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Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease
In this study, the authors found that sTREM2 attenuates tau hyperphosphorylation by activating transgelin-2. They developed an active peptide that mimics the protective effect of sTREM2, which may be an innovative therapeutic intervention for AD.
- Xingyu Zhang
- , Li Tang
- & Zhentao Zhang
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Article
| Open Access
Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice
Here the authors show in female mice at mid-life that deletion of estrogen receptor β in astrocytes induced cognitive impairment, hippocampal atrophy, glial activation and synaptic loss. ERβ ligand treatment restored cognition and decreased neuropathology in these animals.
- Noriko Itoh
- , Yuichiro Itoh
- & Rhonda R. Voskuhl
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Article
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C3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease
In this work, the authors report the utilization of nano-inhibito C3N nanodots to inhibit Aβ peptides aggregation and fibrils disassembly, and show how they induce a cognitive enhancement in treated AD mice.
- Xiuhua Yin
- , Hong Zhou
- & Ruhong Zhou
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Article
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Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice
Exercise has positive effects on the brain during aging. Here the authors show that in mice, platelet-released exerkine PF4 mediates the effects of exercise on the brain.
- Odette Leiter
- , David Brici
- & Tara L. Walker
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Perspective
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An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
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The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization
Observational studies have found overlap between Alzheimer’s disease and other diseases and phenotypes, although the causal relationships are unclear. Here, the authors perform an age-stratified phenome-wide association study of Alzheimer’s disease (AD) genetic liability and follow-up Mendelian randomization analyses to examine whether these phenotypes have a causal effect on AD.
- Roxanna Korologou-Linden
- , Laxmi Bhatta
- & Neil M. Davies
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Article
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Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health
Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers.
- Danni A. Gadd
- , Robert F. Hillary
- & Riccardo E. Marioni
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Lower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals
Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer’s disease.
- Prokopis C. Prokopiou
- , Nina Engels-Domínguez
- & Heidi I. L. Jacobs
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Article
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Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus
Decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Here the authors provide evidence that environmental enrichment delays age-related DNA methylation alterations in the mouse hippocampus.
- Sara Zocher
- , Rupert W. Overall
- & Gerd Kempermann
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Article
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.
- Itziar de Rojas
- , Sonia Moreno-Grau
- & Agustín Ruiz
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Article
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Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease
Cortical thickness is asymmetric, and cortical thinning occurs with age and in disease. Here the authors investigate if both cortices thin at the same rate or if the thicker hemisphere declines faster in aging and in Alzheimer’s disease.
- James M. Roe
- , Didac Vidal-Piñeiro
- & Michael Vacher
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Article
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Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals
Previously it was shown that an N-terminal tau fragment (NT1) measured in plasma can differentiate individuals with Alzheimer’s disease from healthy controls. Here the authors show that plasma levels of NT1 can associate with future cognitive decline in cognitively normal elderly individuals.
- Jasmeer P. Chhatwal
- , Aaron P. Schultz
- & Dennis J. Selkoe
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Article
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Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging
Previous work showed that the caspase 1 inhibitor VX-765 rescued cognitive deficits in the J20 mouse model of Alzheimer’s disease, and this may occur via reduced inflammation. Here the authors show that administration of the drug prior to onset of cognitive deficits and pathology in mice delays the onset of deficits.
- Joseph Flores
- , Anastasia Noël
- & Andréa C. LeBlanc
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Article
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Cerebrovascular risk factors impact frontoparietal network integrity and executive function in healthy ageing
Cerebrovascular risk factors reduce cognitive performance via changes in the integrity of a frontoparietal brain network in ageing. Modification of blood pressure, with antihypertensive treatment in mid-life, mitigates against cognitive decline over a specific blood pressure range.
- Michele Veldsman
- , Xin-You Tai
- & Masud Husain
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Article
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Aging alters neural activity at event boundaries in the hippocampus and Posterior Medial network
Although our lives are continuous, we perceive and remember experiences as discrete events. Here, the authors show that neural responses at event boundaries in the hippocampus and Posterior Medial cortical network decline as we age, and predict memory for narrative events.
- Zachariah M. Reagh
- , Angelique I. Delarazan
- & Charan Ranganath
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Article
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Sources of path integration error in young and aging humans
Path integration abilities, important for spatial navigation, vary widely across individuals and deteriorate in old age. This work shows that path integration errors in general, as well as age-related path integration deficits, are mainly caused by accumulating noise in people’s velocity estimation.
- Matthias Stangl
- , Ingmar Kanitscheider
- & Thomas Wolbers
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Article
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HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
Defects in DNA repair have been linked to brain aging and neurodegenerative disorders. Here the authors reveal a role for HDAC1 in stimulating OGG1 activity to alleviate 8-oxoG lesions with implications in the aging brain and neurodegenerative diseases.
- Ping-Chieh Pao
- , Debasis Patnaik
- & Li-Huei Tsai
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Article
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Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences
Alterations of locus coeruleus signal intensity have been associated with functional changes in health and disease. Here, the authors tested a pre-registered hypothesis on a large number of subjects as part of the Cam-CAN consortium.
- Kathy Y. Liu
- , Rogier A. Kievit
- & Dorothea Hämmerer
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Article
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Neurology-related protein biomarkers are associated with cognitive ability and brain volume in older age
Late-life cognitive dysfunction is common, but the biological substrates are largely unknown. Here, the authors examined a panel of 90 neurology-related protein biomarkers and show that plasma levels of 22 of these proteins are associated with general fluid cognitive ability in later life.
- Sarah E. Harris
- , Simon R. Cox
- & Ian J. Deary
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Article
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Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life
Ageing affects several brain areas causing a decrease in cognitive abilities and memory. We find that increasing the endogenous potential of the hippocampus to generate new neurons throughout life rejuvenates learning and memory, indicating that neural reserves can be exploited during ageing to compensate for age- or disease-related cognitive impairments.
- Gabriel Berdugo-Vega
- , Gonzalo Arias-Gil
- & Federico Calegari
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Article
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Tau deposition is associated with functional isolation of the hippocampus in aging
Deposition of tau protein aggregates occurs during aging and Alzheimer disease. Here, the authors show that tau burden in the anterior-temporal memory network is associated with disrupted fMRI connectivity and functional isolation of the hippocampus from other memory network components.
- Theresa M. Harrison
- , Anne Maass
- & William J. Jagust
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Article
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Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age
Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
- Aliza P. Wingo
- , Eric B. Dammer
- & Thomas S. Wingo
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Article
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Reductions in prefrontal activation predict off-topic utterances during speech production
The ability to speak coherently is essential for effective communication, but little is known about the neural systems that support coherence. Here, the authors show that activity in two prefrontal cortex regions, BA10 and BA45, predicts the level of coherence in the speech of healthy older adults.
- Paul Hoffman
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Article
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Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory
Circadian rhythms are known to modulate memory, but it’s not known whether clock genes in the hippocampus are required for memory consolidation. Here, the authors show that epigenetic regulation of clock gene Period1 in the hippocampus regulates memory and contributes to age-related memory decline, independent of circadian rhythms.
- Janine L. Kwapis
- , Yasaman Alaghband
- & Marcelo A. Wood
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Article
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Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner
Microglia cells in the brain regulate immune responses, but in ageing can negatively affect brain function. Here the authors show that the chronic presence of type I interferon in aged mouse brain impedes cognitive ability by altering microglia transcriptome and limiting Mef2C, a microglia ‘off’ signal.
- Aleksandra Deczkowska
- , Orit Matcovitch-Natan
- & Michal Schwartz
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Article
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Aging affects the balance of neural entrainment and top-down neural modulation in the listening brain
The changes that accompany age-related decreases in speech comprehension are not yet understood. Here, authors show that older adults are less able to entrain to speech-paced auditory rhythms and that the behavioural consequences can be counteracted by top-down neural modulation.
- Molly J. Henry
- , Björn Herrmann
- & Jonas Obleser
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Article
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Preserved cognitive functions with age are determined by domain-dependent shifts in network responsivity
Cognitive abilities change with age, but why some decline and some do not is not clear. Here, the authors use data from the Cam-CAN cohort to show that distributed, multi-component brain responsivity and default-mode deactivation supports and characterizes preserved cognition across the adult lifespan.
- Dávid Samu
- , Karen L. Campbell
- & Lorraine K. Tyler
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Article
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Neuroanatomy accounts for age-related changes in risk preferences
Tolerance for risk decreases with age, but it is not known whether this shift can be accounted for by a neurobiological marker. Here, authors show that the age-related decrease in risk tolerance is better accounted for by grey matter decreases in right posterior parietal cortex than by age per se.
- Michael A. Grubb
- , Agnieszka Tymula
- & Ifat Levy
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Article
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Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology
Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.
- Taylor W. Schmitz
- , R. Nathan Spreng
- & Ansgar J. Furst
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Article
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Ageing increases reliance on sensorimotor prediction through structural and functional differences in frontostriatal circuits
Decline in sensorimotor skills with age may be due to an overreliance on the prediction of the sensory consequences of one’s actions. Here the authors show that sensorimotor attenuation increases with age, and that this is associated with structural and functional changes in frontostriatal circuits.
- Noham Wolpe
- , James N. Ingram
- & James B. Rowe
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Article
| Open Access
Age differences in learning emerge from an insufficient representation of uncertainty in older adults
The ability to learn decreases with old age especially in a dynamically changing environment, however the precise nature of this decline is not understood. Nassar and colleagues report that older adults show a reduced ability to learn from uncertain outcomes compared to younger adults.
- Matthew R. Nassar
- , Rasmus Bruckner
- & Ben Eppinger
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Article
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Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug
The leukotriene receptor antagonist montelukast is an anti-asthmatic drug. Here, the authors show that montelukast reduces neuroinflammation, promotes hippocampal neurogenesis and restores learning and memory in old rats suffering from ageing-associated cognitive dysfunction.
- Julia Marschallinger
- , Iris Schäffner
- & Ludwig Aigner
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Article
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Distinct aspects of frontal lobe structure mediate age-related differences in fluid intelligence and multitasking
Executive functions are affected by ageing but it is unclear how. Kievit et al.use brain imaging and modelling approaches to show how multifactorial explanations outperform single-factor models when relating age-related differences in grey and white matter to differences in fluid intelligence and multitasking.
- Rogier A. Kievit
- , Simon W. Davis
- & Richard N.A. Henson
Functional alterations of the prefrontal circuit underlying cognitive aging in mice