Diagnose Alzheimer’s Disease with Clinical and Biomarker Assessments
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This interactive case study was organised and funded by Eli Lilly.
Medical writing support was provided by Jessica Jinks, EMJ, London, UK.
This interactive case study is provided for educational and disease awareness purposes only and does not constitute clinical guidance, a recommendation for treatment, or an endorsement of any diagnostic product. Healthcare professionals should always consult applicable local regulations, guidelines, and prescribing information before making clinical decisions. The blood-based biomarkers discussed herein, including plasma P-tau217 assays, are currently under evaluation for clinical use worldwide and may not be approved, cleared, or available for diagnostic use in all countries or jurisdictions. The patient case presented is hypothetical, and outcomes may not be reflective of clinical studies or real-life circumstances.
The content of this interactive case study was created by Eli Lilly and Company and is inspired by clinical scenarios.
Learning Objectives
By reviewing this patient case, you will have a deeper understanding of:
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How to integrate clinical and biomarker assessments to make an accurate diagnosis of AD in the earliest symptomatic stages.
The role of blood-based biomarkers in the diagnostic pathway of patients with early symptomatic AD (MCI and mild dementia due to AD).
Abbreviations
Abbreviations: AD: Alzheimer’s disease; MCI: mild cognitive impairment.
Patient Background and Past Medical History
Maria, a 72-year-old female patient, has experienced onset of the following symptoms, which have gradually progressed over the past year:
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Difficulty remembering dates and events Problems with word finding
She is independent in all activities of daily life, although her daughter reports that she has been late with her bills on a few occasions.
Patient details:
Married with four children and three grandchildren University educated Accountant (retired)
Family history:
Cardiovascular disease Type 2 diabetes Alzheimer’s disease (mother)
This is a hypothetical patient case.
Click to Explore Maria’s Medical History
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Abbreviations: ACE: angiotensin-converting enzyme; bpm: beats per minute; SSRI: selective serotonin reuptake inhibitor.
Depressive episode successfully treated with SSRI around 10 years ago Type 2 diabetes Hypertension
ACE inhibitor Biguanide
Heart rate: 72 bpm Blood pressure: 138/70 mmHg
Initial Clinical Assessment
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Abbreviations: MoCA: Montreal Cognitive Assessment.
References
References: 1. Nasreddine ZS et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9. Erratum in: J Am Geriatr Soc. 2019;67(9):1991. 2. MoCA Cognition. MoCA test paper versions. Available at: https://mocacognition.com/paper#paper_form_full. Last accessed: 21 April 2026.
General neurological exam: Normal
Mental status: Alert, insightful, good effort on testing
Cognitive assessment MoCA: 25/30 (normal ≥26)1,2
Cognitive assessment Figure copy: incorrect
Cognitive assessment Clock drawing: 3/3 Draw CLOCK (ten past eleven; 3 points)
Additional Testing
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Comprehensive neuropsychological tests
Daily functioning and mood symptoms assessment
Standard blood tests
Footnote
Footnote: *Other blood tests to consider per patient history: syphilis and HIV, heavy metals.
References: 1. González DA et al. Comprehensive evaluation of the functional activities questionnaire (FAQ) and its reliability and validity. Assessment. 2022;29(4):748-63. 2. Brañez-Condorena A et al. Accuracy of the Geriatric Depression Scale (GDS)-4 and GDS-5 for the screening of depression among older adults: a systematic review and meta-analysis. PLoS One. 2021;16(7):e0253899. 3. Greenberg SA et al. The Geriatric Depression Scale (GDS). 2012. Available at: https://nclhealthandcare.org.uk/wp-content/uploads/2022/04/Diagnosing-mental-health-in-care-homes-geriatric-depression-scale.pdf. Last accessed: 21 April 2026. 3. Greenberg SA. How to try this: the Geriatric Depression Scale: Short Form. Am J Nurs. 2007;107(10):60-9.
Abbreviations: BUN: blood urea nitrogen; FAQ: Functional Activities Questionnaire; GDS: Geriatric Depression Scale.
Comprehensive neuropsychological tests Memory Executive functions Language Constructional praxis Visual perception Conclusion: Impairment in verbal and non-verbal episodic memory and mild weakening of executive functions.
Daily functioning and mood symptoms assessment Function1 FAQ: 4/30 (≥9 = impaired function) Mood2-4 GDS: 4/15
Standard blood tests Basic routine panel: glucose, creatinine, BUN, liver function, electrolytes* Thyroid hormones Folate and vitamin B12 Complete blood count and clotting test Lipid profile All normal
Maria’s MRI Findings
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Mild cortical atrophy without a pattern to suggest a specific neurodegenerative process Mild ventriculomegaly, most likely related to cortical atrophy Mild periventricular white matter disease, likely ischaemic
MRI findings:
T1
FLAIR
GRE
Adapted from Ferreira et al.1
Adapted from Debette et al.2
Adapted from Agarwal et al.3
This represents a fictitious patient. The images have been sourced from literature for educational purposes.
Footnotes
Footnotes: T1: Adapted from Ferreira D et al. Subtypes of Alzheimer's disease display distinct network abnormalities extending beyond their pattern of brain atrophy. Front Neurol. 2019;10:524. Free-to-use figure under the Creative Commons Attribution 4.0 International License (CC BY 4.0): https://creativecommons.org/licenses/by/4.0/. Modified from original by cutting. FLAIR: Adapted from Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. With permission from BMJ Publishing Group Ltd. Modified from original by cutting. GRE: Adapted from Agarwal A et al. Amyloid-related imaging abnormalities in Alzheimer disease treated with anti-amyloid-β therapy. Radiographics. 2023;43(9):e230009. With permission from RSNA RadioGraphics. Modified from original by cutting.
Abbreviations: FLAIR: fluid-attenuated inversion recovery; GRE: gradient recalled echo.
References: 1. Ferreira D et al. Subtypes of Alzheimer's disease display distinct network abnormalities extending beyond their pattern of brain atrophy. Front Neurol. 2019;10:524. 2. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. 3. Agarwal A et al. Amyloid-related imaging abnormalities in Alzheimer disease treated with anti-amyloid-β therapy. Radiographics. 2023;43(9):e230009.
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Maria is presenting with clinical symptoms consistent with the early symptomatic stages of AD, which are corroborated by clinical assessment. Her MRI results suggest a mild vascular contribution to her symptoms, but are not definitive, which can be typical for someone of her age and early clinical presentation.
Which other evaluations could be performed to ensure an accurate diagnosis?
D
Biomarker testing to confirm underlying AD pathology
C
Psychiatric evaluation
B
Functional neuroimaging to assess cerebral metabolic patterns
A
EEG
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Abbreviations: AD: Alzheimer’s disease.
Continue to learn more about biomarker testing in the context of AD diagnosis.
Current Indications for AD Biomarker Testing in Clinical Practice
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Patients in whom AD is a potential cause of cognitive impairment
AND biomarker testing is expected to affect diagnosis and/or management by...
a. improving the accuracy of dementia diagnosis1-3 b. and/or determining whether patients may be candidates for AD-specific treatments, such as amyloid-targeted therapies.4,5
Patients who are undergoing an evaluation who have objective evidence of cognitive impairment.
Footnotes: German S3 guideline does not recommend the diagnosis of cerebral amyloid pathology based solely on blood biomarkers.
References: 1. Johnson KA et al.; Alzheimer's Association; Society of Nuclear Medicine and Molecular Imaging; Amyloid Imaging Taskforce. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. Alzheimers Dement. 2013;9(1):e-1-16. 2. Shaw LM et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement. 2018;14(11):1505-21. 3. Palmqvist S et al. Alzheimer's Association Clinical Practice Guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings. Alzheimers Dement. 2025;21(7):e70535. 4. Cummings J et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2023;10(3):362-77. 5. Rabinovici GD et al. Donanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2025;12(5):100150.
Plasma P-tau217 is a Superior Biomarker of Amyloid Pathology1*†
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P-tau217 is the highest performing biomarker of amyloid pathology in early-stage AD and performs better than plasma Aβ42/40.1 Tau phosphorylation at position 217 (P-tau217) is a sensitive and specific indicator of amyloid pathology.1 Peripheral sources of Aβ peptides (e.g., platelets) reduce the associations between plasma Aβ42/40 and amyloid pathology.1,2 Even combining p-tau181, Aβ42/40, and NfL is not as good as P-tau217 alone in classifying amyloid status in early symptomatic AD.1,2
Footnotes: *Plasma P-tau217 has shown consistently higher amyloid concordance in early-stage AD. †Blood biomarkers are currently under evaluation for clinical use worldwide. German S3 guideline does not recommend the diagnosis of cerebral amyloid pathology based solely on blood biomarkers.
Abbreviations: Aβ: amyloid beta; AD: Alzheimer’s disease; AUC: area under the curve; GFAP: glial fibrillary acidic protein; NfL: neurofilament light chain; P-tau: phosphorylated tau.
References: 1. Schindler SE et al.; Alzheimer's Disease Neuroimaging Initiative (ADNI) Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in Alzheimer's Disease Project Team. Head-to-head comparison of leading blood tests for Alzheimer's disease pathology. Alzheimers Dement. 2024;20(11):8074-96. 2. Shi M et al. Peripheral blood amyloid-β involved in the pathogenesis of Alzheimer's disease via impacting on peripheral innate immune cells. J Neuroinflammation. 2024;21(1):5.
Example of BBM Test with P-tau217 Used for Confirmation or Triaging
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A positive result would increase confidence that Maria’s symptoms are linked to amyloid pathology.2
P-tau217/Aβ421
Tested in specialty care For triaging or confirmation (rule-out or rule-in) Two cut-off approach Performing lab must validate cut-offs
Positive Confirms (rule-in) amyloid pathology in some people.
Intermediate Should be <15–20% of people; CSF, PET, or repeat BBM* in 1 year depending on urgency.
Negative Rules out amyloid pathology in some people.
100%
HIGH cut-off
LOW cut-off
0%
Adapted from Schindler et al.2
Footnotes: *Blood biomarkers are currently under evaluation for clinical use worldwide. German S3 guideline does not recommend the diagnosis of cerebral amyloid pathology based solely on blood biomarkers.
Abbreviations: Aß: amyloid beta; BBM: blood-based biomarker; CSF: cerebrospinal fluid; P-tau: phosphorylated tau.
References: 1. FDA. FDA approval document. 2025. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf24/K242706.pdf. Last accessed: 23 April 2026. 2. Schindler SE et al. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer’s disease. Nat Rev Neurol. 2024;20(7):426-39.
Integration of BBM Tests in the Care Pathway as Triaging or Confirmatory Tools1
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Triaging Use
Individuals with cognitive complaints
Confirmatory Use
Footnotes: This pathway applies to secondary care and does not display the full patient flow, including primary care. German S3 guideline does not recommend the diagnosis of cerebral amyloid pathology based solely on blood biomarkers.
Abbreviations: Aß: amyloid beta; AD: Alzheimer's disease; BBM: blood biomarker; CSF: cerebrospinal fluid.
References: 1. Mielke MM et al. Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease. Alzheimers Dement. 2024;20(11):8216-24. 2. Schindler SE et al. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's disease. Nat Rev Neurol. 2024;20(7):426-39. 3. Palmqvist S et al. Alzheimer's Association Clinical Practice Guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings. Alzheimers Dement. 2025;21(7):e70535.
Minimum acceptable performance
Aß+ or intermediate result
Clinical and structural imaging workup
Triaging AD BBM test
Confirmatory biomarker test
Results indicate AD pathology
Results do not indicate AD pathology
Aß+
Aß-
Further evaluation for non-AD causes of symptoms
Discuss biomarkers results and therapeutic options with patient and family
A triaging test:3 A negative result rules out AD pathology with high probability. A positive result should be confirmed using another method (CSF AD biomarkers or amyloid PET).
Minimum acceptable performance standards for triage BBM test: ≥90% sensitivity and ≥75–85% specificity for amyloid PET status.2,3
A confirmatory test:3 A negative result rules out AD pathology. A positive test confirms AD pathology with a high probability.
Maria’s AD Biomarker Results
Maria underwent a plasma P-tau217/Aβ42 ratio test, which yielded an intermediate value that was read as indeterminate.1 The subsequent CSF analysis showed: Aß42/Aß40: Low P-tau181 and P-tau181/Aß42: High T-tau: High
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Abbreviations: Aß: amyloid beta; CSF: cerebrospinal fluid; P-tau: phosphorylated tau.
Reference
Reference: 1. FDA. FDA approval document. 2025. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf24/K242706.pdf. Last accessed: 23 April 2026.
Given the patient information presented, what is the diagnosis?
Subjective cognitive decline
MCI due to AD
Dementia of uncertain aetiology
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E
Other
Abbreviations: AD: Alzheimer's disease; CSF: cerebrospinal fluid; MCI: mild cognitive impairment.
Vascular cognitive impairment
QUESTION 2
Maria’s symptoms are consistent with the early symptomatic stages of AD The clinical assessment indicates AD and confirms the level of severity of cognitive decline, consistent with MCI CSF biomarker results confirm AD pathology
Key Learnings from Maria’s Case
Cognitive symptoms often have multiple causes.1
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Cognitive symptoms often have multiple causes, and misdiagnosis may result in inappropriate treatment and inaccurate prognoses.1 Many conditions other than AD can cause or exacerbate cognitive impairment; therefore, a comprehensive assessment should be used to identify the potential alternatives.
Comprehensive clinical assessment.1
A comprehensive clinical assessment involves:1 Medical evaluation Neurological exam Cognitive testing Laboratory assessment of potential reversible aetiologies of cognitive impairment Structural neuroimaging
AD biomarker testing should always be combined with a comprehensive clinical assessment.1,2
AD biomarker testing is not intended as a standalone diagnostic test for symptomatic AD; it should always be integrated with a comprehensive clinical assessment.1,2
Abbreviations: AD: Alzheimer's disease.
References: 1. Schindler SE et al. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer’s disease. Nat Rev Neurol. 2024;20(7):426-39. 2. 2. Mielke MM et al. Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease. Alzheimers Dement. 2024;20(11):8216-24.
Key Learnings Continued
Blood biomarker tests, including those that measure P-tau217, can provide evidence of amyloid pathology as a potential cause of symptoms. However, even highly accurate BBM tests can return intermediate/indeterminant results.1* The two-cut-off approach, used by the BBM Workgroup, defines three categories of results:1
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1. POSITIVE
Footnotes: *The BBM Workgroup states that 5–20% of individuals have borderline amyloid levels, which are values near the cut-off such that repeat testing may yield discordant results. To address this, the Workgroup considered two-cut offs to define three result categories: positive, intermediate/indeterminant, and negative.1 German S3 guideline does not recommend the diagnosis of cerebral amyloid pathology based solely on blood biomarkers.
Abbreviations: BBM: blood biomarker; CSF: cerebrospinal fluid; P-tau217: phosphorylated tau at position 217.
References: 1. Schindler SE et al. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer’s disease. Nat Rev Neurol. 2024;20(7):426-39. 2. FDA. FDA approval document. 2025. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf24/K242706.pdf. Last accessed: 23 April 2026.
1. POSITIVE Values above the upper cut-off indicate a high likelihood of brain amyloid pathology.1,2
2. INTERMEDIATE/INDETERMINANT Values in between the two cut-offs warrant further evaluation with amyloid PET imaging or amyloid CSF assays.1,2
2. INTERMEDIATE/ INDETERMINANT
3. NEGATIVE
3. NEGATIVE Values below the lower cut-off suggest brain amyloid pathology is unlikely.1,2
BBM tests are anticipated to play two key roles: supporting triage decisions and confirming amyloid pathology.1,2
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Triaging BBM tests
Confirmatory BBM tests
Abbreviations: BBM: blood biomarker; CSF: cerebrospinal fluid.
References: 1. Schindler SE et al. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer’s disease. Nat Rev Neurol. 2024;20(7):426-39. 2. Palmqvist S et al. Alzheimer's Association Clinical Practice Guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings. Alzheimers Dement. 2025;21(7):e70535.
Performance threshold
Performance threshold ≥90% sensitivity with 85% specificity in primary care and ≥75–85% specificity in secondary care, depending on the availability of follow-up test.1
Positive result
Positive result A positive result indicates a higher likelihood of amyloid pathology, which should be confirmed with another method such as CSF biomarkers or amyloid PET imaging.1,2
Negative result
Negative result A negative result suggests an individual is unlikely to have amyloid pathology and may benefit from evaluation for other causes of cognitive impairment.1
Positive result Positive result identifies the presence of amyloid pathology with strong concordance to amyloid PET.1
Performance threshold ≥90% sensitivity and ≥90% specificity.1
CMAT-35803| CMAT-35803 | MMAT-04724 | CMAT-35364 | CMAT-36439 | PP-ALZ-PT-0019 | CMAT-36454 | MMAT-05922 | PP-NB-CO-0884 | CMAT-35803 | PP-ALZ-PT-0019
