Alzheimer's disease has an increasing prevalence in the population world-wide, yet current diagnostic methods based on recommended biomarkers are only available in specialized clinics. Due to these circumstances, Alzheimer's disease is usually diagnosed late, which contrasts with the currently available treatment options that are only effective for patients at an early stage. Blood-based biomarkers could fill in the gap of easily accessible and low-cost methods for early diagnosis of the disease. In particular, immune-based blood-biomarkers might be a promising option, given the recently discovered cross-talk of immune cells of the central nervous system with those in the peripheral immune system. With the help of machine learning algorithms and mechanistic modeling approaches, such as agent-based modeling, an in-depth analysis of the simulation of cell dynamics is possible as well as of high-dimensional omics resources indicative of pathway signaling changes. Here, we give a background on advances in research on brain-immune system cross-talk in Alzheimer's disease and review recent machine learning and mechanistic modeling approaches which leverage modern omics technologies for blood-based immune system-related biomarker discovery.

Scientists have identified an immune brain cell unique to humans that gives us higher cognitive abilities over other animals, but what makes us specials also leaves us vulnerable to neurological disorders like schizophrenia, autism and epilepsy, a new study finds. A team of neuroscientists from Yale analyzed cells found in the dorsolateral prefrontal cortex, the region involved in executive control functions, which is shared among humans and primates and narrowed it down to just five found only in the human brain, including an immune cell called microglia. Microglia helps maintain the brain rather than warding off diseases and includes a gene, not present in primates, associated with neuropsychiatric diseases. Lead author Nenad Sestan stated that we can'view the dorsolateral prefrontal cortex as the core component of human identity, but still we don't know what makes this unique in humans and distinguishes us from other primate species.' Scientists have been on a long quest to find what in the brain gives humans higher cognitive abilities over other animals.

Few of life's experiences evoke greater apprehension than a diagnosis of Alzheimer's disease (AD). Virtually unknown to the public until the 1980s, it is alone among the 10 most common fatal diseases of developed nations in lacking a disease-modifying treatment. AD affects people of all ethnicities; in the United States, African Americans have twice the prevalence of European Americans ([ 1 ][1]). The cumulative financial cost to society of late-life dementias (of which AD comprises ∼60%) is estimated to exceed those of heart disease and cancer ([ 2 ][2]). This dismal reality may now be changing. The properties of the key proteins comprising the amyloid plaques [amyloid-β (Aβ)] and neurofibrillary tangles (tau) that define the neuropathology of AD have been identified. Coupled with extensive genetic studies, a sequence of lesion formation in brain networks serving memory and cognition is suggested. Antibodies that target these proteins are in advanced trials, and aducamumab, which clears Aβ, was recently approved, though not without controversy. Through longitudinal analyses of humans with rare, causative mutations in APP (the Aβ precursor protein) and presenilin (the catalytic subunit of γ-secretase, which cleaves APP to generate Aβ), it has become clear that biochemical alterations in the brain begin at least two decades before cognitive symptoms develop. During this long presymptomatic interval, extracellular accumulation of the self-aggregating Aβ42 peptide into initially soluble oligomers and then increasingly large polymers and insoluble fibrils is accompanied by binding of the oligomers to the plasma membranes of microglia, astrocytes, and myriad neurites and synapses (see the figure). Although this amyloid hypothesis of AD is often drawn linearly for simplicity ([ 3 ][3]), many of the changes likely arise in temporal proximity ([ 4 ][4]). Genome-wide association studies in typical late-onset AD (i.e., after age 65) have converged on risk alleles in diverse genes mediating cholesterol and lipid regulation, synaptic network functions, and especially microgliosis (altered microglia) and neuroinflammation. The most potent genetic risk factor is the apolipoprotein E ( APOE ) ϵ4 variant: Heterozygosity raises AD risk 2- to 5-fold, and homozygosity increases it >5- to 10-fold. Its pathogenic mechanism appears to involve decreased glial-mediated clearance of Aβ from the brain's extracellular space, leading to more amyloid in cerebral plaques and microvessels ([ 5 ][5]). In mice, the APOE4 protein can also promote tau-mediated neurodegeneration and glial activation, both in the presence and absence of amyloid ([ 6 ][6]). Some other AD genetic risk factors have likewise been linked to enhanced Aβ deposition and/or the macrophage and microglial reaction to it. Two decades ago, theories about AD pathogenesis seemed divided over the primacy of amyloid versus tau deposition. This false dichotomy has been supplanted by a growing consensus that Aβ aggregation in the brain [indicated by declines in soluble Aβ monomers in cerebrospinal fluid (CSF) and accrual of insoluble plaques seen on amyloid-PET (positron emission tomography) scans] begins early in people destined to develop AD and is followed by glia-mediated inflammation and the accumulation and spread of tau tangles in brain regions that serve cognition ([ 7 ][7], [ 8 ][8]). Rising amounts of extracellular Aβ lead to aggregates, including soluble oligomers, that appear to enhance the accrual of tau tangles and altered neurites beyond the medial temporal lobe, where these lesions are often present in older people without AD. Such tau accumulation and spread in the brain, perhaps via neuron-to-neuron connections, seems necessary for the development of cognitive symptoms in AD ([ 9 ][9]). In APP transgenic mice, deletion of the gene that encodes tau does not alter amyloid plaques but significantly lessens their behavioral consequences. Thus, Aβ oligomerization appears to initiate AD neuropathology, leading to altered tau in neurites and cell bodies as well as microgliosis and blood monocyte infiltration into the brain. The failure to reach primary and secondary outcomes in numerous trials of potentially AD-modifying agents may be explained in one or more ways: failure of the agent to achieve robust and selective target engagement in the brain; initiating treatment at a clinical stage that is too advanced to be effective; underpowered trials; adverse side effects on cognition; and faulty trial execution. The precise reasons differ among the unsuccessful trials to date. But a few recent trials appear to have met their primary endpoints or come close to them and have also achieved some secondary endpoints. ![Figure][10] Drug targets for Alzheimer's disease Alzheimer's disease neuropathology includes extracellular amyloid plaques containing myriad amyloid-β (Aβ) oligomers and intraneuronal tangles containing phosphorylated tau. Microglia and astrocytes become activated, leading to neuroinflammation and the spread of neuropathology. Antibodies to Aβ, administered intravascularly, can clear amyloid plaques. GRAPHIC: KELLIE HOLOSKI/ SCIENCE The clearest evidence of disease modification so far has come from secondary biomarker endpoints, principally a substantial decrease in amyloid plaques over 18 months, as measured by amyloid-PET. For example, this occurred in the two phase 3 trials of aducanumab, an Aβ monoclonal antibody that was approved by the US Food and Drug Administration (FDA) on 7 June 2021. Additional biomarker changes included a decrease in the elevated CSF concentration of phosphorylated tau protein and a reduction of brain tau-PET signal, but these outcomes were only measured in a small minority of aducanumab recipients. Although the marked decrease in amyloid deposits can be viewed as biological evidence of disease modification, this was accompanied by a decidedly mixed outcome on cognitive testing, with one aducanumab trial (EMERGE, NCT02484547) meeting its prespecified primary and secondary endpoints at the highest dose, whereas the other (ENGAGE, NCT02477800) did not achieve them. Although differences in cumulative dosing and uneven trial execution have been offered as explanations for this discrepancy, an FDA advisory committee was unconvinced and voted against approval. Nonetheless, the FDA granted an “accelerated approval,” citing robust amyloid lowering across both trials and an expectation that this should lead to less cognitive decline. It also required that a confirmatory trial be performed while marketing commences. The controversy over aducanumab should be considered in the context of other recent AD immunotherapy trials. A large phase 2 trial of the monoclonal antibody lecanemab, designed to bind and clear Aβ protofibrils and oligomers, achieved its primary and secondary endpoints, including substantial amyloid plaque lowering and significantly less cognitive decline ([ 10 ][11]), and has advanced to phase 3 (NCT03887455). Another Aβ monoclonal antibody, gantenerumab, produced amyloid plaque reductions in phase 2 with less cognitive decline ([ 11 ][12]) and is in phase 3 (NCT03443973). Moreover, the antibody donanemab, which targets a low-abundance but aggregation-prone variant of Aβ with a modified amino terminus containing pyroglutamate-3, was recently shown in a moderate-sized phase 2 trial to markedly lower amyloid burden, accompanied by significant slowing of decline in psychometric tests and daily activities ([ 12 ][13]). Notably, donanemab conferred its cognitive effects in patients with relatively low tau burdens at trial entry (as judged by tau-PET), not in those with higher tau concentrations. Stratifying patients by tau burden was wise and could be used in future anti-Aβ trials. Unfortunately, however, both tau-PET and amyloid-PET only quantify fibrillar deposits, not soluble oligomers that appear to be responsible for neurotoxicity. These four antibodies against Aβ unambiguously clear amyloid deposits from brain regions that are important for cognition, and this effect is accompanied by a variable 20 to 40% slowing of cognitive decline in 18-month trials. Collectively, these data represent the closest the AD field has come to a disease-modifying approach. So far, cognitive benefits are modest, and the challenge of assessing their clinical meaningfulness for patients and caregivers remains. But this challenge has been experienced in other chronic diseases, e.g., the controversy over the initial limited benefits of the antiretroviral drug zidovudine for HIV and AIDS when it was first approved ([ 13 ][14]). Disease-modifying agents for AD are expected to slow cognitive decline more effectively the longer—and earlier—they are given. Indeed, treating amyloid-positive individuals in the presymptomatic period is more likely to be efficacious. In mouse models of AD, early treatment with aducanumab reduced Aβ deposition and downstream neuropathology later in life. Gaining real-world experience with a first, albeit modest, treatment should encourage development of more potent second-generation agents. Overnight, managing an untreatable, ultimately fatal disease has been converted into the complex challenge of offering treatment plans to myriad AD patients. Surprisingly, the indication on the aducanumab label initially read “Alzheimer's disease,” but after facing criticism, the FDA soon changed that to mild cognitive impairment and mild AD, mirroring the entry criteria for the phase 3 trials. AD clinicians will likely also require evidence of amyloid pathology. The latter can be established through amyloid-PET imaging, but this is not widely accessible, so CSF profiling will be relied upon to document the characteristic decrease in Aβ42 monomers and increase in phospho-tau that has long been used to confirm AD. A special challenge to clinicians will be considering amyloid-positive patients who are more impaired than those in the trials for treatment. AD practices offering aducanumab should establish transparent guidelines for patient eligibility, hopefully with limited variation among sites. The drug label specifies dose and infusion intervals, but criteria for how long to treat patients will evolve as any slowing of cognitive decline becomes apparent. The practical challenges of an infusible therapeutic will lead to subcutaneous formulations that can be administered at home. Parenthetically, the slower-release subcutaneous route may lessen the occurrence of the key adverse effect of antibodies against Aβ: focal cerebral edema (ARIA-E), which is self-limited and asymptomatic in three-quarters of those who develop it and may be a sign of amyloid clearance or an inflammatory response at local vessels. Occasional microhemorrhages (ARIA-H) developed in a minority of those aducanumab recipients who had ARIA-E, and these appeared to be asymptomatic. The initial price of aducanumab (∼$56,000/year) is very high and will need to be covered by insurance or national health care providers. These and other challenges in the march to implement the first approved AD therapeutic require thoughtful planning and resourcefulness, but this is just the process that patients and caregivers have long awaited. A key advance has been the emergence of blood tests that can detect AD neuropathology. Plasma assays for certain fragments ([ 14 ][15]) and phospho-epitopes ([ 15 ][16]) of tau appear particularly promising, because tau alteration follows Aβ accumulation in those who develop AD symptoms. Comparison of various tau and Aβ plasma assays for their sensitivity in diagnosing AD and monitoring progression is needed. Accelerating the development of plasma biomarkers is critical to meet the challenge of screening innumerable patients globally for eligibility for AD-modifying agents. Additional therapeutic approaches are crucial. Among small-molecule approaches, β-secretase inhibitors have been thwarted by mechanism-based side effects, although lower doses are being considered. An understudied class is the γ-secretase modulators that allosterically alter the conformation of presenilin and thereby shift APP processing from longer, amyloidogenic forms (Aβ42, Aβ43) to shorter, anti-amyloidogenic forms (Aβ37, Aβ38). Beyond Aβ, effort is focused on slowing tau accumulation, e.g., by immunotherapy or antisense oligonucleotides. Modulating the pathological responses of macrophages and microglia is of great interest, given the strong genetic evidence for their involvement in AD. Nonpharmacological approaches toward preventing AD must also be pursued, including exercise, sleep hygiene, a Mediterranean diet, and intellectual and social enrichment. For many chronic diseases, the initial therapeutic compounds have limited efficacy and are often steadily replaced by more effective drugs. The emerging immunotherapeutics slow the AD biological process but confer modest clinical benefit. The approval of aducanumab may provide a proof of concept that can be rapidly improved upon. It may also enable combination treatments, as is typical in chronic diseases. In therapeutics, as in life, one must walk before one can run. 1. [↵][17]1. K. B. Rajan, 2. J. Weuve, 3. L. L. Barnes, 4. R. S. Wilson, 5. D. A. Evans , Alzheimers Dement. 15, 1 (2019). [OpenUrl][18][CrossRef][19] 2. [↵][20]1. M. D. Hurd, 2. P. Martorell, 3. A. Delavande, 4. K. J. Mullen, 5. K. M. Langa , N. Engl. J. Med. 368, 1326 (2013). [OpenUrl][21][CrossRef][22][PubMed][23][Web of Science][24] 3. [↵][25]1. D. 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In the year just past, Alzheimer's researchers, families, and stakeholders felt renewed hope that new treatments might be within grasp. While the Lazarus story of aducanumab may or may not be enough for FDA approval this year, data from its Phase 3 program solidified a broader signal across four different anti-amyloid antibodies that amyloid can be removed from the brain and that maybe--just maybe--this will also benefit cognition and function if given early at a sufficient dose. The prospect that the amyloid hypothesis is druggable, alone, was enough to re-energize the field. The hope that further trials to define the best doses, patient groups, and treatment regimens will eventually pay off was cause for even more enthusiasm. A boost in funding announced as the U.S. Congress headed for its holiday break also gave cause for celebration going into 2020, though the funding picture is less rosy in other countries. The NIH budget for AD research now stands at $2.8 billion, a $350 million ...

Brain development is a remarkable self-organization process in which cells proliferate, differentiate, migrate, and wire to form functional neural circuits. In humans, this process takes place over a long fetal phase and continues into the postnatal period, but it is largely inaccessible for direct, functional investigation at a cellular level. Therefore, the features that make the human central nervous system unique and the sequence of molecular and cellular events underlying brain disorders remain largely uncharted. Human pluripotent stem (hPS) cells, including those obtained by reprogramming somatic cells, have the ability to self-organize and differentiate when grown in three-dimensional (3D) aggregates rather than in direct contact with a flat plastic surface (1). Such 3D neural cultures, also known as organoids and organ spheroids, recapitulate many aspects of human brain development in vitro (1) and have the potential to accelerate progress in human neurobiology.

In the first years of her career in brain research, Beth Stevens thought of microglia with annoyance if she thought of them at all. When she gazed into a microscope and saw these ubiquitous cells with their spidery tentacles, she did what most neuroscientists had been doing for generations: she looked right past them and focused on the rest of the brain tissue, just as you might look through specks of dirt on a windshield. "What are they doing there?" she thought. Stevens never would have guessed that just a few years later, she would be running a laboratory at Harvard and Boston's Children's Hospital devoted to the study of these obscure little clumps. Or that she would be arguing in the world's top scientific journals that microglia might hold the key to understanding not just normal brain development but also what causes Alzheimer's, Huntington's, autism, schizophrenia, and other intractable brain disorders. Microglia are part of a larger class of cells--known collectively as glia--that carry out an array of functions in the brain, guiding its development and serving as its immune system by gobbling up diseased or damaged cells and carting away debris. Along with her frequent collaborator and mentor, Stanford biologist Ben Barres, and a growing cadre of other scientists, Stevens, 45, is showing that these long-overlooked cells are more than mere support workers for the neurons they surround.