Integrative proteomic analysis identifies CSF biomarker panels linked to brain-based pathophysiologies in Alzheimer’s disease.

Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress (OS) status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. The study design is that of a longitudinal cohort study within the setting of a large academic institution with participants being university employees (n = 511), mean age 49 years, 68% women, and 23% African-American. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein (CRP) were measured. Lower levels of glutathione at baseline was associated with a decline in the executive domain over 4 years (covariate-adjusted relative risk (RR) for glutathione = 1.70 (95% CI = 1.02–2.85), p = 0.04). Furthermore, a longitudinal decline in glutathione level was associated with a faster decline in the executive domain (p = 0.03). None of the other OS markers or CRP were linked to cognitive decline over 4 years. Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging.

Identifying the early stages of Alzheimer disease (AD) is becoming an important part of the clinical assessment of mild cognitive impairment (MCI) and is standard in almost all recent clinical trials of AD prevention and therapies.^1-3 This prodromal stage heavily relies on identifying evidence of AD neuropathologic changes, namely β-amyloidosis and tauopathy.³ The National Institute on Aging and the Alzheimer’s Association issued a biological research framework for the predementia stages of AD based on the presence of β-amyloidosis, tauopathy, and neurodegeneration.⁴ This biological framework depends on thresholds or cutoffs of the relevant biomarkers for detection of amyloidosis, tauopathy, and neurodegeneration.⁴

Although there is strong evidence that hypertension leads to cognitive decline, especially in the executive domain, the relationship between blood pressure and cognition has been conflicted. Hypertension is characterized by blood pressure elevation and increased arterial stiffness. We aimed at investigating whether arterial stiffness would be superior to blood pressure in predicting cognitive decline and explaining the hypertension-executive decline association. A randomly selected asymptomatic population (n=591, age=49.2 years, 70% women, 27% black, and education=18 years) underwent annual vascular and cognitive assessments. Cognition was assessed using computerized versions commonly used cognitive tests, and principal component analysis was used for deriving cognitive scores for executive function, memory, and working memory. Arterial stiffness was measured by carotid–femoral pulse wave velocity (PWV). Higher PWV, but not blood pressure, was associated with a steeper decline in executive ( P =0.0002), memory ( P =0.05), and working memory ( P =0.02) scores after adjusting for demographics, education, and baseline cognitive performance. This remained true after adjusting for hypertension. Hypertension was associated with greater decline in executive score ( P =0.0029) and those with combined hypertension and elevated PWV (>7 m/s) had the greatest decline in executive score ( P value hypertension×PWV=0.02). PWV explained the association between hypertension and executive function ( P value for hypertension=0.0029 versus 0.24 when adjusting for PWV). In healthy adults, increased arterial stiffness is superior to blood pressure in predicting cognitive decline in all domains and in explaining the hypertension-executive function association. Arterial stiffness, especially in hypertension, may be a target in the prevention of cognitive decline.

Clinical trials have suggested that lowering blood pressure (BP) using antihypertensive therapy provides cognitive protection in individuals without impaired cognition.^1,2 It is unclear if this is also true in individuals who have symptoms of cognitive impairment. Studies designed to compare the neurocognitive effects of antihypertensive classes in individuals who are cognitively impaired are limited. It is also unclear if these effects are related to the reduction in BP or to possible pleiotropic BP-independent effects of certain antihypertensive medications. Comparing antihypertensive drug classes independent of the degree of BP lowering is critical to determine if these effects on cognition are only secondary to their BP or other non-BP effects. Such pleiotropic effects of antihypertensive drugs may be leveraged to repurpose drugs for cognitive disorders, including Alzheimer disease (AD).

Importance: Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored.Objectives: To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences.Design, Setting, and Participants: This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020.Main Outcomes and Measures: Main outcomes were plasma and CSF amyloid-β (Aβ) 42, Aβ40, phosphorylated tau₁₈₁ (p-tau₁₈₁), and neurofilament light. General linear models were used for key comparisons.Exposures: Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state).Results: This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aβ42 (adjusted mean difference, −1.20 pg/mL; 95% CI, −2.33 to −0.07 pg/mL), Aβ40 (adjusted mean difference, −37.78 pg/mL; 95% CI, −60.16 to −15.39 pg/mL), p-tau₁₈₁ (adjusted mean difference, −4.66 pg/mL; 95% CI, −7.05 to −1.90 pg/mL), and neurofilament light (adjusted mean difference, −1.58; 95% CI, −2.83 to −0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aβ42 and Aβ40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index.Conclusions and Relevance: In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau₁₈₁, Aβ40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.