Blood-Brain Biomarkers for Alzheimer’s Disease PDF

Blood-Brain Biomarkers for Alzheimer’s Disease Reviewed Study Questions Readings Lecture Notes Overview Alzheimer’s disease Brain pathology Current biomarkers in clinical...

Blood-Brain Biomarkers for Alzheimer’s Disease Reviewed Study Questions Readings Lecture Notes Overview Alzheimer’s disease Brain pathology Current biomarkers in clinical practice Blood biomarkers Clinical utility Future research Outcomes To be able to define Alzheimer’s disease (AD) and describe its key pathological characteristics. To be aware of the amyloid cascade hypothesis To define the biomarkers used in clinical diagnosis and the barriers to their use To learn about the potential of an AD blood-based biomarker To learn about current research to aid and evaluate the clinical utility of a blood-based biomarker for AD What is Alzheimer’s disease? Dementia is a general term used to describe a significant decline in cognitive ability that interferes with a person's activities of daily living. Alzheimer’s disease (AD) is a neurodegenerative condition with insidious onset and can cause progressive impairment of behavioural and cognitive functions. Dementia Subtypes Blood-Brain Biomarkers for Alzheimer’s Disease 1  Alzheimer’s dementia is the most prevalent dementia type AD accounts for 60% to 80% of dementia cases (with less than half expected to be pure AD and the majority expected to be mixed dementias). Why is Alzheimer’s disease important? Prevalence ~1 million people in UK have dementia ~55 million people globally Cost Economic burden in UK £42 billion per year. Morbidity Dementia is one of the main causes of disability later in life. Mortality Dementia and Alzheimer’s disease leading cause of death 2022 in England and Wales (11.4% of all deaths) What are the risk factors for late-onset AD? Non-modifiable: Age most significant 65–74 years: 5% of people have Alzheimer's dementia 75–84 years: 13.1% of people have Alzheimer's dementia 85 years and older: 33.3% of people have Alzheimer's dementia Genetics (e.g., APOE e4 allele) Family History Modifiable risk factors: Blood-Brain Biomarkers for Alzheimer’s Disease 2  Pathology What changes occur in the brain? The amyloid cascade hypothesis Neuropathological staging Braak staging of tau neurofibrillary tangles Blood-Brain Biomarkers for Alzheimer’s Disease 3  What changes occur in the brain? Macroscopic Neurodegeneration Blood-Brain Biomarkers for Alzheimer’s Disease 4  Protein misfolding accumulation → Network spread; neuronal loss; neuroinflammation → Neuronal loss, Hypometabolism → Clinical manifestations Summary We need early and accurate dementia diagnosis As of February 2022, only 61.7% of those aged 65 or over thought to be living with dementia in England have a diagnosis. Getting a dementia diagnosis is key to unlocking access to personalised care and support as well as existing treatments. It will enable people to plan ahead and identify any potential ways to improve their brain health. An accurate diagnosis will directly impact how a person’s medicines are prescribed and managed, as clinical recommendations differ depending on the causes(s) of dementia - Alzheimer’s Research UK Blood-Brain Biomarkers for Alzheimer’s Disease 5  What is a biomarker? A measurable indicator of a pathological process, in the blood, other bodily fluids, or tissues. What types of AD biomarkers are used currently in clinical practice? Lumbar puncture Cerebrospinal fluid (CSF) CSF Clinical utility of fluid biomarkers in the evaluation of cognitive impairment: a systematic review and meta-analysis Pooled percentage change in diagnosis of 25% (95% CI 14-37) An increase in diagnostic confidence of 14% (95% CI 9-18) A pooled proportion of patients whose management changed of 31% (95% CI 12-50) What types of AD biomarkers are used currently in clinical practice? Blood-Brain Biomarkers for Alzheimer’s Disease 6  Amyloid-PET Molecular biomarkers - focus on Alzheimer’s Blood-Brain Biomarkers for Alzheimer’s Disease 7  Defining Alzheimer’s disease Alzheimer neuropathologic changes necessary but not sufficient for establishing the diagnosis of AD Blood biomarkers How are they measured? Blood biomarkers in the research setting Plasma p-tau217 Blood-Brain Biomarkers for Alzheimer’s Disease 8  Pilot study Previous studies indicate large variation in clinician decision making. Memory service clinicians have limited experience with specialist test results. There are identifiable gaps in training needs for clinicians using a blood biomarker for Alzheimer’s disease. Data from my pilot study indicated the gap between clinicians’ self-rating of understanding and their behaviour in applying the test result in diagnosis. Blood-Brain Biomarkers for Alzheimer’s Disease 9  Interpretation Continuous measure Medical co-morbidities/Diverse populations/ Co-pathology Specificity (e.g. age) Clinical picture/holistic Conflicting results Interpretation Supporting clinicians to use a novel Alzheimer’s disease blood test Memory Service Barriers/Enablers Accessibility Acceptability Knowledge Utility COM-B Model & Behaviour Change Wheel Framework Study Overview Blood-Brain Biomarkers for Alzheimer’s Disease 10  Aims To establish plasma p-tau217 as a widely available NHS test To demonstrate utility and cost-effectiveness in real-life NHS memory clinics across the UK To provide evidence sufficient to apply for MHRA licensing and NICE approval Year 1 Year 2 Year 3 Year 4 Year 5 Jan-Dec 24 Jan-Dec 25 Jan-Dec 26 Jan-Dec 27 Jan-Dec 28 P-tau217 as NHS test Stage 1 Cut-points, confounders UCL/H MHRA approval p-tau217 in n>500 existing plasma samples + PET/CSF Two different platforms Blood-Brain Biomarkers for Alzheimer’s Disease 11  Interpretation tool Establish plasma p-tau217 as NHS test MHRA approval for use in an RCT Year 1 Year 2 Year 3 Year 4 Jan-Dec 24 Jan-Dec 25 Jan-Dec 26 Jan-Dec 27 P-tau217 as NHS test Stage 1 Cut-points, UCL/H confounders MHRA approval Ongoing Stage 2 validation of Ethics Imperial cut-points vs amyloid PET Samples from patients with amyloid PET status available Sent in real time Ongoing validation of cut-points Year 1 Year 2 Year 3 Year 4 Jan-Dec 24 Jan-Dec 25 Jan-Dec 26 Jan-Dec 27 Pt-au217 as NHS test Stage 1 Cut-points, UCL/H confounders MHRA approval Ongoing Stage 2 validation of Ethics Imperial cut-points vs amyloid PET RCT embedded in >20 memory clinics in the CRN network Early (3m) vs late (12m) disclosure of Stage 3 Ethics, set-up, ptau-217 result Memory clinics training, MHRA NHS clinic visits at 0, 3m, 12m. Research telephone clinics at 6m, 15m RCT embedded in >20 memory services in CRN network Early (3m) vs late (12m) disclosure of p-tau217 result NHS clinic visits at 0, 3, 12m; research phone calls at 6, 15m Year 1 Year 2 Jan-Dec 24 Jan-Dec 25 Stage 1 UCL/H P-tau217 as NHS test Blood-Brain Biomarkers for Alzheimer’s Disease 12  Cut-points, confounders MHRA approval Ongoing Stage 2 validation of Ethics Imperial cut-points vs amyloid PET RCT embedded in >20 memory clinics in the CRN network Early (3m) vs late (12m) disclosure of Stage 3 Ethics, set-up, ptau-217 result Memory clinics training, MHRA NHS clinic visits at 0, 3m, 12m. Research telephone clinics at 6m, 15m Outputs MHRA submission Blood-Brain Biomarkers for Alzheimer’s Disease 13 Blood-Brain Biomarkers for Alzheimer’s Disease 14