Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central nervous system ...(CNS) is separated from the blood circulation by the blood-brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily mediated by CNS-resident microglia. APOE (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS. Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease.
As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer's disease (AD) can develop sleep problems even before memory and other cognitive ...deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep-wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep-wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.
Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological ...protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.
Neurodegenerative diseases (NDDs) are a heterogeneous group of disorders characterized by progressive loss of neurons in the central or peripheral nervous system. This review highlights the eight key hallmarks of NDDs and presents a hallmark-based framework for unifying and categorizing NDDs, for stratifying NDD patients, and for designing personalized therapeutic strategies.
Alzheimer’s disease (AD) is a slowly progressing disorder in which pathophysiological abnormalities, detectable in vivo by biomarkers, precede overt clinical symptoms by many years to decades. Five ...AD biomarkers are sufficiently validated to have been incorporated into clinical diagnostic criteria and commonly used in therapeutic trials. Current AD biomarkers fall into two categories: biomarkers of amyloid-β plaques and of tau-related neurodegeneration. Three of the five are imaging measures and two are cerebrospinal fluid analytes. AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping manner. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. In this Review, we discuss several time-dependent models of AD that take into consideration varying age of onset (early versus late) and the influence of aging and co-occurring brain pathologies that commonly arise in the elderly.
Jack and Holtzman review the major biomarkers of Alzheimer’s disease and relate them to specific pathophysiological processes. They also outline a framework for temporal evolution of AD biomarkers in the context of both early- and late-onset disease.
Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have ...long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer's disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.
Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of ...hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.
Long & Holtzman provide a comprehensive overview of the molecules, cells, and mechanisms of Alzheimer disease pathobiology and therapeutic strategies, critically discussing failed strategies and offering a path forward.
The amyloid hypothesis, which has been the predominant framework for research in Alzheimer's disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that ...amyloid-β peptide (Aβ) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Aβ acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. Aβ appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process.
Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus ...(T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.
Alzheimer’s disease (AD) is the most common neurodegenerative disease, with characteristic extracellular amyloid-β (Aβ) deposition and intracellular accumulation of hyperphosphorylated, aggregated ...tau. Several key regulators of innate immune pathways are genetic risk factors for AD. While these genetic risk factors as well as in vivo data point to key roles for microglia, emerging evidence also points to a role of the adaptive immune response in disease pathogenesis. We review the roles of innate and adaptive immunity, their niches, their communication, and their contributions to AD development and progression. We also summarize the cellular compositions and physiological functions of immune cells in the parenchyma, together with those in the brain border structures that form a dynamic disease-related immune niche. We propose that both innate and adaptive immune responses in brain parenchyma and border structures could serve as important therapeutic targets for treating both the pre-symptomatic and the symptomatic stages of AD.
Chen and Holtzman review the emerging roles of both innate and adaptive immunity, their alterations, their interplay, and their contributions to the development and progression of Alzheimer’s disease. They proposed that targeting dysregulated innate and adaptive immune responses in both brain parenchyma and border structures could lead to important therapeutics for preventing and treating the disease.
Alzheimer's disease (AD) is the leading cause of dementia. The two histopathological markers of AD are amyloid plaques composed of the amyloid-β (Aβ) peptide, and neurofibrillary tangles of ...aggregated, abnormally hyperphosphorylated tau protein. The majority of AD cases are late-onset, after the age of 65, where a clear cause is still unknown. However, there are likely different multifactorial contributors including age, enviornment, biology and genetics which can increase risk for the disease. Genetic predisposition is considerable, with heritability estimates of 60-80%. Genetic factors such as rare variants of TREM2 (triggering receptor expressed on myeloid cells-2) strongly increase the risk of developing AD, confirming the role of microglia in AD pathogenesis. In the last 5 years, several studies have dissected the mechanisms by which TREM2, as well as its rare variants affect amyloid and tau pathologies and their consequences in both animal models and in human studies. In this review, we summarize increases in our understanding of the involvement of TREM2 and microglia in AD development that may open new therapeutic strategies targeting the immune system to influence AD pathogenesis.
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