Amyloid Positivity Research Articles

The AHA/ASA and DSM-V diagnostic criteria for vascular cognitive impairment identify cases with predominant vascular pathology.

There are major challenges in determining the etiology of vascular cognitive impairment (VCI) clinically, especially in the presence of mixed pathologies, such as vascular and amyloid. Most recently, two criteria (American Heart Association/American Stroke Association (AHA/ASA) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V)) have been proposed for the clinical diagnosis of VCI but have not as yet been validated using neuroimaging. This study aims to determine whether the AHA/ASA and DSM-V criteria for VCI can distinguish between cases with predominantly vascular pathology and cases with mixed pathology. A total of 186 subjects were recruited from a cross-sectional memory clinic-based study at the National University Hospital, Singapore. All subjects underwent clinical and neuropsychological assessment, magnetic resonance imaging (MRI) and carbon 11-labeled Pittsburgh Compound B ([11C] PiB) positron emission tomography (PET) scans. Diagnosis of the etiological subtypes of VCI (probable vascular mild cognitive impairment (VaMCI), possible VaMCI, non-VaMCI, probable vascular dementia (VaD), possible VaD, non-VaD) were performed following AHA/ASA and DSM-V criteria. Brain amyloid burden was determined for each subject with standardized uptake value ratio (SUVR) values ⩾1.5 classified as amyloid positive. Using κ statistics, both criteria had excellent agreement for probable VaMCI, probable VaD, and possible VaD (κ = 1.00), and good for possible VaMCI (κ = 0.71). Using the AHA/ASA criteria, the amyloid positivity of probable VaMCI (3.8%) and probable VaD (15%) was significantly lower compared to possible VaMCI (26.7%), non-VaMCI (33.3%), possible VaD (73.3%), and non-VaD (76.2%) (p < 0.001). Similarly, using the DSM-V criteria, the amyloid positivity of probable VaMCI (3.8%) and probable VaD (15%) was significantly lower compared to possible VaMCI (26.3%), non-VaMCI (32.1%), possible VaD (73.3%), and non-VaD (76.2%) (p < 0.001). In both criteria, there was good agreement in differentiating individuals with non-VaD and possible VaD, with significantly higher (p < 0.001) global [11C]-PiB SUVR, from individuals with probable VaMCI and probable VaD, who had predominant vascular pathology. The AHA/ASA and DSM-V criteria for VCI can identify VCI cases with little to no concomitant amyloid pathology, hence supporting the utility of AHA/ASA and DSM-V criteria in diagnosing patients with predominant vascular pathology. Data supporting this study are available from the Memory Aging and Cognition Center, National University of Singapore. Access to the data is subject to approval and a data sharing agreement due to University policy.

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Protein fibril aggregation on red blood cells: a potential biomarker to distinguish neurodegenerative diseases from healthy aging.

Neurodegenerative diseases like Alzheimer's disease are characterized by the accumulation of misfolded proteins into fibrils in the brain. Atomic force microscopy is a nanoscale imaging technique that can be used to resolve and quantify protein aggregates from oligomers to fibrils. Recently, we characterized protein fibrillar aggregates adsorbed on the surface of red blood cells with atomic force microscopy from patients with neurocognitive disorders, suggesting a novel Alzheimer's disease biomarker. However, the age association of fibril deposits on red blood cells has not yet been studied in detail in healthy adults. Here, we used atomic force microscopy to visualize and quantify fibril coverage on red blood cells in 50 healthy adults and 37 memory clinic patients. Fibrillar protein deposits sporadically appeared in healthy individuals but were much more prevalent in patients with neurodegenerative disease, especially those with Alzheimer's disease as confirmed by positive CSF amyloid beta 1-42/1-40 ratios. The prevalence of fibrils on the red blood cell surface did not significantly correlate with age in either healthy individuals or Alzheimer's disease patients. The overlap in fibril prevalence on red blood cells between Alzheimer's disease and amyloid-negative patients suggests that fibril deposition on red blood cells could occur in various neurodegenerative diseases. Quantifying red blood cell protein fibril morphology and prevalence on red blood cells could serve as a sensitive biomarker for neurodegeneration, distinguishing between healthy individuals and those with neurodegenerative diseases. Future studies that combine atomic force microscopy with immunofluorescence techniques in larger-scale studies could further identify the chemical nature of these fibrils, paving the way for a comprehensive, non-invasive biomarker platform for neurodegenerative diseases.

APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease.

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

Inferior Frontal Sulcal Hyperintensities on Brain MRI Are Associated with Amyloid Positivity beyond Age-Results from the Multicentre Observational DELCODE Study.

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer's disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05-3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57-2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00-1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26-0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age.

Clinical and Neuroimaging Predictors of Alzheimer's Dementia Conversion in Patients with Mild Cognitive Impairment Using Amyloid Positron Emission Tomography by Quantitative Analysis over 2 Years.

Patients with mild cognitive impairment (MCI) have a relatively high risk of developing Alzheimer's dementia (AD), so early identification of the risk for AD conversion can lessen the socioeconomic burden. In this study, 18F-Florapronol, newly developed in Korea, was used for qualitative and quantitative analyses to assess amyloid positivity. We also investigated the clinical predictors of the progression from MCI to dementia over 2 years. From December 2019 to December 2022, 50 patients with MCI were recruited at a single center, and 34 patients were included finally. Based on visual analysis, 13 (38.2%) of 34 participants were amyloid-positive, and 12 (35.3%) were positive by quantitative analysis. Moreover, 6 of 34 participants (17.6%) converted to dementia after a 2-year follow-up (p = 0.173). Among the 15 participants who were positive for amyloid in the posterior cingulate region, 5 (33.3%) patients developed dementia (p = 0.066). The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) at baseline was significantly associated with AD conversion in multivariate Cox regression analyses (p = 0.043). In conclusion, these results suggest that amyloid positivity in the posterior cingulate region and higher CDR-SOB scores at baseline can be useful predictors of AD conversion in patients with MCI.

Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals.

Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. A total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8years, mean follow-up 5.1years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and β = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: β = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and β = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (β = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (β = - 0.02mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]). In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

The diagnostic and prognostic value of tau-PET in amnestic MCI with different FDG-PET subtypes.

Mild cognitive impairment presenting with an amnestic syndrome (aMCI) and amyloid positivity is considered due to AD. Many subjects, however, can show an overall very slow progression relevant for differential diagnosis, prognosis, and treatment. This study assessed PET biomarkers, includingbrain glucose metabolism, tau, and amyloid load, in a series of comparable aMCI at baseline, clinically evaluated at follow-up. We included 72 aMCI subjects from Geneva Memory Center (N = 31) and ADNI cohorts (N = 41), selected based on available FDG-PET, tau-PET, amyloid-PET, and clinical follow-up (2.3 years ± 1.2). A data-driven algorithm classified brain metabolic patterns into subtypes that were then compared for clinical and PET biomarker measures and cognitive decline. Voxel-wise comparisons were performed both with FDG-PET and tau-PET data. The algorithm classified three metabolic subtypes, namely "Hippocampal-sparing with cortical hypometabolism" (Type1; N = 27), "Hippocampal and cortical hypometabolism" (Type 2; N = 23), and "Medial temporal hypometabolism" (Type 3; N = 22). Amyloid positivity and tau accumulation in the medial temporal and neocortical regions characterized Type 1 and Type 2, whereas Type 3 showed no significant tau pathology, variable amyloid positivity, and stability at follow-up. All tau-positive patients, independently of the FDG-based subtype, showed faster cognitive decline. aMCI subjects can differ in metabolic patterns, tau and amyloid pathology, and clinical progression. Here, we complemented with PET tau biomarker the specific brain hypometabolic patterns at the individual level in the prodromal phase, contributing to the patient's classification. Tau PET is the most accurate biomarker in supporting or excluding the AD diagnosis in aMCI across metabolic subtypes and also predicting the risk of decline.

Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. 445 cross-sectional participants (aged≥50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. We found both tau metrics significantly elevated across increasing disease stages (p<0.0001) and as a function of increasing amyloid burden for participants with preclinical (p<0.0001, p=0.0056) and symptomatic (p=0.010, p=0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p=0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (β=0.59), but then tau burden elevated relative to spread (β=0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R=0.83). Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design. This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Contribution of Global Amyloid-PET Imaging for Predicting Future Cognition in the MEMENTO Cohort.

Global amyloid-PET is associated with cognition and cognitive decline, but most research on this association does not account for past cognitive information. We assessed the prognostic benefit of amyloid-PET measures for future cognition when prior cognitive assessments are available, evaluating the added value of amyloid measures beyond information on multiple past cognitive assessments. The French MEMENTO cohort (a cohort of outpatients from French research memory centers to improve knowledge on Alzheimer disease and related disorders) includes older outpatients with incipient cognitive changes, but no dementia diagnosis at inclusion. Global amyloid burden was assessed using positron emission tomography (amyloid-PET) for a subset of participants; semiannual cognitive testing was subsequently performed. We predicted mini-mental state examination (MMSE) scores using demographic characteristics (age, sex, marital status, and education) alone or in combination with information on prior cognitive measures. The added value of amyloid burden as a predictor in these models was evaluated with percent reduction of the mean squared error (MSE). All models were conducted separately for evaluating the added value of dichotomous amyloid positivity status compared with a continuous amyloid-standardized uptake-value ratio. Our analytic sample comprised 510 individuals who underwent amyloid-PET scans with at least 4 MMSE assessments. The mean age at the PET scan was 71.6 (standard deviation 7.4) years; 60.7% were female. The median follow-up was 4.6 years (interquartile range: 0.9 years). Adding amyloid burden when adjusting for only demographic characteristics reduced the MSE of predictions by 5.08% (95% CI 0.97%-10.86%) and 12.64% (95% CI 3.35%-25.28%) for binary and continuous amyloid, respectively. If the model included 1 past MMSE measure, the MSE improvement was 3.51% (95% CI 1.01%-7.28%) when adding binary amyloid and 8.83% (95% CI 2.63%-16.37%) when adding continuous amyloid. Improvements in model fit were smaller with the addition of amyloid burden when more than 1 past cognitive assessment was included. For all models incorporating past cognitive assessments, differences in predictions amounted to a fraction of 1 MMSE point on average. In a clinical setting, global amyloid burden did not appreciably improve cognitive predictions when past cognitive assessments were available. ClinicalTrials.gov Identifier: NCT02164643.

CSF Biomarkers in Longitudinal Alzheimer Disease Cohorts: Pre-Analytic Challenges.

The sensitivity of amyloid to pre-analytic factors complicates cerebrospinal fluid (CSF) diagnostics for Alzheimer disease. We report reliability and validity evidence for automated immunoassays from frozen and fresh CSF samples in an ongoing, single-site research program. CSF samples were obtained from 2 Wisconsin cohorts (1256 measurements; 727 participants). Levels of amyloid beta 1-42 (Aβ42), phosphorylated tau 181 (pTau181), and total tau (tTau) were obtained using an Elecsys cobas e 601 platform. Repeatability and fixed effects of storage tube type, extraction method, and freezing were assessed via mixed models. Concordance with amyloid positron emission tomography (PET) was investigated with 238 participants having a temporally proximal PET scan. Repeatability was high with intraclass correlation (ICC) ≥0.9, but tube type strongly affected measurements. Discriminative accuracy for PET amyloid positivity was strong across tube types (area under the curve [AUC]: Aβ42, 0.87; pTau181Aβ42 , 0.96), although optimal thresholds differed. Under real-world conditions, the Elecsys platform had high repeatability. However, strong effects of pre-analytic factors suggest caution in drawing longitudinal inferences.

The Bio-Hermes Study: Biomarker database developed to investigate blood-based and digital biomarkers in community-based, diverse populations clinically screened for Alzheimer's disease.

Alzheimer's disease (AD) trial participants are often screened for eligibility by brain amyloid positron emission tomography/cerebrospinal fluid (PET/CSF), which is inefficient as many are not amyloid positive. Use of blood-based biomarkers may reduce screen failures. We recruited 755 non-Hispanic White, 115 Hispanic, 112 non-Hispanic Black, and 19 other minority participants across groups of cognitively normal (n=417), mild cognitive impairment (n=312), or mild AD (n=272) participants. Plasma amyloid beta (Aβ)40, Aβ42, Aβ42/Aβ40, total tau, phosphorylated tau (p-tau)181, and p-tau217 were measured; amyloid PET/CSF (n=956) determined amyloid positivity. Clinical, blood biomarker, and ethnicity/race differences associated with amyloid status were evaluated. Greater impairment, older age, and carrying an apolipoprotein E (apoE) ε4 allele were associated with greater amyloid burden. Areas under the receiver operating characteristic curve for amyloid status of plasma Aβ42/Aβ40, p-tau181, and p-tau217 with amyloid positivity were ≥ 0.7117 for all ethnoracial groups (p-tau217, ≥0.8128). Age and apoE ε4 adjustments and imputation of biomarker values outside limit of quantitation provided small improvement in predictive power. Blood-based biomarkers are highly associated with amyloid PET/CSF results in diverse populations enrolled at clinical trial sites. Amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)181, and p-tau 217 blood-based biomarkers predicted brain amyloid positivity. P-tau 217 was the strongest predictor of brain amyloid positivity. Biomarkers from diverse ethnic, racial, and clinical cohorts predicted brain amyloid positivity. Community-based populations have similar Alzheimer's disease (AD) biomarker levels as other populations. A prescreen process with blood-based assays may reduce the number of AD trial screen failures.

Visual associative learning to detect early episodic memory deficits and distinguish Alzheimer's disease from other types of dementia.

We investigated how well a visual associative learning task discriminates Alzheimer's disease (AD) dementia from other types of dementia and how it relates to AD pathology. 3,599 patients (63.9 ± 8.9 years old, 41% female) from the Amsterdam Dementia Cohort completed two sets of the Visual Association Test (VAT) in a single test session and underwent magnetic resonance imaging. We performed receiver operating curve analysis to investigate the VAT's discriminatory ability between AD dementia and other diagnoses and compared it to that of other episodic memory tests. We tested associations between VAT performance and medial temporal lobe atrophy (MTA), and amyloid status (n = 2,769, 77%). Patients with AD dementia performed worse on the VAT than all other patients. The VAT discriminated well between AD and other types of dementia (area under the curve range 0.70-0.86), better than other episodic memory tests. Six-hundred forty patients (17.8%) learned all associations on VAT-A, but not on VAT-B, and they were more likely to have higher MTA scores (odds ratios range 1.63 (MTA 0.5) through 5.13 for MTA ≥ 3, all p < .001) and to be amyloid positive (odds ratio = 3.38, 95%CI = [2.71, 4.22], p < .001) than patients who learned all associations on both sets. Performance on the VAT, especially on a second set administered immediately after the first, discriminates AD from other types of dementia and is associated with MTA and amyloid positivity. The VAT might be a useful, simple tool to assess early episodic memory deficits in the presence of AD pathology.

Predicting amyloid positivity from FDG-PET images using radiomics: A parsimonious model

Background and ObjectiveAmyloid plaques are one of the physical hallmarks of Alzheimer's disease. The objective of this study is to predict amyloid positivity non-invasively from FDG-PET images using a radiomics approach. MethodsWe obtained FDG-PET images of 301 individuals from various groups, including control normal (CN), mild cognitive impairment (MCI), and Alzheimer's Disease (AD), from the ADNI database. Following the utilization of the CSF Aβ1–42 (192) and Standardized Uptake Value Ratio (SUVR) (1.11) thresholds derived from Florbetapir scans, the subjects were categorized into two categories: those with a positive amyloid status (n = 185) and those with a negative amyloid status (n = 116). The process of segmenting the entire brain into 95 classes using the DKT-atlas was utilized. Following that, we obtained 120 characteristics for each of the 95 regions of interest (ROIs). We employed eight feature selection methods to analyze the features. Additionally, we utilized eight different classifiers on the 20 most significant features extracted from each feature selection method. Finally, in order to improve interpretability, we selected the most important features and ROIs. ResultWe found that the GNB classifier and the LASSO feature selection method had the best performance with an average accuracy of (AUC=0.924) while using 18 features on 15 ROIs. We were then able to reduce the model to three regions (Hippocampus, inferior parietal, and isthmus cingulate) and three gray-level based features (AUC=0.853). ConclusionThe FDG-PET images which serve to study metabolic activity can be used to predict amyloid positivity without the use of invasive methods or another PET tracer and study. The proposed method has superior prediction accuracy with respect to similar studies reported in the literature using other imaging modalities. Only three brain regions had a high impact on amyloid positivity results.

Small vessel cerebrovascular disease is associated with cognition in prospective Alzheimer’s clinical trial participants

BackgroundSecondary prevention clinical trials for Alzheimer’s disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a secondary prevention trial.MethodsData from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status.ResultsIncreased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status.ConclusionThese results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.

It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7-11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was -0·34 [effect size -0·52; 95% CI -0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [-0·21 to 0·47], 0·03 [-0·30 to 0·36], and 0·10 [-0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was -3·01 pg/mL (-4·45 to -1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required. Toulouse Gérontopôle, French Ministry of Health and Pierre Fabre Research Institute.

Abstract TP23: Differentiated Para-Vascular Distribution of Amyloid Plaques in Normal versus Cognitively Impaired

Introduction: The vascular contribution to Alzheimer’s disease (AD) and AD-related dementias is increasingly recognized. Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina, vascular changes and amyloid plaque deposition. The relationship between retinal vascular changes and peri-vascular amyloid deposition in the continuum of neurodegeneration is imperfectly understood. In this exploratory topographic analysis of a cohort of subjects with normal and impaired cognition that underwent SLO, we investigated the retinal vascular-adjacent (para-vascular) amyloid plaque distribution and its correlation with cognitive measures. Methods: 34 subjects with cognitive decline underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal para-arteriolar and para-venular curcumin positive amyloid plaques were quantified in the supero-temporal retinal quadrant, in the first-, second- and third-order retinal vascular branches. The para-venous and para-arteriolar amyloid count were compared between patients with normal and impaired cognition, and their correlation with brain volumes and white matter hyperintensities was determined. Results: We analyzed retinal para-venous and para-arteriolar amyloid and vascular-structural parameters derived from 29 subjects, mean (SD) age 65(7), 48% female. Para-arteriolar plaque was higher than para-venular plaque in the entire cohort (p&lt;0.0001). Secondary branch para-venular amyloid plaque count was higher in patients with impaired cognition, CDR ≥1 and MOCA ≤26. The para-arterial plaque count in the secondary branches significantly correlated with hippocampal volume and white matter hyperintensities scores. Conclusion: Our topographic analysis of the amyloid plaque distribution in retinal para-vascular regions shows higher amyloid accumulation in the para-arteriolar regions overall, and specifically in the secondary para-venular branches in patients with impaired cognition. Larger longitudinal studies are needed to study the temporal and spatial relationship between vascular dysfunction and para-vascular amyloid deposition in AD.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia.

This study investigated the role of proactive semantic interference (frPSI) in predicting the progression of amnestic Mild Cognitive Impairment (aMCI) to dementia, taking into account various cognitive and biological factors. The research involved 89 older adults with aMCI who underwent baseline assessments, including amyloid PET and MRI scans, and were followed longitudinally over a period ranging from 12 to 55 months (average 26.05 months). The findings revealed that more than 30% of the participants diagnosed with aMCI progressed to dementia during the observation period. Using Cox Proportional Hazards modeling and adjusting for demographic factors, global cognitive function, hippocampal volume, and amyloid positivity, two distinct aspects of frPSI were identified as significant predictors of a faster decline to dementia. These aspects were fewer correct responses on a frPSI trial and a higher number of semantic intrusion errors on the same trial, with 29.5% and 31.6 % increases in the likelihood of more rapid progression to dementia, respectively. These findings after adjustment for demographic and biological markers of Alzheimer's Disease, suggest that assessing frPSI may offer valuable insights into the risk of dementia progression in individuals with aMCI.

Brain structural indicators of β-amyloid neuropathology

Recent efforts demonstrated the efficacy of identifying early-stage neuropathology of Alzheimer’s disease (AD) through lumbar puncture cerebrospinal fluid assessment and positron emission tomography (PET) radiotracer imaging. These methods are effective yet are invasive, expensive, and not widely accessible. We extend and improve the multiscale structural mapping (MSSM) procedure to develop structural indicators of β-amyloid neuropathology in preclinical AD, by capturing both macrostructural and microstructural properties throughout the cerebral cortex using a structural MRI. We find that the MSSM signal is regionally altered in clear positive and negative cases of preclinical amyloid pathology (N = 220) when cortical thickness alone or hippocampal volume is not. It exhibits widespread effects of amyloid positivity across the posterior temporal, parietal, and medial prefrontal cortex, surprisingly consistent with the typical pattern of amyloid deposition. The MSSM signal is significantly correlated with amyloid PET in almost half of the cortex, much of which overlaps with regions where beta-amyloid accumulates, suggesting it could provide a regional brain ‘map’ that is not available from systemic markers such as plasma markers.

Rescreening on RBANS Delayed Memory Index? Forget About It!

To assess the value of rescreening patients with Alzheimer's disease who do not meet the inclusion criteria for the Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) at the initial assessment. Participants (aged 50-85years, without dementia, Mini-Mental State Examination score ≥22, valid Clinical Dementia Rating [CDR] global score, and amyloid status at baseline) were identified in the European Prevention of Alzheimer's Dementia database. Changes from baseline in RBANS DMI were estimated using a mixed model for repeated measurements. Logistic regressions were used to estimate the probability of participants with baseline RBANS DMI 86-95 having RBANS DMI ≤85, CDR global score ≥0.5, and amyloid positivity at 6 and 12 months. There was significant variability in the change in RBANS DMI scores over time (median change at 6months: 2.0). An estimated 15% of participants with RBANS DMI 86-95 at baseline progressed to ≤85 at 6 months; 8% also achieved CDR global score ≥0.5 and 5% were also amyloid positive. The results from our analysis indicate that there is limited value in rescreening patients based on their initial RBANS DMI score.