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Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

Immersive virtual reality has become increasingly popular to improve the assessment and treatment of health problems. This rising popularity is likely to be facilitated by the availability of affordable headsets that deliver high quality immersive experiences. As many health problems are more prevalent in older adults, who are less technology experienced, it is important to know whether they are willing to use immersive virtual reality. In this study, we assessed the initial attitude towards head-mounted immersive virtual reality in 76 older adults who had never used virtual reality before. Furthermore, we assessed changes in attitude as well as self-reported cybersickness after a first exposure to immersive virtual reality relative to exposure to time-lapse videos. Attitudes towards immersive virtual reality changed from neutral to positive after a first exposure to immersive virtual reality, but not after exposure to time-lapse videos. Moreover, self-reported cybersickness was minimal and had no association with exposure to immersive virtual reality. These results imply that the contribution of VR applications to health in older adults will neither be hindered by negative attitudes nor by cybersickness.

Two decades ago, α-synuclein was identified as a key player in Parkinson's disease pathogenesis. Wong and Krainc review the upstream factors and downstream cellular mechanisms associated with α-synuclein toxicity and discuss therapeutic efforts to target synucleinopathies. Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies. In this Review, we discuss these emerging themes, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation. Finally, we summarize recent efforts toward the development of targeted therapies for PD and related synucleinopathies.

Communication within the glial cell ecosystem is essential for neuronal and brain health 1 – 3 . The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions 4 , 5 . Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD. Interleukin-3 signalling from astrocytes to microglia readies microglia to defend against Alzheimer’s disease.

Aducanumab’s fast-tracking has researchers both worried and hopeful about the future of drugs for neurodegenerative diseases such as Huntington’s and Parkinson’s. Aducanumab’s fast-tracking has researchers both worried and hopeful about the future of drugs for neurodegenerative diseases such as Huntington’s and Parkinson’s.

Hopes were high for drugs designed to lower levels of a mutant protein, but development has stalled. Hopes were high for drugs designed to lower levels of a mutant protein, but development has stalled. Immunofluorescent light micrograph of a nerve cell from the striatum of the brain

RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n  = 1112 and ADNI, n  = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM 3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation. The onset and pathology of Alzheimer’s disease (AD) is associated with changes to lipid metabolism. Here, the authors analysed 569 lipids from 32 classes and subclasses in two independent patient cohorts to identify key lipid pathways to link the plasma lipidome with AD and the future onset of AD.

As the development of treatments for Alzheimer’s disease continues to stumble, is it time for researchers to broaden their list of the condition’s potential causes? As the development of treatments for Alzheimer’s disease continues to stumble, is it time for researchers to broaden their list of the condition’s potential causes?