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Abstract Background The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer’s disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. Methods Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. Results 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = − 0.22, OR = 0.80, p

Abstract Background Plasma assays for the detection of Alzheimer’s disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer 11C-Deuterium-L-Deprenyl (11C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer’s disease. Methods Twenty-four individuals from families with known Autosomal Dominant Alzheimer’s Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer’s disease were included. The individuals underwent PET imaging with 11C-DED, 11C-PIB and 18F-FDG, as markers of reactive astrogliosis, amyloid-β deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer’s Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging. Results In mutation carriers, plasma GFAP levels and 11C-PIB binding increased, while 11C-DED binding and 18F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with 11C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with 11C-PIB binding and a significant negative correlation with 18F-FDG in the whole sample. The longitudinal levels of 11C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval. Conclusions Plasma GFAP concentration and astrocyte 11C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and 11C-DED binding in Autosomal Dominant and sporadic Alzheimer’s disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased 11C-DED brain binding seems to be an earlier phenomenon in Alzheimer’s disease progression than increased plasma GFAP concentration.

Abstract Plasma biomarkers have shown promising performance in research cohorts in discriminating between different stages of Alzheimer’s disease (AD). Studies in clinical populations are necessary to provide insights on the clinical utility of plasma biomarkers before their implementation in real-world settings. Here we investigated plasma biomarkers (glial fibrillary acidic protein (GFAP), tau phosphorylated at 181 and 231 (pTau181, pTau231), amyloid β (Aβ) 42/40 ratio, neurofilament light) in 126 patients (age = 65 ± 8) who were admitted to the Clinic for Cognitive Disorders, at Karolinska University Hospital. After extensive clinical assessment (including CSF analysis), patients were classified as: mild cognitive impairment (MCI) (n = 75), AD (n = 25), non-AD dementia (n = 16), no dementia (n = 9). To refine the diagnosis, patients were examined with [18F]flutemetamol PET (Aβ-PET). Aβ-PET images were visually rated for positivity/negativity and quantified in Centiloid. Accordingly, 68 Aβ+ and 54 Aβ– patients were identified. Plasma biomarkers were measured using single molecule arrays (SIMOA). Receiver-operated curve (ROC) analyses were performed to detect Aβ-PET+ using the different biomarkers. In the whole cohort, the Aβ-PET centiloid values correlated positively with plasma GFAP, pTau231, pTau181, and negatively with Aβ42/40 ratio. While in the whole MCI group, only GFAP was associated with Aβ PET centiloid. In ROC analyses, among the standalone biomarkers, GFAP showed the highest area under the curve discriminating Aβ+ and Aβ– compared to other plasma biomarkers. The combination of plasma biomarkers via regression was the most predictive of Aβ-PET, especially in the MCI group (prior to PET, n = 75) (sensitivity = 100%, specificity = 82%, negative predictive value = 100%). In our cohort of memory clinic patients (mainly MCI), the combination of plasma biomarkers was sensitive in ruling out Aβ-PET negative individuals, thus suggesting a potential role as rule-out tool in clinical practice.

Abstract Background It is possible to calculate the number of years to the expected clinical onset (YECO) of autosomal-dominant Alzheimer’s disease (adAD). A similar time scale is lacking for sporadic Alzheimer’s disease (sAD). The purpose was to design and validate a time scale in YECO for patients with sAD in relation to CSF and PET biomarkers. Methods Patients diagnosed with Alzheimer’s disease (AD, n = 48) or mild cognitive impairment (MCI, n = 46) participated in the study. They underwent a standardized clinical examination at the Memory clinic, Karolinska University Hospital, Stockholm, Sweden, which included present and previous medical history, laboratory screening, cognitive assessment, CSF biomarkers (Aβ42, total-tau, and p-tau), and an MRI of the brain. They were also assessed with two PET tracers, 11C-Pittsburgh compound B and 18F-fluorodeoxyglucose. Assuming concordance of cognitive decline in sAD and adAD, YECO for these patients was calculated using equations for the relationship between cognitive performance, YECO, and years of education in adAD (Almkvist et al. J Int Neuropsychol Soc 23:195-203, 2017). Results The mean current point of disease progression was 3.2 years after the estimated clinical onset in patients with sAD and 3.4 years prior to the estimated clinical onset in patients with MCI, as indicated by the median YECO from five cognitive tests. The associations between YECO and biomarkers were significant, while those between chronological age and biomarkers were nonsignificant. The estimated disease onset (chronological age minus YECO) followed a bimodal distribution with frequency maxima before (early-onset) and after (late-onset) 65 years of age. The early- and late-onset subgroups differed significantly in biomarkers and cognition, but after control for YECO, this difference disappeared for all except the APOE e4 gene (more frequent in early- than in late-onset). Conclusions A novel time scale in years of disease progression based on cognition was designed and validated in patients with AD using CSF and PET biomarkers. Two early- and late-disease onset subgroups were identified differing with respect to APOE e4.

Abstract Background Subtypes and patterns are defined using tau-PET (tau pathology) and structural MRI (atrophy) in Alzheimer’s disease (AD). However, the relationship between tau pathology and atrophy across these subtypes/patterns remains unclear. Therefore, we investigated the biological association between baseline tau-PET patterns and longitudinal atrophy in the AD continuum; and the methodological characterization of heterogeneity as a continuous phenomenon over the conventional discrete subgrouping. Methods In 366 individuals (amyloid-beta-positive cognitively normal, prodromal AD, AD dementia; amyloid-beta-negative cognitively normal), we examined the association between tau-PET patterns and longitudinal MRI. We modeled tau-PET patterns as a (a) continuous phenomenon with key dimensions: typicality and severity; and (b) discrete phenomenon by categorization into patterns: typical, limbic predominant, cortical predominant and minimal tau. Tau-PET patterns and associated longitudinal atrophy were contextualized within the Amyloid/Tau/Neurodegeneration (A/T/N) biomarker scheme. Results Localization and longitudinal atrophy change vary differentially across different tau-PET patterns in the AD continuum. Atrophy, a downstream event, did not always follow a topography akin to the corresponding tau-PET pattern. Further, heterogeneity as a continuous phenomenon offered an alternative and useful characterization, sharing correspondence with the conventional subgrouping. Tau-PET patterns also show differential A/T/N profiles. Conclusions The site and rate of atrophy are different across the tau-PET patterns. Heterogeneity should be treated as a continuous, not discrete, phenomenon for greater sensitivity. Pattern-specific A/T/N profiles highlight differential multimodal interactions underlying heterogeneity. Therefore, tracking multimodal interactions among biomarkers longitudinally, modeling disease heterogeneity as a continuous phenomenon, and examining heterogeneity across the AD continuum could offer avenues for precision medicine.

Abstract Neuropathology and neuroimaging studies have identified several subtypes of Alzheimer’s disease (AD): hippocampal sparing AD, typical AD, and limbic predominant AD. An unresolved question is whether hippocampal sparing AD cases can present with neurofibrillary tangles (NFT) in association cortices while completely sparing the hippocampus. To address that question, we conducted a systematic review and performed original analyses on tau positron emission tomography (PET) data. We searched EMBASE, PubMed, and Web of Science databases until October 2022. We also implemented several methods for AD subtyping on tau PET to identify hippocampal sparing AD cases. Our findings show that seven out of the eight reviewed neuropathologic studies included cases at Braak stages IV or higher and therefore, could not identify hippocampal sparing cases with NFT completely sparing the hippocampus. In contrast, tau PET did identify AD participants with tracer retention in the association cortex while completely sparing the hippocampus. We conclude that tau PET can identify hippocampal sparing AD cases with NFT completely sparing the hippocampus. Based on the accumulating data, we suggest two possible pathways of tau spread: (1) a canonical pathway with early involvement of transentorhinal cortex and subsequent involvement of limbic regions and association cortices, and (2) a less common pathway that affects association cortices with limbic involvement observed at end stages of the disease or not at all.

BackgroundAmyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and ‘Small and Medium-sized enterprises’ (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population.The AMYPAD studiesIn the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method.ResultsAMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine.Future stepsThe AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

Reactive astrogliosis is an early event in the continuum of Alzheimer’s disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity—more than one subtype of astrocyte involved—in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages.

Abstract Introduction A rapid transition from a clinical‐based classification to a pathology‐based classification of neurodegenerative conditions, largely promoted by the increasing availability of imaging biomarkers, is emerging. The Framework for Innovative Multi‐tracer molecular Brain Imaging, funded by the EU Joint Program ‐ Neurodegenerative Disease Research 2016 “Working Groups for Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration,” aimed at providing a roadmap for the applications of established and new molecular imaging techniques in dementia. Methods We consider current and future implications of adopting a pathology‐based framework for the use and development of positron emission tomography techniques. Results This approach will enhance efforts to understand the multifactorial etiology of Alzheimer's disease and other dementias. Discussion The availability of pathology biomarkers will soon transform clinical and research practice. Crucially, a comprehensive understanding of strengths and caveats of these techniques will promote an informed use to take full advantage of these tools.

Abstract Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer’s Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members. Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating

Abstract Background The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years. Methods Two brothers (A and B), both carriers of the H163Y mutation, were followed between 1995 and 2017. They underwent repeated clinical evaluations, neuropsychological assessments, and cerebrospinal fluid analyses, as well as brain imaging examinations with structural magnetic resonance, [18F]fluorodeoxyglucose positron emission tomography, and [11C]Pittsburgh compound B positron emission tomography. Results Brother A was followed between 44 and 64 years of age. Cognitive symptoms due to Alzheimer’s disease set in at the age of 54. Gradual worsening of symptoms resulted in admittance to a nursing home owing to dependence on others for all activities of daily living. He showed a curvilinear decline in cognitive function on neuropsychological tests, and changes on magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid supported a clinical diagnosis of Alzheimer’s disease. Brother A died at the age of 64 and fulfilled the criteria for definitive Alzheimer’s disease according to neuropathological examination results. Brother B was followed between the ages of 43 and 65 and showed no cognitive deterioration on repeated neuropsychological test occasions. In addition, no biomarker evidence of Alzheimer’s disease pathology was detected, either on imaging examinations or in cerebrospinal fluid. Conclusions The average (SD) age of symptom onset for PSEN1 H163Y is 51 ± 7 years according to previous studies. However, we present a case of a biomarker-verified reduction in penetrance in a mutation carrier who was still symptom-free at the age of 65. This suggests that other genetic, epigenetic, and/or environmental factors modify the onset age.

Positron emission tomography (PET) neuroimaging with the Pittsburgh Compound_B (PiB) is widely used to assess amyloid plaque burden. Standard quantification approaches normalize PiB-PET by mean cerebellar gray matter uptake. Previous studies suggested similar pons and white-matter uptake in Alzheimer's disease (AD) and healthy controls (HC), but lack exhaustive comparison of normalization across the three regions, with data-driven diagnostic classification.We aimed to compare the impact of distinct reference regions in normalization, measured by data-driven statistical analysis, and correlation with cerebrospinal fluid (CSF) amyloid β (Aβ) species concentrations.243 individuals with clinical diagnosis of AD, HC, mild cognitive impairment (MCI) and other dementias, from the Biomarkers for Alzheimer's/Parkinson's Disease (BIOMARKAPD) initiative were included. PiB-PET images and CSF concentrations of Aβ38, Aβ40 and Aβ42 were submitted to classification using support vector machines. Voxel-wise group differences and correlations between normalized PiB-PET images and CSF Aβ concentrations were calculated.Normalization by cerebellar gray matter and pons yielded identical classification accuracy of AD (accuracy-96%, sensitivity-96%, specificity-95%), and significantly higher than Aβ concentrations (best accuracy 91%). Normalization by the white-matter showed decreased extent of statistically significant multivoxel patterns and was the only method not outperforming CSF biomarkers, suggesting statistical inferiority. Aβ38 and Aβ40 correlated negatively with PiB-PET images normalized by the white-matter, corroborating previous observations of correlations with non-AD-specific subcortical changes in white-matter. In general, when using the pons as reference region, higher voxel-wise group differences and stronger correlation with Aβ42, the Aβ42/Aβ40 or Aβ42/Aβ38 ratios were found compared to normalization based on cerebellar gray matter.

Abstract Ligands targeting tau for use with positron emission tomography have rapidly been developed during the past several years, enabling the in vivo study of tau pathology in patients with Alzheimer's disease and related non‐Alzheimer's disease tauopathies. Several candidate compounds have been developed, showing good in vitro characteristics with respect to their ability to bind tau deposits; off‐target binding, however, has also been observed. In this short commentary, we briefly summarize the available in vivo and in vitro evidence pertaining to their off‐target binding and discuss the different approaches that are needed for the future development of tau positron emission tomography tracers.

Abstract Background The aim of this study was to compare the binding properties of several tau positron emission tomography tracers—THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3—head to head in the same human brain tissue. Methods Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer’s disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. Results Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-l-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70–80% and 60–77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. Conclusions THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351.

Alzheimer’s disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid (CSF) and whether levels of these CSF biomarkers correlate with in vivo AChE activity and nicotinic binding sites in the brain assessed by positron emission tomography (PET). Protein concentrations and activities of ChAT and AChE were measured in CSF of 18 patients with mild AD prior to and after 3 months of treatment with galantamine (n = 12) or placebo (n = 6), followed by nine additional months of galantamine treatment in all patients. A Cholinergic index was defined as the ratio of ChAT to AChE in CSF and was evaluated in relation to the in vivo AChE activity, the nicotinic binding sites and different measures of cognition. Besides an expected inhibition of AChE activity, galantamine treatment was accompanied by a mild increase in CSF ChAT activity. Thereby, the Cholinergic index was significantly increased in the Galantamine group (60% ± 14) after 3 months compared to baseline (p < 0.0023) or (p < 0.0004). This index remained high in the Galantamine group compared to baseline (54% ± 11) at 12 months follow-up, while it showed an increase in the Placebo group when they switched to active galantamine treatment (44% ± 14 vs. baseline, 61% ± 14 vs. 3 months, all p-values < 0.05). Furthermore, the in vivo brain AChE activity (assessed by PET) correlated with the CSF Cholinergic index at 12 months (r = 0.98, p < 0.001). The CSF Cholinergic index also correlated with ADAS-Cog and some other neuropsychological tests at 12 months. This is the first study assessing a CSF Cholinergic index in relation to treatment with a cholinesterase inhibitor. The treatment-specific increase in CSF ChAT activity suggests that cholinesterase-inhibitors may also increase the ACh-biosynthesis capacity in the patients. Additional studies are warranted to evaluate the utility of the CSF Cholinergic index as a biomeasure of therapeutic effect in AD.

Background: A fundamental question in Alzheimer’s disease (AD) is whether amyloid-β (Aβ) peptides and their deposition in the brain signify a direct pathological role or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of Aβ, often studied outside the crucial AD characteristics, i.e.: (i) the slow, decades-long disease progression that precedes clinical symptoms; (ii) the link to apolipoprotein-E ε4 allele as major risk factor; (iii) the selective early degeneration of cholinergic neurons. Previous studies, in vitro and cerebrospinal fluid (CSF) only, indicated one possible native function of Aβ peptides is the allosteric modulation of acetylcholine homeostasis, via molecular interactions between Aβ, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in the formation of acetylcholine-hydrolyzing complexes (BAβACs).Methods: Here, by combining sucrose-density gradient fractionation of post-mortem brains and in-house developed sensitive ELISA assays on the obtained fractions, we investigated the presence, levels and molecular interactions between Aβ, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples.Results: We report that both monomeric and oligomeric (homomeric and heteromeric) forms of Aβ peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric Aβ was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of APOE genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble Aβ forms were closely matched between CSF and brain samples. This evinces that the detected Aβ-apolipoprotein-E complexes and BAβACs in CSF most likely originate from the interstitial fluids of the brain.Conclusions: In conclusion, both light homomeric Aβ oligomers and heteromeric Aβ-ApoE and BAβACs are present and readily detectable in the brain, regardless of disease status and APOE4 genotype. Deeper knowledge of the physiological function of Aβ is crucial for better understanding the early pathological events that decades later lead to manifestation of AD.

[18F]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [18F]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R1) parametric images. Nine AD patients and nine controls underwent 90 min [18F]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 ± 4 min for AD patients and in putamen at 20 ± 0 min in controls. Over all regions and subjects, SUVR20–40-1 correlated best with DVR-1, R2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R2 = 0.93 for SUVR20–40-1; R2 = 0.94 for R1). SUVR20–40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R1 with 40 min scan duration. Keywords: Alzheimer's disease, PET, Parametric images, Supervised clustering, Tau imaging

There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor. We show here that there is a 4-fold accumulation of 27OHC in different regions of the cortexes of patients carrying the Swedish amyloid precursor protein (APPswe) 670/671 mutation. The brain levels of sitosterol and campesterol were not significantly different in the AD patients compared with the controls, suggesting that the blood-brain barrier was intact in the AD patients. We conclude that accumulation of 27OHC is likely to be secondary to neurodegeneration, possibly a result of reduced activity of CYP7B1, the neuronal enzyme responsible for metabolism of 27OHC. We discuss the possibility of a vicious circle in the brains of the patients with familial AD whereby neurodegenerative changes cause an accumulation of 27OHC that further accelerates neurodegeneration.

Stimulating regeneration in the brain has the potential to rescue neuronal networks and counteract progressive pathological changes in Alzheimer’s disease (AD). This study investigated whether drugs with different mechanisms of action could enhance neurogenesis and improve cognition in mice receiving human neural stem cell (hNSC) transplants. Six- to nine-month-old AD Tg2576 mice were treated for five weeks with the amyloid-modulatory and neurotrophic drug (+)-phenserine or with the partial α7 nicotinic receptor (nAChR) agonist JN403, combined with bilateral intrahippocampal hNSC transplantation. We observed improved spatial memory in hNSC-transplanted non-drug-treated Tg2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker for newly generated neurons. Treatment with (+)-phenserine did however improve graft survival in the hippocampus. An accumulation of α7 nAChR-expressing astrocytes was observed around the injection site, suggesting their involvement in repair and scarring processes. Interestingly, JN403 treatment decreased the number of α7 nAChR-expressing astrocytes, correlating with a reduction in the number of DCX-positive cells in the dentate gyrus. We conclude that transplanting hNSCs enhances endogenous neurogenesis and prevents further cognitive deterioration in Tg2576 mice, while simultaneous treatments with (+)-phenserine or JN403 result in countertherapeutic effects.

The objective of this study was to investigate the effects of modulating brain amyloid-β (Aβ) levels at different stages of amyloid pathology on synaptic function, inflammatory cell changes and hippocampal neurogenesis, i.e. processes perturbed in Alzheimer's disease (AD). Young (4- to 6-month-old) and older (15- to 18-month-old) APP(SWE) transgenic (Tg2576) mice were treated with the AD candidate drug (+)-phenserine for 16 consecutive days. We found significant reductions in insoluble Aβ1-42 levels in the cortices of both young and older transgenic mice, while significant reductions in soluble Aβ1-42 levels and insoluble Aβ1-40 levels were only found in animals aged 15-18 months. Autoradiography binding with the amyloid ligand Pittsburgh Compound B ((3)H-PIB) revealed a trend for reduced fibrillar Aβ deposition in the brains of older phenserine-treated Tg2576 mice. Phenserine treatment increased cortical synaptophysin levels in younger mice, while decreased interleukin-1β and increased monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels were detected in the cortices of older mice. The reduction in Aβ1-42 levels was associated with an increased number of bromodeoxyuridine-positive proliferating cells in the hippocampi of both young and older Tg2576 mice. To determine whether the increased cell proliferation was accompanied by increased neuronal production, the endogenous early neuronal marker doublecortin (DCX) was examined in the dentate gyrus (DG) using immunohistochemical detection. Although no changes in the total number of DCX(+)-expressing neurons were detected in the DG in Tg2576 mice at either age following (+)-phenserine treatment, dendritic arborization was increased in differentiating neurons in young Tg2576 mice. Collectively, these findings indicate that reducing Aβ1-42 levels in Tg2576 mice at an early pathological stage affects synaptic function by modulating the maturation and plasticity of newborn neurons in the brain. In contrast, lowering Aβ levels in Tg2576 mice when Aβ plaque pathology is prominent mainly alters the levels of proinflammatory cytokines and chemokines.

Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress, toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with the Aβ lowering AD experimental drugs (+)-phenserine and (-)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APP(SWE)), and retained in the presence of Aβ and oxidative stress challenge. (+)-Phenserine, together with its (-) enantiomer as well as its N1- and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).

Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the β-amyloid (Aβ) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric Aβ1-40 and Aβ1-42 (nM-µM concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Aβ1-40 increased the number of functional neurons, whereas oligomeric Aβ1-42 suppressed the number of functional neurons. Interestingly, oligomeric Aβ exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Aβ1-40 and Aβ1-42 induced gliogenesis. These findings indicate that Aβ1-42 oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Aβ.