Springer2024047Alzheimer'sRoom1

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SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Serial MRI of the brain, especially early in the treatment course 2 Lumbar puncture at 3 and 6 months 3 Amyloid PET imaging at 1, 3, and 12 months 4 Abigail is not eligible for treatment with an anti-amyloid therapy 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Amyloid PET results Patient ID: 12345678 Date of birth: March 14, 1952 Date of scan: May 13, 2025 Type of scan: Amyloid PET Indication: Cognitive decline under investigation; concern for possible AD Results: There is diffuse increased tracer uptake in the bilateral frontal, parietal, temporal, and posterior cingulate cortices, consistent with abnormal cortical amyloid deposition. Uptake is greater than expected for age-matched controls without amyloid pathology. White matter shows physiologic uptake. Cerebellum and sensorimotor cortex appear spared, as is typical in AD pathology. No evidence of focal lesions or mass effect. Clinical interpretation: Positive amyloid PET scan, indicating the presence of significant beta-amyloid plaque deposition. This result is supportive of a diagnosis within the AD spectrum, in the appropriate clinical context.

Question 3 background

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GlossaryAD, Alzheimer’s disease APOE, apolipoprotein E gene ARIA, amyloid-related imaging abnormalities CBC, complete blood count CKD, chronic kidney disease CMP, complete metabolic panel CSF, cerebrospinal fluid CT, computed tomography DMT, disease-modifying therapy MCI, mild cognitive impairment MoCA, Montreal Cognitive Assessment MRI, magnetic resonance imaging PCP, primary care physician PET, positron emission tomography p-tau, phosphorylated tau QD, once daily TSH, thyroid-stimulating hormone

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Genetic testing report: APOE genotyping Patient ID: 12345678 Date of birth: March 14, 1952 Date of report: May 27, 2025 Test performed: APOE genotyping Results: APOE genotype: ε3/ε4 Clinical interpretation: The patient carries one copy of the APOE ε4 allele and one copy of the APOE ε3 allele.

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SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Amyloid PET scans are graded on a 5-point scale to report probability of AD 2 Changes in tau are present before beta-amyloid in the CSF of patients with early AD 3 There are now international, standardized cut off values for blood-based biomarker testing 4 The rate of serious complications after lumbar puncture in suspected AD is approximately 1% 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

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SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 “We have to face some unpleasant facts.” 2 “Can we discuss your memory today?” 3 “Can you bring in a family member next week to help with your visit?” 4 “You have dementia, remember your positive beta-amyloid PET scan? 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

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Question 1 background

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CONTINUE TO ESCAPE QUESTION 1

Atri A, et al. Alzheimers Dement. 2025;21(6):e14333. Willis DR, Summanwar D, Brosch JR. Fam Pract Manag. 2025;32(3)17-20.

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Congratulations on completing the escape room!

What would you tell the patient and her mother, assuming that anti-amyloid therapies are available in your region? (required)

A cognitive assessment is performed using the Montreal Cognitive Assessment (MoCA); however, the rest of Abigail’s neurological examination yields normal results. The opportunity to utilize new blood-based biomarkers* is available (specifically p-tau217 and Aβ42:Aβ40 ratio); therefore, a blood test is also ordered. Removed extra
bullet Date of test May 10, 2025 Medical history Hypertension and CKD Cognitive assessment score (MoCA) 20 Blood p-tau217 Markedly elevated Blood plasma Aẞ42:Aẞ40 ratio Markedly reduced

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RETURN TO THE MAIN SITE (OPENS IN A NEW TAB) TO EXPLORE OTHER ESCAPE ROOMS AND LEARN HOW EACH TEAM MEMBER CONTRIBUTES TO COLLABORATIVE PATIENT CARE

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SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 “You are not a candidate for anti-amyloid therapy because your disease is not severe enough yet.” 2 “You are not a candidate for anti-amyloid therapy because the MRI demonstrated ischemic changes in your brain.” 3 “The presence of APOE ε4 gene increases the risk of complications from anti-amyloid therapy.” 4 “You are not a candidate for anti-amyloid therapy because of your age.” 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Dubois B, et al. Lancet Neurol. 2022;20(6):484-496. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169.

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Cummings J, et al. J Prev Alzheimers Dis. 2023;10(3):362-377. Foley KE, et al. Front Aging Neurosci. 2024;16:1412006. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12(5):100150. Sims JR, et al. JAMA. 2023;330(6):512-527. van Dyck CH, et al. N Engl J Med. 2023;388(1):9-21.

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Blood plasma Aẞ42:Aẞ40 ratio

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Clue 2: Abigail’s MoCA and blood-based biomarker results

Question 2

Dr Chuck Vega on the interpretation of imaging and fluid biomarkers

May 10, 2025

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A 68-year-old woman presents to primary care with progressive memory loss over the past 18 months.

Date of test

Question 3

A cognitive screen in the office indicates that she has mild cognitive impairment (MCI).

Atri A, et al. Alzheimers Dement. 2025;21(6):e14333. O’Brien K, Largent E, Karlawish J. Alzheimers Dement. 2024;21(1):e14200.

Baseline question

Hypertension and CKD

Name: Abigail Jones Age: 73 years old Sex: Female

How many Alzheimer's disease patients do you see on average per week? (required)

Medical history

TYPE YOUR ANSWER IN THE FIELD PROVIDED

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA

*Blood-based biomarkers are still under investigation. Further validation, standardization, and regulatory alignment are needed before routine clinical implementation worldwide.

Question 4 background

Clue 1: Abigail’s patient chart

CLAIM CREDITS

The day after her appointment, her son (with his mother next to him) calls to discuss her case with you and states, “Her memory is just getting old. It happens to everyone.”

Answer

MAIN SITE

Cognitive assessment score (MoCA)

Dr Chuck Vega on applying biomarker testing to guide treatment decisions

Family history

Invalid response. Please type in a number value.

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Blood pressure: 165/94 mmHgpressure: 165/94 mmHg

Dr Chuck Vega on shared decision-making

Vitals

3. Hotspots will be a mixture of questions and patient scenarios. Answer each by selecting the best choice and then 'Submit'. You must answer each question to proceed and obtain a clue.

Has a daughter, who lives across the country and does not accompany her to appointments

5. Use the arrow buttons to navigate.

Blood pressure: 165/94 mmHg

Clue 3: Abigail’s radiology and genetic testing reports

Markedly elevated

Medical history

4. Clues you collect will appear in the Clues panel. They will give you the information you need to answer the final questions to escape the clinic. You can also click on the Clues to review the clue pages.

Blood p-tau217

• Hypertension and chronic kidney disease (CKD) for the past 10 years: well-controlled with daily medication • Mammogram 2 months ago: missed appointment • Laboratory appointment for wellness examination: not completed • Patient of the practice for 8 years, has previously followed through on all orders

Presenting reason Annual wellness examination Social history Retired accountant Family history Has a daughter, who lives across the country and does not accompany her to appointments Vitals Blood pressure: 165/94 mmHg Medical history Hypertension and chronic kidney disease (CKD) for the past 10 years: well-controlled with daily medicationMammogram 2 months ago: missed appointmentLaboratory appointment for wellness examination: not completedPatient of the practice for 8 years, has previously followed through on all ordersCurrent medications Lisinopril 20 mg once daily (QD)Dapagliflozin 10 mg QDCurrent symptoms Abigail reports no symptoms but has forgotten to take her blood pressure medication today. She has also missed some recent medical appointments. When reminded, she says “That’s right! Sorry that I forgot. I’ll get those done right away”.

Annual wellness examination

Markedly reduced

Current medications

Presenting reason

Welcome to the primary care physician (PCP) escape room with Dr Chuck Vega.

Question

“I knew I had an appointment at the doctor’s today because I'd written it on my calendar, but I’m not really sure what the appointment is for. But I was already running late when I left the house, and when I got to the clinic, I couldn’t find the entrance even though I’ve been coming here for 8 years. It looked different. I asked the receptionist why they’d changed it, but she just gave me a strange look. I’m probably just getting old. I live alone and handle things myself. There’s no one really checking in on me so it’s a lot to handle sometimes. My daughter lives across the country and we don’t talk much. I manage my groceries, my bills, my appointments, even if I have to write everything down.”

• Lisinopril 20 mg once daily (QD) • Dapagliflozin 10 mg QD

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How to use

SUBMIT

Retired accountant

BEGIN

Social history

1. This room has multiple hotspots which will be presented one at a time. Select each hotspot to access more information and a question.

Based on Abigail’s patient chart in Clue 1, what would you select as the most appropriate next step?

Abigail Jones

2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question.

Patients with MCI and early-stage AD can present in different ways. Primary care physicians need to stay alert to identify cognitive or behavioral changes and approach assessments with empathy.Timely detection is essential in early-stage AD. Intervening before progression to dementia, before widespread neurodegeneration, offers a better chance of changing the patient’s clinical course.Biomarkers are becoming key tools to aid in timely diagnosis of AD and help to initiate earlier treatment. Several imaging, CSF, and blood-based biomarkers have been adopted in clinical practice, with varying indications for diagnosis, staging, and indicating biological treatment effect.Blood-based biomarkers represent a promising and accessible screening tool for AD in primary care settings. However, further validation is required to develop standardized interpretation criteria and determine cutoffs before they can be widely adopted in clinical practice.Amyloid-targeting therapies can modify the disease course in early-stage AD; however, appropriate patient selection with biomarkers and monitoring for treatment side effects using MRI is essential.Greater awareness, patient choice, and access to biomarker testing and amyloid-targeting therapies will lead to improvements in diagnosis and care. While amyloid plays a role, developing combination treatments that target multiple disease processes will be key to improving outcomes.

Escape question 1

6. After each hotspot question, a video will be available with expert commentary and guidance.

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Q5-only styles Start of question set 1 Perform a screening test for cognitive impairment 2 Order a complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), and brain MRI 3 Refer the patient to a memory specialist for CSF or PET biomarker testing 4 Carry out blood-based biomarker testing for AD pathology 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

6. After each hotspot question, a video will be available with expert commentary and guidance.

7. Use the toolbar to access this help guide, the main menu, glossary, and references.

What is the best next step in Abigail’s care, based on her cognitive assessment and blood-based biomarker results in Clue 2? (required)

Menu WITHIN EACH SECTION, USE THE BUTTONS TO NAVIGATE. Title Baseline question PCP medical office Hotspot 1 Background Question 1 Expert commentary Clue 1 Hotspot 2 Question 2 Expert commentary Clue 2 Hotspot 3 Background Question 3 Expert commentary Clue 3 Hotspot 4 Background Question 4 Expert commentary Clue 4 Escape door Clue 1 Escape question 1 Clue 2 Escape question 2 Clue 3 Escape question 3 Clue 4 Escape question 4 Key takeaways Conclusion and next steps

CONTINUE TO HOW TO USE

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Brain magnetic resonance imaging (MRI) with contrast 2 Amyloid positron emission tomography (PET) scan 3 Blood Aβ42:Aβ40 ratio 4 Blood p-tau217 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

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7. Use the toolbar to access this help guide, the main menu, glossary, and references.

Clue 4: Abigail’s experience

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Which of the following statements about AD biomarkers is most accurate? (required)

Bornhorst JA, et al. Neurology. 2025;104(3):e210287. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169. Zhang B, et al. Front Aging Neurosci. 2023;15:1150510.

Hotspot 1

Hotspot 2

You have reached the end of Room 1: PCP medical office

Her medical history includes hypertension and hyperlipidemia, which are well-controlled.

Hotspot 3

You are considering referring her for further testing to support a diagnosis of Alzheimer’s disease (AD).

Hotspot 4

Atri A, et al. Alzheimers Dement. 2025;21(6):e14333. O’Brien K, Largent E, Karlawish J. Alzheimers Dement. 2024;21(1):e14200.

Duits FH, et al. Alzheimers Dement. 2016;12(2):154-163. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169. Jack CR Jr, et al. Lancet Neurol. 2022;10(10):866-869. Palmqvist S, et al. JAMA. 2024;332(15):1245-1257.

Escape door

Which of the following diagnostic approaches would you select to provide the most reliable evidence of underlying AD pathology in this patient?

Room 1: PCP medical office

SELECT EACH GLOWING HOTSPOT TO ANSWER THE CORRESPONDING QUESTION. YOU CAN RETURN TO COMPLETED HOTSPOTS AT ANY TIME TO REVIEW YOUR RESPONSES.

Abigail reports no symptoms but has forgotten to take her blood pressure medication today. She has also missed some recent medical appointments. When reminded, she says “That’s right! Sorry that I forgot. I’ll get those done right away”.

Foley KE, et al. Front Aging Neurosci. 2024;16:1412006. Sims JR, et al. JAMA. 2023;330(6):512-527. van Dyck CH, et al. N Engl J Med. 2023;388(1):9-21.

Question 1

Given Abigail’s test results in Clue 3, what would be your primary monitoring approach if she initiates treatment with an anti-amyloid therapy? (required)

Escape question 3

Based on Abigail’s experience provided in Clue 4, how would you approach the subject of cognitive impairment with her? (required)

A memory specialist has diagnosed her with mild AD.

Escape question 4

Your 80-year-old patient with memory loss and challenges with executive function has a positive amyloid PET scan.

Key takeaways

Her initial MRI demonstrated diffuse ischemic white matter changes, and her apolipoprotein E (APOE) ε4 testing is positive for one copy (heterozygous).

Her daughter brings the patient to you, as her trusted primary care provider, and asks to start treatment with an anti-amyloid therapy.

You diagnose a 66-year-old woman with MCI and start a diagnostic workup to establish an etiology.

PLEASE COMPLETE THE FORM (OPENS IN A NEW TAB) TO COLLECT YOUR CME CREDITS, AND TO PROVIDE FEEDBACK

Dr Chuck Vega on the utility of AD biomarkers

Current symptoms

This educational content is intended for a global audience. Local regulations, clinical guidelines, and approval statuses may vary. Learners should always refer to and follow the guidance, policies, and requirements applicable in their own country or institution. This activity is supported by an educational grant from Lilly.

How would you respond? (required)

PREPARING THE MULTIDISCIPLINARY CARE TEAM

CONTINUE TO ESCAPE QUESTION 3

Question 4

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SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 “Is it OK if I explain my diagnosis to the both of you?” 2 “MCI is a serious condition, so please take it seriously.” 3 “Can I speak with your mother privately for a moment?” 4 “What if I told you that I could help slow her cognitive decline with a disease-modifying therapy (DMT)?” 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question.

CONTINUE TO CLUE 4

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BACK TO THE BACKGROUND QUESTION

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Escape question 2

CONTINUE TO THE ESCAPE ROOM

CONTINUE TO KEY TAKEAWAYS

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Refer for laboratory work, including syphilis and hepatitis studies 2 Discuss the possibility of MCI and role of further biomarker testing to confirm the results 3 Diagnose AD based on her blood-based biomarker results 4 Order either computed tomography (CT) or MRI imaging of the brain 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

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BACK TO KEY TAKEAWAYS

Question 2 Which of the following statements about AD biomarkers is most accurate? (required) SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON 1Amyloid PET scans are graded on a 5-point scale to report probability of AD2Changes in tau are present before beta-amyloid in the CSF of patients with early AD3There are now international, standardized cut off values for blood-based biomarker testing4The rate of serious complications after lumbar puncture in suspected AD is approximately 1%5Unsure Centered Submit Button SUBMIT Feedback box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 4: Expert commentary

MAIN MENU

How to Use 1 1. This room has multiple hotspots which will be presented one at a time. Select each hotspot to access more information and a question. 2 2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question. 3 3. Hotspots will be a mixture of questions and patient scenarios. Answer each by selecting the best choice and then ‘Submit’. You must answer each question to proceed and obtain a clue. 4 4. Clues you collect will appear in the Clues panel. They will give you the information you need to answer the final questions to escape the clinic. You can also tap on the Clues to review the clue pages. 5 5. After each hotspot question, a video will be available with expert commentary and guidance. 6 6. Use the arrow buttons to navigate. 7 7. Use the header bar to access the glossary and the main menu. 8 8. Use the toolbar to access this help guide, clues, glossary, and references.

TAP THE “NEXT” BUTTON FOR CLUE 4

Atri A, et al. Alzheimers Dement. 2025;21(6):e14333. Willis DR, Summanwar D, Brosch JR. Fam Pract Manag. 2025;32(3)17-20.

Clue 1: Abigail’s patient chart ✅ Centered patient card clipboard top abi image Name: Abigail Jones Age: 73 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Presenting reason Annual wellness examination Social history Retired accountant Family history Has a daughter who lives across the country and does not accompany her to appointments Vitals Blood pressure: 165/94 mmHg Right-column bullets Medical history Hypertension and chronic kidney disease (CKD) for the past 10 years: well-controlled with daily medicationMammogram 2 months ago: missed appointmentLaboratory appointment for wellness examination: not completedPatient of the practice for 8 years, has previously followed through on all ordersCurrent medications Lisinopril 20 mg once daily (QD)Dapagliflozin 10 mg QDCurrent symptoms Abigail reports no symptoms but has forgotten to take her blood pressure medication today. She has also missed some recent medical appointments. When reminded, she says “That’s right! Sorry that I forgot. I’ll get those done right away.”

Title Question 1 Question text Which of the following diagnostic approaches would you select to provide the most reliable evidence of underlying AD pathology in this patient? Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Brain magnetic resonance imaging (MRI) with contrast2Amyloid positron emission tomography (PET) scan3Blood Aβ42:Aβ40 ratio4Blood p-tau2175Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Title Escape question 2 Question text What is the best next step in Abigail’s case, based on her cognitive assessment and blood-based biomarker results in Clue 2? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Refer for laboratory work, including syphilis and hepatitis studies2Discuss the possibility of MCI and role of further biomarker testing to confirm the results3Diagnose AD based on her blood-based biomarker results4Order either computed tomography (CT) or MRI imaging of the brain5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Clue Title Clue 4: Abigail’s experience Abigail image + quote Left: image and name Abigail Jones Right: quote text “I knew I had an appointment at the doctor’s today because I'd written it on my calendar, but I’m not really sure what the appointment is for. But I was already running late when I left the house, and when I got to the clinic, I couldn’t find the entrance even though I’ve been coming here for 8 years. It looked different. I asked the receptionist why they’d changed it, but she just gave me a strange look. I’m probably just getting old. I live alone and handle things myself. There’s no one really checking in on me so it’s a lot to handle sometimes. My daughter lives across the country and we don’t talk much. I manage my groceries, my bills, my appointments, even if I have to write everything down.” Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

Hotspot 4

Hotspot 1: Expert commentary

BACK

Hotspot 2

TAP THE “NEXT” BUTTON FOR CLUE 1

Clue 2: Abigail’s MoCA and blood-based biomarker results clipboard top abi image Name: Abigail Jones Age: 73 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets A cognitive assessment is performed using the Montreal Cognitive Assessment (MoCA); however, the rest of Abigail’s neurological examination yields normal results. The opportunity to utilize new blood-based biomarkers* is available (specifically p-tau217 and Aβ42:Aβ40 ratio); therefore, a blood test is also ordered. Right-column bullets Date of test May 10, 2025 Medical history Hypertension and CKD Cognitive assessment score (MoCA) 20 Blood p-tau217 Markedly elevated Blood plasma Aβ42:Aβ40 ratio Markedly reduced ✅ Italicized note *Blood-based biomarkers are still under investigation. Further validation, standardization, and regulatory alignment are needed before routine clinical implementation worldwide.

Question 3 background Your 80-year-old patient with memory loss and challenges with executive function has a positive amyloid PET scan. A memory specialist has diagnosed her with mild AD. Her initial MRI demonstrated diffuse ischemic white matter changes, and her apolipoprotein E (APOE) ε4 testing is positive for one copy (heterozygous). Her daughter brings the patient to you, as her trusted primary care provider, and asks to start treatment with an anti-amyloid therapy. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 3

Hotspot 1

Escape Door

Title Escape question 3 Question text Given Abigail’s test results in Clue 3, what would be your primary monitoring approach if she initiates treatment with an anti-amyloid therapy? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Serial MRI of the brain, especially early in the treatment course2Lumbar puncture at 3 and 6 months3Amyloid PET imaging at 1, 3, and 12 months4Abigail is not eligible for treatment with an anti-amyloid therapy5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Clue Title Clue 3: Abigail’s radiology and genetic testing reports Amyloid PET scan results Amyloid PET scan resultsPatient ID: 12345678 Date of birth: March 14, 1952 Date of scan: May 13, 2025 Type of scan: Amyloid PET Indication: Cognitive decline under investigation; concern for possible AD Results: There is diffuse increased tracer uptake in the bilateral frontal, parietal, temporal, and posterior cingulate cortices, consistent with abnormal cortical amyloid deposition. Uptake is greater than expected for age-matched controls without amyloid pathology. White matter shows physiologic uptake. Cerebellum and sensorimotor cortex appear spared, as is typical in AD pathology. No evidence of focal lesions or mass effect. Clinical interpretation: Positive amyloid PET scan, indicating the presence of significant beta-amyloid plaque deposition. This result is supportive of a diagnosis within the AD spectrum, in the appropriate clinical context. Genetic testing report Genetic testing report: APOE genotyping Patient ID: 12345678 Date of birth: March 14, 1952 Date of report: May 27, 2025 Test performed: APOE genotyping Results: APOE genotype: ε3/ε4 Clinical interpretation: The patient carries one copy of the APOE ε4 allele and one copy of the APOE ε3 allele.TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 3

Bornhorst JA, et al. Neurology. 2025;104(3):e210287. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169. Zhang B, et al. Front Aging Neurosci. 2023;15:1150510.

Dubois B, et al. Lancet Neurol. 2022;20(6):484-496. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169.

Question 4 background You diagnose a 66-year-old woman with MCI and start a diagnostic workup to establish an etiology. The day after her appointment, her son (with his mother next to him) calls to discuss her case with you and states, “Her memory is just getting old. It happens to everyone.” TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 4

Hotspot 3

Title Key takeaways Bullet Box Patients with MCI and early-stage AD can present in different ways. Primary care physicians need to stay alert to identify cognitive or behavioral changes and approach assessments with empathy.Timely detection is essential in early-stage AD. Intervening before progression to dementia, before widespread neurodegeneration, offers a better chance of changing the patient’s clinical course.Biomarkers are becoming key tools to aid in timely diagnosis of AD and help to initiate earlier treatment. Several imaging, CSF, and blood-based biomarkers have been adopted in clinical practice, with varying indications for diagnosis, staging, and indicating biological treatment effect.Blood-based biomarkers represent a promising and accessible screening tool for AD in primary care settings. However, further validation is required to develop standardized interpretation criteria and determine cutoffs before they can be widely adopted in clinical practice.Amyloid-targeting therapies can modify the disease course in early-stage AD; however, appropriate patient selection with biomarkers and monitoring for treatment side effects using MRI is essential.Greater awareness, patient choice, and access to biomarker testing and amyloid-targeting therapies will lead to improvements in diagnosis and care. While amyloid plays a role, developing combination treatments that target multiple disease processes will be key to improving outcomes. Next Button Box TAP THE “NEXT” BUTTON TO CONTINUE

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Room 1: PCP medical office

Title Question 3 Question text What would you tell the patient and her mother, assuming that anti-amyloid therapies are available in your region? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1“You are not a candidate for anti-amyloid therapy because your disease is not severe enough yet.”2“You are not a candidate for anti-amyloid therapy because the MRI demonstrated ischemic changes in your brain.”3"The presence of APOE ε4 gene increases the risk of complications from anti-amyloid therapy.”4“You are not a candidate for anti-amyloid therapy because of your age.”5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 3: Expert commentary

Question 1 rationale Auto-expanding background box Amyloid PET imaging and cerebrospinal fluid (CSF) biomarkers, such as the Aβ42:Aβ40 ratio and p‑tau217, currently offer the most established and reliable evidence for AD pathology. While blood-based biomarkers have shown promising development, they do not yet match the diagnostic reliability and validation record of PET imaging and CSF biomarkers. Currently, two blood-based biomarkers have received FDA clearance for clinical use: p‑tau181, which can be used in primary care settings to help rule out AD-related pathology, and the p‑tau217/Aβ1‑42 ratio. Cognitive screening and clinical assessment should precede biomarker testing, to help identify patients with the highest pre-test probability of AD pathology. This ensures that biomarker testing is used judiciously and interpreted in the appropriate clinical context. Structural MRI is recommended in the diagnostic workup to rule out non-dementia causes of cognitive impairment and assess patterns of atrophy, but it lacks accuracy and specificity for AD, as these changes can overlap with other conditions and normal aging. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

TAP THE “NEXT” BUTTON FOR CLUE 3

Question 4 rationale Auto-expanding background box In this case, you should acknowledge the values of the patient and her family but should still provide your opinion regarding the best course forward. Asking permission automatically signals respect for the patient and her family and will bring their guard down. Trying to cut out the patient’s son could be harmful in helping to advance the patient’s care, and it would be too soon to promise a DMT at this point in the diagnostic process. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

How many Alzheimer's disease patients do you see on average per week? (required) TYPE YOUR ANSWER IN THE FIELD PROVIDED

Title Question 4 Question text How would you respond? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1“Is it OK if I explain my diagnosis to the both of you?”2“MCI is a serious condition, so please take it seriously.”3“Can I speak with your mother privately for a moment?”4“What if I told you that I could help slow her cognitive decline with a disease-modifying therapy (DMT)?”5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 1 rationale Auto-expanding background box Abigail has symptoms of cognitive impairment, so a screening test in the office is the most appropriate initial step. A positive screening result can help guide the next phase of evaluation, such as laboratory tests, brain imaging, and specialist referral. Screening prior to biomarker testing ensures that diagnostic resources are used appropriately, minimizes unnecessary procedures, and helps identify patients who are most likely to benefit from further investigation and potential treatment. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 2

Title Escape question 1 Question text Based on Abigail’s patient chart in Clue 1, what is the most appropriate next step? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Perform a screening test for cognitive impairment2Order a complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), and brain MRI3Refer the patient to a memory specialist for CSF or PET biomarker testing4Carry out blood-based biomarker testing for AD pathology5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Title Congratulations on completing the escape room! ✅ Completion Box with Confetti Inside You have reached the end of Room 1: PCP medical office ✅ Form Button Box PLEASE COMPLETE THE FORM (OPENS IN A NEW TAB) TO COLLECT YOUR CME CREDITS, AND TO PROVIDE FEEDBACK CLAIM CREDITS ✅ Main Site Box RETURN TO THE MAIN SITE (OPENS IN A NEW TAB) TO EXPLORE OTHER ESCAPE ROOMS AND LEARN HOW EACH TEAM MEMBER CONTRIBUTES TO COLLABORATIVE PATIENT CARE MAIN SITE

Atri A, et al. Alzheimers Dement. 2025;21(6):e14333. O’Brien K, Largent E, Karlawish J. Alzheimers Dement. 2024;21(1):e14200.

Hotspot 2: Expert commentary

TAP THE “NEXT” BUTTON FOR CLUE 2

Foley KE, et al. Front Aging Neurosci. 2024;16:1412006. Sims JR, et al. JAMA. 2023;330(6):512-527. van Dyck CH, et al. N Engl J Med. 2023;388(1):9-21.

Escape question 2 rationale Auto-expanding background box The next best step in Abigail’s care is to discuss the likely diagnosis of MCI. Further biomarker testing to confirm beta-amyloid positivity by a memory specialist will be necessary prior to initiation of amyloid-targeted therapies, and this testing should be completed expediently before she suffers further cognitive decline. While blood-based biomarkers may represent a useful screening tool for AD, they cannot be used for diagnosis at this time. There are currently no standardized cutoff criteria for interpretation of blood-based biomarkers and the results may be impacted by patient factors, such as Abigail’s CKD. A laboratory evaluation should be performed but should include syphilis and hepatitis testing only among selected at-risk individuals. An MRI is preferred over CT for initial brain imaging. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 3

Escape question 4 rationale Auto-expanding background box This approach offers empathy and respects Abigail’s autonomy by asking permission to discuss her memory. It opens the conversation gently and non-confrontationally, which is crucial when speaking with someone who is highly independent and potentially unaware or confused about their diagnosis. Asking her to bring a family member is not appropriate, given her lack of support system. While Abigail has previously been diagnosed with AD, her cognitive impairment limits her ability to retain or recall that information. Telling her straight away that she has dementia is not ideal. It may come across as blunt or accusatory. Asking her to recall the PET scan assumes not only memory of a prior conversation but also understanding of a technically complex diagnostic test. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 4

Question 2 rationale Auto-expanding background box Amyloid PET scans are interpreted visually by trained clinicians and reported as either positive or negative for amyloid deposition. A positive scan supports the presence of AD pathology, particularly in the setting of cognitive symptoms. Similarly, CSF testing showing decreased Aβ42 or a decreased Aβ42:Aβ40 ratio are consistent with early-stage AD. In the pathophysiological progression of AD, beta-amyloid accumulates first, followed by rising levels of p‑tau in CSF. Lumbar puncture, used to obtain CSF, has a low rate of serious complications (~1%), making it a low-risk procedure for biomarker analysis. Blood-based biomarkers, including plasma Aβ42:Aβ40 and p‑tau217, are emerging tools with growing clinical utility, though standardized interpretation criteria and cutoffs are still evolving. Currently, two blood-based biomarkers have received FDA clearance for clinical use: p‑tau181, which can be used in primary care settings to help rule out AD–related pathology, and the p‑tau217/Aβ1‑42 ratio. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

1 1. This room has multiple hotspots which will be presented one at a time. Select each hotspot to access more information and a question. 2 2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question. 3 3. Hotspots will be a mixture of questions and patient scenarios. Answer each by selecting the best choice and then ‘Submit’. You must answer each question to proceed and obtain a clue. 4 4. Clues you collect will appear in the Clues panel. They will give you the information you need to answer the final questions to escape the clinic. You can also tap on the Clues to review the clue pages. 5 5. After each hotspot question, a video will be available with expert commentary and guidance. 6 6. Use the arrow buttons to navigate. 7 7. Use the header bar to access the glossary and the main menu. 8 8. Use the toolbar to access this help guide, clues, glossary, and references.

Title Escape question 4 Question text Based on Abigail’s experience provided in Clue 4, how would you approach the subject of cognitive impairment with her? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1“We have to face some unpleasant facts.”2“Can we discuss your memory today?”3“Can you bring in a family member next week to help with your visit?”4“You have dementia, remember your positive beta-amyloid PET scan?”5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 3 rationale Auto-expanding background box Treatment with an anti-amyloid therapy, such as lecanemab or donanemab, requires serial MRI monitoring of the brain for ARIA. Although CSF biomarkers and amyloid PET imaging can be used to monitor biological treatment effect, they are not sufficient to monitor for ARIA. Abigail is eligible for anti-amyloid therapy because she has confirmed amyloid pathology on PET imaging. While her heterozygous APOE ε3/ε4 status places her at a higher risk of developing ARIA, this does not disqualify her from treatment. Instead, it necessitates appropriate monitoring through serial MRI to ensure safety during therapy. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 4

Question 3 rationale Auto-expanding background box This patient can receive anti-amyloid therapy, which is indicated for MCI and mild AD. However, the risk of amyloid-related imaging abnormalities (ARIA) increases with the number of APOE ε4 alleles the patient carries, and patients should be carefully educated on and monitored for treatment side effects using MRI. Ischemic changes of the brain are very common among older adults with cognitive impairment, and neither they nor age are contraindications to treatment. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 1 background A 68-year-old woman presents to primary care with progressive memory loss over the past 18 months. A cognitive screen in the office indicates that she has mild cognitive impairment (MCI). Her medical history includes hypertension and hyperlipidemia, which are well-controlled. You are considering referring her for further testing to support a diagnosis of Alzheimer’s disease (AD). TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 1

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA PREPARING THE MULTIDISCIPLINARY CARE TEAM Welcome to the primary care physician (PCP) escape room with Dr Chuck Vega. BEGIN footer This educational content is intended for a global audience. Local regulations, clinical guidelines, and approval statuses may vary. Learners should always refer to and follow the guidance, policies, and requirements applicable in their own country or institution. This activity is supported by an educational grant from Lilly.end div container