High Soluble Amyloid-ß42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations.

BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-ß (Aß42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. OBJECTIVE: To test the hypothesis that high Aß42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aß42 levels were higher among CDR non-progressors than CDR progressors. Higher Aß42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aß42 levels predicting lower risk of progression increased with higher SUVR levels. CONCLUSION: High CSF Aß42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

High cerebrospinal amyloid-ß 42 is associated with normal cognition in individuals with brain amyloidosis.

BACKGROUND: Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid ß amyloid (Aß42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis. METHODS: This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aß42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18]F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels. FINDINGS: Higher soluble Aß42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aß42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aß42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aß42 levels were also associated with better neuropsychological function and larger hippocampal volume. INTERPRETATION: Normal cognition and hippocampal volume are associated with preservation of high soluble Aß42 levels despite increasing brain amyloidosis. FUNDING: Please refer to the Funding section at the end of the article.

Soluble Amyloid-ß Consumption in Alzheimer's Disease.

Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-ß conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer's disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-ß levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-ß, however, would only exemplify 'rescue medicine.' Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer's disease and other neurodegenerative disorders.

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

BACKGROUND: 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. OBJECTIVE: To determine self-reported cancer history's effect on longitudinal AD progression in an observational study. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid.

INTRODUCTION: Blood-brain barrier (BBB) breakdown and loss of brain capillary pericytes contributes to cognitive impairment. Pericytes express platelet-derived growth factor receptor-ß (PDGFRß) that regulates brain angiogenesis and blood vessel stability. Elevated soluble PDGFRß (sPDGFRß) levels in cerebrospinal fluid (CSF) indicate pericyte injury and BBB breakdown, which is an early biomarker of human cognitive dysfunction. METHODS: A combination of reagents and conditions were tested, optimized, and validated on the Meso Scale Discovery electrochemiluminescence platform to develop a new sPDGFRß immunoassay that was used to measure sPDGFRß in human CSF from 147 individuals. RESULTS: We developed standard operating procedures for a highly sensitive and reproducible sPDGFRß immunoassay with a dynamic range from 100 to 26,000 pg/mL, and confirmed elevated CSF sPDGFRß levels in individuals with cognitive dysfunction. DISCUSSION: This assay could be applied at different laboratories to study brain pericytes and microvascular damage in relation to cognition in disorders associated with neurovascular and cognitive dysfunction.

The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease.

BACKGROUND: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD.Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance.Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD.Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs.The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. CONCLUSION: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.

Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.

OBJECTIVE: PhytoSERM is a selective estrogen receptor beta (ERß) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS: In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS: Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION: Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.

Safety and feasibility of estrogen receptor-ß targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial.

OBJECTIVE: PhytoSERM is a formulation of genistein, daidzein, and S-equol that has an 83-fold selective affinity for estrogen receptor-ß (ERß); and may enhance neuron function and estrogenic mechanisms in the brain without having peripheral estrogenic activity. METHODS: We conducted an overarching, two-stage, dose-ranging, double-blinded, randomized, placebo-controlled trial of 12 weeks duration comparing 50 and 100 mg/d of phytoSERM with placebo for noncognitively impaired, perimenopausal women aged 45 to 60, with intact uteri and ovaries, with at least one cognitive complaint, and one vasomotor-related symptom. Primary objectives were to assess safety and tolerability of a 50 and 100 mg daily dose; and, secondly, to evaluate potential indicators of efficacy on cognition and vasomotor symptoms over 4 and 12 weeks, and using an embedded, 4-week, 2-period, placebo-controlled crossover trial for a subset of participants. RESULTS: Seventy-one women were randomized to treatment; 70 were evaluated at 4 weeks; 12 were entered into the crossover study; 5 did not complete 12 weeks. Reasons for discontinuation were withdrawal of consent (n = 1) and lost to follow-up (n = 4). Adverse events occurred in 16.7% (n = 4) placebo, 39.1% (n = 9) 50 mg/d, and 29.2% (n = 7) 100 mg/d treated participants; 85% were mild and none was severe. Vaginal bleeding occurred in 0, placebo; 1, 50 mg; and 3, 100 mg/d participants. CONCLUSIONS: The phytoSERM formulation was well tolerated at 50 and 100 mg daily doses. Based on safety outcomes, vaginal bleeding at the 100 mg dose, and vasomotor symptoms and cognitive outcomes at 12 weeks, a daily dose of 50 mg was considered preferable for a phase 2 efficacy trial.

Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor ß-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.

OBJECTIVE: Selected estrogen receptor ß-selective phytoestrogen (phytoSERM), a preparation of genistein, daidzein, and S-equol, has an 83-fold selective affinity for estrogen receptor (ER) ß, and may promote neuronal survival and estrogenic mechanisms in the brain without exerting feminizing activity in the periphery. The aim of this study was to assess the safety, tolerability, and single-dose pharmacokinetics of the phytoSERM formulation in perimenopausal and postmenopausal women. METHODS: Eighteen women aged 45 to 60 years from a 12-week clinical trial evaluating cognitive performance and vasomotor symptoms were randomly assigned to placebo, 50 mg, or 100 mg phytoSERM treatment groups. Plasma levels of the three parent phytoestrogens and their metabolites were measured before and at 2, 4, 6, 8, and 24 hours after ingestion by isotope dilution high-performance liquid chromatography (HPLC) electrospray ionization tandem mass spectrometry. RESULTS: Plasma concentrations of genistein, daidzein, and S-equol peaked at 9, 6, and 4 hours, respectively, for the 50-mg dose, and at 6, 6, and 5 hours, respectively, for the 100-mg dose. The maximum concentration (Cmax) and area under the curve (AUC) for the three parent compounds were greater in the 100-mg dose group, indicating a dose-dependent change in concentration with the phytoSERM treatment. No adverse events were elicited. CONCLUSIONS: A single-dose oral administration of the phytoSERM formulation was well-tolerated and did not elicit any adverse events. It was rapidly absorbed, reached high plasma concentrations, and showed a linear dose-concentration response in its pharmacokinetics. These findings are consistent with previously reported parameters for each parent compound (Clinicaltrials.gov NCT01723917).

Accelerating stem cell trials for Alzheimer's disease.

At present, no effective cure or prophylaxis exists for Alzheimer's disease. Symptomatic treatments are modestly effective and offer only temporary benefit. Advances in induced pluripotent stem cell (iPSC) technology have the potential to enable development of so-called disease-in-a-dish personalised models to study disease mechanisms and reveal new therapeutic approaches, and large panels of iPSCs enable rapid screening of potential drug candidates. Different cell types can also be produced for therapeutic use. In 2015, the US Food and Drug Administration granted investigational new drug approval for the first phase 2A clinical trial of ischaemia-tolerant mesenchymal stem cells to treat Alzheimer's disease in the USA. Similar trials are either underway or being planned in Europe and Asia. Although safety and ethical concerns remain, we call for the acceleration of human stem cell-based translational research into the causes and potential treatments of Alzheimer's disease.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Early intervention with an estrogen receptor ß-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer's disease.

Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-ß-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype ß (ERß) over ERα. Earlier studies indicate that the phyto-ß-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-ß-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-ß-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-ß-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-ß deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERß and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERß-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-ß-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.

Estrogen receptor ß-selective phytoestrogenic formulation prevents physical and neurological changes in a preclinical model of human menopause.

OBJECTIVE: As an alternative to estrogen therapy, the efficacy of an estrogen receptor ß-selective phytoestrogenic (phyto-ß-SERM) formulation to regulate climacteric symptoms and decline in brain responses associated with ovarian hormone loss in menopause was assessed. METHODS: A phyto-ß-SERM formulation-containing diet was compared with a commercial soy extract diet and a phytoestrogen-free base/control diet in an ovariectomized (OVX) mouse model of human menopause. Two treatment studies were conducted: (1) a 2-month study assessed the effects of experimental diets on tail skin temperature as a model of menopausal hot flashes, and (2) a 9-month study assessed the long-term impact of the diets on overall health, hair thinning/loss, spatial working memory, and associated protein expression in the hippocampus. RESULTS: The phyto-ß-SERM diet prevented OVX-induced menopause-like changes including the rise in skin temperature, hair thinning/loss, deficit in spatial memory function, and reversed OVX-induced decline in the expression of hippocampal proteins involved in neural plasticity and ß-amyloid degradation/clearance. The soy extract diet had no effect or exacerbated OVX-induced changes. CONCLUSIONS: Overall, the phyto-ß-SERM diet induced physical and neurological responses comparable with ovary-intact mice, suggesting the therapeutic potential of the phyto-ß-SERM formulation for the prevention/alleviation of climacteric symptoms and decline in brain responses induced by ovarian hormone loss, which provides the basis for further work in postmenopausal women.

Developing a national strategy to prevent dementia: Leon Thal Symposium 2009.

Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27-28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Sex, race, and smoking impact olanzapine exposure.

Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.

Increasing ethnic minority participation in Alzheimer disease research.

The Alzheimer's Association and National Institutes of Health have emphasized the need for participation of racial/ethnic populations in Alzheimer disease (AD) clinical research. Many articles have described strategies to enhance participation including establishing enduring ties to the community and tailoring the site to be more culturally welcoming or user-friendly to the community. Yet, most of these reports are not data driven. To get a better indication of the knowledge base, this review summarizes research across a broad range of domains (e.g., cancer, kidney disease, AD) that used systematic approaches to identify methods and factors that reduce barriers to recruitment, participation, and retention of a more racially and ethnically diverse population. Overall, 121 reports were found with 8 of these in AD. As a relatively new area of investigation, the literature was primarily descriptive; outcome data were seldom provided. While these studies help to identify areas of potential importance in racial/ethnic participation, hypothesis-driven research remains necessary to tease apart the key techniques that engender racial/ethnic participation in AD studies. This article suggests several recommendations, including the need for prospective research of specific recruitment methods. Fundamentally, researchers should consider that these strategies apply to all potential research participants, and not simply to traditionally underserved racial/ethnic populations.