APOE4 is the strongest genetic risk factor for Alzheimer’s disease1–3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4–8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2–6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease.

Background: Hypertension is associated with cognitive deficits, particularly executive function, and decreased cerebral microvascular responsiveness to CO<inf>2</inf> (CO<inf>2</inf> vasoreactivity). The relation between CO<inf>2</inf> vasoreactivity and executive function is not known. Protocols to assess CO<inf>2</inf> vasoreactivity are cumbersome and require inhaling a CO<inf>2</inf> -enriched gas. We explored the ability to measure CO<inf>2</inf> vasoreactivity using endtidal CO<inf>2</inf> fluctuations during normal breathing and the association of this measure with cognitive function in hypertension. Methods: Executive function (Trail-Making Test parts A/B), memory, attention and blood flow velocity (BFV) in the middle cerebral artery using transcranial Doppler were measured in hypertensive subjects who were tapered off their treatment for 3 weeks. BFV was measured while sitting and normally breathing for 5 min, followed by breathing 5% CO<inf>2</inf> gas and hyperventilation for 2 min each. We calculated CO<inf>2</inf> vasoreactivity as the rate of BFV change from hypoventilation to hyperventilation, and as a model-derived measure using the normal breathing data. The latter was derived using non-linear principal dynamic modes (PDM), which modelled the dynamic effect of fluctuations in end-tidal CO<inf>2</inf> and blood pressure upon BFV during normal room-air respiration. Multiple regression analyses were used to correlate cerebral hemodynamics with cognitive measures. Results: Data were collected from 41 individuals with hypertension (mean age 71 years, 24% African Americans, 61% women, off antihypertensive therapy). Lower CO<inf>2</inf> vasoreactivity was associated with a worse executive function test score using both calculation methods: p value using the hyper/hypoventilation data was 0.04 and from the PDM analysis was 0.009. PDM calculations showed a stronger correlation with executive function (0.41 vs. 0.21 using the hyper/hypoventilation data). There were no associations with memory or attention measures. There was a weak but statistically significant correlation between the two calculation methods of CO<inf>2</inf> vasoreactivity (R 2 = 14%, p = 0.02). Conclusion: This study suggests that the decrease in CO<inf>2</inf> vasoreactivity in hypertension is associated with lower executive function. This may offer new insight into the vascular underpinning of cognitive decline in hypertension. We demonstrate that calculating CO<inf>2</inf> vasoreactivity is possible during normal breathing. If replicated in future studies, this may offer a more convenient clinical way to assess CO<inf>2</inf> vasoreactivity in hypertension and cognitive disorders.

Objectives To investigate the associations between the apolipoprotein E (APOE) ε4 allele, carbon dioxide (CO2) vasoreactivity, and cognitive performance and to explore the effect of CO2 vasoreactivity and hypertension on the associations between APOE and cognition. Design Observational. Setting Community. Participants Older adults (N = 625) enrolled in the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly of Boston Study. Measurements Change in cerebral blood flow velocity in response to CO2 challenge (CO2), measured using transcranial Doppler ultrasonography, Trail-Making Test Part B - A (TMT), Hopkins Verbal Learning Test delayed recall (HVLT). Results APOE-ε4 was associated with lower CO2 vasoreactivity (P =.009) and poorer performance on the TMT (P <.001) and HVLT (P <.001). Having hypertension and APOE-ε4 was associated with worse cognitive and CO2 vasoreactivity measures than having neither or either alone (P <.001 for TMT and HVLT, P =.01 for CO2 vasoreactivity). The association between APOE-ε4 and cognition was only significant if it was present concurrent with low CO2 vasoreactivity, defined as below the median of the sample (APOE by CO2 vasoreactivity interaction: P =.04 for TMT, P =.04 for HVLT). In hypertension, the association between APOE-ε4 and executive function was also only significant in participants with lower CO2 vasoreactivity (P =.005 for APOE by CO2 vasoreactivity). Conclusion Individuals at risk of Alzheimer's disease (AD) because they have APOE-ε4 may have lower CO2 vasoreactivity, which in turn may be contributing to the observed lower cognitive performance associated with this allele. The cognitive effect of APOE-ε4 is magnified in hypertension and low CO2 vasoreactivity. This study offers evidence that APOE-ε4 may be associated with microvascular brain injury even in the absence of clinical 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..

Background The impact of COVID-19 severity on development of long-term sequelae remains unclear, and symptom courses are not well defined. Methods This ambidirectional cohort study recruited adults with new or worsening symptoms lasting >3 weeks from confirmed SARS-CoV-2 infection between August 2020–December 2021. COVID-19 severity was defined as severe for those requiring hospitalization and mild for those not. Symptoms were collected using standardized questionnaires. Multivariable logistical regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between clinical variables and symptoms. Results Of 332 participants enrolled, median age was 52 years (IQR 42–62), 233 (70%) were female, and 172 (52%) were African American. Antecedent COVID-19 was mild in 171 (52%) and severe in 161 (48%). In adjusted models relative to severe cases, mild COVID-19 was associated with greater odds of fatigue (OR:1.83, CI:1.01–3.31), subjective cognitive impairment (OR:2.76, CI:1.53–5.00), headaches (OR:2.15, CI:1.05–4.44), and dizziness (OR:2.41, CI:1.18–4.92). Remdesivir treatment was associated with less fatigue (OR:0.47, CI:0.26–0.86) and fewer participants scoring >1.5 SD on PROMIS Cognitive scales (OR:0.43, CI:0.20–0.92). Fatigue and subjective cognitive impairment prevalence was higher 3–6 months after COVID-19 and persisted (fatigue OR:3.29, CI:2.08–5.20; cognitive OR:2.62, CI:1.67–4.11). Headache was highest at 9–12 months (OR:5.80, CI:1.94–17.3). Conclusions Mild antecedent COVID-19 was associated with highly prevalent symptoms, and those treated with remdesivir developed less fatigue and cognitive impairment. Sequelae had a delayed peak, ranging 3–12 months post infection, and many did not improve over time, underscoring the importance of targeted preventative measures.

Background: Cerebral microvascular dysfunction is commonly seen in Alzheimer’s disease (AD) and vascular cognitive impairment (VCI). Cerebrovascular reactivity (CVR) to CO2 reflects cerebral microvascular health and may be modulated by the renin–angiotensin system (RAS). This study aimed to investigate the effects of RAS modulation on CVR in individuals with mild cognitive impairment (MCI) due to underlying vascular or AD etiologies. Methods: This study presents findings of candesartan’s effects on the secondary outcomes of two double-blind randomized clinical trials of 12-month therapy of candesartan versus lisinopril in VCI (CALIBREX (Candesartan vs Lisinopril Effects on the Brain and Endothelial Function in Executive MCI)) and candesartan versus placebo in prodromal AD (Candesartan’s Effects on Alzheimer’s Disease and Related Biomarkers (CEDAR)). Primary outcome results of these trials have been reported in previous publications. Participants underwent identical brain blood oxygenation level dependent (BOLD)-CVR in response to a 2-min CO2 challenge at baseline and 12 months. Regions of interest and voxel-wise CVR maps were derived from BOLD signal changes during CO2 challenge. CVR effects were compared between candesartan and lisinopril (CALIBREX) and candesartan and placebo (CEDAR) using mixed-model repeated measures. Results: Data from 102 participants in the CALIBREX study (mean age = 65 years, 45% female, 63% African American) and 59 in the CEDAR study (mean age = 67 years, 32% female, 20% African American) were analyzed. Candesartan was associated with improved whole brain CVR compared to placebo in the CEDAR study (adjusted within-group mean difference for candesartan = 0.27 (95% confidence interval (CI) = 0.006, 0.53) vs placebo = −0.17 (95% CI = 0.42, 0.08), p-value = 0.018), and compared to lisinopril in the CALIBREX study (adjusted within-group mean difference for candesartan = 0.28 (95% CI = 0.10, 0.46) vs lisinopril = −0.08 (95% CI = −0.31, 0.14), p-value = 0.012), independent of blood pressure. In an exploratory meta-analysis of the two trials, improved CVR in the hippocampus was linked to improved attention and working memory (p = 0.044) and a trend for improved executive function (p = 0.087) with candesartan therapy. Conclusion: This study suggests that candesartan is associated with improved microvascular function in MCI, and these findings are independent of its blood pressure effect in these VCI and prodromal AD populations.

Background: Functional decline in Alzheimer's disease (AD) is impacted by impaired ability to integrate and modulate complex cognitive and motor abilities, commonly known as motor-cognitive integration. Impaired motor-cognitive integration occurs in the early stages of AD, prodromal AD (pAD), and may precede other symptoms. Combined motor and cognitive training have been recommended for people with pAD and need to be better researched. Our data suggest that partnered rhythmic rehabilitation (PRR) improves motor-cognitive integration in older adults with cognitive impairment. PRR is an ideal intervention to simultaneously target cardiovascular, social, and motor-cognitive domains important to AD. Objective/Methods: We propose to conduct a 1-year Phase II, single-blind randomized controlled trial using PRR in 66 patients with pAD. Participants will be assigned to three months of biweekly sessions, followed by nine months of weekly sessions of PRR or group walking (WALK) with 1:1 allocation. Group walking in the control group will allow us to compare physical exercise alone versus the added benefit of the cognitively engaging elements of PRR. Results/Conclusion: Using an intent-To-Treat approach, this innovative pilot study will 1) Determine acceptability, safety, tolerability, and satisfaction with PRR; 2) Compare efficacy of PRR versus WALK for improving motor-cognitive integration and identify the most sensitive endpoint for a Phase III trial from a set of motor-cognitive, volumetric MRI, and cognitive measures. The study will additionally explore potential neural, vascular, and inflammatory mechanisms by which PRR affects pAD to derive effect size of these intermediary measures and aid us in estimating sample size for a future trial.

IMPORTANCE Perceived stress can have long-term physiological and psychological consequences and has shown to be a modifiable risk factor for Alzheimer disease and related dementias. OBJECTIVE To investigate the association between perceived stress and cognitive impairment in a large cohort study of Black and White participants aged 45 years or older. DESIGN, SETTING, AND PARTICIPANTS The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a national population-based cohort of 30 239 Black and White participants aged 45 years or older, sampled from the US population. Participants were recruited from 2003 to 2007, with ongoing annual follow-up. Data were collected by telephone, selfadministered questionnaires, and an in-home examination. Statistical analysis was performed from May 2021 to March 2022. EXPOSURES Perceived stresswas measured using the 4-item version of the Cohen Perceived Stress Scale. It was assessed at the baseline visit and during 1 follow-up visit. MAIN OUTCOMES AND MEASURES Cognitive function was assessed with the Six-Item Screener (SIS); participants with a score below 5 were considered to have cognitive impairment. Incident cognitive impairment was defined as a shift from intact cognition (SIS score >4) at the first assessment to impaired cognition (SIS score_4) at the latest available assessment. RESULTS The final analytical sample included 24 448 participants (14 646 women [59.9%]; median age, 64 years [range, 45-98 years]; 10 177 Black participants [41.6%] and 14 271 White participants [58.4%]). A total of 5589 participants (22.9%) reported elevated levels of stress. Elevated levels of perceived stress (dichotomized as low stress vs elevated stress) were associated with 1.37 times higher odds of poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio [AOR], 1.37; 95%CI, 1.22-1.53). The association of the change in the Perceived Stress Scale score with incident cognitive impairment was significant in both the unadjusted model (OR, 1.62; 95%CI, 1.46-1.80) and after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (AOR, 1.39; 95%CI, 1.22-1.58). There was no interaction with age, race, and sex. CONCLUSIONS AND RELEVANCE This study suggests that there is an independent association between perceived stress and both prevalent and incident cognitive impairment. The findings suggest the need for regular screening and targeted interventions for stress among older adults.

Greater psychological distress is associated with cognitive impairment in healthy adults. Whether such associations also exist in patients with coronary artery disease (CAD) is uncertain. We assessed cognitive function in 496 individuals with CAD using the verbal and visual memory subtests of the Wechsler Memory Scale and executive functioning measured by the Trail Making Test Parts A and B. We used a composite score of psychological distress derived through summation of Z-transformed psychological distress symptom scales (depression, posttraumatic stress, anxiety, anger, hostility and perceived stress) and scores for each individual psychological scale. Multivariable linear regression models were used to determine the association between memory scores (as outcomes) and the psychological distress scores (both composite score and individual scales). After adjusting for demographic and cardiovascular risk factors, a higher psychological distress score was independently associated with worse memory and executive functioning. Each standard deviation increase in psychological distress score was associated with 3% (95% confidence interval [CI], 1%–5%) to 5% (95% CI, 3–7%) worse cognitive performance (higher Trail A and Trail B, and lower verbal and visual memory scores). Among individuals with CAD, a higher level of psychological distress is independently associated with worse cognitive performance. These findings suggest that psychological risk factors play a role in cognitive trajectories of persons with CAD.

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.