Danni Li

Background: Low-density lipoprotein cholesterol (LDL-C) is associated with brachial-ankle pulse wave velocity (baPWV). However, its relationship with femoral-ankle PWV (faPWV) or carotid-femoral PWV (cfPWV) is less consistent. In addition to its lipid cargo, LDL also has protein cargo. This study aims to examine and compare cross-sectional associations between LDL protein cargo or LDL-C and segment-specific PWV measures in an aging population. Methods: The study included 65 participants without dementia from the Atherosclerosis Risk in Communities (ARIC) study, with LDL separated from their plasma. LDL cargo proteins were quantified using a proteomic method based on mass spectrometry. Linear regression was utilized to evaluate the cross-sectional associations between LDL cargo protein or LDL-C and baPWV, faPWV, or cfPWV, after adjusting for covariates. Results: The 65 participants had a mean age of 76.3 years (SD = 5.4), 53.8% (35/65) were female, 30.8% (20/65) were Black. In the fully adjusted models, each SD increment of apolipoprotein B (apoB) in LDL and LDL-C was positively associated with an increase in baPWV of 103.0 cm/s (95% CI [43.3, 162.6]; p = 0.001) and 54.3 cm/s (95% CI [−5.9, 114.6]; p = 0.08), respectively. Each SD increment of complement component 3 (C3) in LDL was positively associated with an increase in cfPWV of 80.9 cm/s (95% CI [14.0, 147.7]; p = 0.02), but each SD increment of LDL-C was negatively associated with a decrease in cfPWV of 62.4 cm/s (95% CI [−123.1, −1.8]; p = 0.04). Conclusion: We identified differential associations of LDL cargo protein apoB and C3 as well as LDL-C with baPWV or cfPWV.

Background: It remains unclear whether blood biomarkers of Alzheimer's disease are surrogate endpoints for non‐pharmacological interventions. The ACT Trial blood biomarker study aimed to evaluate neuropathological, neurotrophic, and neuroinflammation biomarkers as surrogate outcomes in older adults with mild cognitive impairment (MCI). This presentation assessed whether any ACT intervention group (ACT, cycling only, SOP only) had significant changes in biomarkers compared to the attention control group over 6 months. Also, we evaluated the effect sizes of interventions on blood biomarkers over 6 months. Method: We collected blood samples from 95, 81, 76, 53, and 39 ACT Trial participants ( n = 344) over five time points (baseline, 3, 6, 12, and 18 months). We biochemically analyzed neuropathological biomarkers (plasma Ab ₄₂ , Ab ₄₀ , NfL, p ‐Tau 217), neurotrophic biomarkers (plasma IGF‐1, IGFBP‐3, and serum free‐BDNF), and neuroinflammation biomarkers (plasma GFAP and clusterin). We used mixed effects models to examine whether any intervention group was associated with a significant difference in biomarkers (3 or 6 months compared to baseline [i.e., 0‐3 m or 0‐6m]) compared to the control group. We also calculated effect size estimates (Cohen's d) for within‐group differences in biomarkers. Result: The mean (SD) age of the 102 participants with MCI was 73.83 (6.07) years old, 45.10% (46/102) female, and 34.31% (35/101, 1 missing) APOE4 carriers. There were no significant differences of 0‐3 m or 0‐6 m in biomarkers of any intervention group compared to that of the control. Most biomarkers had small within‐group Cohen's d (less than 0.2) except 0‐6 months plasma p ‐Tau 217 (d=0.27) and 0‐6 m serum free‐BDNF (d=0.71) in the control group. Conclusion: We did not find a significant effect of interventions on blood biomarkers. Plasma p ‐Tau 217 and serum free‐BDNF had small and moderate effect sizes to detect changes in the control group of older adults with MCI over 6 months, respectively.

Background: Low-density lipoprotein cholesterol (LDL-C) has been associated with Alzheimer's disease (AD) pathology and other neuroimaging measures, such as brain volume and white matter hyperintensity (WMH) volume. Objective: In this exploratory study, we examined cross-sectional associations between LDL cargo proteins and AD-related outcomes. Methods: We randomly selected 65 participants without dementia with amyloid PET and brain MRI data available in the Atherosclerosis Risk in Communities. We used a mass spectrometry-based technique to quantify proteins in LDL isolated from plasma collected at the ARIC Visit 5. Linear or logistic regression was applied to evaluate the associations between individual LDL protein or LDL-C and (1) brain amyloid deposition (yes or no), (2) temporal-parietal meta-ROI brain volume (a biomarker of AD-related neurodegeneration), or (3) WMH volume, adjusting for covariates. Results: Participants' average age was 76.3 years with a standard deviation of 5.4, and females comprised 53.8% (35 out of 65). The estimated effect sizes of many LDL protein's associations with these neuroimaging measures were larger than that of LDL-C. The strongest association was higher LDL apolipoprotein C1 (apoC1) and lower WMH volume. Each SD increment of LDL apoC1 LDL was associated with a lower WMH volume of 7243.1 mm ³ (95% CI [−10482.0, −4004.1]; a BH-adjusted p = 0.002). In comparison, each SD increment of LDL-C (in mg/dL) was associated with a lower WMH volume of 1676.1 mm ³ (95% CI [−5425.9, 2073.7]; a BH-adjusted p of 0.90) . Conclusions: This study suggests that increased LDL apoC1 was linked to decreased WMH volume in older adults without dementia.

Background: Studies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown. Objective: The main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity. Methods: We assessed whether plasma p-tau 181 and Aβ _42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD. Results: Plasma Aβ _42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ _42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ _42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity. Conclusion: Plasma Aβ _42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.

INTRODUCTION: Little is known about the factors underpinning discordant cerebrospinal fluid (CSF) amyloid beta (Aβ)₄₂ versus p‐tau181/Aβ₄₂ or CSF Aβ₄₂ versus Aβ positron emission tomography (PET).METHODS: We stratified 570 non‐demented Alzheimer's Disease Neuroimaging Initiative (ADNI) participants by Aβ PET and further by CSF Aβ₄₂ or p‐tau181/Aβ₄₂. We used analysis of covariance testing adjusting for covariates, followed by Tukey post hoc pairwise comparisons, to compare CSF soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) across four participant groups: CSF+ _Aβ42 with CSF− _{p‐tau/Aβ42}, CSF− _Aβ42 with CSF+ _{p‐tau/Aβ42}, and concordant CSF_Aβ42/CSF_{p‐tau/Aβ42}. We also compared sTREM2 across discordant and concordant CSF_Aβ42/PET.RESULTS: Regardless of Aβ PET status, CSF+_Aβ42 with CSF−_{p‐tau/Aβ42} had lower sTREM2 than CSF−_Aβ42 with CSF+_{p‐tau/Aβ42}. CSF sTREM2 was similarly also associated with discordant CSF Aβ42 /PET.DISCUSSION: Our study suggests the potential roles of sTREM2 in discordant CSF Aβ₄₂ and p‐tau181/Aβ₄₂ and discordant CSF_Aβ42/PET. Low‐ and high‐CSF sTREM2 may affect the accuracy of p‐tau181/Aβ₄₂ during the clinical work‐up of AD.Highlights: 17% of non‐demented older adults had discordant CSF Aβ₄₂ versus p‐tau181/Aβ₄₂. sTREM2 differed between discordant cases of CSF Aβ₄₂ versus p‐tau181/Aβ₄₂. 20% of non‐demented older adults had discordant CSF Aβ₄₂ versus Aβ PET. sTREM2 also differed between discordant cases of CSF Aβ₄₂ versus Aβ PET. p‐tau181/Aβ₄₂ may miss 6.7% of PET+ non‐demented older adults with low sTREM2.

Background: High-density lipoprotein (HDL) modulates the blood-brain barrier and cerebrovascular integrity, likely influencing the risk of Alzheimer's disease (AD), neurodegeneration, and cognitive decline. Objective: This study aims to identify HDL protein cargo associated with brain amyloid deposition and brain volume in regions vulnerable to AD pathology in older adults. Methods: HDL was separated from the plasma of 65 non-demented participants of the Atherosclerosis Risk in Communities (ARIC) study using a fast protein liquid chromatography method. HDL cargo proteins were measured using a label-free, untargeted proteomic method based on mass spectrometry and data-independent acquisition. Linear regression with multiple imputations assessed the associations between each HDL cargo protein (log2-transformed) and brain amyloid deposition or temporal-parietal meta-ROI volume, adjusting for covariates. Results: The mean (SD) age of the participants was 76.3 (5.4) years old, 53.8% (35/65) female, 30.8% (20/65) black, and 28.1% (18/64, 1 missing) APOE4 carriers. We found few HDL cargo proteins associated with brain amyloid deposition and considerably more HDL cargo proteins associated with temporal-parietal meta-ROI volume. Two HDL cargo proteins mostly associated with temporoparietal meta-ROI volume were fibrinogen B (FGB) and plasminogen (PLG). A doubling of FGB in HDL was associated with a greater temporoparietal meta-ROI volume of 1638 mm ³ (95% CI [688, 2589]). In comparison, a doubling of PLG in HDL was associated with a lower temporoparietal meta-ROI of 2025 mm ³ (95% CI [-3669, −1034]). Conclusions: This study suggests that HDL cargo proteins associated with temporal-parietal meta-ROI volume are involved in complement and coagulation pathways.

Background: Alzheimer’s disease (AD) pathophysiology is complex. Decrease in CSF soluble Aβ_42/40 and accumulation of amyloid plaques (by amyloid PET) are two distinct biomarkers of amyloid pathology. However, the pathophysiologic process associated with each biomarker is not clear. To this end, we examined CSF protein difference across biological stages defined by biomarkers, with emphasize on early stages of AD where CSF and amyloid PET evaluations are discordant.Method: 392 nondemented participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were biologically defined based on CSF Aβ₄₂, amyloid PET, and CSF p‐tau into four groups (controls [Aβ₄₂‐/ PET‐], Stage 1a [Aβ₄₂+/ PET‐], Stage 1b [Aβ₄₂‐/ PET+], Stage 2 [Aβ₄₂+/ PET+]). Of note, Abnormal CSF Aβ₄₂(+) was defined as < 976.6 pg/mL and normal (‐) as ≥ 976.6 pg/mL; abnormal brain amyloid by PET (+) was defined as ¹⁸F‐florbetapir > 1.11 SUVR and normal (‐) as ≤ 1.11 SUVR. All 4 groups had normal CSF p‐tau (defined as ≤ 26.47 ng/mL). SomaScan was used to measure over 7000 proteins in CSF proteome.Result: There was no significant protein difference between controls (Aβ₄₂‐/PET‐) and Stage 1b (Aβ₄₂‐/ PET+), or between Stage 1a (Aβ₄₂+/ PET‐) and Stage 2 (Aβ₄₂+/ PET+), after Benjamini‐Hochberg adjustment. We found 1462 proteins differentially expressed between controls (Aβ₄₂‐/PET‐) and Stage 1a (Aβ₄₂+/PET‐) related to abnormality in CSF soluble Aβ₄₂. This number was much higher than 62 proteins differed between Stage 1b (Aβ₄₂‐/ PET+) and Stage 1a (Aβ₄₂+/PET‐) related to abnormality in amyloid PET. GO enrichment analysis of biological pathways and cellular components suggested neuropeptide signaling pathway and extracellular process are the most significant pathway and cellular components related to amyloid PET; whereas numerous pathways in neuron, synapse, axon were enriched and represented by protein differences related to CSF soluble Aβ_42.Conclusion: Our results reveal distinct pathophysiologic process associated with decrease in CSF soluble Aβ₄₂ and increase in amyloid plaques measure by amyloid PET. Decrease in CSF Aβ₄₂ appears to be more neurotoxic and are associated with more pathophysiological changes than increase in amyloid plaques at the early stages of AD.

Alzheimer disease (AD) is the most common cause of dementia. In the USA, AD dementia affects an estimated 6.9 million Americans or 1 in 9 people age 65 or older in 2024. While AD was previously defined according to clinical symptoms such as memory loss and dementia, it is now biologically defined as the pathological accumulation of abnormal amyloid-β (Aβ) and phosphorylated tau (p-tau). The transition from a clinically to biologically defined disease is largely thanks to the increased capability to measure and understand AD pathology in vivo using biomarkers. These pathological proteins that define AD can accumulate for years to decades before symptom onset. The biomarker progression of AD was first proposed in 2010 by Jack and colleagues, who conceptualized AD as a pathophysiologic cascade involving a long pre-symptomatic stage. The first abnormal pathological step was reported to be abnormal cerebral spinal fluid (CSF) Aβ₄₂ and amyloid positron emission tomography (PET), followed by CSF p-tau or total tau, then abnormal ¹⁸F-fluorodeoxyglucose PET, then atrophy on structural MRI, and finally the appearance of clinical symptoms ( 1). Bateman and colleagues confirmed this model in a well-characterized cohort of patients with autosomal dominant AD ( 2). These studies’ limitations are the lack of long-term longitudinal follow-up and reliance on cross-sectional, short-term longitudinal, or estimated age-of-symptom-onset data.

Background: Vascular factors are increasingly recognized for their roles in the pathogenesis and progression of Alzheimer’s dementia (AD). Cardiorespiratory fitness (CRF), a physiologic indicator of cardiovascular health, and plasma neurotrophic factors, endogenous soluble proteins in the periphery, have been linked to cognition, brain structure and function, and AD and are modifiable by aerobic exercise (AEx), but their interplay remains poorly understood. The objective of this pilot study was to estimate the effect sizes of 6‐month AEx on resting plasma neurotrophic factors and the relationships of CRF and exercise dose with change in resting plasma neurotrophic factors in AD.Method: This study was a pilot blood ancillary study of the FIT‐AD Trial that randomized participants to 6‐month AEx or stretching control on a 2:1 allocation ratio. The blood study enrolled 26 participants (AEx Group [n = 18] and stretching control [n = 8]). Resting plasma brain‐derived neurotrophic factor (BDNF), irisin, fibroblast growth factor‐21 (FGF‐21], and insulin‐like growth factor‐1 (IGF‐1), and CRF (peak oxygen consumption) were assessed at baseline, 3 and 6 months. Exercise dose was calculated by the heart rate physical activity score (HRPAS) method.Result: The sample was 77.6±6.99 years of age and had 15.4±3.00 years of education on average. Sixty‐five percent of the participants were male and 96.2% carried at least one copy of APOE e4. Most 6‐month between‐group effect sizes were small except for irisin (d = ‐0.44), indicating that the irisin levels decreased in the AEx group relative to stretching control. The association between exercise dose and changes in CRF with changes in neurotrophic biomarker were weak (r² ≤ 0.025).Conclusion: The effects of exercise on BDNF, irisin, IGF‐1, and FGF‐21 may be heterogeneous in AD. Weak associations of exercise dose and CRF changes with changes in resting neurotrophic biomarkers were seen. There were weak associations of exercise dose and CRF changes with changes in resting neurotrophic biomarkers. Our findings need to be validated in future, adequately powered exercise studies in AD.

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.