Brain Amyloid Research Articles

Association between amyloid, tau and cerebral small vessel disease

AbstractBackgroundControversy exists with respect to the etiological role of cerebral small vessel disease (CSVD) in Alzheimer’s disease (AD). We thus evaluated the association between white matter hyperintensity (WMH), an MRI marker of CSVD, with brain amyloid β (Aβ) and tau burden and their plasma markers among subjects with varying severity levels of cognitive impairment.MethodsWe recruited 84 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had varying severity levels of cognitive impairment: 10 healthy controls [HC], 32 with subjective cognitive decline [SCD], 26 with mild cognitive impairment [MCI] and 16 with dementia. All subjects underwent structural MRI, 11C‐ PIB, and 18F‐T807 positron emission tomography (PET), to measure WMH volume, and pathological Aβ deposition (A+) and tau burden (T+), respectively. WMH volume was quantified by automatic segmentation using AccuBrain® IV 1.1. Plasma levels of Aβ40, Aβ42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181) and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays among 71 subjects.ResultsThe mean age of the subjects was 67.5. 34 (40.8%) were male. No significant associations were found between WMH volume and global 11C‐PIB or 18F‐T807 standardized uptake value ratio (SUVR) on PET. Interestingly, we found that increasing WMH volume significantly correlated with higher plasma p‐tau181 level (β = 0.10; 95% C.I.: 0.012 – 0.188; P = 0.03). There were no associations between WMH volume and plasma Aβ40, Aβ42, t‐tau or NfL levels.ConclusionBrain WMH volume was associated with plasma p‐tau181 level but not with PET tau positivity in the brain. Our results suggest that CSVD burden may contribute to elevated plasma phosphorylated tau in AD, and such change may precede PET‐detectable elevated tau burden in the brain.

Apolipoprotein C proteins in plasma non‐high‐density lipoprotein fractions and development of Alzheimer’s disease, central arterial stiffness, and cerebral small vessel disease in older adults

AbstractBackgroundPlasma non‐high‐density lipoproteins impact development of central arterial stiffness and cerebral small vessel disease (cSVD), significantly contributing to Alzheimer’s disease (AD) and related dementias (ADRDs) through an increase in cerebral amyloid beta (Aβ) burden and acceleration of atrophy in susceptible brain regions. We sought to identify proteins in three non‐HDL plasma lipoproteins (very‐low density lipoprotein [VLDL], intermediate‐density lipoprotein [IDL], low‐density lipoprotein [LDL]) and their cross‐sectional associations with brain amyloid deposition, central arterial stiffness, neuroimaging features of cSVD (e.g., white matter hyperintensity volume), brain volumes susceptible to AD and cSVD, and incidence of dementia.MethodPlasma samples from 66 participants of the Atherosclerosis Risk in Communities (ARIC) study were fractionated to isolate VLDL, IDL, and LDL and analyzed using label‐free liquid chromatography‐mass spectrometry (LC‐MS) with Data‐Independent Acquisition. Acquired MS spectra were processed using Spectronaut™ to give protein identification and relative protein abundances were calculated using R. Linear regression models were used to examine the cross‐sectional associations between protein abundances in VLDL, IDL or LDL and brain amyloid deposition (measured by amyloid PET scan), white matter hyperintensities (WMH) volume (measured by brain MRI), central arterial stiffness (carotid‐femoral and heart‐femoral pulse wave velocity), AD‐signature region, frontal, parietal, and hippocampal brain region volumes (measured by brain MRI), and incidence of dementia. Regression models were adjusted for age, sex, race, number of APOε4 alleles, and cholesterol level (if applicable). Additionally, differential analysis (student’s t‐test) was used to compare protein abundances in non‐HDL lipoproteins between participants with elevated versus normal brain amyloid deposition.ResultWe identified 50, 78, 81 proteins in VLDL, IDL, and LDL, respectively. The most significant findings were: 1) higher levels of apolipoprotein C proteins in VLDL, IDL, and LDL were associated with lower WMH volume or less central arterial stiffness; 2) lower levels of apolipoprotein C proteins in VLDL, IDL, and LDL were associated with less incidence of dementia; 3) lower levels of apolipoprotein C proteins in VLDL, IDL, and LDL for participants with elevated amyloid deposition.ConclusionThese results suggest the possible role of apolipoprotein C proteins present in non‐HDL‐lipoproteins in the development of AD, central arterial stiffness, and cSVD.

Quantifying AD‐related brain amyloid with linearised progression models: Model‐based vs. data‐based

AbstractBackgroundBrain amyloid‐β (Aβ) is the pathological hallmark of Alzheimer’s disease (AD). In logistic disease models, Aβ accumulation is a sigmoid function of time‐since‐disease‐onset (TSDO) (figure 1). Previous positron emission tomography (PET)‐based models vary accumulation onset(t50) and duration(r) globally; capacity(K) and baseline(NS) regionally (Whittington2018). We confirm existing approaches and propose a more powerful ICA‐based approach to quantify disease severity and estimate TSDO.MethodWe used 1071 18F‐florbetapir standard uptake value ratio (SUVR) images from the ADNI‐2 study (adni.loni.usc.edu/data‐samples/data‐types/pet). Images were mapped into MNI space. Averages were extracted using the Harvard‐Oxford brain‐atlas. Whole‐brain tracer‐specific sigmoid parameters (Jack2013) obtained from the literature were used to estimate TSDO.Of 16 models of regional Aβ accumulation (each of the 4 regional sigmoid parameters varied either regionally or globally), the optimal Bayesian information criterion was found with global t50 and r, and regional NS and K (figure 1) with global values r = 6.16y and t50 = 4.10y.Linearised maps of NS and K were obtained by regressing the SUVR maps onto the global sigmoid. We also estimated these maps as independent components, using a 2‐component ICA on the SUVR maps. Both outcomes were used to quantify Aβ accumulation from SUVR images as weighting factors of the accumulation map.We compared the weights from the logistic model and the ICA model in ADNI, using effect size measured with Hedges' g between cognitively normal (CN), subjective memory complaints (SMC), mild cognitive impairment (EMCI/MCI/LMCI) and AD groups. We compared 3 longitudinal visits (N = 112) in the OASIS‐3 study (see www.oasis‐brains.org) with both methods, global SUVR and Centiloid (Klunk2015) using 11C‐PiB PET SUVR images.ResultMaps of accumulation capacity from both models had spatial correlation of 0.86 (figure 2); baseline maps had spatial correlation of 0.95. Hedges' g between ADNI groups was 2.25 for K, and 2.42 for ICA (1.46 for global SUVR). In OASIS‐3, Hedges' g between visits was 1.24 for K, 1.46 for ICA (global SUVR 0.15, Centiloid 0.4).ConclusionWe demonstrate that linear accumulation models can be used to quantify brain Aβ with PET; maps obtained by ICA yield larger effect sizes than the logistic method for differentiating groups and measuring changes between visits.

Head‐to‐Head comparison between Philips Gemini TF64 and Siemens Biograph Vision 600 for brain amyloid Centiloid quantitation

AbstractBackgroundThe Centiloid (CL) scale calibrates the beta‐amyloid (Aβ) deposition from different PET tracers to a standardised 0‐100 CL unit scale. As imaging sites update their PET cameras, most are switching to digital detector systems with superior resolution and sensitivity that may affect quantitation. This has significant implications for dementia clinical trials. In this study, we examine the impact on CL quantification between Philips Gemini TF64 and Siemens Biograph Vision 600.MethodSeven subjects (76.4±2.2 yo) were imaged with 18F‐NAV4694 on both Gemini TF64 and Biograph Vision consecutively with an average scan interval of 25.1±11.2 weeks. The injected doses were 200MBq and 100MBq, respectively. On the Gemini TF64, the PET images were reconstructed by LOR‐RAMLA algorithm with smoothing parameter setup as ‘SHARP’. On Biograph Vision, the PET images were reconstructed by OSEM‐3D (8 iterations and 5 subsets, TOF enabled) with 3mm post Gaussian smoothing. A T1 MRI image was acquired for each subject. As per the standard Centiloid method the whole cerebellum was used as the reference in SUVR images, and all images were processed using CapAIBL to calculate the CL using both MR‐based and MR‐Less spatial normalisation.ResultFigure 1 shows the CL images of a subject scanned on Gemini TF64 and Biograph Vision within sixteen weeks. The Biograph Vision images have higher contrast and higher spatial resolution despite using half of the dose. Figure 2 shows the linear regression plot of the scanner comparison. Biograph Vision CL are progressively higher than those obtained from the Gemini TF64 as the CL value rises (Table 1). There were no significant differences between the MR‐based and MR‐less results.ConclusionBiograph Vision yields higher SUVR and therefore CL values compared to Gemini TF64 in a head‐to‐head comparison. These results show that the selection of PET camera has a significant impact on CL quantification, which needs to be considered when merging cohorts from different studies or changing cameras during longitudinal studies or trials. These initial results indicate that the CL difference could be corrected by a linear transform.

ABTEST‐IA: A new reliable tool for the quantification of Aβ40 and Aβ42 in CSF

AbstractBackgroundThe ratio Aβ42/Aβ40 in cerebrospinal fluid (CSF) is considered one of the most reliable biomarkers of Alzheimer’s Disease. ABtest40‐IA and ABtest42‐IA have been widely used for amyloid‐β (Aβ) quantification in plasma samples. The aim of this study was to validate these tests for the quantification of Aβ40 and Aβ42 in CSF.MethodAnalytical validation of ABtest40‐IA and ABtest42‐IA was accomplished following FDA and EMA reference guidelines. Calibration curves, sensitivity, specificity, accuracy, precision, recovery and dilution linearity were evaluated.Correlations between ABtest‐IA and an independent fully automated IVD test, (Lumipulse ® G β‐amyloid 1‐40 and 1‐42, Fujirebio), were estimated using 93 CSF samples of PET‐Aβ positive (75%) and PET‐Aβ negative (25%) individuals. Differences in CSF Aβ42/Aβ40 levels between both PET‐Aβ groups were analyzed (Mann Whitney test).The ability of CSF Aβ42/Aβ40 ratio to discriminate between PET‐Aβ positive and PET‐Aβ negative subjects was evaluated by means of Receiver Operating Characteristic (ROC) curve analysis, considering PET‐Aβ the gold standard.ResultCalibration curves ranges were set at 43.9 to 500 pg/mL for ABtest40‐IA and 5 to 100 pg/mL for ABtest42‐IA. Intra‐assay, inter‐assay and inter‐lot coefficients of variation were below 5.2% and 7.4% for ABtest40‐IA and ABtest42‐IA respectively. Accuracy evaluation provided mean relative errors of 4.6% and 7.5%.Spearman correlation coefficients between ABtest‐IA and Lumipulse® were 0.96, 0.95 and 0.93 for Aβ40, Aβ42 and Aβ42/Aβ40 respectively (p values < 0.0001). As expected, Aβ42/Aβ40 ratio levels were significantly lower in the PET‐Aβ positive group (p < 0.0001).ROC analysis of CSF Aβ42/Aβ40 gave an AUC of 0.85 (95% CI 0.74 to 0.97), very similar to that obtained with Lumipulse®: 0.84 (95% CI 0.72 to 0.98). The overall agreement of PET‐Aβ and ABtest‐IA Aβ42/Aβ40 was 90%, being false positives the majority (78%) of the misclassified subjects. Results are supporting that CSF Aβ42/Aβ40 is an early biomarker of cerebral amyloid deposition.ConclusionABtest40‐IA and ABtest42‐IA were successfully validated as new precise and accurate tools for the quantification of Aβ40 and Aβ42 in CSF samples. ABtest‐IA measures of Aβ42/Aβ40 ratio in CSF identified individuals with brain amyloid deposition with equivalent ability to other test commercially available.

Cross‐sectional and longitudinal associations of plasma makers of amyloid and tau pathology and neurodegeneration with gait speed

AbstractBackgroundHigher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.MethodThis study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.ResultAt baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.ConclusionBoth cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.

Amyloid on autopsy in the oldest‐old may be associated with sleep duration thirty years earlier: The 90+ Study

AbstractBackgroundAmyloid production and clearance from the brain are thought to be related to sleep duration. The association between brain amyloid accumulation and self‐reported sleep duration has been mostly established in cross‐sectional studies using PET. Our aim is to examine the longitudinal association between amyloid in the oldest‐old (90+ years), measured on autopsy and PET, with sleep duration self‐reported ∼30 years earlier.MethodWe analyzed data on 289 individuals with one‐time report of their usual nocturnal sleep duration as part of Leisure World Cohort Study (LWCS) in the early 1980s, and brain autopsy or 18F‐florbetapir (amyloid) PET between 2004 and 2021 with The 90+ Study. Sleep duration was analyzed as continuous and categorical variables (<7(short), 7‐8(optimal, reference) and >8 hours(long)). National Institute on Aging Alzheimer Association (NIA‐AA) amyloid (A) and neuritic (C) plaque scores were dichotomized as negative (0‐1, reference) and positive (2‐3). Standardized uptake value ratio (SUVr) for the posterior cingulate/precuneuswas analyzed as continuous and binary (SUVr <0.76 vs. ≥0.76) variables. We analyzed sleep duration, as predictor, in relation to amyloid on autopsy (A and C scores) and PET (SUVr), as outcomes, using multiple logistic and multiple linear regressions, controlling for age, sex, education, positive items from the Zung depression scale, and time between sleep report and PET or autopsy.ResultSleep was reported on average at 68 years, autopsy was done ∼29 years and PET was done ∼32 years later (Table 1). Long sleep, compared to optimal sleep, was associated with 67% decrease in the odds of being NIA‐AA A positive (Table 2). Although PET amyloid results were not significant, they suggest that every hour increase in sleep duration may be associated with 0.01 unit decrese in SUVr and with 11% lower odds of being PET amyloid positive (Table 3). PET amyloid by sleep group analysis was underpowered and not done.ConclusionIn this group of oldest‐old individuals, long, compared to optimal, sleep duration self‐reported 29 years earlier is associated with lower odds of amyloid deposition on autopsy. One of the plausible mechanisms is that longer sleep duration may support greater amyloid clearance and decreased production.

Midlife insulin resistance, APOE genotype, and change in late‐life brain amyloid accumulation – a 5‐year follow‐up 11C‐PIB‐PET study

AbstractBackgroundMidlife insulin resistance has been associated with an increased risk for cognitive decline (1) and amyloid accumulation (2). We hypothesized that midlife insulin resistance would predict amyloid accumulation 20 years later, and the change in brain amyloid accumulation during the 5‐year imaging follow‐up.MethodsWe studied 60 cognitively normal participants from the Finnish population‐based Health2000 study in 2014‐2016 with 11C‐PIB‐PET (2). They were recruited according to their homeostatic model assessment of insulin resistance (HOMA‐IR) values measured 15 years earlier in 2000, and their APOEε4 genotype. The insulin resistance group (IR+, HOMA‐IR <1.25) and the control group (IR−, HOMA‐IR > 2.17) both included 30 participants and 50% APOEε4 carriers. In 2019‐2021 43 participants took part in the 5‐year 11C‐PIB‐PET‐imaging follow‐up. Here, we report the change in amyloid accumulation in the IR+ group (n = 19, 57% APOE ε4 carriers) and the IR‐ group (n = 24, 46% APOEε4 carriers) during this 5‐year interval. 11C‐PIB‐PET images were analyzed with an in‐house pipeline and standard uptake value ratio (SUVR) composite scores were calculated. Kruskal‐Wallis test and the Steel‐Dwass method was used to analyze the difference in amyloid accumulation rates between groups, and Spearman’s correlation was utilized to assess the association between HOMA‐IR and amyloid accumulation.ResultAt the 20‐year follow‐up, amyloid accumulation was significantly higher in the IR+ group than the IR‐ group (composite SUVR 2.43 vs. 1.96, p = 0.03) (Fig. 1). The change in amyloid accumulation during 5 years was significantly higher in the IR+/APOEε4+ group than in either IR−/APOEε4− (mean change in composite SUVR 0.79 vs. 0.32, p = 0.02) or IR+/APOEε4− groups (mean change in composite SUVR 0.79 vs. 0.26, p = 0.046,) (Fig. 2). HOMA‐IR in 2000 (rS = 0.39, p = 0.01) and 2014‐2016 (rS = 0.34, p = 0.03), but not in 2019‐2021 (rS = 0.24, p = 0.13), correlated with 11C‐PIB composite SUVR at the 20‐year follow‐up.ConclusionThese results suggest that IR could be an additive risk factor for late‐life amyloid accumulation in APOEε4 carriers, and that midlife, but not late‐life IR associates with amyloid accumulation.1) Ekblad et al., Diabetes Care 20172) Ekblad et al., Neurology 2018

Higher plasma proinflammatory cytokines and reduced microglial TREM2 signaling in Late‐life Major Depression

AbstractBackgroundElevated circulating cytokines leading to microglia activation have been implicated in the increased risk for Alzheimer’s Disease (AD) in depression. However, correlations between peripheral and central inflammatory markers have been inconclusive. Additionally, only some depressives show evidence of increased inflammation.Microglia can assume anti‐inflammatory states via increased signaling of their TREM2 receptor with potential protective effects against AD including increased phagocytosis and NFkB inflammatory pathway inhibition. This process generates a soluble cleavage product, sTREM2, detected in CSF. Importantly in longitudinal human studies, higher CSF sTREM2 is associated with less brain amyloid deposition, less cognitive decline, and fewer degenerative changes.These considerations prompted us to determine if higher levels of plasma proinflammatory cytokines were associated with decreased TREM2 signaling in late‐life major depression (LLMD).MethodFifty‐one cognitively‐intact subjects aged 60 years and older, completed a 3‐year longitudinal study and an optional lumbar puncture (LP). Of these individuals, 49 were included in the analysis (29 LLMD and 20 controls). Independent‐samples Mann‐Whitney‐U Tests were used to compare groups. Non‐parametric correlations were run between CSF sTREM2 and plasma IL‐1B, Il‐6, Il‐8, TNFα, and CSF C3.ResultIn LLMD, higher plasma IL‐6 (r = ‐0.45, p = 0.02) and TNFα (r = ‐0.41, p = 0.30) were both associated with lower CSF sTREM2, but not with higher CSF C3 (p = 0.19) or other pro‐inflammatory markers consistent with a reduction in TREM2 signaling. These findings were not observed for controls.There were no group differences in Plasma IL‐1B, IL‐6, TNFα and CSF C3. Plasma IL8 was significantly higher in LLMD vs controls (p = 0.03). No correlations between plasma and CSF levels were observed for cytokines within the LLMD group.ConclusionHigher plasma pro‐inflammatory cytokines were associated with lower CSF sTREM2 in LLMD, consistent with a reduction in TREM2 signaling. Future studies should determine if lower CSF sTREM2 levels predict increased AD biomarkers, progressive decline and conversion to AD in LLMD.

A peripheral signature of Alzheimer’s disease featuring microbiota-gut-brain axis markers

BackgroundIncreasing evidence links the gut microbiota (GM) to Alzheimer’s disease (AD) but the mechanisms through which gut bacteria influence the brain are still unclear. This study tests the hypothesis that GM and mediators of the microbiota-gut-brain axis (MGBA) are associated with the amyloid cascade in sporadic AD.MethodsWe included 34 patients with cognitive impairment due to AD (CI-AD), 37 patients with cognitive impairment not due to AD (CI-NAD), and 13 cognitively unimpaired persons (CU). We studied the following systems: (1) fecal GM, with 16S rRNA sequencing; (2) a panel of putative MGBA mediators in the blood including immune and endothelial markers as bacterial products (i.e., lipopolysaccharide, LPS), cell adhesion molecules (CAMs) indicative of endothelial dysfunction (VCAM-1, PECAM-1), vascular changes (P-, E-Selectin), and upregulated after infections (NCAM, ICAM-1), as well as pro- (IL1β, IL6, TNFα, IL18) and anti- (IL10) inflammatory cytokines; (3) the amyloid cascade with amyloid PET, plasma phosphorylated tau (pTau-181, for tau pathology), neurofilament light chain (NfL, for neurodegeneration), and global cognition measured using MMSE and ADAScog. We performed 3-group comparisons of markers in the 3 systems and calculated correlation matrices for the pooled group of CI-AD and CU as well as CI-NAD and CU. Patterns of associations based on Spearman’s rho were used to validate the study hypothesis.ResultsCI-AD were characterized by (1) higher abundance of Clostridia_UCG-014 and decreased abundance of Moryella and Blautia (p < .04); (2) elevated levels of LPS (p < .03), upregulation of CAMs, Il1β, IL6, and TNFα, and downregulation of IL10 (p < .05); (3) increased brain amyloid, plasma pTau-181, and NfL (p < 0.004) compared with the other groups. CI-NAD showed (1) higher abundance of [Eubacterium] coprostanoligenes group and Collinsella and decreased abundance of Lachnospiraceae_ND3007_group, [Ruminococcus]_gnavus_group and Oscillibacter (p < .03); (2) upregulation of PECAM-1 and TNFα (p < .03); (4) increased plasma levels of NfL (p < .02) compared with CU. Different GM genera were associated with immune and endothelial markers in both CI-NAD and CI-AD but these mediators were widely related to amyloid cascade markers only in CI-AD.ConclusionsSpecific bacterial genera are associated with immune and endothelial MGBA mediators, and these are associated with amyloid cascade markers in sporadic AD. The physiological mechanisms linking the GM to the amyloid cascade should be further investigated to elucidate their potential therapeutic implications.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies. We examined the temporal order of changes in plasma amyloid-β ratio ( ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( , ) relative to 11 C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n=199) were cognitively normal at index visit with a median 6.1-year follow-up. PiB groups exhibited different rates of longitudinal change in . Change in brain amyloid correlated with change in GFAP (r=0.5, 95% CI=[0.26, 0.68]). The greatest relative decline in (-1%/year) preceded brain amyloid positivity by 41 years (95% CI=[32, 53]). Plasma may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aβ42 ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in may precede brain amyloid positivity by decades.

Association of Caffeine Consumption and Brain Amyloid Positivity in Cognitively Normal Older Adults.

Several epidemiological studies have reported the protective role of caffeine on health outcomes; however, it remained debatable on caffeine consumption and brain amyloid positivity. We aimed to determine the relationship between caffeine consumption and brain amyloid pathology in cognitively normal older adults. The dataset used for analysis in this cross-sectional study was selected from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. Multivariable logistic regression analyses were performed to explore the association between caffeine consumption and amyloid positivity using odds ratios (ORs) and 95% confidence intervals (CIs). In total, 4,394 participants were included in the final analysis. No significant association between caffeine consumption and amyloid positivity was observed in the whole participants (OR, 0.95; 95% CI, 0.78-1.14; p = 0.558). Subgroup analysis showed that caffeine intake was significantly associated with decreased amyloid positivity in males (OR, 0.72; 95% CI, 0.54-0.97; p = 0.032) but not in females (OR, 1.14; 95% CI, 0.90-1.46; p = 0.280), and the association between caffeine and amyloid positivity was not affected by age or APOE genotypes. In addition, different levels of caffeine were not associated with amyloid positivity. The findings suggest that caffeine consumption was not significantly associated with amyloid positivity in the whole sample. However, caffeine consumption may be inversely associated with amyloid positivity among males but not females. More studies are needed to explore the mechanisms underlying caffeine consumption and brain amyloid positivity.

Association of Hearing Loss With Anatomical and Functional Connectivity in Patients With Mild Cognitive Impairment

Hearing loss is the most important modifiable risk factor for cognitive impairment; however, the association of hearing loss with anatomical and functional connectivity is not fully understood. This association may be elucidated by evaluating the findings of newer imaging technologies. To evaluate the association of hearing loss with anatomical and functional connectivity in patients with mild cognitive impairment (MCI) by using multimodal imaging technology. This was a prospective cross-sectional study of patients with MCI under the care of a neurology clinic at the Soonchunhyang University Bucheon Hospital (Republic of Korea) from April to September 2021. Data were analyzed from April 1 to June 30, 2022. Pure tone averages (PTA) and word recognition scores were used to measure hearing acuity. Magnetic resonance imaging (MRI) and positron emission tomography scans of the brain were used to assess functional and anatomical connectivity. Results of diffusion MRI, voxel- and surface-based morphometric imaging, and global brain amyloid standardized uptake ratio were analyzed. Neuroimaging parameters of patients with MCI plus hearing loss were compared with those of patients with MCI and no hearing loss. Correlation analyses among neuroimaging parameters, PTA, and word recognition scores were performed. Of 48 patients with MCI, 30 (62.5%) had hearing loss (PTA >25 dB) and 18 (37.5%) did not (PTA ≤25 dB). Median (IQR) age was 73.5 (69.0-78.0) years in the group with hearing loss and 75.0 (65.0-78.0) years in the group with normal hearing; there were 20 (66.7%) and 14 (77.8%) women in each group, respectively. The group with MCI plus hearing loss demonstrated decreased functional connectivity between the bilateral insular and anterior divisions of the cingulate cortex, and decreased fractional anisotropy in the bilateral fornix, corpus callosum forceps major and tapetum, left parahippocampal cingulum, and left superior thalamic radiation. Fractional anisotropy in the corpus callosum forceps major and bilateral parahippocampal cingulum negatively correlated with the severity of hearing loss shown by PTA testing. The 2 groups were not significantly different in global β-amyloid uptake, gray matter volume, and cortical thickness. The findings of this prospective cross-sectional study suggest that alterations in the salience network may contribute to the neural basis of cognitive impairment associated with hearing loss in patients who are on the Alzheimer disease continuum.

Early Brain Amyloid Accumulation at PET in Military Instructors Exposed to Subconcussive Blast Injuries.

Background Traumatic brain injury (TBI) is the leading cause of disability in young adults. Recurrent TBI is associated with a range of neurologic sequelae, but the contributing factors behind the development of such chronic encephalopathy are poorly understood. Purpose To quantify early amyloid β deposition in the brain of otherwise healthy adult men exposed to repeated subconcussive blast injury using amyloid PET. Materials and Methods In this prospective study from January 2020 to December 2021, military instructors who were routinely exposed to repeated blast events were evaluated at two different points: baseline (before blast exposure from breacher or grenade) and approximately 5 months after baseline (after blast exposure). Age-matched healthy control participants not exposed to blasts and without a history of brain injury were evaluated at similar two points. Neurocognitive evaluation was performed with standard neuropsychologic testing in both groups. Analysis of PET data consisted of standardized uptake value measurements in six relevant brain regions and a whole-brain voxel-based statistical approach. Results Participants were men (nine control participants [median age, 33 years; IQR, 32-36 years] and nine blast-exposed participants [median age, 33 years; IQR, 30-34 years]; P = .82). In the blast-exposed participants, four brain regions showed significantly increased amyloid deposition after blast exposure: inferomedial frontal lobe (P = .004), precuneus (P = .02), anterior cingulum (P = .002), and superior parietal lobule (P = .003). No amyloid deposition was observed in the control participants. Discriminant analysis on the basis of regional changes of amyloid accumulation correctly classified the nine healthy control participants as healthy control participants (100%), and seven of the nine blast-exposed participants (78%) were correctly classified as blast exposed. Based on the voxel-based analysis, whole-brain parametric maps of early abnormal early amyloid uptake were obtained. Conclusion Early brain amyloid accumulation was identified and quantified at PET in otherwise healthy adult men exposed to repetitive subconcussive traumatic events. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Haller in this issue.

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.

Association of Long-term Exposure to Ambient Air Pollution With Cognitive Decline and Alzheimer’s Disease–Related Amyloidosis

BackgroundAir pollution induces neurotoxic reactions and may exert adverse effects on cognitive health. We aimed to investigate whether air pollutants accelerate cognitive decline and affect neurobiological signatures of Alzheimer’s disease (AD). MethodsWe used a population-based cohort from the Chinese Longitudinal Healthy Longevity Survey with 31,573 participants and a 10-year follow-up (5878 cognitively unimpaired individuals in Chinese Longitudinal Healthy Longevity Survey followed for 5.95 ± 2.87 years), and biomarker-based data from the Chinese Alzheimer’s Biomarker and Lifestyle study including 1131 participants who underwent cerebrospinal fluid measurements of AD-related amyloid-β (Aβ) and tau proteins. Cognitive impairment was determined by education-corrected performance on the China-Modified Mini-Mental State Examination. Annual exposures to fine particulate matter (PM2.5), ground-level ozone (O3), and nitrogen dioxide (NO2) were estimated at areas of residence. Exposures were aggregated as 2-year averages preceding enrollments using Cox proportional hazards or linear models. ResultsLong-term exposure to PM2.5 (per 20 μg/m3) increased the risk of cognitive impairment (hazard ratio, 1.100; 95% CI: 1.026–1.180), and similar associations were observed from separate cross-sectional analyses. Exposures to O3 and NO2 yielded elevated risk but with nonsignificant estimates. Individuals exposed to high PM2.5 manifested increased amyloid burdens as reflected by cerebrospinal fluid–AD biomarkers. Moreover, PM2.5 exposure-associated decline in global cognition was partly explained by amyloid pathology as measured by cerebrospinal fluid–Aβ42/Aβ40, P-tau/Aβ42, and T-tau/Aβ42, with mediation proportions ranging from 16.95% to 21.64%. ConclusionsLong-term exposure to PM2.5 contributed to the development of cognitive decline, which may be partly explained by brain amyloid accumulation indicative of increased AD risk.

Neuropharmacology of Lecanemab-irmb: A new drug granted in the treatment of Alzheimer's disease

United state food and drug administration approved on 6 January 2023, Lecanemab-irmb via the accelerated approval pathway for the treatment of Alzheimer’s disease. Researchers evaluated Lecanemab-irmb’s efficacy in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed the presence of amyloid beta pathology. Patients receiving the treatment had significant dose and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque. These results support the accelerated approval of Lecanemab-irmb, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease. The amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.

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)

ALUMNI AD Study Design: Evaluation of Subcutaneous Gantenerumab in Historically Underrepresented US Populations With Early Symptomatic Alzheimer’s Disease (S26.006)

ALUMNI AD Study Design: Evaluation of Subcutaneous Gantenerumab in Historically Underrepresented US Populations With Early Symptomatic Alzheimer’s Disease (S26.006)

HARBOR: ABBV-916 In Subjects With Early Alzheimer’s Disease Combined Multiple-Ascending Dose/Proof-Of-Concept Study Design (P7-6.008)

<h3>Objective:</h3> This study evaluates safety, tolerability, pharmacokinetics, immunogenicity, and amyloid reduction associated with ABBV-916, a recombinant humanized immunoglobulin G1 monoclonal antibody, in subjects with early AD. <h3>Background:</h3> Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. <h3>Design/Methods:</h3> Approximately 163 subjects will be enrolled in this Phase 1b/2 multicenter, randomized, placebo-controlled, double-blind, dose-finding study (NCT05291234), which consists of 2 stages: multiple-ascending dose (MAD; Phase 1b; Stage A) and proof-of-concept (POC; Phase 2; Stage B). Each stage has a 60-day screening period, 24-week double-blind period (ABBV-916 or placebo administered intravenously once every 4 weeks) and a 16-week safety follow-up period, with the option of a 2-year open-label extension. Subjects must meet the following inclusion criteria: be between 50 and 90 years of age, diagnosis of Stage 3 or 4 AD, as defined by the 2018 NIA-AA Research Framework, a Mini-Mental State Examination score between 20 and 28, a positive Precivity AD-Aβ blood test, and an amyloid PET scan consistent with amyloid pathology. <h3>Results:</h3> Safety evaluations include adverse events reports, clinical laboratory tests, MRI, vital signs, electrocardiograms, and the Columbia-Suicide Severity Rating Scale. Cerebrospinal fluid collection is required for subjects in Stage A and optional for subjects in Stage B. Change from baseline in brain amyloid plaque deposition is measured by amyloid PET scan in Stage B. <h3>Conclusions:</h3> This study tests the hypothesis that ABBV-916 will lead to rapid and robust removal of amyloid plaques from the brain of subjects with AD. <b>Disclosure:</b> Dr. Watson has nothing to disclose. Shau Yu Lynch has received personal compensation for serving as an employee of AbbVie. Shau Yu Lynch has received personal compensation for serving as an employee of Eisai. Shau Yu Lynch has stock in AbbVie. Hana Florian has received personal compensation for serving as an employee of AbbVie. Hana Florian has stock in AbbVie. Dr. Wang has received personal compensation for serving as an employee of AbbVie Inc.. Dr. Wang has stock in AbbVie Inc.. Mr. Bachhav has received personal compensation for serving as an employee of AbbVie Inc, USA. Mr. Bachhav has stock in AbbVie Inc. USA. Dr. Boiser has received personal compensation for serving as an employee of AbbVie. Dr. Boiser has stock in AbbVie. Dr. Bannon has received personal compensation for serving as an employee of AbbVie. Dr. Bannon has stock in AbbVie. Dr. Stage has received personal compensation for serving as an employee of AbbVie. Dr. Stage has stock in AbbVie.. Dr. Graff has received personal compensation for serving as an employee of AbbVie. Dr. Graff has stock in AbbVie.