Alzheimer's Trials Research Articles

GAP rater certification program transforms the rater certification process

AbstractBackgroundRater certification is a key component in successful study startup and Alzheimer’s disease (AD) trial execution, but the current certification process is time consuming and redundant across trials. Existing rater training has not changed substantially in years, has become more complex, and offers raters limited opportunity to enhance cognitive assessment skills.MethodThe GAP Rater Certification Program is designed to transform rater certification. The GAP‐Net Rater Certification Matrix defines scale‐specific standards for proven, experienced, and developing raters (Figure 1). Standards are based on education, experience, previous certification, and demonstration of mastery. Rater training and certification follow defined processes and include the option to recertify after one year (Figure 2). Training is appropriately targeted to the rater’s level of experience and effectively tests the rater’s knowledge of each cognitive assessment. Rater qualifications maintained in a single database eliminate the need to complete Rater Experience Surveys (RES) on every trial.ResultThe GAP Rater Certification Program has been delivered to over 50 raters across 20 GAP‐Net sites. GAP is surveying participating raters and will share results of the Program’s implementation and impact. Initial results indicate the following: GAP’s Demonstration of Mastery provides effective ‘applied training’ by assessing rater’s knowledge of scales and administration competency and also providing a platform to share strategies that deliver meaningful outcomes. A rater certification process across AD trials is highly likely to save time during the qualification process and accelerate study startup. Expanding the Program to new / developing raters will increase the pool of raters at sites and eliminate potential startup bottlenecks. The applied training is appropriately targeted to rater’s level of experience. Redundant training will be minimized. One model predicts 84 hours would be saved using the Program over 6 trials for every site. GAP Rater Certification Database (InvestigatorSpace) facilitates information collection and sharing and increases efficiency during site selection and study startup.ConclusionThe GAP Rater Certification Program removes redundancies in study startup and incorporates targeted training and Demonstration of Mastery designed to ensure quality raters and study data. Further enhancements will continue to focus on improving efficiencies and precision in rater qualification.

Assessing the relationship between cognitive dysfunction and brain atrophy in Alzheimer's disease

AbstractBackgroundBrain atrophy can be reliably measured through volumetric analysis of structural MRI and is a valid biomarker of neurodegeneration in Alzheimer’s disease (AD) pathology1. The Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog12) is a neuropsychological test designed to assess the level of cognitive dysfunction in AD within cognitive domains such as memory2. This study aimed to assess the relationship between brain atrophy and ADAS‐Cog12 score in patients with AD.Methods172 patients with mild‐to‐moderate Alzheimer’s disease (Age range 51‐58, Mean=71, SD=+/‐8) underwent a T1‐weighted MPRAGE MRI scan and neuropsychological testing using the ADAS‐Cog12. Volumetric MRI measures extracted using Freesurfer for the hippocampus, medial temporal lobe, temporal lobe and total grey matter were individually correlated with each patient’s ADAS‐Cog12 score using Pearson’s correlation coefficient following removal of outliers in each data set (+/‐ 2SD from the mean).ResultsIncreasing ADAS‐Cog12 score was significantly correlated with decreasing volume of the hippocampus (r=‐0.280, p<0.001), medial temporal lobe (r=‐0.246, p=0.001), temporal lobe (r=‐0.300, p<0.001) and total grey matter (r=‐0.236, p=0.002).ConclusionsThis study demonstrated that the ADAS‐Cog12 correlated with AD‐related regional brain atrophy, suggesting that ADAS‐Cog could be used as an outcome measure in AD trials and reflects underlying neuronal damage along with cognitive function.

Engaging the Down syndrome community: Overcoming barriers to clinical trial recruitment

AbstractBackgroundWith improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly with a life expectancy of >55 years of age compared to just 25 year of age in the 1980’s. It is estimated that there are 210 K people with DS in the USA and 40% are over the age of 30 years old.1 However, with longevity comes a very high risk of Alzheimer’s disease (AD). It is estimated that by age 55–60 years at least 70% will develop Alzheimer’s dementia.2, 3 Despite the Alzheimer’s crisis facing the DS population, very few people with DS have participated in clinical trials.MethodThis talk will explore common barriers and potential solutions to the recruitment of adults with DS. DS organizations, such as LuMind IDSC, continuously work to gain the trust of participants and their families in ethical research which is a key component for successful recruitment.ResultThe NIH, LuMind IDSC, and other DS advocacy organizations are developing tools to engage, support and educate adults with DS and their caregivers about the risk of AD to help solve the issue of DS recruitment into trials.ConclusionUnique recruitment strategies are needed for successful enrollment of adults with DS in AD trials.

Accelerated forgetting is sensitive to β‐amyloid pathology and cerebral atrophy in cognitively normal 72‐year‐olds

AbstractBackgroundAccelerated Forgetting (AF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). AF has been observed in presymptomatic carriers of mutations causing familial Alzheimer’s disease (AD) (doi:10.1016/S1474‐4422(17)30434‐9). To our knowledge, no studies have investigated whether AF is sensitive to preclinical AD pathology in cognitively‐normal older adults.MethodParticipants in the Insight 46 study, a sub‐study of the British 1946 birth cohort, completed baseline cognitive and neuroimaging assessments at age 69‐71. For the follow‐up visits (∼29 months later), we complemented the clinic visit assessments of Complex Figure Drawing and the Face‐Name test (FNAME‐12) with a 7‐day delay version administered by telephone (Figure 1). AF scores were calculated as the percentage of material retained after 7 days, relative to retention after 30 minutes. Cerebral atrophy between baseline and follow‐up was quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status at baseline (positive / negative) was determined from 18F‐Florbetapir‐PET.As follow‐up assessments are still underway, preliminary interim analyses have been conducted based on 195 cognitively‐normal individuals with complete neuroimaging data (see Table 1 for characteristics). Multivariable regression models were used to investigate the effects of β‐amyloid status and BBSI on AF, and to explore interactions between these two predictors, adjusting for potential confounders including prospectively‐collected measures of childhood cognitive ability and education.ResultDespite no statistically‐significant differences after a 30‐minute delay, β‐amyloid‐positive participants retained a lower percentage of Complex Figure material over 7 days (71.8% vs. 80.7%, p=0.010) and a trend to a lower percentage of FNAME‐12 material (69.4% vs. 77.2%, p = 0.083) (Table 2, Figure 2). Higher education predicted better retention of the Complex Figure. Among β‐amyloid‐positive participants only, greater cerebral atrophy predicted poorer retention of the Complex Figure (Table 2, Figure 3).ConclusionThese results provide novel evidence of AF in cognitively‐normal β‐amyloid‐positive 72‐year‐olds. AF may be a sensitive outcome measure for therapeutic trials in preclinical AD, as it may reveal subtle memory decline at an earlier stage than traditional assessments. The interaction between β‐amyloid pathology and cerebral atrophy merits longitudinal investigation.

Neurofilament light chain in psychiatric and neurodegenerative disorders: A ‘c‐reactive protein’ for the brain?

AbstractBackgroundAccurate diagnosis of a neurodegenerative disorder, in particular distinguishing primary psychiatric from neurological disorders, can be challenging. There is a need for biomarkers to reduce the diagnostic odyssey and improve outcomes. Neurofilament light (NfL) has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of disorders. Our ‘Biomarkers in Younger Onset Neurocognitive Disorders’ (BeYOND) and ‘Markers in Neuropsychiatric Disorders’ (MiND) studies aim to build on our pilot study (Eratne et al, 2019, ANZJP), to explore the diagnostic and broader utility of plasma and cerebrospinal fluid (CSF) NfL, in a broad range of psychiatric and neurodegenerative/neurological disorders.MethodThese studies assess plasma and/or CSF NfL concentrations using Simoa technology in a broad range of cohorts, including: patients assessed for neurocognitive/psychiatric symptoms at Neuropsychiatry and Melbourne Young Onset Dementia service; Australian National Creutzfeldt‐Jakob Disease Registry (ANCJDR); treatment trials in Alzheimer’s disease (AD) and frontotemporal dementia (FTD); treatment‐resistant schizophrenia (TRS) biobank; FTD; autoimmune encephalitis; Niemann‐Pick Type C; epilepsy; and patients in primary care with cognitive or psychiatric symptoms. The most recent primary consensus diagnosis informed by established diagnostic criteria is categorised: psychiatric disorder (PSY), neurodegenerative/neurological disorder (NND), or healthy controls (HC).ResultAs of January 2020, data from 485 patients/participants (NND:325, PSY:100, HC:60) demonstrates significantly elevated plasma and/or CSF NfL levels in a broad range of NND compared to a broad range of PSY, and HC, with areas under the curve of>0.90 and sensitivity and specificity>90%: improving on results from our pilot study. As recruitment, sample analysis, data collection is ongoing, more detailed, up to date results will be presented from over 600 patients/participants, including in‐depth findings from TRS, ANCJDR, AD and FTD treatment trials, and general practice cohorts.ConclusionNfL shows great promise as a diagnostic test to assist with the common, but challenging diagnostic dilemma of distinguishing psychiatric from neurodegenerative and neurological disorders. A significantly elevated NfL concentration in a patient with a psychiatric diagnosis should prompt consideration of neurological or neurodegenerative differentials. Plasma NfL could dramatically alter clinical care of patients with neurological/neurodegenerative and psychiatric disorders, improving outcomes for patients, their families, the healthcare system, and clinical trials.

Behavioural symptoms in Alzheimer’s disease are associated with white matter lesions (WML) volume and are independent of atrophy and hypometabolism

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) are highly prevalent in Alzheimer’s disease (AD) and associated with adverse outcomes. There is increasing interest in identifying the risk factors for developing BPSD among AD patients. However, the pathophysiological mechanisms underlying BPSD remain poorly understood. Here we evaluated whether BPSD are associated with WMLs volume, brain atrophy and brain metabolism in AD subjects.Method130 AD subjects form the Evaluating Liraglutide in Alzheimer's Disease (ELAD) trial (NCT01843075) were enrolled. The presence of BPSD was evaluated with the Neuropsychiatric Inventory Questionnaire (NPI). FLAIR and T1‐weighted imaging were performed on 3T scans. WMLs was determined on FLAIR images using the Lesion Segmentation Tool (LST) in SPM12. Hippocampal and grey matter volumes were estimated using the FreeSurfer analysis on T1 MRI. Glucose metabolism (rCMRGlc) was calculated by parametric images generated using spectral analysis with an arterial plasma input function.ResultIn this AD population, NPI scores were correlated with WMLs volume (Spearman's rho=.197, p=.02), also after correcting for age. NPI scores were not correlated to hippocampal or grey matter volume and to rCMRGlc in frontal, temporal, parietal or occipital lobes. When looking at the NPI sub‐scores, WMLs volume was significantly associated with agitation/aggression (Spearman's rho=.177, p=.05) and with appetite and eating disorders (Spearman's rho=.233, p=.00).ConclusionIn this study of a clinical AD population, BPSD were associated with WMLs but not with brain atrophy and hypometabolism. This suggests that vascular changes and the prevention of vascular risk factors might play an important role in reducing the impact of BPSD in AD dementia.

Gene‐ and age‐informed enrichment method for preclinical Alzheimer’s disease trials: Approach and estimated cost savings

AbstractBackgroundElevated β‐amyloid (Aβ) is used to enroll clinically normal (CN) individuals in preclinical Alzheimer’s disease (AD) trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment of these individuals while reducing costs. We hypothesized that by combining a polygenic hazard score (PHS) and age‐specific risk for AD we could predict elevated Aβ in CN individuals.MethodAD incidence rates and each participant’s PHS were used to adjust the participant’s chronological age based on protective or deleterious genetic factors, thus creating an ADAge. An individual’s ADAge is defined as the chronological age at which there is equivalent AD risk in the population. Meng’s test was used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to assess whether the ADAge was more correlated with Aβ than was chronological age. An ADAge cutpoint was chosen to optimally predict Aβ positivity among 306 CN participants from the ADNI and applied to 1000 bootstrap samples of an independent validation cohort of 80 CN participants from the UC San Diego Shiley‐Marcos Alzheimer’s Disease Research Center. The differences in means between samples enrolled by each strategy (ADAge enrichment vs no enrichment) were calculated to determine the efficiency of ADAge‐informed Aβ screening for preclinical AD trials as well as to determine the impact of ADAge enrichment on trial population demographics. The screening cost for enrolling 1000 Aβ+ CN participants in a clinical trial using each enrollment strategy was compared.ResultCompared to chronological age, ADAge was more correlated with Florbetapir SUVR in the ADNI cohort (p < .001). In the validation cohort, the ADAge‐enriched sample had a higher proportion of individuals with elevated Aβ (difference[95% CI] 0.19[0.07–0.33]) than the unenriched sample. The ADAge‐enriched sample was older than the unenriched sample (difference 3.00[0.94 – 5.22]). However, the samples were similar in the proportion of APOE ε4 carriers, the dementia rating scale score, and the proportion of female participants. ADAge enrichment lowered screening costs by $5.3 million (34%) in a clinical trial scenario.ConclusionADAge enrichment provides for a more efficient and cost‐effective means to enroll CN individuals with elevated Aβ in clinical trials.

Gene- and age-informed screening for preclinical Alzheimer's disease trials.

Elevated β-amyloid is used to enroll individuals into preclinical Alzheimer's disease trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment. Alzheimer's disease incidence rates and a polygenic hazard score were used to create a gene- and age-defined ADAge. An ADAge cutpoint was chosen to optimally predict β-amyloid positivity among clinically normal Alzheimer's Disease Neuroimaging Initiative participants and applied to an independent Alzheimer's Disease Research Center validation cohort. The impact of ADAge enrichment on screening costs was evaluated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial data. In the validation cohort, the ADAge-enriched sample had a higher proportion of individuals with elevated β-amyloid (difference [95% CI] 0.19[0.07 to 0.33]) than the unenriched sample. ADAge enrichment lowered screening costs by $4.41 million (31.00%) in the real-world clinical trial scenario. ADAge enrichment provides for a more efficient and cost-effective means to enroll clinically normal individuals with elevated β-amyloid in clinical trials.

The preclinical amyloid sensitive composite to determine subtle cognitive differences in preclinical Alzheimer\u2019s disease

Recently, the focus of Alzheimer’s disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (Aβ+) and negative (Aβ−) status in cognitively normal (CN) participants. A total of 423 CN participants with Aβ positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the Aβ+ and Aβ− groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the Aβ+ group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ε4 for distinguishing between Aβ+ and Aβ− was adequate (AUC = 0.764; 95% CI = 0.667–0.860) in the external validation set (N = 179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.

Current and evolving treatment strategies for the Alzheimer disease continuum.

The burden of Alzheimer disease (AD) on the US healthcare system is substantial and increasing. AD progresses along a continuum from preclinical disease characterized by normal cognition and abnormal brain biomarkers to mild cognitive impairment and then clinically apparent dementia. Diagnosis early in the AD continuum has benefits for patients and caregivers and appears cost-effective, but often, the clinical diagnosis of AD may be delayed. Currently available biomarkers include β-amyloid positron emission tomography and cerebrospinal fluid tests. Collectively, they are expensive, may lead to adverse effects, are not widely available, and are not suited for primary care. Currently available treatment options, cholinesterase inhibitors and memantine, do not alter disease progression, but can help with some symptoms. Benefits of currently available treatments on cognition are difficult to quantify and are offset by a burden of adverse effects that often go unrecognized. More accurate diagnostic biomarkers and disease-modifying drug therapies are critical unmet needs of patients with AD despite decades of clinical research. Because many phase 3 clinical trials that enrolled patients with symptomatic AD have failed, researchers believe that disease-modifying treatment is more likely to demonstrate benefit when utilized early in the disease continuum. Within the past few years, significant achievements that will advance clinical trials in early AD include the Research Framework to define and stage the AD continuum, FDA guidance on study design in early AD, and development of scales to measure cognition that are suitable for early AD. In October 2019, the AD community was re-invigorated by unexpected news that a Biologics License Application will be submitted for aducanumab to treat AD. This article explores the current state of biomarker-driven drug development across the AD continuum and reviews investigational drugs in phase 2/3 clinical development for AD.

The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy.

Abnormally hyperphosphorylated tau is a defining pathological feature of tauopathies, such as Alzheimer's disease (AD), and accumulating evidence suggests a role for iron in mediating tau pathology that may lead to cognitive decline in these conditions. The metal chelator deferiprone (DFP), which has a high affinity for iron, is currently in clinical trials for AD and Parkinson's disease. However, the effect of DFP on tau pathology remains underexplored. We aimed to investigate the impact of chronic DFP treatment on tau pathology using a well-characterized mouse model of tauopathy (rTg(tauP301L)4510). Animals were treated daily with DFP (100 mg/kg) via oral gavage for 16 weeks. After 14 weeks, mice were tested in the Y-maze, open field, Morris water maze, and rotorod. At the end of the study, brain tissue was collected to examine metal levels (using inductively coupled plasma-mass spectrometry) and for western blot analysis of DFP on tau and iron associated pathways. DFP significantly reduced anxiety-like behavior, and revealed a trend toward improved cognitive function. This was accompanied by a decrease in brain iron levels and sarkosyl-insoluble tau. Our data also showed downregulation of the tau kinases glycogen synthase kinase 3β and cyclin dependent kinase-5 in DFP treated mice and an increase in the methylation of the catalytic subunit of protein phosphatase 2A. These data support the hypothesis that suggests that iron plays a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders.

Progression of Alzheimer's Disease by Self-Reported Cancer History in the Alzheimer's Disease Neuroimaging Initiative.

Cross-sectional studies suggest self-reported cancer history is associated with decreased risk of Alzheimer's disease (AD). However, little is known about how self-reported cancer affects longitudinal AD progression, the primary outcome in clinical trials and observational studies. To determine self-reported cancer history's effect on longitudinal AD progression in an observational study. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to evaluate progression to AD by self-reported all-cancer, breast, prostate, colorectal, or non-melanoma skin cancer history. Linear mixed effects models were used to examine baseline differences and rates of progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) by self-reported cancer history. Age at AD onset was examined using consensus clinical diagnoses with Cox proportional hazards regression. Among 1,271 participants, models revealed no significant differences in progression over time but did reveal significantly lower baseline ADAS-Cog score, indicating better cognition at a given age in those with self-reported cancer history. Cox models indicated those with self-reported cancer history had significantly later age of AD onset (HR: 0.67, 95% CI: 0.53-0.85) after adjustment for covariates. Participants with self-reported cancer history entered ADNI with better cognition and later age of AD onset, but progressed similarly to participants without such history, indicating differences in AD between those with and without self-reported cancer history emerge early in the disease course. Such differences in longitudinal progression by self-reported cancer history could affect AD trials and observational studies, given the current focus on early disease course. Further investigation is warranted with detailed longitudinal assessment of cancer and AD.

Inter-individual differences in the responses to aerobic exercise in Alzheimer's disease: Findings from the FIT-AD trial

BackgroundDespite the strong evidence of aerobic exercise as a disease-modifying treatment for Alzheimer's disease (AD) in animal models, its effects on cognition are inconsistent in human studies. A major contributor to these findings is inter-individual differences in the responses to aerobic exercise, which was well documented in the general population but not in those with AD. The purpose of this study was to examine inter-individual differences in aerobic fitness and cognitive responses to a 6-month aerobic exercise intervention in community-dwelling older adults with mild-to-moderate dementia due to AD. MethodsThis study was a secondary analysis of the Effects of Aerobic Exercise for Treating Alzheimer's Disease (FIT-AD) trial data. Aerobic fitness was measured by the shuttle walk test (SWT), the 6-min walk test (6MWT), and the maximal oxygen consumption (VO2max) test, and cognition by the AD Assessment Scale-Cognition (ADAS-Cog). Inter-individual differences were calculated as the differences in the standard deviation of 6-month change (SDR) in the SWT, 6MWT, VO2max, and ADAS-Cog between the intervention and control groups. ResultsSeventy-eight participants were included in this study (77.4 ± 6.3 years old, mean ± SD; 15.7 ± 2.8 years of education; 41% were female). VO2max was available for 26 participants (77.7 ± 7.1 years old; 14.8 ± 2.6 years of education; 35% were female). The SDR was 37.0, 121.1, 1.7, and 2.3 for SWT, 6MWT, VO2max, and ADAS-Cog, respectively. ConclusionThere are true inter-individual differences in aerobic fitness and cognitive responses to aerobic exercise in older adults with mild-to-moderate dementia due to AD. These inter-individual differences likely underline the inconsistent cognitive benefits in human studies.

Application of Deep Learning to Predict Standardized Uptake Value Ratio and Amyloid Status on 18F-Florbetapir PET Using ADNI Data.

Cortical amyloid quantification on PET by using the standardized uptake value ratio is valuable for research studies and clinical trials in Alzheimer disease. However, it is resource intensive, requiring co-registered MR imaging data and specialized segmentation software. We investigated the use of deep learning to automatically quantify standardized uptake value ratio and used this for classification. Using the Alzheimer's Disease Neuroimaging Initiative dataset, we identified 2582 18F-florbetapir PET scans, which were separated into positive and negative cases by using a standardized uptake value ratio threshold of 1.1. We trained convolutional neural networks (ResNet-50 and ResNet-152) to predict standardized uptake value ratio and classify amyloid status. We assessed performance based on network depth, number of PET input slices, and use of ImageNet pretraining. We also assessed human performance with 3 readers in a subset of 100 randomly selected cases. We have found that 48% of cases were amyloid positive. The best performance was seen for ResNet-50 by using regression before classification, 3 input PET slices, and pretraining, with a standardized uptake value ratio root-mean-square error of 0.054, corresponding to 95.1% correct amyloid status prediction. Using more than 3 slices did not improve performance, but ImageNet initialization did. The best trained network was more accurate than humans (96% versus a mean of 88%, respectively). Deep learning algorithms can estimate standardized uptake value ratio and use this to classify 18F-florbetapir PET scans. Such methods have promise to automate this laborious calculation, enabling quantitative measurements rapidly and in settings without extensive image processing manpower and expertise.

AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

Grifols' recent Alzheimer Management by Albumin Replacement (“AMBAR”) study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects

Alzheimer's disease (AD) is the most common form of dementia and is associated with the accumulation of amyloid-β (Aβ), a peptide whose aggregation has been associated with neurotoxicity. Drugs targeting Aβ have shown great promise in 2D in vitro models and mouse models, yet preclinical and clinical trials for AD have been highly disappointing. We propose that current in vitro culture systems for discovering and developing AD drugs have significant limitations; specifically, that Aβ aggregation is vastly different in these 2D cultures carried out on flat plastic or glass substrates vs. in a 3D environment, such as brain tissue, where Aβ confinement alters aggregation kinetics and thermodynamics. In this work, we identified attenuation of Aβ cytotoxicity in 3D hydrogel culture compared to 2D cell culture. We investigated Aβ structure and aggregation in solution vs. hydrogel using Transmission Electron Microscopy (TEM), Fluorescence Correlation Spectroscopy (FCS), and Thioflavin T (ThT) assays. Our results reveal that the equilibrium is shifted to stable extended β-sheet (ThT positive) aggregates in hydrogels and away from the relatively unstable/unstructured presumed toxic oligomeric Aβ species in solution. Volume exclusion imparted by hydrogel confinement stabilizes unfolded, presumably toxic species, promoting stable extended β-sheet fibrils. Statement of SignificanceAlzheimer's disease (AD) is a devastating disease and has been studied for over 100 years. Yet, no cure exists and only 5 prescription drugs are FDA-approved to temporarily treat the AD symptoms of declining brain functions related to thinking and memory. Why don't we have more effective treatments to cure AD or relieve AD symptoms? We propose that current culture methods based upon cells cultured on flat, stiff substrates have significant limitations for discovering and developing AD drugs. This study provides strong evidence that AD drugs should be tested in 3D culture systems as a step along the development pathway towards new, more effective drugs to treat AD.

Sex and gender differences in Alzheimer's disease: current challenges and implications for clinical practice: Position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

Neuron‐Targeted Caveolin‐1 gene therapy preserves hippocampal neuroplasticity and memory in Alzheimer’s Disease mice

Alzheimer’s disease (AD) is a neurodegenerative condition with severe cognitive deficits which is closely correlated with loss of synapses and neurons, thus, targeting neuroprotective mechanisms specifically to neuronal cells that changes the synaptic strength and resistance to toxic Ab and the following inflammation response may restore functional neuronal and synaptic plasticity independent of removing toxic amyloid species. One potential molecular target is caveolin‐1 (Cav‐1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic proteins and associated synaptic signaling components (e.g., neurotrophin and neurotransmitter receptors). Recent pre‐clinical and clinical evidence showed that Cav‐1 and Cav‐1 associated signaling complexes (TrkA, TrkB, GluN2B, dopaminergic, cholinergic receptors, and adenylyl cyclase) were decreased in degenerating neurons from a variety of neurodegenerative conditions which included AD, CTE, and ALS. Here we show that Cav‐1 expression decreases in the hippocampus occurs at early stages of cognitive loss (6 months (m)) and correlates to the progression of pathological of AD. Furthermore, one‐time hippocampal administration of adeno‐associated virus that encodes neuron‐targeted Cav‐1 using a synapsin promoter (AAV‐SynCav1) at 3 months (m) preserves learning and memory in 9 and 11 m old amyloid‐positive APPSwePS1d9 mice (i.e., AD). At 9 month, immunoblot and proteomic analysis of hippocampus MLR confirmed decreased Cav‐1 in AD‐SynRFP and preserved Cav‐1 in AD‐SynCav1. Bioinformatics analysis identified 80 up‐regulated proteins in AD‐SynCav1 MLR and gene ontology analysis found several proteins are related to synaptic function (Shisa9, an AMPAR regulatory protein critical for memory; Piccolo, scaffolding protein in synaptic active zones) and cholesterol homeostasis (Kiaa1468, Ap2a2). At 11 m, Golgi‐Cox histology demonstrated that SynCav1 preserved CA1 dendritic arbor in AD mice compared to AD‐SynRFP mice. Electron microscopy (EM) of CA1 apical dendrites revealed preserved ultrastructural indicators of synaptic plasticity (e.g., total type I excitatory synapses, presynaptic vesicles per axonal bouton, normal dendritic spine morphology), preserved mossy fiber area, and preserved myelinated CA3 Schaffer collaterals in 11 m AD‐SynCav1 mice. These findings offer important proof‐of‐concept evidence for the use of neuron‐targeted Cav‐1 (i.e., SynCav1) gene therapy to future AAV‐9‐based clinical trials in AD as well as other neurodegenerative diseases.Support or Funding InformationVeterans Affairs Merit Award from the Department of Veterans Affairs BX003671 (B. P. Head); National Institutes of Health, Bethesda, MD, U.S.A., NS073653 (B. P. Head); and GM085179 (P. M. Patel).SynCav1gene delivery preserves fear learning and contextual memory recall in 9 month and 11 month‐old APPSwePS1d9 mice, respectively.Figure 1SynCav1gene delivery preserved hippocampal Cav‐1 expression and MLR‐localized synaptic proteins in 9 month‐old APPSwePS1d9 mice.Figure 2

Fasting blood glucose and cerebrospinal fluid Alzheimer's biomarkers in non-diabetic cognitively normal elders: the CABLE study.

It is unclear how blood glucose levels mediate the pathology of Alzheimer's disease (AD). This study aimed to investigate whether fasting blood glucose (FBG) levels are associated with cerebrospinal fluid (CSF) biomarkers preferentially affected by AD in non-diabetic cognitively normal elders. A total of 499 non-diabetic cognitively normal elders were from the Chinese Alzheimer’s Biomarker and LifestyLE (CABLE) study. We detected the associations of FBG with individual CSF measures using multiple linear regression models controlling for age, sex, educational level, and apolipoprotein E (APOE) ε4 genotype. Fasting blood glucose level was positively correlated with CSF Aβ42 level (β = 0.045, p = 0.010), CSF Aβ42/Aβ40 ratio (β = 0.005, p < 0.001), Aβ42/P-tau ratio (β = 0.282, p = 0.013), and Aβ42/T-tau ratio (β = 0.050, p = 0.040). Interaction analysis indicated that gender affected the correlations of FBG level with CSF Aβ40 (p < 0.001) and Aβ42/Aβ40 ratio (p < 0.001). This study raises additional questions about the role of blood glucose in the predisposition to AD and supports the possibility of targeting these processes in pre-symptomatic AD trials in non-diabetic elders.

Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer's Disease.

Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far. Using quantitative mass spectrometry (IP-MS, MRM) we observed increased concentrations of the presynaptic protein beta-synuclein (βSyn) in CSF and blood of AD patients (n = 64, p < 0.01) and confirmed this finding in two validation cohorts (AD: n = 40 and n = 49, controls: n = 44 and n = 25). βSyn was already increased in patients with mild cognitive impairment (p < 0.01) and was also markedly increased in Creutzfeldt-Jakob disease (CJD; n = 25, p < 0.001) but not behavioral variant frontotemporal dementia (n = 16), dementia with Lewy bodies/Parkinson's disease dementia (n = 13), Parkinson's disease (n = 25), or amyotrophic lateral sclerosis (n = 30). The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ≥96%. These findings suggest βSyn as a candidate blood marker for synaptic degeneration that might be used in clinical AD trials and patient follow-up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.