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Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau. Proteomic analysis of cerebrospinal fluid from individuals with autosomal dominant Alzheimer’s disease reveals how this complex and chronic disease evolves over many decades.

Background Although separate lines of research indicated a moderating role of sex in both sleep-wake disruption and in the interindividual vulnerability to Alzheimer’s disease (AD)-related processes, the quantification of sex differences in the interplay between sleep-wake dysregulation and AD pathology remains critically overlooked. Here, we examined sex-specific associations between circadian rest-activity patterns and AD-related pathophysiological processes across the adult lifespan. Methods Ninety-two cognitively unimpaired adults (mean age = 59.85 ± 13.77 years, range = 30–85, 47 females) underwent 10 days of actigraphic recordings, and blood drawing. Standard non-parametric indices of 24-h rest-activity rhythm fragmentation (intradaily variability, IV) and stability (interdaily stability, IS) were extracted from actigraphy data using the GGIR package. Plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-β 42/40 (Aβ 42/40 ), total tau, and tau phosphorylated at threonine 181 (p-tau 181 ) or threonine 231 (p-tau 231 ) were measured using Single molecule array technology. Multiple linear regression models were adjusted for age, sex, education, body mass index, and actigraphic recording duration. Results Higher IV, indicating worse 24-h rest-activity rhythm fragmentation, was associated with elevated levels of plasma NfL ( t (85) = 4.26, P  < 0.0001), GFAP ( t (85) = 2.49, P  = 0.01), and at trend level with lower Aβ 42/40 ratio values ( t (85) = -1.95, P  = 0.054). Lower IS, reflecting less day-to-day stability in the 24-h rest-activity rhythm, was linked to elevated levels of plasma NfL ( t (85) = -2.24, P  = 0.03), but not with the other plasma biomarkers. Importantly, interaction models demonstrated that male participants were driving the observed relationships between IV and plasma NfL ( t (84) = 4.05, P  < 0.001) or GFAP ( t (84) = 3.60, P  < 0.001), but also revealed a male vulnerability in models testing interactions with p-tau 181 (IV: t (76) = 3.71, P  < 0.001; IS: t (76) = -3.30, P  = 0.001) and p-tau 231 (IV: t (82) = 3.28, P  = 0.002). Sensitivity analyses further showed that accounting for potential confounding factors such as APOE genotype, depression, and self-reported symptoms of possible sleep apnea did not modify the observed relationships. Conclusions These findings suggest that the association between disrupted circadian rest-activity patterns and AD pathophysiological processes may be more evident in cognitively unimpaired males. Our results contribute to the precision medicine approach, and they have clinical implications for improved early detection and selection of at-risk individuals to be enrolled in preventive interventions.

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

The transentorhinal cortex (tErC) is one of the first regions affected by Alzheimer’s disease (AD), often showing changes before clinical symptoms appear. Understanding its role in cognition is key to detecting early cognitive impairments in AD. This study tested the hypothesis that the tErC supports fine-grained representations of unique individual objects, sensitively to the granularity of the demanded discrimination, influencing both perceptual and mnemonic functions. We examined the tErC’s role in object versus scene discrimination, using objective (based on a pretrained convolutional neural network, CNN) and subjective (human-rated) measures of visual similarity. Our results show that the structural integrity of the tErC is specifically related to the sensitivity to visual similarity for objects, but not for scenes. Importantly, this relationship depends on how visual similarity is measured: it appears only when using CNN visual similarity measures in perceptual discrimination, and solely when using subjective similarity ratings in mnemonic discrimination. Furthermore, in mnemonic discrimination, object sensitivity to visual similarity was specifically associated with the integrity of tErC-BA36 connectivity, only when similarity was computed from subjective ratings. Altogether, these findings suggest that discrimination sensitivity to object visual similarity may represent a specific marker of tErC integrity after accounting for the type of similarity measured. Measuring the granularity of the representation required for object discrimination across perceptual and memory tasks brings new evidence on the role of the transentorhinal cortex in representing unique entities.

Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral–central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral–central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.Evidence is accumulating that both central and peripheral immune responses are dysregulated in Alzheimer disease (AD). This roadmap reviews the current status of this research and provides a new research prospectus to advance our understanding of peripheral–central immune crosstalk in AD.

Background Alzheimer’s disease may compromise several musical competences, though no clear data is available in the scientific literature. Furthermore, music is capable of communicating basic emotions, but little is known about the emotional aspect of music in patients with Alzheimer’s disease. We present a systematic investigation of music processing in relation to extra-musical skills, in particular emotional skills in patients with Alzheimer’s disease. Methods We tested 30 patients with mild or moderate Alzheimer’s disease and 30 control subjects. We essentially evaluated (a) musical competences, using the extra-linguistic test, Solfeggio test and the recognition test of musical emotions—elaborated by our research team—and the Seashore test, and (b) emotional capacities using emotional memory and emotional prosody tests—made by our research group. Results We significantly observed lower total results of every test assessing cognitive, emotional and music competences in Alzheimer’s disease patients than those in control subjects, but the score of musical emotion recognition test did not reach to a significant difference between the subjects groups. Conclusions Our findings found a global impairment of music competences in Alzheimer patients with cognitive and emotional troubles. Nevertheless, the performances in the recognition test of musical emotions showed a trend towards a performance difference. We can suggest that Alzheimer’s disease currently presents an aphaso-agnoso-apractic-amusia syndrome.

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging–Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

In this Review, Salter and Stevens discuss the role of microglia in CNS disorders such as autism, neurodegenerative disorders, Alzheimer’s disease, and chronic pain. There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

Dysfunction in 24-h circadian rhythms is a common occurrence in ageing adults; however, circadian rhythm disruptions are more severe in people with age-related neurodegenerative diseases, including Alzheimer's disease and related dementias, and Parkinson's disease. Manifestations of circadian rhythm disruptions differ according to the type and severity of neurodegenerative disease and, for some patients, occur before the onset of typical clinical symptoms of neurodegeneration. Evidence from preliminary studies suggest that circadian rhythm disruptions, in addition to being a symptom of neurodegeneration, might also be a potential risk factor for developing Alzheimer's disease and related dementias, and Parkinson's disease, although large, longitudinal studies are needed to confirm this relationship. The mechanistic link between circadian rhythms and neurodegeneration is still not fully understood, although proposed underlying pathways include alterations of protein homoeostasis and immune and inflammatory function. While preliminary clinical studies are promising, more studies of circadian rhythm disruptions and its mechanisms are required. Furthermore, clinical trials are needed to determine whether circadian interventions could prevent or delay the onset of neurodegenerative diseases.

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.