Dysfunction of the glymphatic system has been proposed as a mechanistic link between sleep disruption and Alzheimer’s disease (AD). In animal models, glymphatic impairment alone can drive AD pathology. Whether this system clears amyloid beta (Aβ) and tau in humans remains unknown. In a randomized crossover trial with 39 participants, we found that glymphatic clearance during normal sleep increased morning plasma levels of AD biomarkers compared to sleep deprivation. Participants underwent overnight monitoring using an investigational device that measured dynamic changes in synaptic-metabolic release and glymphatic activity. The observed changes mirrored predictions from a multicompartment model based on published data on Aβ and tau release and clearance. Our findings indicate that sleep-active physiological processes, particularly reduced brain parenchymal resistance, enhance overnight glymphatic clearance of AD biomarkers to plasma. These results support a key role for glymphatic function in AD pathophysiology and suggest its enhancement as a potential therapeutic strategy to slow disease progression. Sleep-active physiological processes enhance overnight glymphatic clearance of Alzheimer’s disease biomarkers into plasma in humans, supporting the critical role of glymphatic function in Alzheimer’s pathophysiology and its potential as a therapeutic target.

The diagnostic performance of the Amyloid Probability Score 2 (APS2; the algorithmic result of the PrecivityAD2™ blood test) was originally trained and validated in two cohorts of cognitively impaired (CI) individuals and is in clinical use. Here, we further test the repeatability and reliability of the prespecified APS2 algorithm and cut point in an independent cohort. APS2 diagnostic performance was determined using amyloid positron emission tomography (PET) as the reference standard. Concordance with amyloid PET was high (AUC-ROC 0.95 (95% CI): 0.93-0.98); 54% of participants had a positive APS2. The previously validated APS2 cut point yielded an overall accuracy of 91% (95% CI: 86-94%), sensitivity 90% (95% CI: 83-94%) and specificity 92% (95% CI: 84-96%). Our findings demonstrate that the prespecified APS2 algorithm and cut point are repeatable, reliable, robust, accurate, and generalizable for identifying brain beta-amyloid pathology in patients with cognitive impairment and being evaluated in a clinical care setting.

INTRODUCTION:Plasma biomarkers sensitive to Alzheimer's disease (AD) proteinopathy prior to the onset of dementia have significant implications for early detection. METHODS:In 304 individuals without dementia, we investigated whether C2N Diagnostics' mass spectrometry (MS)-based plasma biomarkers (amyloid beta 42/40, %phosphorylated tau [p-tau]181, and %p-tau217) and amyloid probability scores (APS, PrecivityAD and APS2, PrecivityAD2) are associated with brain amyloid, brain tau, or preclinical cognitive decline. RESULTS:In this cohort study, %p-tau217 and the APS2 had high discriminative accuracy (area under the curve > 0.93) for identifying elevated brain amyloid and tau and were associated with faster preclinical cognitive decline. Using %p-tau217 or the APS2 in a theoretical AD trial screening scenario reduced amyloid positron emission tomography imaging costs up to 41% or 45%, respectively. DISCUSSION:These findings suggest that C2N Diagnostics' MS-based plasma biomarkers can detect brain amyloid and tau with high accuracy prior to dementia and could aid in identifying candidates for clinical trials or therapeutic intervention. HIGHLIGHTS:C2N plasma biomarkers differentiated Alzheimer's disease proteinopathy status prior to dementia. Plasma %phosphorylated tau (p-tau)217 and the C2N Diagnostics PrecivityAD2 (APS2) were concordant with amyloid and tau positron emission tomography status. Plasma %p-tau217 and the APS2 were associated with preclinical cognitive decline.

Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder that represents a major global public health concern. Traditionally, AD is diagnosed using cerebrospinal fluid biomarker analysis or brain imaging modalities. Recently, less burdensome, more widely available blood biomarker (BBM) assays for amyloid-beta (Aβ42/40) and phosphorylated-tau concentrations have been found to accurately identify the presence/absence of brain amyloid plaques and tau tangles and have helped to streamline AD diagnosis. However, few BBMs have been rigorously analytically validated. Herein, we report the analytical validation of a novel liquid chromatography–tandem mass spectrometry (LC-MS/MS) multiplex method for quantifying plasma phosphorylated-tau217 (p-tau217) and non-phosphorylated-tau217 (np-tau217) peptide concentrations. We combined the p-tau217/np-tau217 concentrations ratio (%p-tau217) and the previously validated LC-MS/MS multiplex assay for plasma Aβ42/40 into a new multianalyte assay with algorithmic analysis (MAAA; PrecivityAD2™ test) that identifies brain amyloid status based on brain amyloid positron emission tomography. We found (a) the %p-tau217 assay is precise, accurate, sensitive, and linear over a wide analytical measurement range, and free from carryover and interference; (b) the pre-analytical specimen collection, processing, storage, and shipping conditions that maintain plasma tau peptide stability; and (c) using the measured analytical imprecision for plasma Aβ42/40 and p-tau217/np-tau217 levels in a worst-case scenario model, the PrecivityAD2 test algorithm for amyloid pathology classification changed for only 3.5% of participants from brain amyloid positive to negative, or from negative to positive. The plasma sample preparation and LC-MS/MS methods underlying the PrecivityAD2 test are suitable for use in the clinical laboratory and valid for the test’s intended purpose: to aid in the diagnostic evaluation of individuals aged 55 and older with signs or symptoms of mild cognitive impairment or dementia.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-β plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-β pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453-459.

BackgroundThe current study examined the sensitivity of two memory subtests and their corresponding learning slope metrics derived from the African Neuropsychology Battery (ANB) to detect amyloid pathology and APOEε4 status in adults from Kinshasa, the Democratic Republic of the Congo.Methods85 participants were classified for the presence of β-amyloid pathology and based on allelic presence of APOEε4 using Simoa. All participants were screened using CSID and AQ, underwent verbal and visuospatial memory testing from ANB, and provided blood samples for plasma Aβ42, Aβ40, and APOE proteotype. Pearson correlation, linear and logistic regression were conducted to compare amyloid pathology and APOEε4 status with derived learning scores, including initial learning, raw learning score, learning over trials, and learning ratio.ResultsOur sample included 35 amyloid positive and 44 amyloid negative individuals as well as 42 without and 39 with APOEε4. All ROC AUC ranges for the prediction of amyloid pathology based on learning scores were low, ranging between 0.56–0.70 (95% CI ranging from 0.44–0.82). The sensitivity of all the scores ranged between 54.3–88.6, with some learning metrics demonstrating good sensitivity. Regarding APOEε4 prediction, all AUC values ranged between 0.60–0.69, with all sensitivity measures ranging between 53.8–89.7. There were minimal differences in the AUC values across learning slope metrics, largely due to the lack of ceiling effects in this sample.DiscussionThis study demonstrates that some ANB memory subtests and learning slope metrics can discriminate those that are normal from those with amyloid pathology and those with and without APOEε4, consistent with findings reported in Western populations.

Background:Alzheimer's Disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-β42/40 (Aβ42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. Objective:This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. Methods:In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aβ42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Results:Lower plasma Aβ42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p<0.001). These relationships were observed in healthy controls (CSID p=0.01, AQ p=0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOE e4 allele, did not alter these relationships. Conclusion:Understanding relationships between AD-related screening tests and blood-biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.

BACKGROUND:With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS:High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS:The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION:The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Background Benfotiamine provides an important novel therapeutic direction in Alzheimer’s disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. Objective To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. Methods This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. Conclusion The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. Trial registration ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Study Objectives: Given the established racial disparities in both sleep health and dementia risk for African American populations, we assess cross-sectional and longitudinal associations of self-report sleep duration (SRSD) and daytime sleepiness with plasma amyloid beta (A beta) and cognition in an African American (AA) cohort.Methods: In a cognitively unimpaired sample drawn from the African Americans Fighting Alzheimer's in Midlife (AA-FAiM) study, data on SRSD, Epworth Sleepiness Scale, demographics, and cognitive performance were analyzed. A beta 40, A beta 42, and the A beta 42/40 ratio were quantified from plasma samples. Cross-sectional analyses explored associations between baseline predictors and outcome measures. Linear mixed-effect regression models estimated associations of SRSD and daytime sleepiness with plasma A beta and cognitive performance levels and change over time.Results: One hundred and forty-seven participants comprised the cross-sectional sample. Baseline age was 63.2 +/- 8.51 years. 69.6% self-identified as female. SRSD was 6.4 +/- 1.1 hours and 22.4% reported excessive daytime sleepiness. The longitudinal dataset included 57 participants. In fully adjusted models, neither SRSD nor daytime sleepiness is associated with cross-sectional or longitudinal A beta. Associations with level and trajectory of cognitive test performance varied by measure of sleep health.Conclusions: SRSD was below National Sleep Foundation recommendations and daytime sleepiness was prevalent in this cohort. In the absence of observed associations with plasma A beta, poorer self-reported sleep health broadly predicted poorer cognitive function but not accelerated decline. Future research is necessary to understand and address modifiable sleep mechanisms as they relate to cognitive aging in AA at disproportionate risk for dementia.Clinical Trial Information Not applicable.

INTRODUCTION:In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS:Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS:Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P < 0.001). Among plasma eligible participants, PET eligibility did not differ by group. DISCUSSION:These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members. HIGHLIGHTS:Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.

INTRODUCTION:Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. METHODS:Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS:The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION:Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS:gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Sleep abnormalities may play a prominent role in the pathogenesis or exacerbation of Alzheimer’s disease (AD). Sleep is considered a modifiable target for prevention and treatment. Racial sleep health disparities exist, and may contribute to the disproportionately increased risk for developing AD associated with being African American. Yet, the relationships between sleep health and AD pathophysiology in African American individuals are under-studied. This investigation was designed to address research gaps by evaluating the associations of self-report sleep duration, sleep disturbances, and daytime sleepiness with change in plasma-derived amyloid β 42/40 ratio (Aβ42/40) in an African American sample. Archival data from African American participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention study and the Wisconsin Alzheimer’s Disease Research Center were utilized. Data included the Medical Outcomes Study Sleep Scale (MOS-Sleep), Epworth Sleepiness Scale (ESS), and demographic information. Sleep duration was determined by MOS-Sleep #2, sleep disturbances were captured by a related MOS-Sleep subscale (SLPD4), and ESS assessed daytime sleepiness. Participants provided plasma samples across multiple timepoints. PrecivityAD TM assays quantified Aβ42/40. Aβ42/40 rate of change (Aβ42/40_ROC) was computed for follow-up collections to serve as the primary outcome measure. Aβ42/40_ROC was computed as the difference in Aβ42/40 between follow-up and first collection divided by years between collections. Linear mixed-effects models determined associations with Aβ42/40_ROC. Observations were nested within participant. Fully adjusted models included age at collection, gender, BMI, education, parental history of dementia, and APOEe4 carrier status. Data included 339 follow-up collections from 143 participants. Women provided 70.8% of collections, with average age at collection = 66.6 ± 8.84 years, Aβ42/40_ROC = -0.0005 ± 0.003, and sleep duration = 6.35 ± 1.00 hours. Sleep duration significantly associated with Aβ42/40_ROC in the fully adjusted model (β = -0.0005; SE = 0.0002; p = 0.02) (Figure 1). Associations between SLPD4 and ESS with Aβ42/40_ROC were nonsignificant. Longer self-report sleep duration associated with a steeper reduction rate for plasma Aβ42/40, a biomarker for amyloid pathology. Further research is necessary to clarify the relationships between sleep health components and changes in AD-related biomarkers within African American adults to identify focal risk factors and interventional strategies.

Abstract Background As people with human immunodeficiency virus (HIV) (PWH) age, it remains unclear whether they are at higher risk for age-related neurodegenerative disorders—for example, Alzheimer disease (AD)—and, if so, how to differentiate HIV-associated neurocognitive impairment from AD. We examined a clinically available blood biomarker test for AD (plasma amyloid-β [Aβ] 42/Aβ40 ratio) in PWH who were cognitively normal (PWH_CN) or cognitively impaired (PWH_CI) and people without HIV (PWoH) who were cognitively normal (PWoH_CN) or had symptomatic AD (PWoH_AD). Methods A total of 66 PWH (age >40 years) (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale. Participants were categorized by impairment (PWH_CN, n = 43; PWH_CI, n = 23; PWoH_CN, n = 138; PWoH_AD, n = 57). Plasma Aβ42 and Aβ40 concentrations were obtained using a liquid chromatography–tandem mass spectrometry method to calculate the PrecivityAD amyloid probability score (APS). The APS incorporates age and apolipoprotein E proteotype into a risk score for brain amyloidosis. Plasma Aβ42/Aβ40 ratios and APSs were compared between groups and assessed for relationships with hippocampal volumes or cognition and HIV clinical characteristics (PWH only). Results The plasma Aβ42/Aβ40 ratio was significantly lower, and the APS higher, in PWoH_AD than in other groups. A lower Aβ42/Aβ40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH_AD. The Aβ42/Aβ40 ratio and APS were not associated with cognition or HIV clinical measures for PWH. Conclusions The plasma Aβ42/Aβ40 ratio can serve as a screening tool for AD and may help differentiate effects of HIV from AD within PWH, but larger studies with older PWH are needed.

Background With the advent of antiretrovirals, people living with HIV are living near-normal lifespans. However, people living with HIV are at greater risk of experiencing cognitive impairment and reduced brain integrity despite well-controlled viremia. A robust literature supports exercise interventions as a method of improving cognition and structural brain integrity in older individuals without HIV. The effects of exercise on cardiometabolic, neurocognitive, and neural structures in middle-aged to older people living with HIV are less well known, with few prospective studies examining these measures. Objective This prospective randomized clinical trial will examine the effects of a 6-month exercise training intervention compared to a 6-month stretching intervention (control) on cardiorespiratory fitness, physical function and strength, cognition, and neuroimaging measures of brain volumes and cerebral blood flow in people living with HIV. Methods Sedentary middle-aged to older people living with HIV (ages≥40; n=150) with undetectable HIV viral load (<20 copies/mL) will be enrolled in the study. At the baseline and final visit, fasting plasma lipid, insulin, glucose, and brain neurotrophic factor concentrations; cardiorespiratory fitness; cognitive performance; brain volumes; and cerebral blood flow via a magnetic resonance imaging scan will be measured. Participants will be randomized in a 2:1 ratio to either the exercise or control stretching intervention. All participants will complete their assigned programs at a community fitness center 3 times a week for 6 months. A professional fitness trainer will provide personal training guidance at all sessions for individuals enrolled in both arms. Individuals randomized to the exercise intervention will perform endurance and strength training exercises, while those randomized to the control intervention will perform stretches to increase flexibility. A midpoint visit (at 3 months) will assess cognitive performance, and at the end point visit, subjects will undergo cardiorespiratory fitness and cognition testing, and a magnetic resonance imaging scan. Physical activity throughout the duration of the trial will be recorded using an actigraph. Results Recruitment and data collection are complete as of December 2020. Data processing, cleaning, and organization are complete as of December 2021. Data analysis began in January 2022, with the publication of study results for primary aims 1 and 2 expected by early 2023. Conclusions This study will investigate the effects of a 6-month aerobic and resistance exercise training intervention to improve cardiometabolic risk factors, cognitive performance, cerebral structure, and blood flow in sedentary people living with HIV. Results will inform clinicians and patients of the potential benefits of a structured aerobic exercise training program on the cognitive, functional, and cardiometabolic health status of older people living with HIV. Assessment of compliance will inform the development and implementation of future exercise programs for people living with HIV. Trial Registration ClinicalTrials.gov NCT02663934; https://clinicaltrials.gov/ct2/show/NCT02663934 International Registered Report Identifier (IRRID) DERR1-10.2196/41421

The plasma amyloid-beta (A beta) 42/A beta 40 ratio, a blood-based biomarker for brain amyloid in Alzheimer disease, is not abnormal in older cognitively normal or cognitively impaired people with human immunodeficiency virus (HIV), compared with similarly aged, cognitively normal people without HIV. Background As people with human immunodeficiency virus (HIV) (PWH) age, it remains unclear whether they are at higher risk for age-related neurodegenerative disorders-for example, Alzheimer disease (AD)-and, if so, how to differentiate HIV-associated neurocognitive impairment from AD. We examined a clinically available blood biomarker test for AD (plasma amyloid-beta [A beta] 42/A beta 40 ratio) in PWH who were cognitively normal (PWH_CN) or cognitively impaired (PWH_CI) and people without HIV (PWoH) who were cognitively normal (PWoH_CN) or had symptomatic AD (PWoH_Ad). Methods A total of 66 PWH (age >40 years) (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale. Participants were categorized by impairment (PWH_CN, n = 43; PWH_CI, n = 23; PWoH_CN, n = 138; PWoH_Ad, n = 57). Plasma A beta 42 and A beta 40 concentrations were obtained using a liquid chromatography-tandem mass spectrometry method to calculate the PrecivityAD amyloid probability score (APS). The APS incorporates age and apolipoprotein E proteotype into a risk score for brain amyloidosis. Plasma A beta 42/A beta 40 ratios and APSs were compared between groups and assessed for relationships with hippocampal volumes or cognition and HIV clinical characteristics (PWH only). Results The plasma A beta 42/A beta 40 ratio was significantly lower, and the APS higher, in PWoH_AD than in other groups. A lower A beta 42/A beta 40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH_AD. The A beta 42/A beta 40 ratio and APS were not associated with cognition or HIV clinical measures for PWH. Conclusions The plasma A beta 42/A beta 40 ratio can serve as a screening tool for AD and may help differentiate effects of HIV from AD within PWH, but larger studies with older PWH are needed.

BACKGROUND:The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD® blood test that incorporates the plasma Aβ42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease.PURPOSE:This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals.METHODS:The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available.RESULTS:In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9-92.1%) and specificity of 96% (CI: 80.5-99.3%), exclusive of 13 individuals for whom the test was inconclusive.INTERPRETATION:The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired.

Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. Objective: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. Methods: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan ((18)Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n = 100) was processed within 24 h after phlebotomy and analyzed by C2 N. Results: Plasma A beta(42)/A beta(40) demonstrated the highest association for A beta accumulation in the brain with an AUC 0.76 (95% CI = 0.69, 0.82) at C2N and 0.80 (95% CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p < 0.001). Age, sex, and APOE epsilon 4 carrier status did not the diagnostic performance of plasma A beta(42)/A beta(40) to predict amyloid PET positivity in A4 Study participants. Conclusion: Plasma A beta(42)/A beta(40) may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.

Abstract Introduction This study investigates whether plasma biomarkers (Aβ42/40 and p‐tau 181), APS, as well as apolipoprotein E (APOE) proteotype predict cognitive deficits in elderly adults from the Democratic Republic of Congo. Methods Forty‐four with possible AD (pAD) and 41 healthy control (HC) subjects were screened using CSID and AQ, underwent cognitive assessment with the African Neuropsychology Battery (ANB), and provided blood samples for plasma Aβ42, Aβ40, Aβ42/40, and APOE proteotype. Linear and logistic regression were used to evaluate the associations of plasma biomarkers with ANB tests and the ability of biomarkers to predict cognitive status. Results Patients with pAD had significantly lower plasma Aβ42/40 levels, higher APS, and higher prevalence of APOE E4 allele compared to HC. Groups did not differ in levels of Aβ40, Aβ42, or P‐tau 181. Results showed that Aβ42/40 ratio and APS were significantly associated with African Naming Test (ANT), African List Memory Test (ALMT), and African Visuospatial Memory Test (AVMT) scores, while the presence of APOE E4 allele was associated with ANT, ALMT, AVMT, and APT scores. P‐tau 181 did not show any significant associations while adjusting for age, education, and gender. APS showed the highest area under the curve (AUC) value (AUC = 0.78, 95% confidence interval [CI]: 0.68–0.88) followed by Aβ42/40 (AUC = 0.75, 95% CI: 0.66–0.86) and APOE E4 (AUC = 0.69 (CI 0.57–0.81) in discriminating pAD from HC. Discussion These results demonstrate associations between select plasma biomarker of AD pathology (Aβ42/40), APS, and APOE E4 allele) and ANB test scores and the ability of these biomarkers to differentiate pAD from cognitively normal SSA individuals, consistent with findings reported in other settings.

Abstract Introduction It is critical to develop more inclusive Alzheimer's disease (AD) research protocols to ensure that historically excluded groups are included in preclinical research and have access to timely diagnosis and treatment. If validated in racialized groups, plasma AD biomarkers and measures of subtle cognitive dysfunction could provide avenues to expand diversity in preclinical AD research. We sought to evaluate the utility of two easily obtained, low‐burden disease markers, plasma amyloid beta (Aβ)42/40, and intra‐individual cognitive variability (IICV), to predict concurrent and longitudinal cognitive performance in a sample of Black adults. Methods Two hundred fifty‐seven Black participants enrolled in the African Americans Fighting Alzheimer's in Midlife (AA‐FAIM) study underwent at least one cognitive assessment visit; a subset of n = 235 had plasma samples. Baseline IICV was calculated as the standard deviation across participants’ z scores on five cognitive measures: Rey Auditory Verbal Learning Test Delayed Recall, Trail Making Test Parts A and B (Trails A and B), and Boston Naming Test. Using mixed effects regression models, we compared concurrent and longitudinal models to baseline plasma Aβ42/40 or IICV by age interactions. PrecivityAD assays quantified baseline plasma Aβ42/40. Results IICV was associated with concurrent/baseline performance on several outcomes but did not modify associations between age and cognitive decline. In contrast, plasma Aβ42/40 was unrelated to baseline cognitive performance, but a pattern emerged in interactions with age in longitudinal models of Trails A and B and Rey Auditory Verbal Learning Test total learning trials. Although not significant after correcting for multiple comparisons, low Aβ42/40 was associated with faster cognitive declines over time. Discussion Our results are promising as they extend existing findings to an Black American sample using low‐cost, low‐burden methods that can be implemented outside of a research center, thus supporting efforts for inclusive AD biomarker research.