Aducanumab: a new phase in therapeutic development for Alzheimer’s disease?

On 7 June(,) the FDA approved aducanumab, the first new drug for Alzheimer’s disease in almost 20 years—and notably, the first drug with a putative disease‐modifying mechanism for the treatment of this devastating disorder, namely the removal of β‐amyloid (or Aβ) plaques from the brain

Bidirectional associations between word memory and one-legged balance performance in mid and later life

Background: Age-related changes in cognitive and balance capabilities are well-established, as is their correlation with one another. Given limited evidence regarding the directionality of associations, we aimed to explore the direction and potential explanations of associations between word memory and one-legged balance performance in mid-later life. / Methods: A total of 3062 participants in the Medical Research Council National Survey of Health and Development, a British birth cohort study, were included. One-legged balance times (eyes closed) were measured at ages 53, 60–64 and 69 years. Word memory was assessed at ages 43, 53, 60–64 and 69 with three 15-item word-recall trials. Autoregressive cross-lagged and dual change score models assessed bidirectional associations between word memory and balance. Random-effects models quantified the extent to which these associations were explained by adjustment for anthropometric, socioeconomic, behavioural and health status indicators. / Results: Autoregressive cross-lagged and dual change score models suggested a unidirectional association between word memory and subsequent balance performance. In a sex-adjusted random-effects model, 1 standard deviation increase in word memory was associated with 9% (7,12%) higher balance performance at age 53. This association decreased with age (−0.4% /year (−0.6,-0.1%). Education partially attenuated the association, although it remained in the fully-adjusted model (3% (0.1,6%)). / Conclusions: There was consistent evidence that word memory is associated with subsequent balance performance but no evidence of the reverse association. Cognitive processing plays an important role in the balance process, with educational attainment providing some contribution. These findings have important implications for understanding cognitive-motor associations and for interventions aimed at improving cognitive and physical capability in the ageing population

Associations of word memory, verbal fluency, processing speed and crystallised cognitive ability with one-legged balance performance in mid and later life

BACKGROUND: Cognitive integration of sensory input and motor output plays an important role in balance. Despite this, it is not clear if specific cognitive processes are associated with balance and how these associations change with age. We examined longitudinal associations of word memory, verbal fluency, search speed and reading ability with repeated measures of one-legged balance performance. METHODS: Up to 2934 participants in the MRC National Survey of Health and Development, a British birth cohort study, were included. At age 53, word memory, verbal fluency, search speed and reading ability were assessed. One-legged balance times (eyes closed) were measured at ages 53, 60-64 and 69 years. Associations between each cognitive measure and balance time were assessed using random-effects models. Adjustments were made for sex, death, attrition, height, body mass index, health conditions, health behaviours, education, and occupational class. RESULTS: In sex-adjusted models, one SD higher scores in word memory, search speed and verbal fluency were associated with 14.1% (95%CI: 11.3,16.8), 7.2% (4.4,9.9) and 10.3% (7.5,13.0) better balance times at age 53, respectively. Higher reading scores were associated with better balance, although this association plateaued. Associations were partially attenuated in mutually-adjusted models and effect sizes were smaller at ages 60-64 and 69. In fully-adjusted models, associations were largely explained by education, although remained for word memory and search speed. CONCLUSIONS: Higher cognitive performance across all measures was independently associated with better balance performance in midlife. Identification of individual cognitive mechanisms involved in balance could lead to opportunities for targeted interventions in midlife

Associations Between Factors Across Life and One-Legged Balance Performance in Mid and Later Life: Evidence From a British Birth Cohort Study

INTRODUCTION: Despite its associations with falls, disability, and mortality, balance is an under-recognized and frequently overlooked aspect of aging. Studies investigating associations between factors across life and balance are limited. Understanding the factors related to balance performance could help identify protective factors and appropriate interventions across the life course. This study aimed to: (i) identify socioeconomic, anthropometric, behavioral, health, and cognitive factors that are associated with one-legged balance performance; and (ii) explore how these associations change with age. METHODS: Data came from 3,111 members of the MRC National Survey of Health and Development, a British birth cohort study. Multilevel models examined how one-legged standing balance times (assessed at ages 53, 60–64, and 69) were associated with 15 factors across life: sex, maternal education (4 years), paternal occupation (4 years), own education (26 years), own occupation (53 years), and contemporaneous measures (53, 60–64, 69 years) of height, BMI, physical activity, smoking, diabetes, respiratory symptoms, cardiovascular events, knee pain, depression and verbal memory. Age and sex interactions with each variable were assessed. RESULTS: Men had 18.8% (95%CI: 13.6, 23.9) longer balance times than women at age 53, although this difference decreased with age (11.8% at age 60–64 and 7.6% at age 69). Disadvantaged socioeconomic position in childhood and adulthood, low educational attainment, less healthy behaviors, poor health status, lower cognition, higher body mass index (BMI), and shorter height were associated with poorer balance at all three ages. For example, at age 53, those from the lowest paternal occupational classes had 29.6% (22.2, 38.8) worse balance than those from the highest classes. Associations of balance with socioeconomic indicators, cognition and physical activity became smaller with age, while associations with knee pain and depression became larger. There were no sex differences in these associations. In a combined model, the majority of factors remained associated with balance. DISCUSSION: This study identified numerous risk factors across life that are associated with one-legged balance performance and highlighted diverse patterns of association with age, suggesting that there are opportunities to intervene in early, mid and later life. A multifactorial approach to intervention, at both societal and individual levels, may have more benefit than focusing on a single risk factor

Molecular nexopathies: a new paradigm of neurodegenerative disease.

Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases. However, how do protein abnormalities produce network signatures? The answer may lie with 'molecular nexopathies': specific, coherent conjunctions of pathogenic protein and intrinsic network characteristics that define network signatures of neurodegenerative pathologies. Key features of the paradigm that we propose here include differential intrinsic network vulnerability to propagating protein abnormalities, in part reflecting developmental structural and functional factors; differential vulnerability of neural connection types (e.g., clustered versus distributed connections) to particular pathogenic proteins; and differential impact of molecular effects (e.g., toxic-gain-of-function versus loss-of-function) on gradients of network damage. The paradigm has implications for understanding and predicting neurodegenerative disease biology

The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles

Variants in the triggering receptor expressed on myeloid cells 2 gene are linked with an increased risk of dementia, in particular the R47H^{het} triggering receptor expressed on myeloid cells 2 variant is linked to late-onset Alzheimer’s disease. Using human induced pluripotent stem cells-derived microglia, we assessed whether variations in the dynamics of exosome secretion, including their components, from these cells might underlie some of this risk. We found exosome size was not altered between common variant controls and R47H^{het} variants, but the amount and constitution of exosomes secreted were different. Exosome quantities were rescued by incubation with an ATP donor or with lipids via a phosphatidylserine triggering receptor expressed on myeloid cells 2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47H^{heht} microglia were found to contain cytokines, chemokines, APOE and triggering receptor expressed on myeloid cells 2. Differences were observed in the expression of CCL22, IL-1β and triggering receptor expressed on myeloid cells 2 between common variant and R47H^{het} derived exosomes. Furthermore unlike common variant-derived exosomes, R47H^{het} exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47H^{het}derived exosomes to be less protective. These data have ramifications for the responses of microglia in Alzheimer’s disease and may point to further targets for therapeutic intervention

Interoceptive Ability Predicts Survival on a London Trading Floor.

Interoception is the sensing of physiological signals originating inside the body, such as hunger, pain and heart rate. People with greater sensitivity to interoceptive signals, as measured by, for example, tests of heart beat detection, perform better in laboratory studies of risky decision-making. However, there has been little field work to determine if interoceptive sensitivity contributes to success in real-world, high-stakes risk taking. Here, we report on a study in which we quantified heartbeat detection skills in a group of financial traders working on a London trading floor. We found that traders are better able to perceive their own heartbeats than matched controls from the non-trading population. Moreover, the interoceptive ability of traders predicted their relative profitability, and strikingly, how long they survived in the financial markets. Our results suggest that signals from the body - the gut feelings of financial lore - contribute to success in the markets

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia

Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD

Alzheimer's disease

Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, we outline the current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease, before discussing its clinical presentation, and current treatment strategies. Finally, we discuss how our enhanced understanding of Alzheimer pathogenesis and the recognition of a protracted preclinical phase is informing new therapeutic strategies with the aim of moving from treatment to prevention