Knopman, David S.

AbstractINTRODUCTIONWe investigated the usefulness of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) for capturing vascular cognitive impairment (VCI) in the context of amyloidosis.METHODSUsing two independent cohorts (n = 1810), we assessed the relationship of plasma NfL and GFAP with (1) vascular brain indices; (2) diagnostic states using the following definitions: vascular versus not (white matter hyperintensity/total intracranial volume ≥ 1.3%), and cognitively impaired (CI) versus cognitively unimpaired (CU) using Clinical Dementia Rating ([CDR] scale ≥ 0.5); and (3) their upstream predictors using structural equation models (SEMs).RESULTSPlasma NfL and GFAP were associated with vascular brain damage and differed across states (VCI > vascular CU > non‐vascular CI > non‐vascular CU). In a population‐based sample, these biomarkers distinguished vascular CU and VCI from non‐vascular CU groups with greater separation in amyloid negative participants. Pathway analyses showed NfL was primarily influenced by systemic/brain vascular health, whereas amyloid contributed to GFAP variability.DISCUSSIONPlasma biomarkers, particularly NfL, capture vascular brain changes and show promise for VCI identification.Highlights Plasma NfL and glial fibrillary acidic protein (GFAP) were associated with vascular brain indices. Plasma biomarkers differed across diagnostic states (VCI > vascular CU > non‐vascular CI > non‐vascular CU). Plasma markers discriminated vascular from non‐vascular states with greater separation in Aβ− participants. NfL was linked to vascular health, while amyloid influenced GFAP variability in the population‐based sample. Future longitudinal frameworks should consider systemic inflammation markers along with these plasma markers to better understand VCID‐related brain changes and cognitive decline.

Abstract Objective To compare iron deposition in the substantia nigra (SN) as measured with quantitative susceptibility mapping (QSM) on antemortem magnetic resonance imaging (MRI) between individuals with and without Lewy‐related pathology at autopsy. Methods We performed a retrospective cohort study including 54 participants who underwent autopsy and antemortem MRI with QSM. Cases were classified as Lewy body disease (LBD)‐present (n = 13) if they had Lewy‐related pathology and LBD‐absent (n = 41) if they did not have Lewy‐related pathology. QSM was calculated for the whole SN and the two subregions: pars compacta (SNc) and pars reticulata (SNr). Nonparametric Wilcoxon rank‐sum tests were used to compare SN QSM values between LBD‐present and LBD‐absent cases. Area under the receiver operating characteristic (ROC) curve (AUC) analyses tested the accuracy of SN QSM values to distinguish the two groups. Associations of QSM values in the SN and its subregions with clinical features were tested with Spearman's correlations. Results The LBD‐present group had higher QSM values in the SNc ( P = 0.008) than the LBD‐absent group with no differences in SNr. QSM values of the SNc distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC = 0.74) and correlated with the presence of parkinsonism and parkinsonism severity. Conclusions This study provides neuropathological confirmation of the utility of SNc QSM as an in vivo biomarker of Lewy‐related pathology. Imaging evidence of abnormal iron deposition in the SNc could potentially serve as a biomarker for inclusion in emerging research frameworks aimed at defining individuals with LBD based on their biological characteristics. Ultimately, this could facilitate more precise diagnoses and guide treatment strategies in LBD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract INTRODUCTION Temporal cortical microstructural changes precede cortical atrophy during memory decline. We used neurite orientation dispersion and density imaging (NODDI) to assess such early microstructural change. METHODS Cognitively unimpaired (CU, n = 725) and mildly cognitively impaired (MCI, n = 111) participants from the Mayo Clinic Study of Aging underwent 3T magnetic resonance imaging (MRI), including NODDI and neuropsychological evaluation for calculation of memory z scores. Linear mixed effects modelling assessed the relationship between temporal cortical Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and both baseline and mean annual change in memory z scores. RESULTS NDI was significantly associated with both baseline memory z scores and mean annual change of memory z scores, in the hippocampi and amygdalae. Similar significant associations with ODI were seen in hippocampi, parahippocampal, and fusiform gyri. DISCUSSION Temporal cortical NDI and ODI are early imaging biomarkers of cortical microstructural integrity that may predict memory decline in CU and MCI individuals. Highlights We imaged 836 participants in the Mayo Clinic Study of Aging, who were either cognitively unimpaired (CU) or suffered from mild cognitive impairment (MCI). Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion magnetic resonance imaging (MRI) technique We found significant associations between new NODDI imaging biomarkers of microstructural integrity and memory function in CU and MCI individuals These relationships were both cross‐sectional in nature and associated with future memory decline Future application of NODDI imaging biomarkers in the setting of anti‐amyloid monoclonal antibody therapy may provide greater insight into memory decline than current cortical atrophy measures.

ImportanceMidlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.ObjectiveTo quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.Design, Setting, and ParticipantsThis was a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study using 33 years of follow-up (1987-2020). The setting included ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Minneapolis suburbs, Minnesota; Washington County, Maryland). Study baseline in Black and White participants with complete exposure and covariate data was set by age at risk factor measurement (45-54 years, 55-64 years, and 65-74 years). Data were analyzed from August 2023 to December 2024.ExposuresHypertension (systolic blood pressure [BP] ≥130 mm Hg, diastolic BP ≥80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician’s diagnosis, or use of any diabetes medication), and current smoking (self-reported).Main Outcomes and MeasuresIncident dementia. Population attributable fractions were estimated by age 80 years, and separately after 80 years, from having at least 1 vascular risk factor by age at risk factor measurement.ResultsA total of 7731 participants were included in analysis of risk factors measured at age 45 to 54 years (4494 female [58%]; 2207 Black [29%]; 5524 White [71%]), 12 274 contributed to analysis of risk factors measured at age 55 to 64 years (6698 female [55%]; 2886 Black [24%]; 9388 White [76%]), and 6787 contributed to analysis of risk factors measured at age 65 to 74 years (3764 female [56%], 1375 Black [20%]; 5412 White [80%]). There were 801, 995, and 422 dementia cases by 80 years, respectively. The fraction of dementia by 80 years attributable to at least 1 vascular factor at age 45 to 54 years was 21.8% (95% CI, 14.3%-29.3%), at 55 to 64 years was 26.4% (95% CI, 19.1%-33.6%), and at 65 to 74 years was 44.0% (95% CI, 30.9%-57.2%). Attributable fractions for these factors were higher in apolipoprotein ε4 noncarriers at age 55 years and older (range, 33.3%-61.4%), Black individuals at age 45 years and older (range, 25.5%-52.9%), and female individuals at age 55 years and older (range, 29.2%-51.3%). Only 2% to 8% of dementia cases after 80 years were attributable to these factors.Conclusions and RelevanceResults of this cohort study suggest that between 22% and 44% of incident dementia cases by 80 years in the ARIC study were attributed to midlife and late-life vascular risk factors. Assuming causal relationships, maintaining optimal vascular health across the life course could mitigate a sizeable proportion of dementia risk by 80 years.

Introduction: Physical activity (PA) has been identified as a protective factor for dementia, but the mechanisms linking PA to brain health are unclear. To elucidate potential pathways linking PA to brain health, we tested the hypothesis that higher levels of late-life PA are associated with a lower burden of Alzheimer’s disease (AD) pathology, cerebrovascular disease, and neurodegeneration measured through brain imaging and plasma biomarkers. Methods: ARIC-NCS participants without dementia in 2011-13 and with measures of PA, 3T brain magnetic resonance imaging (MRI), and stored plasma samples were examined (n=1,771; mean age: 76.5 years; 40.5% male; 27.6% Black). Participants were classified as meeting or not meeting 2018 aerobic PA guidelines based on a standardized interviewer-administered questionnaire. MRI biomarkers included white matter hyperintensity (WMH) volume (cm 3 ), total brain volume (TBV) (cm 3 ), and cortical thickness (CT) (mm). Plasma biomarkers of the ratio of amyloid beta 42 to 40 (Aβ42/Aβ40), phosphorylated Tau-181 (p-Tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa immunoassays. All biomarkers were standardized to measures in 2011-13 to facilitate comparisons. Covariate-adjusted linear regression models estimated cross-sectional associations of PA with MRI or plasma biomarkers. Covariate-adjusted linear mixed effects models quantified associations of PA with the 5-year rate of change in a subset of participants with MRI (n=669) or plasma (n=651) biomarkers at both baseline and follow-up from 2011-19 (median follow-up: 5.4 years). Results: Meeting versus not meeting aerobic PA guidelines was cross-sectionally associated with lower volumes of WMH (β = -0.16, 95% CI: -0.25, -0.07), higher TBV (β = 0.09; 95% CI: 0.05, 0.13), and lower plasma NfL (β = -0.102, 95% CI: -0.184, -0.021) ( Figure ). Late-life PA was not associated with 5-year rates of change in MRI or plasma biomarkers. Conclusions: Late-life PA was cross-sectionally associated with less neurodegeneration and cerebrovascular disease. Associations with 5-year changes in imaging and plasma biomarkers of AD pathology, cerebrovascular disease, or neurodegeneration were not statistically supported. Longitudinal biomarker studies with wearable devices that quantify other daily intensity-based movement metrics (e.g., light PA) and larger sample sizes are needed to further examine mechanisms linking PA to brain health.

Introduction: Physical activity (PA) has been identified as a modifiable factor inversely associated with cognitive decline and dementia risk. However, most longitudinal studies to date have short follow-up and report inconsistent results on the benefit of PA to support brain health among older adults. In this study, we hypothesized that higher levels of PA measured in late life would be associated with slower rates of global and domain-specific cognitive decline and a lower risk of dementia over ~10 years in late life. Methods: Dementia-free participants (n=5,982; mean age: 76 years; 42% male, 23% Black) who completed the interviewer-administered Modified Baecke PA Questionnaire at ARIC visit 5 (2011-2013) were included. Using the PA component of the American Heart Association’s Life’s Simple 7, participants’ PA levels were categorized as ideal, intermediate, or poor. Cognitive tests were administered at ARIC visits 5 (2011-13), 6 (2016-17), 7 (2018-19), 8 (2020), and 9 (2021-22), and were used to calculate factor scores for global cognitive function and the domains of memory, language, and executive function. Linear mixed models estimated the association of PA with change in cognitive function. Dementia cases were defined by adjudicated review, telephone interviews, informant interviews, hospitalization records, and death certificates. Dementia risk was estimated using Cox proportional hazards regression models. All models adjusted for age, sex, race-center, education, APOE-ε4 allele, smoking, hypertension, body mass index, and diabetes. Results: Participants with ideal or intermediate PA, compared to poor PA, had slower rates of decline in global cognition, but no significant differences in rates of decline across individual cognitive domains. Over a median follow-up of 7.8 years, participants with ideal (adjusted hazard ratio [HR] = 0.62, 95% CI: 0.60, 0.67) or intermediate (adjusted HR = 0.87, 95% CI: 0.80, 0.91) PA had a reduced risk of dementia compared to participants with poor PA. Conclusions: Higher PA levels in late life demonstrated a protective association with long-term global cognitive decline and incident dementia. Although further research with more frequent and objective measures of PA is needed to determine the duration, frequency, and intensity of PA recommended to promote brain health in older adults, our findings suggest that promoting PA among aging populations offers a non-invasive and accessible approach to support brain health.

Introduction: Vascular risk factors of hypertension, diabetes, and smoking in midlife (45-64 years) and possibly early late-life (65-74 years) are associated with increased risk of dementia. Current estimates of population attributable risk for dementia assume vascular factors are independent and do not interact to increase risk of dementia, which may underestimate the combined impact of vascular risk reduction on dementia incidence. In this study, we evaluated the joint association and interaction of vascular risk factors on risk of dementia. Methods: We performed a prospective cohort analysis using the Atherosclerosis Risk in Communities Neurocognitive Study using up to 33 years of follow-up (1987-2020). We used age as baseline (45-54 years, n=7,731; 55-64 years, n=12,273; and 65-74 years, n=6,660). We defined hypertension as systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥80 mm Hg, or anti-hypertension medication use. We defined diabetes as fasting glucose level ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, self-reported physician diagnosis, or use of any diabetes medication. Current smoking was self-reported. We investigated additive and multiplicative interactions for combinations of vascular risk factors on incident (adjudicated) dementia by age 80 using joint effect variables in Cox regression models stratified by age of risk factor measurement (45-54 years, 55-64 years, or 65-74 years). For interaction analyses, parameter values >1 indicate positive interaction (synergy) and values <1 indicate negative interaction (antagonism). Results: In participants with risk factors measured in these baseline age strata, there were 801 (10%), 995 (8%), and 422 (6%) cases of incident dementia by age 80, respectively. Hypertension and diabetes exhibited positive interactions on the additive and multiplicative scales in midlife (Figure 1). Diabetes and smoking in midlife had positive additive interaction (value >1, Figure 2). All vascular risk factor combinations in late-life had negative interactions on the multiplicative scale (values <1, Figures 1-3). Conclusions: Hypertension with diabetes and diabetes with smoking, all measured in midlife, interact to increase risk of dementia by age 80. The overall impact of reducing midlife vascular risk factors on incident dementia could be sizeable. These findings highlight the importance of multifactor interventions addressing combinations of vascular risk factors for dementia prevention strategies.