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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.

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.

Alzheimer disease (AD) is the most common contributor to dementia in the world, but strategies that slow or prevent its clinical progression have largely remained elusive, until recently. This Review highlights the latest advances in biomarker technologies and therapeutic development to improve AD diagnosis and treatment. We review recent results that enable pathological staging of AD with neuroimaging and fluid-based biomarkers, with a particular emphasis on the role of amyloid, tau and neuroinflammation in disease pathogenesis. We discuss the lessons learned from randomized controlled trials, including some supporting the proposal that certain anti-amyloid antibodies slow cognitive decline during the mildly symptomatic phase of AD. In addition, we highlight evidence for newly identified therapeutic targets that may be able to modify AD pathogenesis and progression. Collectively, these recent discoveries—and the research directions that they open—have the potential to move AD clinical care toward disease-modifying treatment strategies with maximal benefits for patients. This Review summarizes recent advances in biomarkers and therapies for Alzheimer disease—the products of decades of research—and discusses the challenges, gaps and clinical implications.

Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future. Unlocking Alzheimer’s: gut microbiota’s pivotal role in disease progression Alzheimer’s disease is a complicated disorder involving the degeneration of nerve cells, marked by the creation of plaques and tangles in the brain, leading to mental decline. Despite much research, the precise origin and development of the disease remain unknown. This study, led by Seo and Holtzman, investigates the role of the gut microbiome (the community of microorganisms in our digestive system) in Alzheimer’s disease. The scientists conducted a narrative review, summarizing recent discoveries and discussing new questions in the field. They discovered that the gut microbiome could impact the development of Alzheimer’s disease by controlling peripheral neurotransmitters, metabolites, and immune signaling molecules. The scientists concluded that targeting the gut bacteria could potentially be a treatment strategy for Alzheimer’s disease. However, they also emphasized the need for more research to fully comprehend this intricate interaction. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

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.

The amyloid cascade is perhaps the most dominant hypothesis in the field of Alzheimer's disease pathogenesis but it is also one of the most controversial. Here, we present two Perspective articles which argue both for and against the amyloid hypothesis. In this piece, Drs. Musiek and Holtzman argue that, despite sometimes conflicting data, there is ample evidence to suggest that Aβ accumulation is a key initiator of AD-related pathology and may act as a trigger of downstream effects such as tau aggregation. 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.

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.

Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes.We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.

Tauopathies are a broad set of neurodegenerative dementias characterized by aggregation of the tau protein into filamentous inclusions that can be found in neurons and glial cells. Activated microglia, astrocytes and elevated levels of proinflammatory molecules are also pathological hallmarks that are found in brain regions affected by tau pathology. There has been abundant research in recent years to understand the role of gliosis and neuroinflammation in neurodegenerative diseases, particularly in Alzheimer’s disease (AD) which is the most common form of dementia. AD is a tauopathy characterized by both extracellular amyloid-β plaques in addition to intracellular neurofibrillary tangles and neuropil threads containing aggregated tau protein. Accumulating evidence suggests that neuroinflammation offers a possible mechanistic link between these pathologies. Additionally, there appears to be a role for neuroinflammation in aggravating tau pathology and neurodegeneration in tauopathies featuring tau deposits as the predominant pathological signature. In this review, we survey the literature regarding inflammatory mechanisms that may impact neurodegeneration in AD and related tauopathies. We consider a physical role for microglia in the spread of tau pathology as well as the non-cell autonomous effects of secreted proinflammatory cytokines, specifically interleukin 1 beta, interleukin 6, tumor necrosis factor alpha and complement proteins. These molecules appear to have direct effects on tau pathophysiology and overall neuronal health. They also indirectly impact neuronal homeostasis by altering glial function. We conclude by proposing a complex role for gliosis and neuroinflammation in accelerating the progression of AD and other tauopathies.

Disturbances in the sleep–wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep–wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep–wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep–wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD. Alzheimer's disease: Under the influence of sleep The onset and progression of Alzheimer's disease may be associated with sleep cycle disturbance even before cognitive symptoms appear. Alzheimer's disease is a neurodegenerative condition that primarily affects older people, leading to dementia. Disturbed sleep patterns and problems with circadian rhythms, physiological processes which follow a natural 24-hour cycle, are often symptoms of the disease. David Holtzman and co-workers at the Washington University School of Medicine, USA, reviewed research suggesting that sleep disruption may actually occur in the early stages of Alzheimer's disease and exacerbate the disease. The team highlighted research linking sleep cycles with the regulation of certain Alzheimer-related peptides in mouse brains, together with studies connecting neurodegenerative processes with the disruption of circadian rhythms. Therapies targeting sleep disruption could therefore help in the fight against Alzheimer's disease in the future.