The successful candidate will work on the Synapsis-foundation funded research project “Real-life activity tracking as pre-screening tool for early stages of Alzheimer disease”. The aim of the project is to investigate whether real-life activity measures, derived from wearable technology (e.g. GPS and accelerometer data), are sensitive to identify early stages of Alzheimer’s disease. Further, we aim to provide evidence that these real-life activity measures are associated with current AD biomarkers (i.e. high Amyloid level and brain atrophy). The student will be expected to disseminate study results in peer reviewed journals, and to supervise Master’s students. The candidate will work in the team of Prof. Nicolas Langer, who is also part of the Neuroscience Center Zurich (ZNZ) (https://www.neuroscience.uzh.ch/en.html), which offers a renowned international PhD programme in Neuroscience. The candidate will work closely with the Institute for Regenerative Medicine (https://www.irem.uzh.ch/en.html), Geographic Information Systems (https://www.geo.uzh.ch/en/units/gis.html), University Research Priority Programme from the University of Zurich “Dynamics of Healthy Aging” (https://www.dynage.uzh.ch/en.html), and the Department of Computer Science at the ETH Zurich (https://www.systems.ethz.ch/). For further information, please visit: https://tinyurl.com/yvyjkvv9

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material." https://doi.org/10.1016/j.cell.2022.09.030

Alterations in sleep are hallmarks of the ageing process and emerges as risk factors for Alzheimer’s disease (AD). While the fine-tuned coalescence of sleep microstructure elements may influence age-related cognitive trajectories, its association with AD-related processes is not fully established. We investigated whether sleep arousals and the coupling of spindles and slow waves, key elements of sleep microstructure, are associated with early amyloid-beta (Aβ) brain burden, hallmark of AD neuropathology, and cognitive change at 2 years in 100 late-midlife healthy individuals. We first found that arousals interrupting sleep continuity were positively linked to Aβ burden, while, by contrast, the more prevalent arousals upholding sleep continuity were associated with lower Aβ burden and better cognition. We further found that young-like co-occurrence of spindles and slow-depolarisation slow waves is associated to lower burden of Aβ over the medial prefrontal cortex and is predictive of memory decline at 2-year follow-up. We provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. We further show the altered coupling of sleep microstructure elements that are key to its mnesic functions may contribute to poorer brain and cognitive trajectories. The presentation will end with preliminary data show that activity of the locus coeruleus, essential to sleep and showing some of the earliest signs of AD-related pathological processes, is associated with sleep quality. These preliminary findings are the first of a project ailed at link sleep and AD through the locus coeruleus.

Identifying biomarkers that predict current and future cognition may improve estimates of Alzheimer’s disease risk among cognitively unimpaired older adults (CU). In vivo measures of amyloid and tau protein burden and task-based functional MRI measures of core memory mechanisms, such as the strength of cortical reinstatement during remembering, have each been linked to individual differences in memory in CU. This study assesses whether combining CSF biomarkers with fMRI indices of cortical reinstatement improves estimation of memory function in CU, assayed using three unique tests of hippocampal-dependent memory. Participants were 158 CU (90F, aged 60-88 years, CDR=0) enrolled in the Stanford Aging and Memory Study (SAMS). Cortical reinstatement was quantified using multivoxel pattern analysis of fMRI data collected during completion of a paired associate cued recall task. Memory was assayed by associative cued recall, a delayed recall composite, and a mnemonic discrimination task that involved discrimination between studied ‘target’ objects, novel ‘foil’ objects, and perceptually similar ‘lure’ objects. CSF Aβ42, Aβ40, and p-tau181 were measured with the automated Lumipulse G system (N=115). Regression analyses examined cross-sectional relationships between memory performance in each task and a) the strength of cortical reinstatement in the Default Network (comprised of posterior medial, medial frontal, and lateral parietal regions) during associative cued recall and b) CSF Aβ42/Aβ40 and p-tau181, controlling for age, sex, and education. For mnemonic discrimination, linear mixed effects models were used to examine the relationship between discrimination (d’) and each predictor as a function of target-lure similarity. Stronger cortical reinstatement was associated with better performance across all three memory assays. Age and higher CSF p-tau181 were each associated with poorer associative memory and a diminished improvement in mnemonic discrimination as target-lure similarity decreased. When combined in a single model, CSF p-tau181 and Default Network reinstatement strength, but not age, explained unique variance in associative memory and mnemonic discrimination performance, outperforming the single-modality models. Combining fMRI measures of core memory functions with protein biomarkers of Alzheimer’s disease significantly improved prediction of individual differences in memory performance in CU. Leveraging multimodal biomarkers may enhance future prediction of risk for cognitive decline.

Dementia with Lewy bodies (DLB) is a synucleinopathy but more than half of patients with DLB also have varying degrees of tau and amyloid-β co-pathology. Identifying and tracking the pathologic heterogeneity of DLB with multi-modal biomarkers is critical for the design of clinical trials that target each pathology early in the disease at a time when prevention or delaying the transition to dementia is possible. Furthermore, longitudinal evaluation of multi-modal biomarkers contributes to our understanding of the type and extent of the pathologic progression and serves to characterize the temporal emergence of the associated phenotypic expression. This talk will focus on the utility of multi-modal imaging in DLB.

Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.

Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here, we analysed the metabolomic changes in flies over-expressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B, are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes, such as PARPs are potential therapies for Alzheimer’s disease.

Age-associated dementias are neuropathologically characterized by the identification of hallmark intracellular and extracellular deposition of proteins, i.e., hyperphosphorylated-tau, amyloid-β, and α-synuclein, or cerebrovascular lesions. The neuropathological assessment and staging of these pathologies allows for a diagnosis of a distinct disease, e.g., amyloid-β plaques and hyperphosphorylated tau pathology in Alzheimer's disease. Neuropathological assessment in large scale cohorts, such as the UK’s Brains for Dementia Research (BDR) programme, has made it increasingly clear that the ageing brain is characterized by the presence of multiple age-associated pathologies rather than just the ‘pure’ hallmark lesion as commonly perceived. These additional pathologies can range from low/intermediate levels, that are assumed to have little if any clinical significance, to a full-blown mixed disease where there is the presence of two distinct diseases. In our recent paper (McAleese et al. 2021 Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia, https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12291, Alzheimer's & Dementia), using the BDR cohort, we investigated the frequency of multimorbidity and specifically investigated the impact of additional low-level pathology on cognition. In this study, of 670 donated post-mortem brains, we found that almost 70% of cases exhibited multimorbidity and only 22% were considered a pure diagnosis. Importantly, no case of Lewy Body dementia or vascular dementia was considered pure. A key finding is that the presence of low levels of additional pathology increased the likelihood of having mild dementia vs mild cognitive impairment by almost 20-fold, indicating low levels of additional pathology do impact the clinical progression of a distinct disease. Given the high prevalence and the potential clinical impact, cerebral multimorbidity should be at the forefront of consideration in dementia research.

The spatial patterning of each neurodegenerative disease relates closely to a distinct structural and functional network in the human brain. This talk will mainly describe how brain network-sensitive neuroimaging methods such as resting-state fMRI and diffusion MRI can shed light on brain network dysfunctions associated with pathology and cognitive decline from preclinical to clinical dementia. I will first present our findings from two independent datasets on how amyloid and cerebrovascular pathology influence brain functional networks cross-sectionally and longitudinally in individuals with mild cognitive impairment and dementia. Evidence on longitudinal functional network organizational changes in healthy older adults and the influence of APOE genotype will be presented. In the second part, I will describe our work on how different pathology influences brain structural network and white matter microstructure. I will also touch on some new data on how brain network integrity contributes to behavior and disease progression using multivariate or machine learning approaches. These findings underscore the importance of studying selective brain network vulnerability instead of individual region and longitudinal design. Further developed with machine learning approaches, multimodal network-specific imaging signatures will help reveal disease mechanisms and facilitate early detection, prognosis and treatment search of neuropsychiatric disorders.

Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].

Alzheimer's disease (AD) is the most common cause of dementia, and its health and socioeconomic burdens are of major concern. Presently, a definite diagnosis of AD is established by examining brain tissue after death. These examinations focus on two major pathological hallmarks of AD in the brain: (i) amyloid plaques consisting of aggregated amyloid beta (Aβ) peptides and (ii) neurofibrillary tangles made of abnormally phosphorylated tau protein. In living individuals, AD diagnosis relies on two main approaches: (i) brain imaging of tau tangles and Aβ plaques using a technique called positron emission tomography (PET) and (ii) measuring biochemical changes in tau (including phosphorylated tau at threonine-181 [p-tau181]) and the Aβ42 peptide metabolized into CSF. Unlike Aβ42, CSF p-tau181 is highly specific for AD but its usability is restricted by the need of a lumbar puncture. Moreover, PET imaging is expensive and only available in specialised medical centres. Due to these shortcomings, a simple blood test that can detect disease-related changes in the brain is a high priority for AD research, clinical care and therapy testing. In this webinar, I will discuss the discovery of p-tau biomarkers in blood and the biochemistry of how these markers differ from those found in CSF. Furthermore, I will critically review the performance of blood p-tau biomarkers across the AD pathological process and how they associate with and predict Aβ and tau pathophysiological and neuropathological changes. Furthermore, I will evaluate the potential advantages, challenges and context of use of blood p-tau in clinical practice, therapeutic trials and population screening.

Tara Spires-Jones’ research focuses on the mechanisms and reversibility of neurodegeneration in Alzheimer’s disease, other degenerative brain diseases, and ageing.  The objective of her research group is to understand why synapses and neurons become dysfunctional and die in these diseases in order to develop effective therapeutic strategies. Her work has shown that soluble forms of the pathological proteins amyloid beta and tau contribute to synapse degeneration, and that lowering levels of these proteins can prevent and reverse phenotypes in model systems. Further, she has pioneered high-resolution imaging techniques in human post-mortem brain and found evidence that these proteins accumulate in synapses in human disease.

Cross-sectional and longitudinal multimodal brain imaging studies using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided detailed insight into the pathophysiological progression of Alzheimer’s disease. It starts at an asymptomatic stage with widespread gradual accumulation of beta-amyloid and spread of pathological tau deposits. Subsequently changes of functional connectivity and glucose metabolism associated with mild cognitive impairment and brain atrophy may develop. However, the rate of progression to a symptomatic stage and ultimately dementia varies considerably between individuals. Mathematical models have been developed to describe disease progression, which may be used to identify markers that determine the current stage and likely rate of progression. Both are very important to improve the efficacy of clinical trials. In this lecture, I will provide an overview on current research and future perspectives in this area.

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s disease called “Logopenic Progressive Aphasia”, which presents with temporo-parietal atrophy yet relative sparing of hippocampal circuitry. Siddharth will discuss how, despite the unusual anatomical basis underlying this AD variant, degeneration of the angular gyrus in the left inferior parietal lobule contributes to memory deficits similar to those of typical amnesic Alzheimer’s disease. Christiana’s abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes severe deterioration of memory, cognition, behavior, and the ability to perform daily activities. The disease is characterized by the accumulation of two proteins in fibrillar form; Amyloid-β forms fibrils that accumulate as extracellular plaques while tau fibrils form intracellular tangles. Here we aim to translate findings from a commonly used AD mouse model to AD patients. Here we initiate and chronically inhibit neuropathology in lateral entorhinal cortex (LEC) layer two neurons in an AD mouse model. This is achieved by over-expressing P301L tau virally and chronically activating hM4Di DREADDs intracranially using the ligand dechloroclozapine. Biomarkers in cerebrospinal fluid (CSF) is measured longitudinally in the model using microdialysis, and we use this same system to intracranially administer drugs aimed at halting AD-related neuropathology. The models are additionally tested in a novel contextual memory task. Preliminary findings indicate that viral injections of P301L tau into LEC layer two reveal direct projections between this region and the outer molecular layer of dentate gyrus and the rest of hippocampus. Additionally, phosphorylated tau co-localize with ‘starter cells’ and appear to spread from the injection site. Preliminary microdialysis results suggest that the concentrations of CSF amyloid-β and tau proteins mirror changes observed along the disease cascade in patients. The disease-modifying drugs appear to halt neuropathological development in this preclincial model. These findings will lead to a novel platform for translational AD research, linking the extensive research done in rodents to clinical applications. Siddharth’s abstract: A distributed brain network supports our ability to remember past events. The parietal cortex is a critical member of this network, yet, its exact contributions to episodic remembering remain unclear. Neurodegenerative syndromes affecting the posterior neocortex offer a unique opportunity to understand the importance and role of parietal regions to episodic memory. In this talk, I introduce and explore the rare neurodegenerative syndrome of Logopenic Progressive Aphasia (LPA), an aphasic variant of Alzheimer’s disease presenting with early, left-lateralized temporo-parietal atrophy, amidst relatively spared hippocampal integrity. I then discuss two key studies from my recent Ph.D. work showcasing pervasive episodic and autobiographical memory dysfunction in LPA, to a level comparable to typical, amnesic Alzheimer’s disease. Using multimodal neuroimaging, I demonstrate how degeneration of the angular gyrus in the left inferior parietal lobule, and its structural connections to the hippocampus, contribute to amnesic profiles in this syndrome. I finally evaluate these findings in the context of memory profiles in other posterior cortical neurodegenerative syndromes as well as recent theoretical models underscoring the importance of the parietal cortex in the integration and representation of episodic contextual information.

Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.

The amyloid cascade hypothesis for Alzheimer disease ((Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Selkoe, 1991), updated in (Karran et al., 2011) provides a linear model for the pathogenesis of AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggregation or Aβ oligomer formation could not be convincingly demonstrated until now. Indeed, many questions (e.g. what causes Aβ toxicity, what is the relation between Aβ and Tau pathology, what causes neuronal death, why is amyloid deposition not correlated with dementia etc…) were already raised when the amyloid hypothesis was conceived 25 years ago. These questions remain in essence unanswered. It seems that the old paradigm is not tenable: the amyloid cascade is too linear, too neurocentric, and does not take into account the long time lag between the biochemical phase i.e. the appearance of amyloid plaques and neuronal tangles and the ultimate clinical phase, i.e. the manifestation of dementia. The pathways linking these two phases must be complex and tortuous. We have called this the cellular phase of AD (De Strooper and Karran, 2016) to suggest that a long period of action and reaction involving neurons, neuronal circuitry but also microglia, astroglia, oligodendrocytes, and the vasculature underlies the disease. In fact it is this long disease process that should be studied in the coming years. While microglia are part of this process, they should not be considered as the only component of the cellular phase. We expect that further clinical investigations and novel tools will allow to diagnose the effects of the cellular changes in the brain and provide clinical signs for this so called preclinical or prodromal AD. Furthermore the better understanding of this phase will lead to completely novel drug targets and treatments and will lead to an era where patients will receive an appropriate therapy according to their clinical stage. In this view anti-amyloid therapy is probably only effective and useful in the very early stage of the disease and AD does no longer equal to dementia. We will discuss in our talk how single cell technology and transplantation of human iPS cells into mouse brain allow to start to map in a systematic way the cellular phase of Alzheimer’s Disease.