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LEFT column Presenting reason Presenting with her family due to memory concernsSocial and family history Recently retired administrative assistantExcessve alcohol intake over the past 3 years; however, substance abuse now ceasedMother had dementia due to AD, based on knowledge at that timeHas a husband, who continues to work full time, and a daughter RIGHT column Medical history Recurrent infections over the past 3 yearsMagnetic resonance imaging (MRI) in the past year shows age-related microvascular changes but no significant areas of atrophy or major processes or eventsLaboratory tests Comprehensive metabolic panel (CMP), complete blood count (CBC), thyroid stimulating hormone (TSH), and glycated hemoglobin (HbA1c) all in normal rangesCurrent medications Medication review negative for contributing factorsCurrent symptoms Unable to maintain her previous (prior to illness) daily routinesHer family finds her mildly repetitive

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

SUBMIT

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Yes, but an MRI is required prior to initiating treatment 2 Yes, but self-monitoring for symptoms of ARIA is necessary 3 No, repeat p-tau217 blood biomarker testing is required before treatment initiation 4 No, her APOE ε3/ε4 genotype excludes her from treatment 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

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.

Date of test

Question 3 background

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

BACK TO EXPERT COMMENTARY

SUBMIT

Name: Susan Age: 67 years old Sex: Female

GlossaryAD, Alzheimer’s disease APOE, apolipoprotein E geneAPP, advanced practice provider ARIA, amyloid-related imaging abnormalities CBC, complete blood count CMP, comprehensive metabolic panel CSF, cerebrospinal fluid DETeCD–ADRD, Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer's Disease and Related Disorders DMT, disease-modifying therapy HbA1c, glycated hemoglobin MCI, mild cognitive impairment MRI, magnetic resonance imaging PET, positron emission tomography p-tau, phosphorylated tau STI, sexually transmitted infection TSH, thyroid stimulating hormone

BACK TO ESCAPE ROOM

Vitals

SUBMIT

Family history

BACK TO ESCAPE ROOM

SUBMIT

Susan decides to undergo blood-based biomarker testing for p-tau217. Her results are as follows:

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 It confirms a diagnosis of AD and rules out other causes of cognitive decline 2 It suggests the presence of AD pathology, but clinical correlation and additional biomarker testing may be needed 3 It is unreliable and should not be used in the workup of early-stage AD 4 It indicates irreversible neuronal loss and late-stage dementia 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

SUBMIT

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Present the option of treatment, including the benefits, risks, eligibility criteria, and role of biomarker testing in informing treatment decisions, and explore the patient’s values and preferences 2 Recommend starting an amyloid-targeting therapy promptly, given the potential for better outcomes with early intervention, and explain that treatment may slow progression 3 Tell her daughter that it is too early to discuss treatment, as Susan is only mildly symptomatic, and suggest delaying treatment discussions until symptoms progress 4 Provide lifestyle advice, and schedule a follow-up in 12 months 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Retired accountant

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

BACK TO BACKGROUND

SUBMIT

Question 1 background

CONTINUE TO EXPERT COMMENTARY

Current symptoms

SUBMIT

Social history

BACK TO QUESTION

CONTINUE TO ESCAPE QUESTION 1

Atri A, et al. Alzheimers Dement. 2025;21:e14333. Dubois B, et al. Alzheimers Res Ther. 2023;15:175. Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169.

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”.

BACK TO CLUE 1

Congratulations on completing the escape room!

As the provider supporting her care, which of the following actions would you take? (required)

SCROLL FOR MORE

CONTINUE TO CLUE 2

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

BACK TO ESCAPE QUESTION 1

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Reassure her that APOE ε4 positivity confirms the diagnosis, and recommend treatment immediately 2 Educate her that APOE ε4 increases the risk of amyloid-related imaging abnormalities (ARIA), and explain the importance of monitoring during treatment 3 Inform her that APOE ε4 status means that disease-modifying therapies (DMTs) will not be effective, and recommend cognitive stimulation instead 4 Explain that APOE testing replaces the need for PET or CSF confirmation of amyloid pathology 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Susan and her family, including her husband and daughter, are hopeful based on what they have seen in the news about amyloid-targeting therapies for AD but also worried based on what they have seen. Her family history and experience with her mother’s AD trajectory weigh heavily on Susan’s mind. She is worried about her husband, who still works full time, and his evolving role as her care partner. They are open to seeing a specialist for care and treatment but also want to hear from you, her long-time primary care APP, about what to expect and what their options are.

Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Mielke MM, et al. Alzheimers Dement. 2024;20:8216-8224.

CONTINUE TO ESCAPE QUESTION 2

Medical history

BACK TO CLUE 2

Clue 4: Susan’s concerns

Cummings J, et al. J Prev Alzheimers Dis. 2023;10(3):362-377. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12(5):100150.

Dr Carolyn Clevenger on using biomarkers to guide treatment selection and monitoring

CONTINUE TO CLUE 3

You are asked for input on next steps in evaluating possible early-stage Alzheimer’s disease (AD).

BACK TO ESCAPE QUESTION 2

100%

Question 2

Annual wellness examination

You are assessing Mr Thompson, a 72-year-old man presenting to your primary care service with concerns about memory changes noted by his wife.

Dr Carolyn Clevenger on the interpretation of AD biomarkers

May 10, 2025

CLOSE CLUE PAGE

You are an APP working in a primary care clinic. A 72-year-old male patient has been referred due to increasing forgetfulness and difficulty managing medications over the past year.

Presenting reason

He is still working part time and says that staying independent is his top priority. His wife is concerned about his safety when driving.

Question 3

Atri A, et al. Alzheimers Dement. 2024;21:e14333.

Answer

Baseline question

Hypertension and CKD

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

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.

TYPE YOUR ANSWER IN THE FIELD PROVIDED

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA

Question 4 background

CLAIM CREDITS

LEFT column Amyloid PET Positive APOE genotyping ε3/ε4

MAIN SITE

Cognitive assessment score (MoCA)

Susan and her family would like to pursue amyloid-targeted therapy. She undergoes confirmatory PET imaging to confirm amyloid pathology, as well as APOE genotype testing to determine her risk for ARIA. Her results are as follows:

Question

Invalid response. Please type in a number value.

Markedly reduced

SUBMIT

Dr Carolyn Clevenger on shared decision-making and AD biomarkers

Clue 3: Susan’s PET scan and APOE genotyping results

Blood plasma Aẞ42:Aẞ40 ratio

Welcome to the advanced practice provider (APP) escape room with Dr Carolyn Clevenger.

How to use

BEGIN

5. Use the arrow buttons to navigate.

Clue 1: Susan’s clinical profile

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

What are the next steps in the evaluation of Susan’s cognitive symptoms listed in Clue 1? (required)

Clue 2: Susan’s blood biomarker test results

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

The definition and understanding of AD have evolved, enabling detection at earlier stages, when interventions may be most effective.Diagnostic tools have expanded, allowing APPs to play a greater role in the early identification and referral of patients with cognitive concerns.Biomarkers are transforming AD diagnosis, supporting earlier, more accurate detection of pathology. While CSF analysis and amyloid PET imaging remain the gold standard, their use in primary care is limited by cost, accessibility, and resource requirements.Blood-based biomarkers (e.g., plasma p-tau217 and p-tau181) are emerging as less invasive, scalable tools that can be used in primary care settings to triage patients and prompt specialist referral. Although further validation is ongoing, these tools hold promise for improving access to timely diagnosis.Confirmation of amyloid pathology via PET or CSF is still essential when considering amyloid-targeting therapies.APPs can play a central role in:- Educating patients and caregivers about biomarker testing options- Performing lumbar punctures for CSF testing and conducting blood-based biomarker testing- Supporting shared, informed decision-making around diagnosis and treatment- Monitoring safety and outcomes in patients receiving DMTs- Facilitating referrals and continuity of care across multidisciplinary teams

Markedly elevated

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 Neuropsychological testing, neurological exam, biomarker testing 2 Neurological exam, biomarker testing, screen for sexually transmitted infection (STI) 3 Neuropsychological testing, neurological exam, trial of acetylcholinesterase inhibitor 4 Neuropsychological testing, genetic counseling, biomarker testing 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.

Blood p-tau217

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

Menu WITHIN EACH SECTION, USE THE BUTTONS TO NAVIGATE. Title Baseline question APP 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 Take no further action because AD cannot be determined until autopsy 2 Recommend immediate cerebrospinal fluid (CSF) analysis via lumbar puncture 3 Refer for amyloid positron emission tomography (PET) scan 4 Order blood-based biomarker testing 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

SUBMIT

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

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Which of the following best describes the appropriate interpretation of an elevated plasma p-tau217 result in a patient presenting with symptoms of mild cognitive impairment (MCI)? (required)

Atri A, et al. Alzheimers Dement. 2025;21:e14333. Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Lai R, et al. J Biomedicines. 2024;12:1836. Mielke MM, et al. Alzheimers Dement. 2024;20:8216-8224. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

Hotspot 1

Hotspot 2

You have reached the end of Room 3: APP office

Hotspot 3

Hotspot 4

Atri A, et al. Alzheimers Dement. 2024;21:e14333. Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Frederiksen KS, et al. Alzheimers Res Ther. 2025;17:116. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

Atri A, et al. Alzheimers Dement. 2025;21:e14333. Lai R, et al. Biomedicines. 2024;12:1836. Mielke MM, et al. Alzheimers Dement. 2024;20:8216-8224.

Escape door

Plasma biomarker results Plasma p-tau217 elevated

Which of the following would you select as an appropriate initial screening step in the diagnostic process? (required)

Room 3: APP office

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

Clevenger C, et al. Geriatr Nurs. 2025;61:400-407. Cummings J, et al. J Prev Alzheimers Dis. 2023;10(3):362-377. Doran SJ, Sawyer R. Front Neurosci. 2024;18:1326784. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12(5):100150.

Question 1

Susan and her family ask you whether she would be eligible for treatment with an amyloid-targeting therapy. What would you tell them, based on the results in Clue 3? (required)

Escape question 3

Based on the concerns listed in Susan’s file in Clue 4, what is the most appropriate next step? (required)

Escape question 4

A patient with early-stage AD is found to carry one copy of the apolipoprotein E (APOE) ε4 allele and is being considered for an amyloid-targeting therapy.

Key takeaways

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

• 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

Dr Carolyn Clevenger on the utility of biomarkers for AD diagnosis

Current medications

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.

Plasma p-tau217 elevated 0.44 pg/mL (elevated)

Before initiating further investigations, such as ordering biomarker tests, what would you choose as an appropriate first step in the diagnostic process? (required)

PREPARING THE MULTIDISCIPLINARY CARE TEAM

CONTINUE TO ESCAPE QUESTION 3

Question 4

BACK TO CLUE 3

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Begin caregiver education to help prepare the family for a potential dementia diagnosis 2 Order biomarker testing to confirm or rule out AD pathology 3 Explore what matters most to Mr Thompson in terms of his values, goals, and daily functioning 4 Assess Mr Thompson’s awareness of his symptoms and their impact on safety and independence 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

SUBMIT

BACK TO ESCAPE QUESTION 3

CONTINUE TO ESCAPE QUESTION 4

BACK TO THE BACKGROUND QUESTION

Based on Susan’s plasma p-tau217 test results provided in Clue 2, which of the following reflects the optimal next step? (required)

BACK TO CLUE 4

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 Begin treatment with an amyloid-targeting therapy immediately, and schedule CSF testing in 12 months to monitor p-tau217 levels 2 Confirm eligibility with amyloid PET scan, confirm treatment preferences, and initiate treatment if patient elects this pathway 3 Hold off on any treatment; wait for symptom progression, and repeat cognitive testing in 6–12 months 4 Explain that the presence of tau elevation suggests late-stage disease and amyloid-targeting therapies are no longer appropriate 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Escape question 2

BACK TO ESCAPE QUESTION 4

BACK TO TITLE PAGE

CONTINUE

BACK TO KEY TAKEAWAYS

BACK

Hotspot 3: 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.

Room 1: PCP medical office

Question 3 background A patient with early-stage AD is found to carry one copy of the apolipoprotein E (APOE) ε4 allele and is being considered for an amyloid-targeting therapy. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 3

TAP THE “NEXT” BUTTON FOR CLUE 3

Title Escape question 2 Question text Based on Susan’s plasma p-tau217 test results provided in Clue 2, which of the following reflects the optimal next step? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Begin treatment with an amyloid-targeting therapy immediately, and schedule CSF testing in 12 months to monitor p-tau217 levels2Confirm eligibility with amyloid PET scan, confirm treatment preferences, and initiate treatment if patient elects this pathway3Hold off on any treatment; wait for symptom progression, and repeat cognitive testing in 6–12 months4Explain that the presence of tau elevation suggests late-stage disease and amyloid-targeting therapies are no longer appropriate5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Clue Title Clue 4: Susan’s concerns Abigail image + quote Left: image and name Right: quote text Susan and her family, including her husband and daughter, are hopeful based on what they have seen in the news about amyloid-targeting therapies for AD but also worried based on what they have seen. Her family history and experience with her mother’s AD trajectory weigh heavily on Susan’s mind. She is worried about her husband, who still works full time, and his evolving role as her care partner. They are open to seeing a specialist for care and treatment but also want to hear from you, her long-time primary care APP, about what to expect and what their options are. Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

Hotspot 4

Room 3: APP office

Hotspot 4: Expert commentary

Hotspot 1

Clue 1: Abigail’s patient chart ✅ Centered patient card clipboard top abi image Name: Susan Age: 67 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Presenting reason Presenting with her family due to memory concernsSocial and family history Recently retired administrative assistantExcessve alcohol intake over the past 3 years; however, substance abuse now ceasedMother had dementia due to AD, based on knowledge at that timeHas a husband, who continues to work full time, and a daughterMedical history Recurrent infections over the past 3 yearsMagnetic resonance imaging (MRI) in the past year shows age-related microvascular changes but no significant areas of atrophy or major processes or eventsLaboratory tests Comprehensive metabolic panel (CMP), complete blood count (CBC), thyroid stimulating hormone (TSH), and glycated hemoglobin (HbA1c) all in normal ranges Right-column bullets Current medications Medication review negative for contributing factorsCurrent symptoms Unable to maintain her previous (prior to illness) daily routinesHer family finds her mildly repetitive

Escape Door

Title Escape question 3 Question text Susan and her family ask you whether she would be eligible for treatment with an amyloid-targeting therapy. What would you tell them, based on the results in Clue 3? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Yes, but an MRI is required prior to initiating treatment2Yes, but self-monitoring for symptoms of ARIA is necessary3No, repeat p-tau217 blood biomarker testing is required before treatment initiation4No, her APOE ε3/ε4 genotype excludes her from treatment5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Question 2 Which of the following best describes the appropriate interpretation of an elevated plasma p-tau217 result in a patient presenting with symptoms of mild cognitive impairment (MCI)? (required) SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON 1It confirms a diagnosis of AD and rules out other causes of cognitive decline2It suggests the presence of AD pathology, but clinical correlation and additional biomarker testing may be needed3It is unreliable and should not be used in the workup of early-stage AD4It indicates irreversible neuronal loss and late-stage dementia5Unsure Centered Submit Button SUBMIT Feedback box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Question 1 rationale Auto-expanding background box Historically, autopsy has been the definitive test for AD pathology. However, advances in biomarker testing have allowed for more timely and accurate diagnosis of early-stage AD. CSF analysis and amyloid PET imaging are accurate tools for detecting AD pathology but may be limited by cost, access to specialized equipment, and the need for trained personnel. Blood-based biomarkers, such as plasma p‑tau217 and p‑tau181, are emerging as reliable, less invasive, and accessible tools in primary care settings. These tests are increasingly available in clinical primary care settings and can serve as practical and informative screening and triaging tools. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Title Question 1 Question text Which of the following would you select as an appropriate initial screening step in the diagnostic process? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Take no further action because AD cannot be determined until autopsy2Recommend immediate cerebrospinal fluid (CSF) analysis via lumbar puncture3Refer for amyloid positron emission tomography (PET) scan4Order blood-based biomarker testing5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 2

Hotspot 3

Question 2 rationale Auto-expanding background box Plasma p‑tau217 is a promising biomarker that reflects underlying AD pathology. An elevated result can support the presence of AD in patients with MCI, adding objective and meaningful data to the clinical picture. However, current evidence does not support using blood-based biomarkers in isolation to confirm an AD diagnosis or rule out other causes of cognitive decline. A full clinical assessment, including detailed history, cognitive testing, and potentially additional PET imaging or CSF biomarkers, is essential for an accurate and comprehensive diagnosis. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Title Key takeaways Bullet Box The definition and understanding of AD have evolved, enabling detection at earlier stages, when interventions may be most effective.Diagnostic tools have expanded, allowing APPs to play a greater role in the early identification and referral of patients with cognitive concerns.Biomarkers are transforming AD diagnosis, supporting earlier, more accurate detection of pathology. While CSF analysis and amyloid PET imaging remain the gold standard, their use in primary care is limited by cost, accessibility, and resource requirements.Blood-based biomarkers (e.g., plasma p‑tau217 and p‑tau181) are emerging as less invasive, scalable tools that can be used in primary care settings to triage patients and prompt specialist referral. Although further validation is ongoing, these tools hold promise for improving access to timely diagnosis.Confirmation of amyloid pathology via PET or CSF is still essential when considering amyloid-targeting therapies.APPs can play a central role in:- Educating patients and caregivers about biomarker testing options- Performing lumbar punctures for CSF testing and conducting blood-based biomarker testing- Supporting shared, informed decision-making around diagnosis and treatment- Monitoring safety and outcomes in patients receiving DMTs- Facilitating referrals and continuity of care across multidisciplinary teams Next Button Box TAP THE “NEXT” BUTTON TO CONTINUE

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Clue 1: Abigail’s patient chart ✅ Centered patient card clipboard top abi image Name:Susan Age: 67 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Presenting reason Presenting with her family due to memory concernsSocial and family history Recently retired administrative assistantExcessve alcohol intake over the past 3 years; however, substance abuse now ceasedMother had dementia due to AD, based on knowledge at that timeHas a husband, who continues to work full time, and a daughterMedical history Recurrent infections over the past 3 yearsMagnetic resonance imaging (MRI) in the past year shows age-related microvascular changes but no significant areas of atrophy or major processes or eventsLaboratory tests Comprehensive metabolic panel (CMP), complete blood count (CBC), thyroid stimulating hormone (TSH), and glycated hemoglobin (HbA1c) all in normal ranges Right-column bullets Current medications Medication review negative for contributing factorsCurrent symptoms Unable to maintain her previous (prior to illness) daily routinesHer family finds her mildly repetitive Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

Hotspot 1: Expert commentary

Title Question 3 Question text As the provider supporting her care, which of the following actions would you take? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Reassure her that APOE ε4 positivity confirms the diagnosis, and recommend treatment immediately2Educate her that APOE ε4 increases the risk of amyloid-related imaging abnormalities (ARIA), and explain the importance of monitoring during treatment3Inform her that APOE ε4 status means that disease-modifying therapies (DMTs) will not be effective, and recommend cognitive stimulation instead4Explain that APOE testing replaces the need for PET or CSF confirmation of amyloid pathology5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Question 3 rationale Auto-expanding background box Carrying the APOE ε4 allele is associated with a higher likelihood of developing ARIA if treated with amyloid-targeting therapies. However, APOE status alone is not diagnostic for AD and does not determine eligibility or treatment effectiveness. Confirmation of amyloid pathology through PET or CSF is required to guide decisions about treatment. As an APP, you can provide patient education around treatment safety and monitoring. You can help the patient understand: Why genetic testing was done (to personalize risk discussions, not confirm diagnosis) What ARIA is and why monitoring (e.g., routine MRIs during the first few months of treatment) is important What the monitoring schedule may include, such as MRI scans at baseline, at regular intervals after infusions, and if any new symptoms (e.g., headache, confusion, dizziness) appear You are also well positioned to facilitate shared decision-making conversations with patients and their care partners by exploring the patient’s priorities, values, and risk tolerance and by clearly outlining the potential benefits and risks of treatment to support informed consent and decision-making. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

TAP THE “NEXT” BUTTON FOR CLUE 1

Clue 3: Susan’s PET scan and APOE genotyping results ✅ Centered patient card clipboard top abi image Name: Susan Age: 67 years old Sex: Female Susan and her family would like to pursue amyloid-targeted therapy. She undergoes confirmatory PET imaging to confirm amyloid pathology, as well as APOE genotype testing to determine her risk for ARIA. Her results are as follows: ✅ Unified grey background for patient chart content Left-column bullets Amyloid PET Positive APOE genotyping ε3/ε4 Instruction TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 3

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.

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

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA PREPARING THE MULTIDISCIPLINARY CARE TEAM Welcome to the advanced practice provider (APP) escape room with Dr Carolyn Clevenger. 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

Title Question 4 Question text Before initiating further investigations, such as ordering biomarker tests, what would you choose as an appropriate first step in the diagnostic process? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Begin caregiver education to help prepare the family for a potential dementia diagnosis2Order biomarker testing to confirm or rule out AD pathology3Explore what matters most to Mr Thompson in terms of his values, goals, and daily functioning4Assess Mr Thompson’s awareness of his symptoms and their impact on safety and independence5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Clue 2: Susan’s blood biomarker test results ✅ Centered patient card clipboard top abi image Name: Susan Age: 67 years old Sex: Female Susan decides to undergo blood-based biomarker testing for p-tau217. Her results are as follows: ✅ Unified grey background for patient chart content Left-column bullets Plasma p-tau217 0.44 pg/mL (elevated) Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

Title Escape question 1 Question text What are the next steps in the evaluation of Susan’s cognitive symptoms listed in Clue 1? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Neuropsychological testing, neurological exam, biomarker testing2Neurological exam, biomarker testing, screen for sexually transmitted infection (STI)3Neuropsychological testing, neurological exam, trial of acetylcholinesterase inhibitor4Neuropsychological testing, genetic counseling, biomarker testing5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

TAP THE “NEXT” BUTTON FOR CLUE 4

Clue 1: Abigail’s patient chart ✅ Centered patient card clipboard top abi image Name:Susan Age: 67 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Presenting reason Presenting with her family due to memory concernsSocial and family history Recently retired administrative assistantExcessve alcohol intake over the past 3 years; however, substance abuse now ceasedMother had dementia due to AD, based on knowledge at that timeHas a husband, who continues to work full time, and a daughterMedical history Recurrent infections over the past 3 yearsMagnetic resonance imaging (MRI) in the past year shows age-related microvascular changes but no significant areas of atrophy or major processes or eventsLaboratory tests Comprehensive metabolic panel (CMP), complete blood count (CBC), thyroid stimulating hormone (TSH), and glycated hemoglobin (HbA1c) all in normal ranges Right-column bullets Current medications Medication review negative for contributing factorsCurrent symptoms Unable to maintain her previous (prior to illness) daily routinesHer family finds her mildly repetitive Instruction TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 1

Escape question 4 rationale Auto-expanding background box APPs play a key role in supporting informed and patient-centered decisions. In early symptomatic AD, it is important to discuss available treatment options, including benefits, risks, and eligibility criteria (e.g., confirmation of amyloid pathology and MRI screening). Exploring the patient’s values and preferences ensures that any next steps align with their goals and preferences. Starting treatment without these conversations undermines shared decision-making, whereas delaying discussion until symptoms worsen risks missing opportunities for early intervention and care planning. Simply offering lifestyle advice and deferring follow-up is not sufficient at this stage of disease. Instruction Box TAP THE “NEXT” BUTTON FOR KEY TAKEAWAYS

Question 4 rationale Auto-expanding background box As outlined in the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer's Disease and Related Disorders (DETeCD–ADRD) guidelines, the first and ongoing step in evaluating patients with cognitive concerns is to explore what matters most to them. For APPs, this means taking time to understand the patient’s values, life goals, and preferences before moving forward with clinical testing. This patient-centered approach is also a core principle of age-friendly and dementia-friendly care, and it ensures that all diagnostic and care planning decisions are aligned with the individual’s priorities. Establishing this foundation supports shared decision-making and builds trust between the patient, family, and healthcare team. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Title Congratulations on completing the escape room! ✅ Completion Box with Confetti Inside You have reached the end of Room 3: APP 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

Escape question 1 rationale Auto-expanding background box Current guidelines recommend a structured evaluation of cognitive symptoms that includes objective cognitive assessment (e.g., neuropsychological testing), a neurological examination, and initial serum biomarker testing. Biomarkers can support a diagnosis of AD by providing evidence of underlying pathological changes, such as amyloid deposition and tau-related neurodegeneration. Their use can increase diagnostic accuracy and facilitate earlier diagnosis, particularly in cases where clinical symptoms are subtle or with atypical clinical presentations. In the primary care setting, blood-based biomarkers are emerging as an accessible tool to triage patients and screen for AD pathology. However, biomarkers alone are not sufficient to inform AD diagnosis and should be used as a supplement to clinical assessment to support or confirm the clinical diagnosis. While STI screening, genetic counseling, and trial of symptom-targeted medications may be relevant in some cases, they are not core components of the initial diagnostic workup for cognitive symptoms. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 2

Question 4 background You are assessing Mr Thompson, a 72-year-old man presenting to your primary care service with concerns about memory changes noted by his wife. He is still working part time and says that staying independent is his top priority. His wife is concerned about his safety when driving. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 4

Escape question 2 rationale Auto-expanding background box Current guidelines recommend a structured evaluation of cognitive symptoms that includes objective cognitive assessment (e.g., neuropsychological testing), a neurological examination, and initial serum biomarker testing. Biomarkers can support a diagnosis of AD by providing evidence of underlying pathological changes, such as amyloid deposition and tau-related neurodegeneration. Their use can increase diagnostic accuracy and facilitate earlier diagnosis, particularly in cases where clinical symptoms are subtle or with atypical clinical presentations. In the primary care setting, blood-based biomarkers are emerging as an accessible tool to triage patients and screen for AD pathology. However, biomarkers alone are not sufficient to inform AD diagnosis and should be used as a supplement to clinical assessment to support or confirm the clinical diagnosis. While STI screening, genetic counseling, and trial of symptom-targeted medications may be relevant in some cases, they are not core components of the initial diagnostic workup for cognitive symptoms. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 2

Hotspot 2: Expert commentary

Escape question 3 rationale Auto-expanding background box Susan is amyloid PET positive and carries one copy of the APOE ε4 allele (heterozygous), which does not exclude her from treatment with amyloid-targeting therapies. However, appropriate use criteria and prescribing information for approved amyloid-targeting agents such as donanemab and lecanemab recommend that patients undergo a brain MRI before starting treatment to assess for pre-existing abnormalities and to establish a baseline for monitoring ARIA. Ongoing MRI monitoring is also required during treatment at predetermined intervals after infusions or if ARIA is suspected based on symptoms. This ensures safe and appropriate use of therapy. Susan should be informed about her increased risk of ARIA associated with her APOE genotype and supported in understanding the safety monitoring that would be required if she decides to proceed with treatment. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 4

Title Escape question 4 Question text Based on the concerns listed in Susan’s file in Clue 4, what is the most appropriate next step? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Present the option of treatment, including the benefits, risks, eligibility criteria, and role of biomarker testing in informing treatment decisions, and explore the patient’s values and preferences2Recommend starting an amyloid-targeting therapy promptly, given the potential for better outcomes with early intervention, and explain that treatment may slow progression3Tell her daughter that it is too early to discuss treatment, as Susan is only mildly symptomatic, and suggest delaying treatment discussions until symptoms progress4Provide lifestyle advice, and schedule a follow-up in 12 months5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

TAP THE “NEXT” BUTTON FOR CLUE 2

Question 1 background You are an APP working in a primary care clinic. A 72-year-old male patient has been referred due to increasing forgetfulness and difficulty managing medications over the past year. You are asked for input on next steps in evaluating possible early-stage Alzheimer’s disease (AD). TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 1