Brain Amyloid Levels Research Articles

Hyperspectral Retinal Imaging as a Non-Invasive Marker to Determine Brain Amyloid Status.

As an extension of the central nervous system (CNS), the retina shares many similarities with the brain and can manifest signs of various neurological diseases, including Alzheimer's disease (AD). To investigate the retinal spectral features and develop a classification model to differentiate individuals with different brain amyloid levels. Sixty-six participants with varying brain amyloid-β protein levels were non-invasively imaged using a hyperspectral retinal camera in the wavelength range of 450-900 nm in 5 nm steps. Multiple retina features from the central and superior views were selected and analyzed to identify their variability among individuals with different brain amyloid loads. The retinal reflectance spectra in the 450-585 nm wavelengths exhibited a significant difference in individuals with increasing brain amyloid. The retinal features in the superior view showed higher inter-subject variability. A classification model was trained to differentiate individuals with varying amyloid levels using the spectra of extracted retinal features. The performance of the spectral classification model was dependent upon retinal features and showed 0.758-0.879 accuracy, 0.718-0.909 sensitivity, 0.764-0.912 specificity, and 0.745-0.891 area under curve for the right eye. This study highlights the spectral variation of retinal features associated with brain amyloid loads. It also demonstrates the feasibility of the retinal hyperspectral imaging technique as a potential method to identify individuals in the preclinical phase of AD as an inexpensive alternative to brain imaging.

Plasma pTau217 predicts continuous brain amyloid levels in preclinical and early Alzheimer's disease.

This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. Quantification of plasma pTau217R and Aβ42/Aβ40 employed immunoprecipitation-mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinicaland early AD subjects and validated on two independent cohorts. Models integrating pTau217R outperformed Aβ42/Aβ40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R-based models for low amyloid levels reduced PET scans by 70.5% to 78.6%. pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aβ42/Aβ40's range. Combining it with plasma Aβ42/Aβ40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility. NCT02956486 (MissionAD1), NCT03036280 (MissionAD2), NCT04468659 (AHEAD3-45), NCT03887455 (ClarityAD) HIGHLIGHTS: Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid-PET Centiloid (CL) across a broad spectrum. Integrating pTau217R with Aβ42/Aβ40 extends the CL prediction upper limit to 89.1 CL. Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals. This modelidentifies subjects above or below various CL thresholds with high accuracy. pTau217R-based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid.

Lecanemab: A Humanized Monoclonal Antibody for the Treatment of Early Alzheimer Disease.

To review current pharmacology, pharmacokinetics/pharmacodynamics, safety, and efficacy of lecanemab in patients with Alzheimer disease. A literature search of PubMed (April 1, 2016-November 15, 2023) and ClinicalTrials.gov search were conducted using the following search terms: lecanemab and BAN2401. Additional articles were identified by hand from references. We included English-language clinical trials, randomized controlled trials, reviews, and systematic reviews evaluating lecanemab pharmacology, efficacy, or safety in humans for the management of Alzheimer disease. In the Clarity AD phase III trial, lecanemab led to a decrease in brain amyloid levels and showed moderate improvement in clinical measures of cognition and function. At 18 months, lecanemab 10 mg/kg biweekly exhibited a lower least squares mean change from baseline (1.21) compared to placebo (1.66) of Clinical Dementia Rating-Sum of Boxes score, signifying a significant difference of -0.45 (95% CI, -0.67 to -0.23; P < 0.001). In a subset of 698 participants, lecanemab reduced brain amyloid burden by -59.1 Centiloids (95% CI, -62.6 to -55.6). Lecanemab demonstrated favorable differences in Alzheimer Disease Assessment Scale-cognitive subscale 14, Alzheimer Disease Composite Score, and Alzheimer Disease Cooperative Study-Mild Cognitive Impairment-Activities of Daily Living scores. Adverse events included infusion-related reactions (26.4%) and amyloid-related imaging abnormalities (12.6%). Lecanemab reduces cognitive decline but raises concerns about intravenous administration, cost, and magnetic resonance imaging needs. Ongoing trials exploring subcutaneous dosing and positron emission tomography scans may offer solutions. Lecanemab is a humanized monoclonal antibody that is selective for soluble amyloid-beta (Aβ) aggregates. Lecanemab has exhibited a decrease in brain Aβ plaques and moderately less decline on clinical measures of cognitive function.

Developing Topics.

TRAILBLAZER-ALZ 4 demonstrated superiority of donanemab versus aducanumab at the 6-month primary endpoint of the percentage of participants achieving amyloid plaque clearance (<24.1 Centiloids [CL]) in patients with early symptomatic AD (Salloway et al. CTAD 2022). Participants (n = 148) were randomized 1:1 to receive donanemab (titration: 700mg IV Q4W [first 3 doses], then 1400mg IV Q4W [subsequent doses]) or aducanumab (titration per USPI: 1mg/kg IV Q4W [first 2 doses], 3mg/kg IV Q4W [next 2 doses], 6mg/kg IV Q4W [next 2 doses] and 10mg/kg IV Q4W [subsequent doses]). The study is ongoing with a total duration of 18 months. Baseline demographics and characteristics were well-balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty-seven donanemab-treated and 28 aducanumab-treated participants had low/medium (intermediate) tau levels based on screening tau PET scans. In all participants at 12 months, 70.2%±6.3% (least square [LS] mean ± standard error [SE]) donanemab-treated vs. 21.9%±5.9% aducanumab-treated participants achieved amyloid plaque clearance (p<0.001) assessed by florbetapir F18 PET scans. In the low/medium tau subpopulation, 80.0%±9.9% donanemab-treated vs. 9.6%±5.4% aducanumab-treated participants achieved amyloid clearance (p<0.001). The percent change (LS mean ± SE) in brain amyloid levels were -82.8%±3.1% (baseline [LS mean ± standard deviation]: 97.59±28.20 CL) and -57.0%±3.1% (baseline: 102.71±35.30 CL) in donanemab and aducanumab arms, respectively (p<0.001). In the low/medium tau subpopulation, percent change in brain amyloid levels were -82.7%±4.6% (baseline: 104.97±25.68 CL) and -57.0%±4.5% (baseline: 102.99±27.87 CL) in donanemab and aducanumab arms, respectively (p<0.001). Adverse events occurred in 78.9% of donanemab-treated and 82.6% of aducanumab-treated participants, respectively. Amyloid-related imaging abnormalities occurred in 29.6% (1.4% serious [n = 1]) and 40.6% (2.9% serious [n = 2]) of participants in the donanemab and aducanumab arms, respectively, with higher rates in ApoE4 carriers. TRAILBLAZER-ALZ 4 provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD and demonstrates the higher brain amyloid reduction of donanemab vs. aducanumab at 12 months when drug titration has been completed and the treatment regime has stabilized.

Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population

AbstractBackgroundAlzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.MethodMeasures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐e4 genotype, ß‐amyloid (Aß) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aß was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aß+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aß levels and cognition covarying for the participant’s age, sex, and years of education where relevant.ResultAs previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aß (p&lt;0.001). The association between Aß and history in both parents remained significant when covarying for APOE‐e4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐e4 and Aß. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p&lt;0.001) and in those with only maternal family history (n = 1776, p&lt;0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: ß = 0.03, p&lt;0.001 in individuals with maternal history, ß = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (ßmaternal = 0.02, pmaternal = 0.01; ßpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.ConclusionWe confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐e4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aß burden among asymptomatic older individuals.

Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population

AbstractBackgroundAlzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.MethodMeasures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐ε4 genotype, β‐amyloid (Aβ) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aβ was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aβ+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aβ levels and cognition covarying for the participant’s age, sex, and years of education where relevant.ResultAs previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aβ (p&lt;0.001). The association between Aβ and history in both parents remained significant when covarying for APOE‐ε4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐ε4 and Aβ. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p&lt;0.001) and in those with only maternal family history (n = 1776, p&lt;0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: β = 0.03, p&lt;0.001 in individuals with maternal history, β = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (βmaternal = 0.02, pmaternal = 0.01; βpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.ConclusionWe confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐ε4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aβ burden among asymptomatic older individuals.

Assessing the associations between plasma C reactive protein, Ab 42/40 ratio, global amyloid and entorhinal tau PET

AbstractBackgroundLower plasma ratio of amyloid beta (Ab42/Ab40) has been associated with brain amyloid, however, the mechanistic link is unclear. Systemic inflammation may contribute to plasma Ab levels and promote or reduce the accumulation of Alzheimer’s disease (AD) neuropathology. C reactive protein (CRP) is an inflammatory marker implicated in amyloidosis. Using a cross sectional analysis, we evaluated the relationship between blood levels of CRP and Ab ratio, global amyloid positron emission tomography (PET), and tau PET in the entorhinal cortex where tau accumulates early. We hypothesized that Ab positivity would modify the relationship between CRP and AD pathology.MethodIn 969 cognitively normal participants (age: 50‐87, 781 Ab‐/188 Ab+) (Table 1) from the Health and Aging Brain Study‐ Health Disparities (HABS‐HD), we acquired 18F‐PI‐2620 tau‐PET, florbetaben amyloid PET scans, and plasma measures of Ab 42/40 and CRP. Subjects were categorized by Ab + or Ab ‐ by a global amyloid PET standardized uptake value ratio (SUVR) cutoff of 1.08. Within Ab groups, we performed multiple regressions to evaluate associations between 1) global amyloid and entorhinal tau‐PET SUVRs and 2) plasma markers of Ab ratio and CRP. We covaried for age, gender, education, APOE4, and scanner and used false discovery rate (FDR) for multiple comparison corrections.ResultIn Ab+ participants, higher amyloid (b = ‐0.31, p = 0.0005) and tau PET (b = ‐0.36, p = 0.004) were significantly associated with low Ab ratio, but not in Ab‐ for amyloid or tau, with significant interactions by Ab positivity for amyloid (b = ‐0.45, p = 2.65×10−6) and tau (b = ‐0.77, p = 0.0002) (Figure 1). In Ab+ participants, higher CRP was associated with higher Ab ratio (b = 0.21, p = 0.04) and a trend toward lower amyloid (b = ‐0.15, p = 0.084) and tau PET (b = ‐0.22, p = 0.084), but not in Ab‐ participants, with a significant interaction by Ab positivity for Ab ratio (b = 0.46, p = 0.011) (Figure 2) and amyloid (b = ‐0.11, p = 0.0006) and tau PET (b = ‐0.17, p = 0.016).ConclusionIn cognitively intact Ab+ but not Ab‐ adults, higher plasma Ab ratio was associated with lower global amyloid and entorhinal tau PET. In Ab+ participants, higher CRP was associated with blood and brain amyloid and tau levels consistent with less AD pathology.

Association of platelet aggregation to amyloid and tau PET in the Framingham Heart Study

AbstractBackgroundPlatelets are key mediators of inflammation and vascular dysfunction. Prior work highlighted a role of platelet function in Ab and tau dynamics, and dementia risk. We hypothesized that platelet aggregation may associate with amyloid and tau brain levels in middled age people at risk of cardiovascular disease.MethodWe examined cross sectional associations of platelet aggregation with brain amyloid and tau PET levels (11C‐labeled Pittsburgh Compound‐B (PiB) and tau (18F‐Flortaucipir (FTP)) in middle aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3 Cohort. Platelet aggregation was measured by light transmission aggregometry. The response to 0.98uM ADP stimulation was primarily evaluated followed by additional agonists and stimulation doses for sensitivity analysis. The associations were explored in multivariate regression models adjusted for age, age squared, sex, the time from blood to PET examination, and PET camera used.ResultThe final study sample included 356 participants (median [Q1,Q3] age, 55 [49, 61]; 51% women) of which 82 (23%) were on preventive platelet modifying treatments (PPT) (Table 1). We found significant interaction between PPT and platelet aggregation in their association with amyloid and tau PET levels, motivating a stratified analysis by the use or not of PPT. The platelet aggregation response was not associated with PiB or FTP retention in non‐PPT users (n = 274) (Table 2). In PPT users, the platelet aggregation response was positively associated with amyloid levels in the precuneus (β±SE: 0.36±0.14, P&lt;0.05), and tau levels in the rhinal (β±SE: 0.49±0.15, P&lt;0.01) and temporal regions (β±SE: 0.39±0.17, P&lt;0.05).ConclusionOur results indicate that platelet aggregation is not associated with amyloid and tau PET levels in the general population. In people who are on PPT for primary prevention of CVD, platelet aggregation associates with amyloid and tau PET in Alzheimer’s disease (AD) relevant brain regions. This result reinforces the need for further examining the mediator role of platelet aggregation in the association of cardiovascular risk and AD.

Later life Body composition and Alzheimer’s disease

AbstractBackgroundMid‐life obesity is linked with increased risk for late‐life dementia, however relationships between later‐life body composition and dementia are less clear.MethodUsing a combined cohort from two major observational studies (AIBL and ADNI) and categorising Body Mass Index (BMI) according to WHO criteria, we computed multivariable linear mixed‐effects models to determine association between BMI category and outcomes: brain beta‐amyloid PET quantification (centiloid); MRI (global, hippocampal and white matter hyperintensity volume); and cognition (PACC [preclinical Alzheimer cognitive composite], composite scores for attention, executive function and episodic memory). All models were adjusted by covariables age, gender, education, APOE ε4, and study (AIBL/ADNI).ResultsThe cohort included 4,668 observations from 2,828 individuals (49.4% male, mean age 73.8 years, 38.2% APOE ε4 carriage, 61.8% normal cognition [NC], 25.6% Mild Cognitive Impairment [MCI], 12.6% dementia due to Alzheimer’s disease). The average BMI was 26.8 kg/m2 (0.6% underweight, 37.7% normal‐range, 41.7% overweight, 20.0% obese [BMI &lt;18, 18‐25, 25‐30 and &gt;30 kg/m2, respectively]).Relative to normal‐range BMI, those with overweight‐or‐obese range BMI had a significant negative association with PET centiloid level, beta = ‐0.150 (0.037 se) and ‐0.309 (0.042), respectively (i.e. greater BMI had lower amyloid level). This remained significant for obese‐range BMI in fully‐adjusted models when restricted to only NC participants. Also, obesity was associated with greater hippocampal volume, beta = 0.192 (0.046), but this was not significant when restricted to NC only. Associations with total grey matter/cortical volume and white matter hyperintensities were not significant. Obese‐range BMI was associated with stronger performance on attention and episodic memory composites, but not for PACC and executive function. For NC‐only, there was only significant negative association between obesity and attention performance. In multivariate analyses, neither obesity category nor BMI were associated with longitudinal change in cognitive scores.ConclusionPresence of obesity in later life was associated with lower brain amyloid levels and less hippocampal atrophy in a mixed cohort including older adults with dementia, mild cognitive impairment and normal cognition. While mid‐life obesity is associated greater risk for AD, later life associations appear influenced by weight loss with emerging dementia.

Age-related hearing loss is not linked to cerebrospinal fluid levels of β-amyloid or p-tau181.

As Hearing loss and dementia affect people with the same profile, several epidemiological studies have evaluated their relationship. However, the link between age-related hearing loss and Alzheimer's disease is still unclear. We selected subjects with no history of exposure to loud noises, blasts, head trauma with hearing loss, or sudden sensorineural hearing loss from a cohort intended to study preclinical phases of Alzheimer's disease. Participants are volunteers over 55years without cognitive impairment. We correlated the results of an objective auditory evaluation with brain amyloid and p-tau181 levels and with the outcomes of a comprehensive neuropsychological assessment. Fifty-five subjects at different stages of the Alzheimer's disease continuum were evaluated. There were no statistically significant correlations between amyloid-β and p-tau levels and any of the objective auditory measures. A weak but significant correlation was found between amyloid-β values and the Hearing Handicap Inventory for the Elderly. The neuropsychological domains more correlated to hearing loss were executive function and processing speed. Age-related hearing loss is not linked to any pathological markers of Alzheimer's disease nor to neuropsychological domains typically affected in this disease. The Hearing Handicap Inventory for the Elderly has an important component of subjectivity and further studies are needed to explore its relationship with amyloid-β levels.

The role of microbiome-host interactions in the development of Alzheimer´s disease.

Alzheimer`s disease (AD) is the most prevalent cause of dementia. It is often assumed that AD is caused by an aggregation of extracellular beta-amyloid and intracellular tau-protein, supported by a recent study showing reduced brain amyloid levels and reduced cognitive decline under treatment with a beta-amyloid-binding antibody. Confirmation of the importance of amyloid as a therapeutic target notwithstanding, the underlying causes of beta-amyloid aggregation in the human brain, however, remain to be elucidated. Multiple lines of evidence point towards an important role of infectious agents and/or inflammatory conditions in the etiology of AD. Various microorganisms have been detected in the cerebrospinal fluid and brains of AD-patients and have thus been hypothesized to be linked to the development of AD, including Porphyromonas gingivalis (PG) and Spirochaetes. Intriguingly, these microorganisms are also found in the oral cavity under normal physiological conditions, which is often affected by multiple pathologies like caries or tooth loss in AD patients. Oral cavity pathologies are mostly accompanied by a compositional shift in the community of oral microbiota, mainly affecting commensal microorganisms and referred to as 'dysbiosis'. Oral dysbiosis seems to be at least partly mediated by key pathogens such as PG, and it is associated with a pro-inflammatory state that promotes the destruction of connective tissue in the mouth, possibly enabling the translocation of pathogenic microbiota from the oral cavity to the nervous system. It has therefore been hypothesized that dysbiosis of the oral microbiome may contribute to the development of AD. In this review, we discuss the infectious hypothesis of AD in the light of the oral microbiome and microbiome-host interactions, which may contribute to or even cause the development of AD. We discuss technical challenges relating to the detection of microorganisms in relevant body fluids and approaches for avoiding false-positives, and introduce the antibacterial protein lactoferrin as a potential link between the dysbiotic microbiome and the host inflammatory reaction.

Key questions for the evaluation of anti-amyloid immunotherapies for Alzheimer's disease.

The clinical benefit associated with anti-amyloid immunotherapies, a new class of drugs for the treatment of Alzheimer's disease, is predicated on their ability to modify disease course by lowering brain amyloid levels. At the time of writing, two amyloid-lowering antibodies, aducanumab and lecanemab, have obtained United States Food and Drug Administration accelerated approval, with further agents of this class in the Alzheimer's disease treatment pipeline. Based on limited published clinical trial data to date, regulators, payors and physicians will need to assess their efficacy, clinical effectiveness and safety, as well as cost and accessibility. We propose that attention to three important questions related to treatment efficacy, clinical effectiveness and safety should guide evidence-based consideration of this important class of drugs. These are: (1) Were trial statistical analyses appropriate and did they convincingly support claims of efficacy? (2) Do reported treatment effects outweigh safety concerns and are they generalizable to a representative clinical population of people with Alzheimer's disease? and (3) Do the data convincingly demonstrate disease course modification, suggesting that increasing clinical benefits beyond the duration of the trials are likely? We suggest specific approaches to interpreting trial results for these drugs and highlight important areas of uncertainty where additional data and a cautious interpretation of existing results is warranted. Safe, effective and accessible treatments for Alzheimer's disease are eagerly awaited by millions of patients and their caregivers worldwide. While amyloid-targeting immunotherapies may be promising disease-modifying Alzheimer's disease treatments, rigorous and unbiased assessment of clinical trial data is critical to regulatory decision-making and subsequently determining their provision and utility in routine clinical practice. Our recommendations provide a framework for evidence-based appraisal of these drugs by regulators, payors, physicians and patients.

TRAILBLAZER-ALZ 4: Topline study results directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease (S26.009)

TRAILBLAZER-ALZ 4: Topline study results directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease (S26.009)

Lecanemab slowed cognitive decline in patients with early Alzheimer's disease

The monoclonal antibody lecanemab reduced brain amyloid levels compared with placebo and slowed decline in cognition and function in patients with early Alzheimer's disease, a Phase 3 study has found. The Food and Drug Administration in January approved lecanemab for the treatment of Alzheimer's disease (see related item in From the FDA section, page 8).

Altered levels of plasma kallikrein‐7 in prodromal Alzheimer’s disease

AbstractBackgroundThe accumulation of Aβ is thought to be dependent on imbalances in production or clearance of the peptide. At the core of the production and the breakdown of Aβ are changes in the activity of proteases. Several studies have suggested that the level and activity of brain proteases involved in the clearance pathway are perturbed in the disease. Given that AD is essentially a protease disease, we sought to determine if key proteases were altered in the blood plasma fraction, reflecting changes that are occur in the brain.MethodWe used a fast commercial tool to investigate the level of 34 proteases in plasma between healthy controls and AD patients. Next we used an ELISA and western blot assays to validate results from the discovery assay.ResultWe discovered that the protease kallikrein‐7 (KLK7) was significantly elevated in AD plasma. We then asked how early in the disease time course is KLK7 elevated. We used plasma from cognitively normal cases (n=120) with either high or low levels of brain amyloid based on PET imaging and found that KLK7 leaves are decreased.ConclusionThese results suggest that the plasma level of Kallikrein‐7 may be an important tool in detecting elevated levels of brain amyloid before symptoms of AD become apparent.

Relationships between metabolic activity in the brain and circulating metabolites vary by sex

AbstractBackgroundGlucose hypometabolism in the brain measured by [F‐18] fluorodeoxyglucose (FDG) positron emission tomography has been observed in a number of neurological disorders. In both Down syndrome (DS) and non‐DS populations, it is associated with higher amyloid load and lower cognitive performance.MethodWe obtained plasma samples, FDG PET and [C‐11] Pittsburgh compound B (PiB) from a sample of 89 adults with DS (mean age [standard deviation] = 38.9[8.3] years). We measured levels of metabolites using targeted mass spectrometry. We calculated correlation constants between glucose uptake in discrete brain regions, global amyloid load, and plasma metabolite levels. We examined the effect of sex and age on these correlations.ResultWe found significant correlations between plasma metabolites, primarily lipids, and FDG PET signal in the brain with regional specificity. Additionally, metabolites which were positively associated with FDG PET signal in a specific brain region were negatively associated with amyloid load and vice versa. While FDG PET signal in each region were not significantly different between males and females, their correlation with metabolites did. When examining females only, we find primarily lipid correlates again. The lipid metabolites negatively associated with FDG PET signal were distinguished from those lipids positively correlated with FDG PET signal by lipid class and not fatty acid length. In males, a completely distinct set of associations between brain regions and metabolites were observed. The number of FDR significant correlations decrease dramatically, however the magnitudes of these correlation constants are higher than those observed in females and there is very little overlap between any of the brain regions correlated with each metabolite.ConclusionThe levels of brain amyloid and regional brain glucose metabolism in adults with DS are both reflected in the concentration of certain metabolites measured in blood plasma. Surprisingly, each brain region has its own orthogonal metabolic correlate. Moreover, these relationships are distinct in males and females. It will be important to explore the basis for these differences and determine if they are present in the general population. Future metabolic analysis of neurological diseases could also benefit from separate analysis in males and females so as not to obscure these differences.

High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations.

In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: An instrumental variable meta-analysis.

Whether the reduction in brain amyloid beta (Aβ) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer's disease (AD) remains debated. An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aβ standardized uptake value ratio (SUVR) on cognitive and functional decline. Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aβ SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively. This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aβ plaque and a reduction in cognitive and functional decline in patients with AD. A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.

The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease.

The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. The focus of this article is on the innovative design of the study. The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

Metabolic Factors Are Related to Brain Amyloid Among Mexican Americans: A HABS-HD Study.

Despite the tremendous amount of research on Alzheimer's disease (AD) biomarkers, very little data is available regarding the fundamental biomarkers of AD among Mexican Americans. Here we sought to examine the link between metabolic markers and brain amyloid among Mexican Americans as compared to non-Hispanic whites from the Health & Aging Brain Study -Health Disparities (HABS-HD) cohort. PET amyloid (florbetaben) data was analyzed from 34 Mexican American and 22 non-Hispanic white participants. Glucagon (t = 3.84, p < 0.001) and insulin (t = -2.56, p = 0.02) were both significantly related to global SUVR levels among Mexican Americans. Glucagon and insulin were both related to most ROIs. No metabolic markers were significantly related to brain amyloid levels among non-Hispanic whites. Metabolic markers are related to brain amyloid burden among Mexican Americans. Given the increased risk for diabetes, additional research is needed to determine the impact of diabetes on core AD biomarkers among this underserved population.