IMPORTANCE Observational studies have suggested that angiotensin receptor blockers are associated with a unique cognitive protection. It is unclear if this is due to reduced blood pressure (BP) or angiotensin receptors type 1 blockade. OBJECTIVE To determine neurocognitive effects of candesartan vs lisinopril in older adults with mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial included participants aged 55 years or older with MCI and hypertension. Individuals were withdrawn from prior antihypertensive therapy and randomized in a 1 to 1 ratio to candesartan or lisinopril from June 2014 to December 2018. Participants underwent cognitive assessments at baseline and at 6 and 12 months. Brain magnetic resonance images were obtained at baseline and 12 months. This intent-to-treat study was double-blind and powered for a sample size accounting for 20% dropout. Data were analyzed from May to October 2019. INTERVENTIONS Escalating doses of oral candesartan (up to 32 mg) or lisinopril (up to 40 mg) once daily. Open-label antihypertensive drug treatments were added as needed to achieve BP less than 140/90 mm Hg. MAIN OUTCOMES AND MEASURES The primary outcome was executive function (measured using the Trail Making Test, Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research tool) and secondary outcomes were episodic memory (measured using the Hopkins Verbal Learning Test-Revised) and microvascular brain injury reflected by magnetic resonance images of white matter lesions. RESULTS Among 176 randomized participants (mean [SD] age, 66.0 [7.8] years; 101 [57.4%] women; 113 [64.2%] African American), 87 were assigned to candesartan and 89 were assigned to lisinopril. Among these, 141 participants completed the trial, including 77 in the candesartan group and 64 in the lisinopril group. Although the lisinopril vs candesartan groups achieved similar BP (12-month mean [SD] systolic BP: 130 [17] mm Hg vs 134 [20] mm Hg; P = .20; 12-month mean [SD] diastolic BP: 77 [10] mm Hg vs 78 [11] mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function measured by Trail Making Test Part B (effect size [ES] = −12.8 [95% CI, −22.5 to −3.1]) but not Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score (ES = −0.03 [95% CI, −0.08 to 0.03]). Candesartan was also superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall (ES = 0.4 [95% CI, 0.02 to 0.8]) and retention (ES = 5.1 [95% CI, 0.7 to 9.5]).

ImportanceDifferences 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.ObjectivesTo investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences.Design, Setting, and ParticipantsThis 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 MeasuresMain 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.ExposuresMain 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).ResultsThis 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 RelevanceIn 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.

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Introduction Advances in natural language processing (NLP), speech recognition, and machine learning (ML) allow the exploration of linguistic and acoustic changes previously difficult to measure. We developed processes for deriving lexical‐semantic and acoustic measures as Alzheimer's disease (AD) digital voice biomarkers. Methods We collected connected speech, neuropsychological, neuroimaging, and cerebrospinal fluid (CSF) AD biomarker data from 92 cognitively unimpaired (40 Aβ+) and 114 impaired (63 Aβ+) participants. Acoustic and lexical‐semantic features were derived from audio recordings using ML approaches. Results Lexical‐semantic (area under the curve [AUC] = 0.80) and acoustic (AUC = 0.77) scores demonstrated higher diagnostic performance for detecting MCI compared to Boston Naming Test (AUC = 0.66). Only lexical‐semantic scores detected amyloid‐β status ( p = 0.0003). Acoustic scores associated with hippocampal volume ( p = 0.017) while lexical‐semantic scores associated with CSF amyloid‐β ( p = 0.007). Both measures were significantly associated with 2‐year disease progression. Discussion These preliminary findings suggest that derived digital biomarkers may identify cognitive impairment in preclinical and prodromal AD, and may predict disease progression. Highlights This study derived lexical‐semantic and acoustics features as Alzheimer's disease (AD) digital biomarkers. These features were derived from audio recordings using machine learning approaches. Voice biomarkers detected cognitive impairment and amyloid‐β status in early stages of AD. Voice biomarkers may predict Alzheimer's disease progression. These markers significantly mapped to functional connectivity in AD‐susceptible brain regions.

Background: Tau positron emission tomography (PET) imaging is used in research, but its relation to cerebrospinal fluid (CSF) tau and other Alzheimer's disease (AD)-related clinical measures is unclear in mild cognitive impairment with AD biomarkers (MCI-AD). Objective: To determine associations between 18 F-flortaucipir PET and CSF AD biomarkers, cognitive functioning, and neuroimaging measures in MCI-AD. Methods: In 29 participants 50 years or older with MCI-AD, 18 F-flortaucipir PET, CSF total tau (T-tau), phosphorylated tau 181p (P-tau), amyloid-␤ (A␤), structural MRI, and neuropsychological testing were collected as baseline assessments of an ongoing clinical trial. 11 C-Pittsburgh compound B PET was simultaneously conducted in 20 participants. Associations between 18 Fflortaucipir PET and these measures were assessed by multiple linear regression adjusted for potential confounders and using global, lobar, and voxel-wise standardized uptake value ratio (SUVr). Results: Whole brain 18 F-flortaucipir SUVr was significantly associated with CSF T-tau (r = 0.68, p < 0.001) and P-tau (r = 0.42, p = 0.04) after adjusting for age, sex, race, and education, with strongest associations in the temporal region (Ttau: r = 0.69, p < 0.001; P-tau: r = 0.49, p = 0.02). Voxel-wise analysis confirmed these regional associations. 18 F-flortaucipir PET was also associated with CSF A␤ (r = -0.45, p = 0.03), episodic memory (r = -0.61, p = 0.001), visuospatial working memory (r = -0.46, p = 0.02), and brain cortical thickness (r = -0.44, p = 0.03) but not hippocampal volume. In the amyloid PET subset, although 11 C-PiB PET associated strongly with 18 F-flortaucipir (r = 0.79, p ≤ 0.001), associations were stronger between 11 C-PiB and key outcomes, compared to 18 F-flortaucipir.