An early and accurate diagnosis of Alzheimer’s Disease (AD) has loaded benefits for a patient living with the disease and their families. Getting an accurate diagnosis has been a challenge for many decades due to the limitations in medical resources available for testing.
Historically, an AD diagnosis was only confirmed on autopsy by elevated levels of beta-amyloid and tau in the brain. Over the years, however, there have been ongoing medical breakthroughs to test, prevent, and slow the progression of AD.
These publications below chronicle the evolution of these breakthroughs and how the innovative biomarkers have significantly changed the testing and diagnosis of AD.
Resolving a Diagnostic Dilemma
On the backdrop of a heated, very public debate regarding CMS coverage determinations and restricted patient access to new drugs to treat Alzheimer’s Disease (AD), there is little to no discussion about the real questions that will face most people suffering from cognitive decline: who is the right candidate for the drug and what other options are available to manage mild cognitive impairment (MCI) and AD dementia for those who are not candidates?
Author of publication:Frederick Huie, MD, Medical Director, CVS/Aetna and Advisory Council Member, SYNAPS Dx Scott C. Howell, DO, Semler Scientific and Philippe Douyon, MD, Inle BrainFit Institute™
Part II: Accurately Diagnosing Alzheimer’s Disease: Shortcomings of Blood Biomarkers and Need for Definitive, Non-invasive Diagnostic Testing
Accurately Diagnosing Alzheimer’s Disease: Shortcomings of Blood Biomarkers and Need for Definitive, Non-invasive Diagnostic Testing Part II
Author: Dr. Daniel Alkon, chief scientific advisor, SDx
Part II. A. A Pathway Forward for Accurate Diagnosis and Effective Treatment B. Diagnosis and Misdiagnosis C. New Drugs Pose Significant Safety Challenges D. Introducing the DISCERNTM Test E. A Bright Horizon
Part I: Accurately Diagnosing Alzheimer’s Disease: Shortcomings of Blood Biomarkers and Need for Definitive, Non-invasive Diagnostic Testing
Accurately Diagnosing Alzheimer’s Disease: Shortcomings of Blood Biomarkers and Need for Definitive, Non-invasive Diagnostic Testing
Author: Dr. Daniel Alkon, chief scientific advisor, SDx
This paper is intended to support stakeholders in the healthcare ecosystem that are impacted by AD. Part I.
A. Complexity and Prevalence of Alzheimer’s Disease vs. Early Dementia or Mild Cognitive Impairment B. Alzheimer’s Association Cautions Use Recommendations for Blood Biomarkers in Diagnosing AD
Author of publication:Dr. Daniel Alkon, chief scientific advisor, SDx
Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients
A definitive diagnosis of Alzheimer’s disease (AD), even in the presence of co-morbid neuropathology
(occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery
of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin
fibroblasts, was used in a double-blind, allcomers (ages 55–90) trial of 3 patient cohorts: AD dementia
patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21—all autopsy or genetically
confirmed; and non-demented control (AHC) patients N = 27.
Author of publication:Florin V. Chirila, Guang Xu, Dan Fontaine, Grant Kern, Tapan K. Khan, Jason Brandt, Yoshihiro Konishi, Gerhard Nebe‑von‑Caron, Charles L. White III & Daniel L. Alkon
Clinical Study of Novel Skin Biomarker Test for Alzheimer’s Disease Gains Vigorous Physician Support in Long-Sought Early Detection Breakthrough
Experts believe science has primarily focused on amyloid to accurately diagnose AD, when in reality, AD is a complex, neurodegenerative form of dementia that requires a more nuanced approach than the linear structure of current diagnostic pathways.iii
While the underlying cause of AD is still unknown, experts agree that changes in the brain due to age, combined with genetic, environmental and lifestyle factors all play an important role in disease progression.iv
Developing AD can be a frightening prospect: it is the most common form of dementia and the fifth cause of death in the U.S. for adults over 65.v AD is a brain disease caused by damage to neurons associated with memory, language and thinking. The condition is progressive, which means it gets worse over time.vi
Furthermore, the economic burden of AD is significant. In 2020, the cost of AD was $305 billion, a figure that is expected to increase to $1 trillion over time. Direct costs include skilled nursing home care, home health care and hospice care for patients with AD. Indirect costs include informal caregiving by family and a decline in quality of life for patients and caregivers.
Author of publication:Frederick Huie, MD, Medical DIrector, CVS/Aetna and Advisory Council Member, SYNAPS Dx Scott C. Howell, D.O.
DISCERN™ PKCƐ Assay for Alzheimer’s Disease Measuring synaptic dysfunction to inform a highly accurate diagnose Alzheimer’s Dementia in early dementia.
The DISCERN™ test identifies Alzheimer’s Disease (AD) early in people diagnosed with dementia informing a definitive diagnosis in a living patient.
The DISCERN™ test is a skin test comprised of three assays that measure several critical factors directly related to AD that regulate memory, the formation of synaptic connections among neurons, the levels of amyloid plaques, and levels of neurofibrillary tangles in the brain.
The PKCε assay in the DISCERN™ test measures an enzyme found in the brain and peripheral tissues such as skin, associated with synaptic loss, amyloid-β elevation, and cognitive deficits in AD.
The level of PKCε has been shown to accurately identify AD in those recently diagnosed with dementia (96% specificity and 100% sensitivity) and to distinguish AD from other causes of dementia, such as multi-infarct dementia, Parkinson’s disease, or Frontal Lobe Dementia.
DISCERN™ Morphometric Imaging Assay for Alzheimer’s Disease Accurately informs diagnosis of Alzheimer’s Disease in early dementia, even in the presence of Mixed dementia
Simple, minimally-invasive test informing a definitive diagnosis for Alzheimer’s Disease (AD) in a living patient.
The DISCERN™ test is comprised of three assays that assess several critical factors directly related to AD that regulate memory, the formation of synaptic connections among neurons, the levels of amyloid plaques and levels of neurofibrillary tangles in the brain. In clinical trials, the morphometric imaging assay has demonstrated high sensitivity and specificity of results correlating with postmortem diagnosis as defined by the NIH Gold Standard.
Diagnostically distinguishes AD from other forms of dementia, even in early-stage AD (≤4 years of a dementia diagnosis).
Able to diagnose AD in mixed co-morbid state with other types of dementia.
Early detection of AD enables earlier therapeutic intervention to prevent cognitive decline.
In clinical trials, demonstrated improved accuracy over traditional clinical diagnostic approaches for AD, even in early-stage disease.
Supporting Payer Treatment Reimbursement Decisions for Alzheimer’s Disease: DISCERN™ Test Provides Definitive Diagnosis of Alzheimer’s Disease and Degenerative Pathologies vs. Other Forms of Dementia
Supporting Payer Treatment Reimbursement Decisions for Alzheimer’s Disease:
DISCERN™ Test Provides Definitive Diagnosis of Alzheimer’s Disease and Degenerative Pathologies vs. Other Forms of Dementia
Highly accurate, minimally invasive test is well positioned to help address a number of key issues that payers, providers and patients face when it comes to getting a definitive diagnosis for ALzheinmer’s Disease early in the patient journey.
Authors:
Dr. Daniel Alkon, Chief Scientific Advisor, SYNAPS Dx
SYNAPS Dx Advisory Council:
Dave Rosa, president and CEO, NeuroOne Medical Technologies Corporation
Michael Gorton, founding CEO, Teladoc and CEO, Recuro Health
Alzheimer dementia with sparse amyloid–AD mimic or variant?
In a new study, one-quarter of individuals with clinical diagnosis of mild to moderate Alzheimer dementia had no or only sparse neuritic amyloid plaques in their brains, and most were also at low or intermediate neurofibrillary tangle stage. The findings have enormous implications for clinical trails of anti-amyloid ant anti-tau therapies.
Author of publication:Alberto Serrano-Pozo and Bradley T. Hyman
Early diagnostic accuracy and pathophysiologic relevance of an autopsy-confirmed Alzheimer’s disease peripheral biomarker
Treatment of Alzheimer’s disease (AD) and the discovery of promising drug candidates depend on early diagnosis. Few currently available diagnostic tests have significantly improved this early uncertainty, while the “gold standard” diagnosis continues to require clinical dementia in life and the presence of pathologic brain lesions of amyloid plaques and neurofibrillary tangles in the brain at autopsy. Here, the inflammatory agonist bradykinin, a small nano-peptide, that induces PKC-mediated phosphorylation of Erk1 and Erk2 in fibroblasts, was applied to punch biopsy-obtained human skin fibroblasts. Quantitative imaging of the phosphorylated Erk1 and Erk2 bands was then used in a ratio that is mathematically configured into an AD-Biomarker Index (AD-Index). In the population described here (N= 264), there were 64 autopsy examinations. Demented individuals were clinically diagnosed as AD with an overall accuracy of 78%. Among the 42 autopsy-confirmed cases for which there were also AD-Biomarker measurements, the overall accuracy of the AD-Biomarker was 98%. Among both the autopsy confirmed and the clinically diagnosed patients, the AD-Index values were inversely correlated with the duration of disease, i.e., the time from the onset of dementia symptoms. Among the autopsy-confirmed cases, the AD-Biomarker diagnosis showed remarkably high sensitivity (97%) and specificity (100%) compared to clinical diagnosis (sensitivity: 78% and specificity: 20%). Using autopsy validation, the clinical diagnosis was only accurate at 52% level vs. the AD-Biomarker accuracy of 100% for cases with dementia not larger than 4 years of duration. Finally, application of soluble A1–42 to the fibroblasts of normal controls induced the abnormal AD-Biomarker phenotype, suggesting the pathophysiologic relevance of this AD-Biomarker measurement. In summary, the AD-Biomarker, as confirmed by autopsy validation, showed significantly higher sensitivity and specificity than did clinical diagnosis, particularly at early stages of disease, and pathophysiological relevance was demonstrated for the mechanistic basis of the AD-Biomarker measurements.
Author of publication:Tapan Kumar Khan a, Daniel L. Alkon
PKC Deficits in Alzheimer’s Disease Brains and Skin Fibroblasts
In Alzheimer’s disease (AD) transgenic mice, activation of synaptogenic protein kinase C (PKC) was found to prevent synaptotoxic amyloid- (A)-oligomer elevation, PKC deficits, early synaptic loss, cognitive deficits, and amyloid plaque formation. In humans, to study the role of PKC in the pathophysiology of AD and to evaluate its possible use as an early AD-biomarker, we examined PKC and A in the brains of autopsy-confirmed AD patients (n = 20) and age-matched controls (AC, n = 19), and in skin fibroblast samples from AD (n = 14), non-AD dementia patients (n = 14), and AC (n = 22). Intraneuronal A levels were measured immunohistochemically (using an A-specific antibody) in hippocampal pyramidal cells of human autopsy brains. PKC was significantly lower in the hippocampus and temporal pole areas of AD brains, whereas A levels were significantly higher. The ratio of PKC to A in individual CA1 pyramidal cells was markedly lower in the autopsy AD brains versus controls. PKC was inversely correlated with A levels in controls, whereas in AD patients, PKC showed no significant correlation with A. In autopsy brains, PKC decreased as the Braak score increased. Skin fibroblast samples from AD patients also demonstrated a deficit in PKC compared to controls and an AD-specific change in the A-oligomer effects on PKC. Together, these data demonstrate that the relationship between A levels and PKC is markedly altered in AD patients’ brains and skin fibroblasts, reflecting a loss of protective effect of PKC against toxic A accumulation. These changes of PKC levels in human skin fibroblasts may provide an accurate, non-invasive peripheral AD biomarker.
Author of publication:Tapan K. Khan, Abhik Sen, Jarin Hongpaisan, Chol S. Lim, Thomas J. Nelson and Daniel L. Alkon
An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin
Cognitive impairment has recently been found to correlate with changes in peripheral inflammatory signals such as TNF- and IL-1. PKC isozymes regulate levels of TNF- and IL-6 and the release of other cytokines and also show deficits in Alzheimer’s disease (AD) brains and skin fibroblasts. Here, we investigate MAPK Erk1 and Erk2 phosphorylation in response to the inflammatory agonist bradykinin, which activates PKC pathways. An internally controlled comparison of Erk1 and Erk2 produced an AD index that accurately distinguished fibroblasts of AD from those of normal controls and of non-AD dementias. This accuracy was demonstrated for Coriell Cell Repository (Coriell Institute of Medical Research, Camden, NJ) samples, as well as for samples analyzed on gels with autopsy diagnostic confirmation. AD Erk1 and Erk2 index values were inversely correlated with disease duration, suggesting maximal efficacy for early diagnosis. Finally, the results also demonstrate that, when the AD index agreed with the clinical diagnosis on the presence of AD, there was a high probability of accuracy based on autopsy validation. Thus, this peripheral molecular biomarker, based on differential Erk1 and Erk2 phosphorylation, could have important clinical utility for providing increased certainty in the positive diagnosis of AD, particularly in the early phase of disease progression.
Author of publication:Tapan K. Khan and Daniel L. Alkon
Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline
Some individuals reach ages beyond 100 years and become centenarians with intact cognitive functions,1-5 which indicates that cognitive impairment is not inevitable at extreme ages. Cross sectional and longitudinal studies in younger age groups (20-90 years) have shown that aging is accompanied by a maintenance in language, semantic knowledge, abstract reasoning, and visuospatial functions, whereas a vulnerability is observed in domains such as processing speed, executive functions, and episodic and working memory.6-11 It is still unclear to what extent individuals who maintain cognitive health until age 100 years escape or delay decline across different cognitive domains. Based on the 40% incidence of dementia at age 100 years, and assuming a continued increase beyond 100, it is to be expected that a decline in cognitive functions will be observable in this age group.12,13 In this study, we aim to identify trajectories of cognitive performance in different domains for cognitively healthy centenarians, and to explore associations with risk factors of cognitive decline, including neuropathology associated with Alzheimer disease (AD) and factors of cognitive reserve.
Author of publication:Nina Beker, PhD; Andrea Ganz, MSc; Marc Hulsman, PhD; Thomas Klausch, PhD; Ben A. Schmand, PhD; Philip Scheltens, MD, PhD
Soluble f-Amyloid Induction of Alzheimer’s Phenotype for Human Fibroblast K+ Channels
Although P-amyloid is the main constituent of neurite plaques and may play a role in the pathophysiology of Alzheimer’s disease, mechanisms by which soluble P-amyloid might produce early symptoms such as memory loss before diffuse plaque deposition have not been implicated. Treatment of fibroblasts with ,B-amyloid (10 nM) induced the same potassium channel dysfunction previously shown to occur specifically in fibroblasts from patients with Alzheimer’s disease-namely, the absence of a 1 1 3-picosiemen potassium channel. A tetraethylammonium-induced increase of intracellular concentrations of calcium, [Ca2+]i, a response that depends on functional 1 1 3-picosiemen potassium channels, was also eliminated or markedly reduced by 10 nM P-amyloid. Increased [Ca2+1] induced by high concentrations of extracellular potassium and 1 66-picosiemen potassium channels were unaffected by 10 nM p-amyloid. In Alzheimer’s disease, then, P-amyloid might alter potassium channels and thus impair neuronal function to produce symptoms such as memory loss by a means other than plaque formation.
Author of publication:Rene Etcheberrigaray, Etsuro Ito, Christopher S. Kim, Daniel L. Alkont
Fibroblast Aggregation Rate Converges with Validated Peripheral Biomarkers for Alzheimer’s Disease
The inaccuracy of the diagnosis for Alzheimer’s disease (AD) has made its therapeutic intervention difficult, particularly early enough to prevent significant neurodegeneration and cognitive dysfunction. Here, we describe a novel, highly accurate peripheral diagnostic for AD patients based on quantitatively measured aggregation rate of human skin fibroblasts. The elevated aggregation rate with increasing cell density in AD cases is the basis of this new biomarker. The new biomarker was successfully cross-validated with two more mature assays, AD-Index, based on the imbalances of ERK1/2, and Morphology, based on network dynamics, and showed 92% overlap. A significant number of cases tested with this new biomarker were freshly obtained (n = 29), and 82% of the cases are hyper-validated cases, i.e., autopsy and/or genetically confirmed AD or non-Alzheimer’s disease demented patients (Non-ADD) and non-demented age-matched controls. Furthermore, we show that by using a simple majority rule, i.e., two out of the three assays have the same outcome, we significantly increase the agreement with clinical AD diagnosis (100%). Based on the high accuracy of this strategy, the biomarker profile appears to accurately identify AD patients for therapeutic intervention.
Author of publication:Florin V. Chirila, Tapan K. Khan and Daniel L. Alkon
Spatiotemporal Complexity of Fibroblast Networks Screens for Alzheimer’s Disease
Drugs to treat Alzheimer’s disease (AD) have been unsuccessful in preventing its devastating cognitive deficits and progressive neurodegeneration. The lack of a definitive diagnostic for AD has been a major obstacle to AD drug discovery. Here, we describe a novel, highly accurate peripheral diagnostic for AD patients based on quantitatively measured complexity of skin-sampled fibroblast networks. A significant number of samples were studied under double-blind conditions and had autopsy and/or genetic validation. An additional sample confirmed the diagnostic discrimination on freshly obtained skin samples. A subsample of these diagnostic differences were induced by oligomerized amyloid-1-42. Based on the accuracy of these measures that utilize physical principles such as fractal dimension and lacunarity as well as the significant correlation with disease duration,this biomarker profile appears to identify accurately AD patients for therapeutic intervention.
Author of publication:Florin V. Chirila, Tapan K. Khan and Daniel L. Alkon