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Abstract Background The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial ( n = 977;ClinicalTrials.gov:NCT03243422) demonstrated that hearing intervention slowed 3‐year cognitive decline by 48% among a subgroup of participants. To further investigate differences by treatment with respect to cognitive benefit, we tested the hypothesis that hearing intervention is associated with improved neurodegeneration blood biomarkers 3‐years post‐randomization and assessed whether combining biomarkers and cognitive results improved power in the trial design. Method The ACHIEVE study is a multicenter, parallel‐arm, randomized trial (hearing intervention vs health education control) on 3‐year cognitive decline among adults 70–84years with untreated hearing loss and without substantial cognitive impairment. Participants were recruited from two populations: (1) a long‐standing cardiovascular health observational study (Atherosclerosis Risk in Communities [ARIC]), and (2) de novo community volunteers. Plasma was collected in year 3 in a subsample ( n = 540) while ARIC participants ( n = 164) also had baseline plasma. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) neurodegenerative biomarkers were derived using the Alamar CNS protein panel. Regression models estimated the association of treatment with 3‐year biomarkers and global cognitive differences in the combined sample and by recruitment source and annualized change from baseline in the ARIC sample. We included a simple composite score of the standardized outcomes (Table 2). Result Among the subsample, baseline characteristics were balanced by treatment. There were no significant differences on 3‐year neurodegeneration biomarker levels by treatment in the combined (Table 1) or de novo groups (Table 2). Among ARIC participants, intervention resulted in lower 3‐year GFAP (mean:‐0.415;95%CI:‐0.712,‐0.118) and NfL (mean:‐0.349;95%CI:‐0.652,‐0.046) (Table 2). Annualized change from baseline analyses among ARIC participants (Table 3) revealed intervention was associated with a slower rate of cognitive decline (difference‐in‐means:0.059;95%CI:0.018,0.100) and a slower rate of increase in GFAP (difference‐in‐means: ‐0.060;95%CI:‐0.112,‐0.009). Differences in estimates suggest combined score, relative to cognition alone, may increase power in clinical trials that show a positive effect (ARIC subgroup: p = 0.02vs. 0.08[Table 2] and p = 0.0009vs.0.048[Table 3]). Conclusion Hearing intervention was associated with positive 3‐year effects on neurodegeneration blood biomarkers in ARIC participants which parallels cognitive decline results. Results provides objective evidence of brain changes following hearing intervention and potential signal of a more powerful combined outcome approach for future brain health clinical trials.

Abstract The Atherosclerosis Risk in Communities (ARIC) study started in 1987‐1989 (visit 1), when participants from four U.S. communities were 45‐64yo. Participants have been seen at up to 10 additional in‐person visits with annual/semi‐annual telephone calls to ascertain clinical events, hospitalizations, and other health outcomes. In 2011‐2013, at ARIC visit 5, the ARIC Neurocognitive Study (ARIC‐NCS) was initiated for surviving participants, incorporating neuropsychological assessments at multiple in‐person visits and informant interviews to support cognitive adjudication. A subset of participants have undergone brain MRI with measurement of brain volumes, cortical thickness, arterial disease and vascular lesions, with a smaller subset having brain florbetapir PET. Blood‐based Alzheimer's disease (AD) biomarkers are available at multiple visits along with extensive measurement of vascular risk factors, vascular markers, and ‐omic (e.g.genomic and proteomic) data. This presentation will focus on the available data in ARIC, the methods underlying its collection and subsequent analysis, and some of the primary contributions of this study to the field. With 37 years of follow‐up, a great strength of ARIC is the ability to evaluate risk factors in midlife; ARIC studies have supported an association of midlife hypertension, diabetes, physical inactivity, and other vascular risk factors with reduced dementia risk, even among those with increased genetic risk for dementia. ARIC studies have demonstrated associations between stroke and dementia, and have linked vascular risk factors with blood‐based and imaging biomarkers of AD‐related dementias. ARIC has demonstrated the importance of hearing loss in dementia risk, and a subset of ARIC participants were recruited into (and were those who most benefited from the intervention of) the ACHIEVE study of hearing aid use for reduction of dementia. Proteomic studies have identified markers of dementia risk when evaluated in midlife. Recently, ARIC data informed updated estimates on lifetime risk of dementia, where it was estimated that among individuals surviving beyond age 55, 42% would develop dementia over their lifetime through age 95. ARIC studies continue to focus on risk factors for dementia, particularly now in the oldest old, and on contributors to cognitive reserve and resilience. ARIC follows a model of data sharing and broad collaboration.

Objective Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease‐associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Methods Participants in the Atherosclerosis Risk in Communities–Positron Emission Tomography study were followed from 1987–1989 (45–64 years old) through 2016–2017 (74–94 years old), with repeat cognitive assessment and dementia adjudication. In 2011–2013, dementia‐free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. Results In 298 individuals, 36 developed dementia (median follow‐up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16–5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72–3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18–5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03–2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83–3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18–4.01). Interpretation Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607–619

Introduction: Several studies report late-life physical activity (PA) to be associated with less brain atrophy. Associations of PA and subclinical brain markers evaluated at older ages may be subject to reverse causality due to comorbidity, age-related changes in lifestyle, or incipient cognitive impairment. Therefore, we aimed to compare late-life cross-sectional estimates of PA and ROI brain volumes to those using prospective PA measures from mid- to late-life. Methods: Participants (n=1549, mean age: 75, 39% male, 20% Black) with repeat assessments of PA from visit 1 (1987-1989) and a brain magnetic resonance imaging (MRI) in 2011-2013 were included. Total volume of PA in metabolic equivalent-min/week was estimated using the Baecke Physical Activity Questionnaire and classified as no, low, middle or high at each visit. Based on visit 1 and 3 (1993-1995) PA assessments, a subset of participants (n=663) were further categorized as habitually inactive or having habitually low, middle, or high PA in mid-life. Brain MRI using 3D-1.5T equipment quantified ROI volumes following a standardized protocol. Weighted linear regression adjusted for intracranial volume, demographics, select cardiovascular risk factors and ApoE4 estimated the standardized difference in ROI volumes. Results: Compared to no PA, high PA was associated with larger ROI brain volumes cross-sectionally in late-life (Table). High mid-life PA was only modestly associated with larger frontal cortical and deep gray matter volumes in late-life (Table). Habitually high PA in mid-life was not associated with less atrophy across brain regions in late-life. Conclusions: Our results do not support a causal interpretation of the cross-sectional associations between PA and brain volumes reported in late-life. Drawing on long-term population-based data, this study provides novel information on the associations of PA across life epochs with brain health, which can inform translational and intervention efforts to reduce age-related cognitive impairment.

Background: Midlife vascular risk factors (MVRF) are associated with incident dementia. Similarly, amyloid β(Aβ) and neurodegeneration (e.g.brain volumes), as parts of the Alzheimer’s Disease (AD) ATN framework, are associated with cognition. Whether vascular and AD-associated factors contribute to dementia independently or interact synergistically to reduce cognitive ability is not well understood. Methods: Recruited from 3 U.S. communities, ARIC-PET participants were followed from 1987-89 (45-64 yo) through 2016-17 (74-94 yo). Cognition was evaluated in 2011-13 (ages 69-88), and twice more, every 2-3 years. In 2011-13, nondemented ARIC-PET participants had a brain MRI, with measurement of white matter hyperintensities (WMH) and brain volumes, with florbetapir (Aβ) PET scans in 2012-14; global cortical standardized uptake value ratio (SUVR) was log-transformed and standardized. Dementia was classified by expert review, as well as phone and medical record surveillance. The relative contributions of vascular risk (MVRF, WMH volume) and AD pathology (elevated Aβ SUVR, smaller AD signature region volumes) to incident dementia were evaluated with Cox proportional hazards regression. Results: In 298 individuals, 36 developed dementia. In models with key MVRF, demographics, and Aβ SUVR, hypertension and Aβ each independently predicted dementia risk (per SD of Aβ SUVR: HR 2.57, 95% CI 1.72-3.84; hypertension: HR 2.57, 95% CI 1.16-5.67), but didn’t interact on dementia risk. WMH (per SD: HR 1.51, 95% CI 1.03-2.20) and Aβ SUVR (per SD: HR 2.52, 95% CI 1.83-3.47) each contributed to incident dementia but WMH lost significance when MVRF were added to the model. Smaller AD signature regions were associated with incident dementia, independent of Aβ SUVR, and remained significant after adjustment for MVRF (HR per SD 2.18, 95% CI 1.18-4.01). Conclusions: Midlife hypertension and late-life Aβ independently contribute to dementia risk, but don’t synergize on a multiplicative scale. Neurodegeneration (e.g.smaller AD signature region volume) is also associated with incident dementia, independent of Aβ and MVRF. Multiple pathways leading to dementia should be considered when evaluating risk factors and interventions to reduce the burden of dementia.

Background: Atrial fibrillation (AF) is a risk factor for cognitive decline, perhaps due to silent cerebral infarction, but it is unknown if it also acts on Alzheimer’s Disease (AD)-specific mechanisms, such as deposition of β-amyloid (Aβ). Left atrial changes in structure or function, or atrial cardiopathy, can lead to AF but may cause infarcts independently, and thus might also impact cognition. We hypothesize that Aβ is associated with AF and atrial cardiopathy, independent of AF, when defined similarly to an ongoing clinical trial (ARCADIA). Methods: 321 participants without dementia from the Atherosclerosis Risk in Communities study underwent florbetapir (FBP) PET, electrocardiogram and 2D echocardiography. Atrial cardiopathy was defined as ≥1 of: 1) left atrial volume index (LAVI) >34 ml/m2; 2) P-wave terminal force >5000 uV x ms and 3) serum NT proBNP>250 pg/mL. Cross-sectional associations between global cortical Aβ (>1.2 standardized uptake value ratio (SUVR)) and adjudicated history of atrial fibrillation and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Results: Participants, with mean age 76 y, were 56% female and 42% black. Odds of elevated FBP SUVR was increased for those with atrial cardiopathy (Model 3) and nearly doubled among those with enlarged LAVI that remained significant after sequential adjustment, including AF (Table). There was no significant association between either P-wave terminal force or NT proBNP and elevated FBP SUVR (Table), nor between elevated SUVR and AF. Conclusions: In this cross-sectional analysis of a cohort of healthy, nondemented community-dwelling older individuals, we report a significant association between atrial cardiopathy as well as LAVI and elevated amyloid, by PET, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede, or occur simultaneously with amyloid deposition.

Background and Purpose— Cardiovascular disease is a known risk factor for cognitive decline, although the mechanisms remain unclear. We hypothesize that Aβ (β-amyloid), a core pathology of Alzheimer's disease, will be associated with subclinical cardiac structure and function echocardiogram indices. Methods— Three hundred six nondemented participants from the ARIC study (Atherosclerosis Risk in Communities Study) underwent florbetapir positron emission tomography and 2D echocardiography (echo). Cross-sectional associations between echo markers of left ventricular structure and function and global cortical Aβ (≥1.2 standardized uptake value ratio were evaluated using multivariable logistic regression with interaction terms when appropriate. Results— Participants ranged in age from 67 to 88 years, were 57% female and 42% black. Per 1 cm increase in end-diastolic left ventricular diameter, the odds of elevated florbetapir standardized uptake value ratio doubled (odds ratio, 2.04 [95% CI, 1.10–3.77]), with similar findings when excluding mild cognitive impairment (odds ratio, 2.61 [95% CI, 1.22–5.59]). Conclusions— We have demonstrated a significant association between a marker of left ventricular structure and elevated florbetapir standardized uptake value ratio, identified using positron emission tomography. Ongoing prospective work will help determine if changes in cardiac structure and function either precede, or occur simultaneously with deposition of amyloid.

Background: Increasing evidence points to intracranial atherosclerosis as a risk factor not only for stroke but also for dementia, but whether it is linked to Alzheimer’s disease-specific pathology itself is less understood. In the community-based Atherosclerosis Risk in Communities (ARIC) study, we evaluated the cross-sectional association between intracranial atherosclerosis and cerebral amyloid deposition, in nondemented participants. Methods: In 2011-2014, a subset of participants from the ARIC Neurocognitive Study underwent both a brain MRI, including high-resolution vessel wall imaging, and florbetapir PET, as a marker of amyloid deposition. We analyzed the association between elevated amyloid (defined as a global cortical florbetapir standardized uptake value ratio (SUVR)>1.2) and intracranial arterial plaque presence, frequency, and extent of stenosis, with adjustment for demographic and vascular risk factors. We tested effect modification by APOE ε4 genotype. Results: In 300 participants (mean age of 76y, 44% African-American, 56% female, 31% carriers of at least one APOE ε4 allele), intracranial plaque was found in 105 (35%) participants. Mean SUVR was higher in individuals with vs without plaque (1.34 ± 0.29 vs 1.27 ± 0.23, p=0.03). In adjusted models, plaque presence was not associated significantly with elevated SUVR in the total sample, nor was number of plaques. Associations between plaque presence and extent were generally stronger in APOE ε4 carriers than noncarriers (p<0.05 for interaction for some plaque features; see Table). Conclusions: Although intracranial arterial plaque or stenosis was not definitively associated with brain amyloid in this sample of nondemented older adults, associations with brain amyloid appeared stronger in carriers of an APOE ε4 allele, consistent with studies demonstrating a similar relationship as that seen with other more traditionally measured vascular risk factors.