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Keywords: Aducanumab, Bapineuzumab, Donanemab, Lecanemab

Attempts to reduce amyloid-β in the brain have yet to show clinical benefits. Starting treatment early is the best hope, says Sam Gandy

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.

TYROBP (also known as DAP12 or KARAP) is a transmembrane adaptor protein initially described as a receptor-activating subunit component of natural killer (NK) cells. TYROBP is expressed in numerous cell types, including peripheral blood monocytes, macrophages, dendritic cells, and osteoclasts, but a key point of recent interest is related to the critical role played by TYROBP in the function of many receptors expressed on the plasma membrane of microglia. TYROBP is the downstream adaptor and putative signaling partner for several receptors implicated in Alzheimer’s disease (AD), including SIRP1β, CD33, CR3, and TREM2. TYROBP has received much of its current notoriety because of its importance in brain homeostasis by signal transduction across those receptors. In this review, we provide an overview of evidence indicating that the biology of TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules. In addition to reviewing the structure and localization of TYROBP, we discuss our recent progress using mouse models of either cerebral amyloidosis or tauopathy that were engineered to be TYROBP-deficient or TYROBP-overexpressing. Remarkably, constitutively TYROBP-deficient mice provided a model of genetic resilience to either of the defining proteinopathies of AD. Learning behavior and synaptic electrophysiological function were preserved at normal physiological levels even in the face of robust cerebral amyloidosis (in APP/PSEN1 ; Tyrobp −/− mice) or tauopathy (in MAPT P301S ; Tyrobp −/− mice). A fundamental underpinning of the functional synaptic dysfunction associated with each proteotype was an accumulation of complement C1q. TYROBP deficiency prevented C1q accumulation associated with either proteinopathy. Based on these data, we speculate that TYROBP plays a key role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype. TYROBP may also play a key role in the loss of markers of synaptic integrity (e.g., synaptophysin-like immunoreactivity) that has long been held to be the feature of human AD molecular neuropathology that most closely correlates with concurrent clinical cognitive function.

Keywords: Alzheimer's disease, Autophagy, Brain fog, Golgi, Glycolipids, Glycosylation, GRASP55, GRASP65, Heparan sulfate proteoglycans, Intracellular trafficking, Myelin, O-GlcNAcylation, Phosphorylation, SARS-CoV-2 infection, Secretion

Traumatic brain injury (TBI) can occur as a single severe cranial impact or as repetitive concussions, and commonly affects professional athletes in contact sports and soldiers exposed to explosions. DeKosky and colleagues describe the distinct pathological changes accompanying each type of TBI, and characteristics of the resultant neuropathology, which frequently involves amyloid-β and tau aggregates. Potential biomarkers of TBI-induced damage are also outlined. Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE)—which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression—has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE. Key Points Traumatic brain injury (TBI) can lead to delayed-onset neurodegenerative syndromes that include Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) CTE has gained attention owing to increasing media coverage of neuropsychiatric dysfunction in players of high-impact sport, such as boxing and American football Brain pathology after single-incident severe TBI is similar to early amyloid pathology in AD, whereas repetitive TBI can produce tauopathy with or without amyloidosis that resembles pathology of boxers' dementia Estimation of the risk and prevalence of CTE remains challenging, and accurate prediction of TBI outcome and CTE risk for soldiers and players of high-impact sports is not yet possible Several genetic risk factors for CTE have been proposed but remain to be established Cerebrospinal fluid and neuroimaging biomarkers of TBI and CTE are emerging and hold promise for antemortem diagnosis of CTE, prediction of CTE risk, and monitoring of neuropathology progression

Studies of microglial gene manipulation in mouse models of Alzheimer’s disease (AD) amyloidopathy can cause unpredictable effects on various key endpoints, including amyloidosis, inflammation, neuritic dystrophy, neurodegeneration, and learning behavior. In this Correspondence , we discuss three examples, microRNA 155 (miR155), TREM2, and INPP5D, in which observed results have been difficult to reconcile with predicted results based on precedent, because these six key endpoints do not reliably track together. The pathogenesis of AD involves multiple cell types and complex events that may change with disease stage. We propose that cell-type targeting and timing of intervention are responsible for the sometimes impossibility of predicting whether any prospective therapeutic intervention should aim at increasing or decreasing the level or activity of a particular molecular target.

In late July, the National Football League introduced a new poster to be hung in league locker rooms, warning players of possible long-term health effects of concussions. Public awareness of the pathological consequences of traumatic brain injury has been elevated not only by the recognition of the potential clinical significance of repetitive head injuries in such high-contact sports as American football and boxing, but also by the prevalence of vehicular crashes and efforts to improve passenger safety features, and by modern warfare, especially blast injuries. Each year, more than 1.5 million Americans sustain mild traumatic brain injuries with no loss . . .