Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies

Alzheimer's disease (AD) is a prevalent, progressive, and ultimately fatal neurodegenerative disorder that is defined pathologically by the accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. There remains an unmet need for therapies that can halt or slow the course of AD. To address this need, the FDA has provided a mechanism, under its Accelerated Approval pathway, for potential therapeutics to be approved based in part on their ability to reduce brain amyloid. Through this pathway, two monoclonal anti-amyloid antibodies, aducanumab and lecanemab, have been approved for clinical use. More recently, another amyloid-lowering antibody, donanemab, generated a statistically significant outcome in a phase 3 clinical trial and will shortly come under FDA review. While these monoclonal antibodies are not yet routinely used in clinical practice, the series of recent positive clinical trials has fostered enthusiasm amongst some AD experts. Here, we discuss three key limitations regarding recent anti-amyloid clinical trials: (1) there is little to no evidence that amyloid reduction correlates with clinical outcome, (2) the reported efficacy of anti-amyloid therapies may be partly, or wholly, explained by functional unblinding, and (3) donanemab in its phase 3 trial had no effect on tau burden, the pathological hallmark more closely related to cognition. Taken together, these observations call into question the efficacy of anti-amyloid therapies.Comment: 11 pages, 2 figures; Update 11/18/2023: Added subheadings to manuscript to improve readability, added a new data point to Figure 1A and Figure 2 for the recently published A4 clinical tria

Recent Consanguinity and Outbred Autozygosity Are Associated With Increased Risk of Late-Onset Alzheimer's Disease

Prior work in late-onset Alzheimer's disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datasets were retrieved through public databases. Our analyses were restricted to eight distinct ethnic groups: African-Caribbean, Ashkenazi-Jewish European, European-Caribbean, French-Canadian, Finnish European, North-Western European, South-Eastern European, and Yoruba African for a total of 21,492 unrelated subjects (11,196 LOAD and 10,296 controls). Recent consanguinity determination was performed using FSuite v1.0.3, according to subjects' ancestral background. The level of autozygosity in the outbred population was assessed by calculating inbreeding estimates based on the proportion (FROH) and the number (NROH) of runs of homozygosity (ROHs). We analyzed all eight ethnic groups using a fixed-effect meta-analysis, which showed a significant association of recent consanguinity with LOAD (N = 21,481; OR = 1.262, P = 3.6 × 10-4), independently of APOE∗4 (N = 21,468, OR = 1.237, P = 0.002), and years of education (N = 9,257; OR = 1.274, P = 0.020). Autozygosity in the outbred population was also associated with an increased risk of LOAD, both for FROH (N = 20,237; OR = 1.204, P = 0.030) and NROH metrics (N = 20,237; OR = 1.019, P = 0.006), independently of APOE∗4 [(FROH, N = 20,225; OR = 1.222, P = 0.029) (NROH, N = 20,225; OR = 1.019, P = 0.007)]. By leveraging the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data, we determined that LOAD subjects do not show an enrichment of rare, risk-enhancing minor homozygote variants compared to the control population. A two-stage recessive GWAS using ADSP data from 201 consanguineous subjects in the discovery phase followed by validation in 10,469 subjects led to the identification of RPH3AL p.A303V (rs117190076) as a rare minor homozygote variant increasing the risk of LOAD [discovery: Genotype Relative Risk (GRR) = 46, P = 2.16 × 10-6; validation: GRR = 1.9, P = 8.0 × 10-4]. These results confirm that recent consanguinity and autozygosity in the outbred population increase risk for LOAD. Subsequent work, with increased samples sizes of consanguineous subjects, should accelerate the discovery of non-additive genetic effects in LOAD

FMRI resting slow fluctuations correlate with the activity of fast cortico-cortical physiological connections

Recording of slow spontaneous fluctuations at rest using functional magnetic resonance imaging (fMRI) allows distinct long-range cortical networks to be identified. The neuronal basis of connectivity as assessed by resting-state fMRI still needs to be fully clarified, considering that these signals are an indirect measure of neuronal activity, reflecting slow local variations in de-oxyhaemoglobin concentration. Here, we combined fMRI with multifocal transcranial magnetic stimulation (TMS), a technique that allows the investigation of the causal neurophysiological interactions occurring in specific cortico-cortical connections. We investigated whether the physiological properties of parieto-frontal circuits mapped with short-latency multifocal TMS at rest may have some relationship with the resting-state fMRI measures of specific resting-state functional networks (RSNs). Results showed that the activity of fast cortico-cortical physiological interactions occurring in the millisecond range correlated selectively with the coupling of fMRI slow oscillations within the same cortical areas that form part of the dorsal attention network, i.e., the attention system believed to be involved in reorientation of attention. We conclude that resting-state fMRI ongoing slow fluctuations likely reflect the interaction of underlying physiological cortico-cortical connections

Validation of non-REM sleep stage decoding from resting state fMRI using linear support vector machines

A growing body of literature suggests that changes in consciousness are reflected in specific connectivity patterns of the brain as obtained from resting state fMRI (rs-fMRI). As simultaneous electroencephalography (EEG) is often unavailable, decoding of potentially confounding sleep patterns from rs-fMRI itself might be useful and improve data interpretation. Linear support vector machine classifiers were trained on combined rs-fMRI/EEG recordings from 25 subjects to separate wakefulness (S0) from non-rapid eye movement (NREM) sleep stages 1 (S1), 2 (S2), slow wave sleep (SW) and all three sleep stages combined (SX). Classifier performance was quantified by a leave-one-subject-out cross-validation (LOSO-CV) and on an independent validation dataset comprising 19 subjects. Results demonstrated excellent performance with areas under the receiver operating characteristics curve (AUCs) close to 1.0 for the discrimination of sleep from wakefulness (S0|SX), S0|S1, S0|S2 and S0|SW, and good to excellent performance for the classification between sleep stages (S1|S2:~0.9; S1|SW:~1.0; S2|SW:~0.8). Application windows of fMRI data from about 70 s were found as minimum to provide reliable classifications. Discrimination patterns pointed to subcortical-cortical connectivity and within-occipital lobe reorganization of connectivity as strongest carriers of discriminative information. In conclusion, we report that functional connectivity analysis allows valid classification of NREM sleep stages

Specifically Progressive Deficits of Brain Functional Marker in Amnestic Type Mild Cognitive Impairment

Background: Deficits of the default mode network (DMN) have been demonstrated in subjects with amnestic type mild cognitive impairment (aMCI) who have a high risk of developing Alzheimer’s disease (AD). However, no longitudinal study of this network has been reported in aMCI. Identifying links between development of DMN and aMCI progression would be of considerable value in understanding brain changes underpinning aMCI and determining risk of conversion to AD. Methodology/Principal Findings: Resting-state fMRI was acquired in aMCI subjects (n = 26) and controls (n = 18) at baseline and after approximately 20 months follow up. Independent component analysis was used to isolate the DMN in each participant. Differences in DMN between aMCI and controls were examined at baseline, and subsequent changes between baseline and follow-up were also assessed in the groups. Posterior cingulate cortex/precuneus (PCC/PCu) hyper-functional connectivity was observed at baseline in aMCI subjects, while a substantial decrement of these connections was evident at follow-up in aMCI subjects, compared to matched controls. Specifically, PCC/PCu dysfunction was positively related to the impairments of episodic memory from baseline to follow up in aMCI group. Conclusions/Significance: The patterns of longitudinal deficits of DMN may assist investigators to identify and monitor the development of aMCI

Resting-State Brain Organization Revealed by Functional Covariance Networks

BACKGROUND: Brain network studies using techniques of intrinsic connectivity network based on fMRI time series (TS-ICN) and structural covariance network (SCN) have mapped out functional and structural organization of human brain at respective time scales. However, there lacks a meso-time-scale network to bridge the ICN and SCN and get insights of brain functional organization. METHODOLOGY AND PRINCIPAL FINDINGS: We proposed a functional covariance network (FCN) method by measuring the covariance of amplitude of low-frequency fluctuations (ALFF) in BOLD signals across subjects, and compared the patterns of ALFF-FCNs with the TS-ICNs and SCNs by mapping the brain networks of default network, task-positive network and sensory networks. We demonstrated large overlap among FCNs, ICNs and SCNs and modular nature in FCNs and ICNs by using conjunctional analysis. Most interestingly, FCN analysis showed a network dichotomy consisting of anti-correlated high-level cognitive system and low-level perceptive system, which is a novel finding different from the ICN dichotomy consisting of the default-mode network and the task-positive network. CONCLUSION: The current study proposed an ALFF-FCN approach to measure the interregional correlation of brain activity responding to short periods of state, and revealed novel organization patterns of resting-state brain activity from an intermediate time scale

Task-Related Effects on the Temporal and Spatial Dynamics of Resting-State Functional Connectivity in the Default Network

Recent evidence points to two potentially fundamental aspects of the default network (DN), which have been relatively understudied. One is the temporal nature of the functional interactions among nodes of the network in the resting-state, usually assumed to be static. The second is possible influences of previous brain states on the spatial patterns (i.e., the brain regions involved) of functional connectivity (FC) in the DN at rest. The goal of the current study was to investigate modulations in both the spatial and temporal domains. We compared the resting-state FC of the DN in two runs that were separated by a 45 minute interval containing cognitive task execution. We used partial least squares (PLS), which allowed us to identify FC spatiotemporal patterns in the two runs and to determine differences between them. Our results revealed two primary modes of FC, assessed using a posterior cingulate seed – a robust correlation among DN regions that is stable both spatially and temporally, and a second pattern that is reduced in spatial extent and more variable temporally after cognitive tasks, showing switching between connectivity with certain DN regions and connectivity with other areas, including some task-related regions. Therefore, the DN seems to exhibit two simultaneous FC dynamics at rest. The first is spatially invariant and insensitive to previous brain states, suggesting that the DN maintains some temporally stable functional connections. The second dynamic is more variable and is seen more strongly when the resting-state follows a period of task execution, suggesting an after-effect of the cognitive activity engaged during task that carries over into resting-state periods

Connectivity of Default-Mode Network Is Associated with Cerebral Edema in Hepatic Encephalopathy

Cerebral edema, a well-known feature of acute liver disease, can occur in cirrhotic patients regardless of hepatic encephalopathy (HE) and adversely affect prognosis. This study characterized and correlated functional HE abnormalities in the brain to cerebral edema using resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Forty-one cirrhotic patients (16 without HE, 14 minimal HE, 11 overt HE) and 32 healthy controls were assessed. The HE grade in cirrhotic patients was evaluated by the West Haven criteria and neuro-psychological examinations. Functional connectivity correlation coefficient (fc-CC) of the default mode network (DMN) was determined by rs-fMRI, while the corresponding mean diffusivity (MD) was obtained from DTI. Correlations among inter-cortical fc-CC, DTI indices, Cognitive Ability Screening Instrument scores, and laboratory tests were also analyzed. Results showed that gradual reductions of HE-related consciousness levels, from “without HE” or “minimal HE” to “overt HE”, correlated with decreased anterior-posterior fc-CC in DMN [F(4.415), p = 0.000)]. The MD values from regions with anterior-posterior fc-CC differences in DMN revealed significant differences between the overt HE group and other groups. Increased MD in this network was inversely associated with decreased fc-CC in DMN and linearly correlated with poor cognitive performance. In conclusion, cerebral edema can be linked to altered cerebral temporal architecture that modifies both within- and between-network connectivity in HE. Reduced fc-CC in DMN is associated with behavior and consciousness deterioration. Through appropriate targets, rs-fMRI technology may provide relevant supplemental information for monitoring HE and serve as a new biomarker for clinical diagnosis

Spontaneous Brain Activity in the Default Mode Network Is Sensitive to Different Resting-State Conditions with Limited Cognitive Load

BACKGROUND: Recent functional MRI (fMRI) studies have demonstrated that there is an intrinsically organized default mode network (DMN) in the resting brain, primarily made up of the posterior cingulate cortex (PCC) and the medial prefrontal cortex (MPFC). Several previous studies have found that the DMN is minimally disturbed during different resting-state conditions with limited cognitive demand. However, this conclusion was drawn from the visual inspection of the functional connectivity patterns within the DMN and no statistical comparison was performed. METHODOLOGY/PRINCIPAL FINDINGS: Four resting-state fMRI sessions were acquired: 1) eyes-closed (EC) (used to generate the DMN mask); 2) EC; 3) eyes-open with no fixation (EO); and 4) eyes-open with a fixation (EO-F). The 2-4 sessions were counterbalanced across participants (n = 20, 10 males). We examined the statistical differences in both functional connectivity and regional amplitude of low frequency fluctuation (ALFF) within the DMN among the 2-4 resting-state conditions (i.e., EC, EO, and EO-F). Although the connectivity patterns of the DMN were visually similar across these three different conditions, we observed significantly higher functional connectivity and ALFF in both the EO and the EO-F conditions as compared to the EC condition. In addition, the first and second resting EC conditions showed significant differences within the DMN, suggesting an order effect on the DMN activity. CONCLUSIONS/SIGNIFICANCE: Our findings of the higher DMN connectivity and regional spontaneous activities in the resting state with the eyes open suggest that the participants might have more non-specific or non-goal-directed visual information gathering and evaluation, and mind wandering or daydreaming during the resting state with the eyes open as compared to that with the eyes closed, thus providing insights into the understanding of unconstrained mental activity within the DMN. Our results also suggest that it should be cautious when choosing the type of a resting condition and designating the order of the resting condition in multiple scanning sessions in experimental design

Local Signal Time-Series during Rest Used for Areal Boundary Mapping in Individual Human Brains

It is widely thought that resting state functional connectivity likely reflects functional interaction among brain areas and that different functional areas interact with different sets of brain areas. A method for mapping areal boundaries has been formulated based on the large-scale spatial characteristics of regional interaction revealed by resting state functional connectivity. In the present study, we present a novel analysis for areal boundary mapping that requires only the signal timecourses within a region of interest, without reference to the information from outside the region. The areal boundaries were generated by the novel analysis and were compared with those generated by the previously-established standard analysis. The boundaries were robust and reproducible across the two analyses, in two regions of interest tested. These results suggest that the information for areal boundaries is readily available inside the region of interest