Timothy M. Hughes

Plasma biomarkers of Alzheimer disease (AD) neuropathology (amyloid-β42 to amyloid β40 [Aβ42/40] ratio, phosphorylated tau at threonine [p-tau181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in late-life are associated with cognitive decline. Whether these biomarkers in midlife are predictive of subsequent cognitive decline, and whether they are associated with different cognitive domains, is uncertain. In this study, we investigated associations of midlife and late-life plasma Aβ42/40, p-tau181, NfL, and GFAP with late-life change in domain-specific (memory, language, and executive function) and global cognitive function. We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Outcome follow-up was from ARIC visit 5 (2011-2013) to visit 9 (2021-2022). We included all individuals from ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; and Minneapolis suburbs, Minnesota) with biomarkers measured from stored specimens in midlife (visit 3, 1993-1995, mean age 59.0 years) and late-life (visit 5, 2011-2013, mean age 76.8 years). Aβ42/40, p-tau181, NfL, and GFAP were measured with the Quanterix Simoa platform and standardized to visit 3 to facilitate cross-biomarker comparisons of their rate of change from midlife to late-life. We estimated change in memory, language, executive function, and global cognition factor scores from visit 5 to visit 9 with linear mixed-effect models. In 1,515 included participants, 60.7% (n = 920) were female and 25.5% (n = 387) were Black. Each SD increase in p-tau181 in midlife was significantly associated with faster late-life memory decline (β = -0.030 [95% CI -0.059 to -0.001] SD. Midlife Aβ42/40, NfL, and GFAP were not associated with subsequent decline in any cognitive domain. In late-life, p-tau181, NfL, and GFAP were significantly associated with faster decline in different cognitive domains, with the strongest associations seen with memory (β = -0.091 [95% CI -0.123 to -0.058] SD; β = -0.064 [95% CI -0.106 to -0.023] SD; and β = -0.048 [95% CI -0.082 to -0.013] SD, respectively). Midlife p-tau181 was associated with faster 11-year memory decline beginning 20 years later in the ARIC cohort, which underscores a potentially long prodromal phase of cognitive decline that could precede dementia onset. In late-life, biomarkers for AD, neurodegeneration, and neuroinflammation were associated with faster decline across different cognitive domains, but associations remained strongest for p-tau181 and memory.

BACKGROUND: Assessment and treatment of orthostatic hypotension (OH) are recommended to prevent falls in older adults. However, the optimal timing of standing blood pressure (BP) assessments to identify clinically relevant OH remains unclear. METHODS: We measured 3 supine BP readings after 5 minutes of rest at 30-second intervals and 6 standing BP readings (timed at 0, 1, 2, 3, 4, and 5 minutes after standing) during the ARIC study (Atherosclerosis Risk in Communities) visit 10. OH was defined as a drop in BP (systolic ≥20 mm Hg or diastolic ≥10 mm Hg) upon standing from the supine position. We quantified the prevalence and predictors of initial OH (immediately after standing), early OH (within 3 minutes), late OH (after 3 minutes), and sustained OH (all 6 minutes). We examined their associations with orthostatic symptoms and falls using logistic regression and negative binomial models, respectively. RESULTS: Of the 863 participants (mean age, 83.7 years), 41.3% had initial OH. Participants on antihypertensive medications had higher odds of all types of OH irrespective of controlled (<130/80 mm Hg) or uncontrolled (≥130/80 mm Hg) hypertension compared with those without hypertension (<130/80 mm Hg) and no antihypertensive use. Initial and early OH were strongly associated with orthostatic symptoms in the process of standing from the supine position (odds ratio, 2.34 [95% CI, 1.42–3.86]; odds ratio, 1.82 [95% CI, 1.11–2.98], respectively). Finally, participants with initial OH had higher fall rates (rate ratio, 1.45 [95% CI, 1.02–2.06]) than those without OH. CONCLUSIONS: Measuring BP within 3 minutes of standing, particularly the first BP measurement immediately after standing, may provide clinicians with important information on falls risk and orthostatic symptoms.

Background and ObjectivesDementia remains without curative treatments, underscoring the need for early identification of high-risk individuals. There may be sex-specific differences in associations...

Background and ObjectivesThe apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 a...

Background: Current clinical guidelines recommend home blood pressure monitoring (HBPM) to confirm hypertension diagnosis, guide therapy, and support long-term control. However, the optimal number of HBPM measurements needed for a valid assessment is not established. Methods: At ARIC Visit 10 (2023), participants completed an 8-day HBPM protocol with morning and evening measurements and 3 readings per session. We evaluated the validity between the 8-day mean (reference) and streamlined protocols (fewer days, less than 3 readings per session, or only morning or evening measurements). In secondary analyses, we assessed the validity of these HBPM protocols relative to ambulatory BP. Results: Among 812 participants (median age 83 years, 24% Black adults, 40% male, 84% using anti-hypertensive medications), median BP varied by less than 3 mm Hg across the 8-day protocol. The greatest improvement in HBPM validity occurred when extending the averaging window from 1 to 2 days. By 3 days, concordance correlation coefficients exceeded 0.95, and ≥97% of participants were within 10 mm Hg of the reference for both systolic and diastolic BP. Averaging ≥2 readings per session, including both morning and evening measurements, yielded greater validity than a single reading or timepoint. Conclusions: In this community-based cohort of older adults, HBPM provided stable BP estimates within 3 days (including non-consecutive measurements within an 8-day period) using morning and evening sessions with ≥2 readings each. While further studies are required to validate generalizability beyond this engaged cohort, these findings support shorter, less burdensome HBPM protocols in clinical guidelines for hypertension management in older adults.

Background: Lacunes are 3-15 mm cavities originating from small perforating artery disease and are a hallmark of cerebral small vessel disease (cSVD). Prior prevalence studies relied on manual rating, which is prone to inter-rater variability and cannot quantify volume. We applied deep learning to quantify lacunes in a diverse community-based cohort. Methods: In this cross-sectional analysis of 1,038 Multi-Ethnic Study of Atherosclerosis (MESA) participants, with longitudinal cognitive follow-up, we quantified lacunes, confirmed them with a trained rater, and classified them as deep or lobar. Regression models examined associations of lacunes with cardiovascular risk factors, other small vessel disease lesions, brain atrophy, and cognition. Structural equation modeling evaluated whether deep lacune burden mediated associations of age or Framingham All-Cardiovascular Disease (CVD) Risk Score with atrophy and cognition. Results: Overall, 182 participants (17.5%) had at least one lacune (deep: 9.2%; lobar: 9.6%). Hispanic participants had lower lacune burden than White participants. Age, Framingham All-CVD Risk Score, PREVENT 10-year Total CVD Risk Score, and hypertension were associated with overall and deep lacunes, while lobar lacunes showed no associations. Deep lacunes were associated with white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds, as well as SPARE-BA, SPARE-AD, and cortical and hippocampal atrophy. Deep lacunes were cross-sectionally associated with decreased global cognition and language/semantic performance, and longitudinally with accelerated executive function decline independent of count. Deep lacune burden significantly mediated associations of age and Framingham All-CVD Risk Score with SPARE-AD, SPARE-BA, and global cognition. Conclusions: In this multi-ethnic community-based cohort, deep lacune burden demonstrated stronger associations with vascular risk, other cerebral small vessel disease markers, brain atrophy, and longitudinal executive function decline than lobar burden. By providing a continuous measure of lesion volume, automated quantification captured information beyond lacune count.

INTRODUCTION: Knowledge about how Alzheimer’s disease (AD) and AD-related dementia (AD/ADRD) plasma biomarkers relate to global and domain-specific cognitive functioning across diagnostic groups remains limited, particularly in heterogeneous, community-dwelling populations with multiple comorbidities. METHODS: We evaluated associations between baseline plasma biomarker levels (Aβ42/40, p-tau181, p-tau217, NfL, GFAP) and cognitive performance at baseline and longitudinally (up to 7 years). Participants (n=590) enrolled in the Wake Forest Alzheimer’s Disease Research Center Clinical Core (314 cognitively unimpaired [CU]; 206 mild cognitive impairment [MCI]; and 70 dementia) completed annual cognitive assessments including the Uniform Data Set (UDSv3; NACC). Domain-specific cognitive composites including memory, executive function, attention, language, visuospatial ability, and phonemic fluency, as well as a modified Preclinical Alzheimer’s Cognitive Composite (PACC5), were evaluated. General linear and mixed-effects models were adjusted for demographics (age, sex, race, education), APOE-ε4 status, comorbidities (estimated glomerular filtration rate; BMI), and cardiometabolic health factors (hypertension, diabetes). Effect modification by cognitive diagnosis was evaluated. RESULTS: Baseline plasma biomarkers, particularly p-tau217, were associated with poorer baseline cognitive performance and greater longitudinal decline on the PACC5 and all cognitive domains assessed, except phonemic fluency (strongest for memory). Post-hoc analyses indicated associations between plasma biomarker levels and cognition were generally more pronounced in MCI compared with CU participants. Effect modification by baseline cognitive status was limited and attenuated when all biomarkers were modeled simultaneously. Comorbidities and cardiometabolic factors modified select associations. DISCUSSION: Plasma AD/ADRD biomarkers, particularly p-tau217, were associated with cognitive impairment and decline in a heterogenous community cohort. HIGHLIGHTS: The WF ADRC is a clinically heterogeneous, comorbidity-rich community-dwelling cohort Plasma AD/ADRD biomarkers were associated with poorer baseline cognition and longitudinal cognitive decline Associations were strongest for the PACC5 composite and memory-related cognitive domains p-tau217 provided the most robust biomarker signal across models

INTRODUCTION: We evaluated associations between an in vivo (magnetic resonance imaging [MRI]) marker of arteriolosclerosis (ARTS) and multimodal neuroimaging and plasma ATN(V) biomarkers. METHODS: Among 238 participants with both amyloid and tau positron emission tomography (PET) scans within 1 year of MRI, we examined multivariable adjusted models relating ARTS with structural MRI (cortical thickness/volume, white matter hyperintensities [WMH]), diffusion MRI (fractional anisotropy [FA], mean diffusivity [MD], NODDI free water [FW]), cerebral blood flow, plasma biomarkers (p‐tau217, Aβ42/40, neurofilament light, glial fibrillary acidic protein [GFAP]), and PET imaging. RESULTS: As expected, ARTS was most strongly linked to age and greater WMH burden and diffusion‐based indices of microstructural disruption (FA, MD, and FW). ARTS was elevated in ATN biomarker‐positive groups (highest in A+T+N+) and was associated with greater neurodegeneration and higher plasma biomarker levels, GFAP in particular. DISCUSSION: ARTS relates to other markers of vascular brain injury, neurodegeneration, amyloid and tau pathology within the ATN(V) framework, and inflammation.

BACKGROUND: Effects of blood pressure (BP) control on the relationships between arterial stiffness and subsequent cognitive impairment remain unclear. METHODS: The Systolic Blood Pressure Intervention Trial Pulse Wave Velocity (PWV) substudy evaluated the effect BP control on total (T‐PWV, in m/s), structural (S‐PWV), and load‐dependent (LD‐PWV) arterial stiffness over 3 years as they related to time to cognitive impairment over 10 years modeled using multivariable proportional hazard models for baseline stiffness and joint longitudinal survival models for changes in stiffness. RESULTS: Six hundred fourteen participants with stiffness measures had 90 cognitive impairment events over follow‐up. Reductions in LD‐PWV under intensive BP control were associated with 21% risk reduction for cognitive impairment. T‐PWV and S‐PWV continued to increase regardless of BP control with each m/s increase in stiffness associated with 11% to 12% increase in risk for cognitive impairment. DISCUSSION: Intensive SBP control reduced LD‐PWV over 3 years, which reduced the risk of cognitive impairment over 10 years of follow‐up.

Background: This study investigates whether proteomic aging clocks (PACs) are associated with cerebral small vessel disease (CSVD). Methods: We included participants from two US community-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study. These analyses leveraged PACs that were developed in ARIC using proteomics measured by SomaScan in midlife (Visit 2; mean age 56 y; n=1,486) and late-life (Visit 5; mean age 76 y; n=1,496), trained on chronological age. Proteomic age acceleration (PAA) was calculated as residuals from regressing PACs on chronological age. 3T brain MRI data were collected in late-life. We examined associations of PAA with log-transformed white matter hyperintensity (WMH) volume using linear regression and with the presence of microbleeds, and subcortical, lacunar, and cortical infarcts using logistic regression. Associations of PACs with WMH volume and microbleeds were tested in MESA using proteins measured at Exam 1 (mean age 57 y; n=932) and Exam 5 (mean age 66 y; n=934). All associations were quantified per 5-year increase in PAA. All models were adjusted for demographics and cardiovascular risk factors. Results: In ARIC, higher midlife PAA was associated with greater WMH volume (percent difference: 25% [95% CI: 13%, 39%]) and higher odds of subcortical infarcts (OR: 1.24 [1.02, 1.51]). Late-life PAA was associated with all CSVD markers: WMH volume (percent difference: 20% [8%, 34%]), cerebral microbleeds (OR: 1.40 [1.15, 1.69]), subcortical (OR: 1.80 [1.47, 2.22]), lacunar (OR: 1.80 [1.46, 2.23]), and cortical infarcts (OR: 1.39 [1.07, 1.82]). In MESA, higher late-life PAA was associated with greater WMH volume (28% [3%, 58%]) but not with microbleeds. Conclusion: Accelerated proteomic aging is associated with a higher prevalence of MRI markers of CSVD, most predominantly in late-life. Understanding this relationship may help stratify those at higher risk of CSVD at an early stage.