagnosed and OGTT-detected type 2 diabetes (23.3% vs 3.9%, p < 0.001), lower high-density lipoprotein (1.53 mmol/L vs 1.67 mmol/L, p = 0.011), higher triglycerides (1.26 mmol/L vs 1.05 mmol/L, p = 0.002) and a higher fatty liver index (6.82 vs 2.47, p < 0.001), were observed even after adjusting for BMI, polycystic ovary syndrome, parity, level of education, physical activity, smoking, and alcohol consumption. The women in the GDM cohort also had more MetS (42.6% vs 21.9%, p < 0.001) and higher risk scores for CVD and fatal events (Framingham 4.95 vs 3.60, p < 0.001; FINRISK 1.71 vs 1.08, p < 0.001). Women with a previous diagnosis of GDM exhibit more risk factors for CVD in midlife and are at a higher risk for cardiovascular events later in life.

The PREVENT dementia programme: baseline demographic, lifestyle, imaging and cognitive data from a midlife cohort study investigating risk factors for dementia.

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological samples (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery and are imaged using multi-modal 3-T MRI scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies that supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data include 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ± 5.47), with the majority female (n = 433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% versus 48.6%) and a relatively high prevalence of APOEɛ4 carriers (n = 264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry (n = 672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (total score 95.6 ± 4.06). Mean white matter hyperintensity volume at recruitment was 2.26 ± 2.77 ml (median = 1.39 ml), with hippocampal volume being 8.15 ± 0.79 ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel data set to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer's Disease Data Initiative platform and Dementia Platforms UK platform pending approval of the data access request from the PREVENT steering group committee.

Lifestyle for brain health and cognitive functioning in midlife to early late-life New Zealanders: Utility of the LIBRA index.

There is enormous potential to improve brain health and reduce the risk of cognitive decline and dementia based on modifiable risk factors. The Lifestyle for Brain Health (LIBRA) index was developed to quantify modifiable dementia risk or room for brain health improvement. The objective of the study was to investigate the utility of the LIBRA index in relation to cognitive functioning in a midlife to early late-life sample of New Zealanders. A subsample (n=1001) of the longitudinal New Zealand Health, Work and Retirement (NZHWR) study completed face-to-face cognitive assessments using the 'Kiwi' Addenbrooke's Cognitive Examination-Revised (ACE-R)in 2010 and again in 2012, in addition to completing biennial NZHWR surveys on socioeconomic, health and wellbeing aspects. The LIBRA index was calculated incorporating information on 8 out of 12 modifiable health and lifestyle factors for dementia. Unadjusted and adjusted regression models and mixed effects models were used to inspect associations of LIBRA with cognitive functioning, cognitive impairment, and cognitive decline. The analytical sample (n=881 [88.0%], after considering exclusion criteria and missing data) had a mean age of 63.1 (SD=6.5) years, 53.3% were female, 26.2% were Māori, and 61.7% were highly educated. Higher LIBRA scores (indicating higher modifiable dementia risk) were associated with lower cognitive functioning (B=-0.33, 95% CI=-0.52;-0.15, p<0.001) and a higher likelihood of cognitive impairment (OR=1.22, 95% CI=1.04; 1.42, p=0.013), but did not predict cognitive decline over 2years (B=-0.03, 95% CI=-0.22; 0.16, p=0.766), adjusted for age, age2, gender, education, and ethnicity. The LIBRA index indicated promising utility for quantifying modifiable dementia risk in midlife and early late-life New Zealanders. For local use, refinement of the LIBRA index should consider cultural differences in health and lifestyle risk factors, and further investigate its utility with a wider range of modifiable factors over a longer observation period.

Abstract 46: Midlife and Late-Life Population Attributable Fractions of Dementia Risk Factors in the United States: A Cohort Study From the Dementia Risk Pooling Project

Introduction: Dementia cases in the US are projected to nearly double from 5.3 million in 2019 to 10.5 million by 2050. Research has suggested that 41% of US dementia cases may be prevented by eliminating several specific modifiable risk factors. Still, few studies examine risk factor variation between midlife and late-life. Previous studies have also been limited by sample diversity and size. The Dementia Risk Pooling Project (DRPP) is a consortium of longitudinal cohorts including several underrepresented racial/ethnic groups pooled at the individual level. Methods: We estimated individual and combined population attributable fractions (PAF) for seven modifiable risk factors in midlife (aged 45-64) and late-life (aged 65+), using data from six US cohorts in DRPP. We also used potential impact fractions (PIF) to estimate dementia cases that could be prevented due to risk factor reduction in midlife and late-life based upon the National Alzheimer’s Advisory Council goal of a 15% reduction in dementia risk factors by 2030. Results: In a sample of 41,432 unique participants (ppts), risk factor exposure was measured in midlife for 29,983 ppts (60% female, 77% white) and in late-life for 30,633 ppts (56% female, 70% white). During follow-up, 4,186 midlife ppts and 4,893 late-life ppts developed dementia. We found that eliminating midlife risk factors could prevent a greater proportion of dementia cases [PAF 41.3%, 27.9%-54.6%] compared to late-life risk factors [23.1%, 12.4%-33.7%]. Midlife physical inactivity [18.8%, 15.1%-22.4%] appeared to be the greatest contributor. Late-life hypertension and depression appeared to contribute to 9.8% [5.5%-13.9%] and 4.2% [3.5%-5.0%] of cases, respectively. Given the US prevalence of dementia in 2020, we estimate that a 15% reduction in physical inactivity alone could prevent 148,339 dementia cases. Conclusion: The importance of modifiable risk factors for dementia may vary with age. These estimates could inform the timing of public health interventions for dementia prevention.

Sleep duration in midlife and old age and risk of mortality over a 48-year follow-up: The Helsinki businessmen study (HBS) cohort

ObjectivesBoth short and long sleep duration have been associated with increased mortality, but there are few truly long-term studies. Study designThis is a cohort study of 2504 men born between 1919 and 1934. In 1974–1975 (mean age 48), participants underwent baseline clinical examinations and sleep duration assessments. A follow-up examination took place 35 years later, in 2010 (mean age 82). Main outcome measureAll-cause mortality data from baseline and from old age were collected through to December 31, 2022. ResultsAt baseline, short sleep duration (≤6 h per night), normal sleep duration (>6 and ≤ 8 h), and long sleep duration (>8 h) was reported by 266, 2019 and 219 men, respectively. Men with short sleep duration had higher levels of smoking, alcohol consumption, body mass index, and poorer self-rated health than those with normal sleep duration. During the 48-year follow-up, 2287 men died. The unadjusted hazard ratio for mortality was 1.20 (95 % confidence interval [CI] 1.05–1.37) for short compared with normal sleep duration, but this association vanished after adjustments (1.01, 95 % CI 0.87–1.17). In old age, the corresponding hazard ratios were 1.41 (1.16–1.72) and 1.19 (0.94–1.51) for short sleep duration and 1.33 (1.09–1.63) and 1.31 (1.02–1.67) for long sleep duration. ConclusionsIn a comprehensive lifespan follow-up, the modestly increased mortality among men with short sleep duration in midlife was attributed to unhealthy lifestyle factors. In old age both long and short sleep duration seemed to be associated with modestly increased mortality.ClinicalTrials.gov identifier for the HBS: NCT02526082

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Health Care Is Not Enough to Prevent Dementia.

With an aging population, an increase in cases of Alzheimer's disease and dementia worldwide poses a significant health burden. While we hope for a cure, preventing dementia by reducing risks is important for global population health. Prevention strategies are difficult to implement when facing inequality across the world for access to healthy lifestyles. An approach that centers on individual responsibility and health professional interventions for targeted groups may risk missing the policy and environmental drivers of change. Barriers and enablers need to be explored and interventions are needed at individual, structural and social levels to normalize mid-life risk reduction.

HEALTH AND WELL-BEING ACROSS ECOLOGICAL SYSTEMS AND TIME IN MID LIFE AND LATE ADULTHOOD

Abstract Health and well-being are shaped by peoples’ experiences and ecological contexts (Bronfenbrenner, 2005), reflecting the influence of complex person-context relationships. For example, experiences (e.g., daily stressors, early childhood adversity) occur within microlevel (e.g., marital relationships, neighborhoods) and macrolevel (e.g., societal inequalities) contexts, impacting both daily well-being and healthy aging. Further, a robust literature highlights the significance of naturally occurring everyday experiences for a range of health outcomes, underscoring how daily experiences have immediate and lasting effects on individual physical and cognitive health and psychological well-being. Drawing on Bronfenbrenner’s Ecological Model, the current symposium features novel research examining health and well-being outcomes across diverse ecological systems and time scales across midlife and old age, with the goal of articulating how innovative approaches for studying person-context interactions can be leveraged to understand both proximal and long-term health and well-being. Polenick and colleagues will examine associations between daily negative and positive events and well-being among heterosexual married couples living with early-stage dementia. Cichy et al. will examine gender differences in the prospective effects of daily stress processes on long-term chronic disease risk in midlife and later life. Next, Turner and Mogle will examine how positive and negative affect mediate the associations between daily memory lapses and psychological well-being. Finally, Choi, Munoz, Scott, and Sliwinski will examine whether current positive (i.e., neighborhood cohesion) and negative (i.e., neighborhood violence) neighborhood contexts moderate the effect of childhood stress exposure on cognitive function in adulthood. Robert Stawski will synthesize the presentations and offer insights for future research.

MIDLIFE MEDIATORS OF EDUCATIONAL DIFFERENCES IN DEMENTIA RISK IN LATER LIFE:PRELIMINARY RESULTS FROM THE HUNT STUDY

Abstract There is a well-known association between education and dementia risk. However, there is limited knowledge of the mediating mechanisms. Using data from the HUNT study linked with registries (n=9745), we examined the mediating role of occupation complexity, smoking, physical inactivity, systolic blood pressure, body mass index(BMI), cardiovascular diseases, hearing impairment, diabetes, and depression score (only in HUNT2) assessed during HUNT1(age 45years) and HUNT2(age 56years) for the association between education and dementia among 70+ years using causal mediation analysis. Among eligible participants, 15.7% had dementia at age 70+ years, completed compulsory education (25.7%), lower-secondary (41.7%), upper-secondary(12%), undergraduate(16.5%), and postgraduate education(4%). For every one-unit increase in educational level from compulsory education to the following levels, a decrease in the odds of having dementia among 70+ years was found (OR=0.74). Midlife mediators assessed at 45 and 56 years jointly explained 17.3% and 26.8% of the effect of education on dementia among 70+ years, respectively. Smoking and systolic blood pressure (each explained 3.7%) followed by BMI(explained 2.3%) showed a significant independent mediating role for the educational differences in dementia among 70+ years. Whereas, among the mediators assessed at the age of 56 years, systolic blood pressure(explained 6.1%), hearing impairment (explained 4.4%), smoking(explained 3.1%) and depression score(explained 2.7%) showed significant independent mediating effects. Midlife risk factors of dementia considered in this study explained nearly one-fourth of the effect of education on dementia in particular, systolic blood pressure, hearing impairment, smoking, depression score and BMI. If truly causal, these factors could indicate potential targets for interventions.