Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical ...symptom-based definition to a clinical-biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categorizes individuals using biomarkers that chart core AD pathophysiological features, namely the amyloid-β (Aβ) pathway (A), tau-mediated pathophysiology (T) and neurodegeneration (N). This biomarker matrix is now expanding towards an ATX(N) system, where X represents novel candidate biomarkers for additional pathophysiological mechanisms such as neuroimmune dysregulation, synaptic dysfunction and blood-brain barrier alterations. In this Perspective, we describe the conceptual framework and clinical importance of the existing AT(N) system and the evolving ATX(N) system. We provide a state-of-the-art summary of the potential contexts of use of these systems in AD clinical trials and future clinical practice. We also discuss current challenges related to the validation, standardization and qualification process and provide an outlook on the real-world application of the AT(N) system.
Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and ...the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.
Hampel et al. review the role of the cholinergic system in cognition and how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology. They document the ...benefits of cholinergic therapies at various stages of disease, and argue that the weight of the evidence confirms their continued value.
Abstract
Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide ...association studies point out several genetic variants-
, and
-potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish
and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
Alzheimer's disease (AD) is a multifactorial, age-related neurological disease characterized by complex pathophysiological dynamics taking place at multiple biological levels, including molecular, ...genetic, epigenetic, cellular and large-scale brain networks. These alterations account for multiple pathophysiological mechanisms such as brain protein accumulation, neuroinflammatory/neuro-immune processes, synaptic dysfunction, and neurodegeneration that eventually lead to cognitive and behavioral decline. Alterations in microRNA (miRNA) signaling have been implicated in the epigenetics and molecular genetics of all neurobiological processes associated with AD pathophysiology. These changes encompass altered miRNA abundance, speciation and complexity in anatomical regions of the CNS targeted by the disease, including modified miRNA expression patterns in brain tissues, the systemic circulation, the extracellular fluid (ECF) and the cerebrospinal fluid (CSF). miRNAs have been investigated as candidate biomarkers for AD diagnosis, disease prediction, prognosis and therapeutic purposes because of their involvement in multiple brain signaling pathways in both health and disease. In this review we will: (i) highlight the significantly heterogeneous nature of miRNA expression and complexity in AD tissues and biofluids; (ii) address how information may be extracted from these data to be used as a diagnostic, prognostic and/or screening tools across the entire continuum of AD, from the preclinical stage, through the prodromal, i.e., mild cognitive impairment (MCI) phase all the way to clinically overt dementia; and (iii) consider how specific miRNA expression patterns could be categorized using miRNA reporters that span AD pathophysiological initiation and disease progression.
Introduction
This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late‐life cognitive decline due to ...progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker‐informed pathophysiological dynamics in de‐novo diagnosed menopausal women.
Methods
We analyzed baseline and longitudinal differences between MHT‐taking and ‐not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid‐β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration.
Results
We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment.
Discussion
To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause.
With population growth and aging, the number of people with dementia and related disorders will grow substantially in the years ahead, bringing with it significant societal, health‐care, and economic ...challenges. Here, we analyze dementia policies of seven major countries in Asia/Pacific, Europe, and North America to identify opportunities for early actions to mitigate disease burden. We find that most countries are addressing this need by including a specific focus on early action in their national dementia strategies (five of seven countries), implementing public health initiatives for risk reduction, prevention, and early detection and diagnosis (six of seven countries); supporting enabling research for early detection and risk reduction (six of seven countries); and enacting a system for early, regular brain health screening (one of seven). We discuss risks and opportunities for integrating early action policies and conducting additional systematic research to understand the potential benefits and impacts of these policies.
•Aging promotes modifications in brain due to estrogen decline, mainly in females.•Adult exposure to estrogens and androgens regulate AD development in women and men.•Sex effect on both neuroimaging ...and fluid biomarkers of AD was explored.•Sex representation in basic/clinical neuroscience, in clinical trials, is inadequate.•A “sex-stratified pathway-based therapy” framework needs to be introduced.
Neurodegenerative diseases (ND) are among the leading causes of disability and mortality. Considerable sex differences exist in the occurrence of the various manifestations leading to cognitive decline. Alzheimer’s disease (AD) exhibits substantial sexual dimorphisms and disproportionately affects women. Women have a higher life expectancy compared to men and, consequently, have more lifespan to develop AD. The emerging precision medicine and pharmacology concepts – taking into account the individual genetic and biological variability relevant for disease risk, prevention, detection, diagnosis, and treatment – are expected to substantially enhance our knowledge and management of AD. Stratifying the affected individuals by sex and gender is an important basic step towards personalization of scientific research, drug development, and care.
We hypothesize that sex and gender differences, extending from genetic to psychosocial domains, are highly relevant for the understanding of AD pathophysiology, and for the conceptualization of basic/translational research and for clinical therapy trial design.
Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease ...(AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood‐based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine‐learning and a cross‐validation‐based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein‐E (APOE) genotype (the major genetic risk factor for late‐onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD‐like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE‐related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1β was the variable most significantly associated with MCI‐to‐dementia conversion over a 2.5 year‐clinical follow‐up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker‐guided pathway‐based therapeutic approaches, within the precision medicine development framework.
Blood cytokines are emerging as potential pathophysiological biomarkers in Alzheimer's Disease (AD). In this paper, it was explored in a population of cognitively healthy participant subjects and patients belonging to the Alzheimer's continuum, whether cytokine blood levels are influenced by biological factors, such as age, sex, and apolipoprotein‐E (APOE) genotypes and how they may be related to the clinical features of the patients. Machine‐learning network analysis shows that IL1β is significantly associated with MCI‐to‐dementia conversion. In parallel, it is demonstrated that sex and age influence interleukin IL12 concentration, while IL10 is related to the APOE genotype. Cytokine analysis may foster biomarker‐guided pathway‐based therapeutic approaches in AD.
Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the ...pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes.
From the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison.
Donepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response.
Our data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment.
ClinicalTrial.gov NCT00403520. Submission Date: November 21, 2006.
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