Default

CONTINUE TO QUESTION

CONTINUE TO CLUE

Name: Mike Age: 73 years old Sex: Male

SUBMIT

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Start an amyloid-targeting therapy immediately 2 Perform APOE genotyping before starting an amyloid-targeting therapy 3 Wait for symptom progression before initiating an amyloid-targeting therapy 4 Refer for psychotherapy 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Question 3 background

BACK TO EXPERT COMMENTARY

SUBMIT

GlossaryAD, Alzheimer’s disease APOE, apolipoprotein E geneARIA, amyloid-related imaging abnormalities CSF, cerebrospinal fluid MCI, mild cognitive impairment MMSE, Mini-Mental State Examination MRI, magnetic resonance imaging NfL, neurofilament light chain QD, once daily PET, positron emission tomography p-tau, phosphorylated tau

BACK TO ESCAPE ROOM

Markedly elevated

SUBMIT

BACK TO ESCAPE ROOM

SUBMIT

Current symptoms

100%

Blood p-tau217

Miguel

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1It confirms AD and rules out other causes 2 It shows that the patient has irreversible neuronal loss 3 Plasma p-tau217 is unreliable in psychiatric populations 4 It suggests AD pathology, but further testing is warranted 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 Start an amyloid-targeting therapy immediately to delay further progression 2 Explore the patient’s values and clearly explain the benefits and risks of available treatment options 3 Defer to the Eve’s decision because she is the primary care partner 4 Focus on reassurance rather than discussing treatment to help ease Miguel and Eve’s anxiety 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Markedly reduced

Social history

BACK TO BACKGROUND

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”.

SUBMIT

Question 1 background

CONTINUE TO EXPERT COMMENTARY

Blood plasma Aẞ42:Aẞ40 ratio

“Now that we know the results point to Alzheimer’s, I just want to help him do the right thing. But the more I read about these new therapies, the more worried I get, especially about the side effects. With how anxious he already is, I’m scared that starting treatment might do more harm than good.”

SUBMIT

LEFT column Presenting reason Recurrent depression and memory issuesPresenting to the clinic to see her biomarker test resultsSocial and family history Previously worked as an office worker, retired 3 years agoHas a daughter, who accompanies her to appointments RIGHT column Medical history Recurrent depression for the past 5 yearsMini-Mental State Examination (MMSE) 23/30 pointsClock-Drawing-Test abnormal (Shulman score 3)Biomarker test results Decreased CSF Aβ42Elevated CSF p-tau181Current medications Fluoxetine 40 mg once daily (QD)Current symptoms Lynda reports being more forgetful lately; however, she thinks this is normal for her ageHer daughter reports that she keeps forgetting to take her antidepressant medication. She has also missed a recent medication review

BACK TO QUESTION

CONTINUE TO ESCAPE QUESTION 1

Chan CK, et al. Alzheimers Dement (Amst). 2020;12(1):e12106. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169.

BACK TO CLUE 1

Congratulations on completing the escape room!

Which of the following pieces of evidence would you use to justify treatment initiation? (required)

Miguel is a 68-year-old patient with MCI and a history of generalized anxiety disorder. He is feeling very anxious after receiving the results of his CSF biomarker tests, which show a decreased Aβ42:Aβ40 ratio and elevated p-tau181, findings consistent with AD pathology. His daughter, Eve, has been reading about amyloid-targeting therapies and is concerned about their potential side effects.

Medical history

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 Apolipoprotein E (APOE ε4) positivity 2 Structural MRI showing hippocampal atrophy 3 PET or CSF evidence showing amyloid pathology 4 Completion of psychotherapy 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Date of test

Liguori C, et al. Front Aging Neurosci. 2018;10:38.

Name: Lynda Age: 68 years old Sex: Female

• 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

CONTINUE TO ESCAPE QUESTION 2

Name: Barbara Age: 73 years old Sex: Female

May 10, 2025

BACK TO CLUE 2

Cummings J, et al. J Prev Alzheimers Dis. 2023;10(3):362-377. Frederiksen KS, et al. Alzheimers Res Ther. 2025;17:116. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12(5):100150.

Clue 1: Lynda’s clinical profile

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Prof Robert Perneczky on using biomarkers for treatment selection and monitoring

CONTINUE TO CLUE 3

Annual wellness examination

Hypertension and CKD

BACK TO ESCAPE QUESTION 2

Presenting reason

Question 2

Barbara is your patient with symptoms of forgetfulness, confusion and low mood. Psychometric testing in the clinic indicates that she has MCI. She expresses interest in starting an amyloid-targeting therapy. You have received her PET scan report back from radiology, and the results are the following:

Medical history

A 71-year-old patient with symptoms of MCI and anxiety presents to your psychiatry service with their daughter.

Prof Robert Perneczky on the interpretation of AD biomarkers

CLOSE CLUE PAGE

A 73-year-old patient presents to your clinic with depressive symptoms and memory difficulties over the past year. Neuropsychological testing confirms mild cognitive impairment (MCI).

You mention to the patient that biomarker testing could be helpful to guide future treatment decisions; however, they are not sure what this means.

Current medications

Question 3

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

Family history

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

Baseline question

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

Answer

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

Cognitive assessment score (MoCA)

Clue 2: Mike’s diagnostic report

TYPE YOUR ANSWER IN THE FIELD PROVIDED

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA

Question 4 background

CLAIM CREDITS

Retired accountant

MAIN SITE

SUBMIT

Invalid response. Please type in a number value.

LEFT column Patient ID 12345678 Date of birth March 1, 1952 RIGHT column Date of scan May 20, 2025 Type of scan Amyloid PET scan performed using a radiotracer (e.g., florbetapir F18). Images acquired and reviewed in axial, sagittal, and coronal planes Indication Evaluation of cognitive decline in the context of depressive symptoms and memory complaints. Concern for possible AD Results Evidence of cortical tracer uptake (frontal and parietal cortex) Clinical interpretation Positive amyloid PET scan, indicating the presence of significant β-amyloid plaque deposition. These findings are consistent with an underlying AD process

SUBMIT

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

Prof Robert Perneczky on shared decision-making

Vitals

Clue 3: Barbara’s amyloid PET scan

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.

Eve

5. Use the arrow buttons to navigate.

Welcome to the psychiatrist escape room with Professor Robert Perneczky.

A 72-year-old patient with a history of anxiety presents to your clinic with memory complaints.

“I’ve seen the results, but I still don’t really understand what they mean for me. I feel overwhelmed and scared about starting treatment. I’m not sure I want to go down a path that might just make me more anxious.”

A blood-based biomarker test shows that plasma p-tau217 is elevated.

How to use

CSF analysis shows decreased Aβ42 and elevated p-tau181.

BEGIN

Medical history Symptoms of MCIDepressive symptoms and withdrawal from social activitiesCognitive assessment score MMSE 25/30 points, Clock-Drawing-Test abnormal (Shulan score 2)Plasma biomarker results Plasma p-tau217 elevatedMagnetic resonance imaging (MRI) Mild hippocampal atrophy

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

Referring to Clue 1, what is the most likely diagnosis based on Lynda’s clinical profile? (required)

Clue 4: Patient dialogue

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

Biomarkers are essential tools for distinguishing early-stage AD from psychiatric conditions like depressionInterpretation of biomarker results must consider psychiatric comorbidities and the overall clinical contextConfirmation of amyloid pathology is required before initiating amyloid-targeting therapies, even in patients with psychiatric symptomsShared decision-making is critical in psychiatric care, especially when discussing complex diagnostic and treatment optionsPsychiatrists play a key role in early identification and referral for patients with cognitive symptoms

Escape question 1

Question 2 background

5. 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 Major depressive disorder 2 Frontotemporal dementia 3 Early-stage AD 4 Normal aging 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.

Question

Menu WITHIN EACH SECTION, USE THE BUTTONS TO NAVIGATE. Title Baseline question Psychiarist medical office Hotspot 1 Background Question 1 Expert commentary Clue 1 Hotspot 2 Question 2 Background 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 The CSF results are suggestive but not definitive; arrange amyloid-PET imaging to further evaluate amyloid deposition 2 Consider the findings nonspecific to AD and attribute cognitive symptoms primarily to depression, deferring further dementia workup 3 The CSF profile supports AD pathology, increasing confidence that the cognitive impairment reflects early-stage AD rather than depression 4 Treat the abnormalities as age-related changes, repeat cognitive testing in one year, and monitor for progression 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

SUBMIT

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

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

How should this result be interpreted? (required)

Chapleau M, et al. J Nucl Med. 2022;63(Suppl 1):13S-19S.

Hotspot 1

Hotspot 2

You have reached the end of Room 2: psychiatrist office

Hotspot 3

Hotspot 4

Brickman AM, et al. Alzheimers Dement. 2021;17(8):1353-1364. Mielke MM, et al. Alzheimers Dement. 2024;20(11):8216-8224. Thijssen EH, et al. Lancet Neurol. 2021;20(9):739-752.

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

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.

Escape door

As the assessing clinician, how would you use these biomarker findings to guide your diagnosis? (required)

Room 2: Psychiatrist office

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

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. Vigneswaran S, et al. Alzheimers Dement. 2025;21(6):e70375.

Question 1

Based on Barbara’s PET scan results in Clue 3, what would you do? (required)

Escape question 3

Based on the information in Clue 4, what is the best next step? (required)

Escape question 4

Your 74-year-old patient with cognitive symptoms and comorbid depression wants to start an amyloid-targeting therapy.

Key takeaways

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

Prof Robert Perneczky on the utility of biomarkers for AD diagnosis

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.

What would you do next? (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 Recommend biomarker testing without discussion to avoid further confusion 2 Ask about patient values before discussing biomarker testing options to avoid further confusion 3 Emphasize that biomarker testing is routine and required for diagnosis 4 Let their care partner decide due to the patient's confusion 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

What action would you take next for Mike’s case, based on the information in Clue 2? (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 Start antidepressants 2 Refer for amyloid PET 3 Reassure him that his cognitive decline is likely due to his mental health, but suggest monitoring 4 Diagnose late-life depression 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

MAIN MENU

Question 2 background A 72-year-old patient with a history of anxiety presents to your clinic with memory complaints. A blood-based biomarker test shows that plasma p‑tau217 is elevated. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 2

Question 4 rationale Auto-expanding background box Shared decision-making is a collaborative process that involves understanding patient values and preferences before making decisions about their care. This is especially important in psychiatric care where insight and emotional responses vary. Recommending biomarker testing without discussion undermines the patient’s role in decision-making and emphasizing that testing is routine may pressure patients into compliance without understanding or agreement, which does not support informed consent. Letting the care partner decide may be appropriate in some specific contexts (e.g., when a patient lacks capacity), but in general, it sidelines the patient and does not align with the principles of shared decision-making. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 2 How should this result be interpreted? (required) SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON 1It confirms AD and rules out other causes2It shows that the patient has irreversible neuronal loss3Plasma p-tau217 is unreliable in psychiatric populations4It suggests AD pathology, but further testing is warranted5Unsure Centered Submit Button SUBMIT Feedback box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Room 1: PCP medical office

Title Congratulations on completing the escape room! ✅ Completion Box with Confetti Inside You have reached the end of Room 2: psychiatrist 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

Question 4 background A 71-year-old patient with symptoms of MCI and anxiety presents to your psychiatry service with their daughter. You mention to the patient that biomarker testing could be helpful to guide future treatment decisions; however, they are not sure what this means. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 4

Title Question 4 Question text What would you do next? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Recommend biomarker testing without discussion to avoid further confusion2Ask about patient values before discussing biomarker testing options to avoid further confusion3Emphasize that biomarker testing is routine and required for diagnosis4Let their care partner decide due to the patient's confusion5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Clue 2: Mike’s diagnostic report ✅ Centered patient card clipboard top abi image Name: Mike Age: 73 years old Sex: Male ✅ Unified grey background for patient chart content Medical history Symptoms of MCIDepressive symptoms and withdrawal from social activitiesCognitive assessment score MMSE 25/30 points, Clock-Drawing-Test abnormal(Shulan score 2) Right-column bullets Current medications Fluoxetine 40 mg once daily (QD)Magnetic resonance imaging (MRI) Mild hippocampal atrophy Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

Escape question 2 rationale Auto-expanding background box Mike has symptoms of MCI with slightly impaired formal psychometric test results in line with this diagnosis. His blood p‑tau217 and MRI findings are in line with AD, but confirmatory biomarker testing is required using CSF or PET. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 3

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

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. Vigneswaran S, et al. Alzheimers Dement. 2025;21(6):e70375.

BACK

Title Escape question 2 Question text What action would you take next for Mike’s case, based on the information in Clue 2? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Start antidepressants2Refer for amyloid PET3Reassure him that his cognitive decline is likely due to his mental health, but suggest monitoring4Diagnose late-life depression5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Title Key takeaways Bullet Box Biomarkers are essential tools for distinguishing early-stage AD from psychiatric conditions like depressionInterpretation of biomarker results must consider psychiatric comorbidities and the overall clinical contextConfirmation of amyloid pathology is required before initiating amyloid-targeting therapies, even in patients with psychiatric symptomsShared decision-making is critical in psychiatric care, especially when discussing complex diagnostic and treatment optionsPsychiatrists play a key role in early identification and referral for patients with cognitive symptoms Next Button Box TAP THE “NEXT” BUTTON TO CONTINUE

Hotspot 1

Clue 3: Barbara’s amyloid PET scan Barbara is your patient with symptoms of forgetfulness, confusion and low mood. Psychometric testing in the clinic indicates that she has MCI. She expresses interest in starting an amyloid-targeting therapy. You have received her PET scan report back from radiology, and the results are the following: ✅ Centered patient card clipboard top abi image Name: Barbara Age: 73 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Patient ID 12345678 Date of birth March 1, 1952 Date of scan May 20, 2025 Type of scan Amyloid PET scan performed using a radiotracer (e.g., florbetapir F18). Images acquired and reviewed in axial, sagittal, and coronal planes Right-column bullets Indication Evaluation of cognitive decline in the context of depressive symptoms and memory complaints. Concern for possible AD Results Evidence of cortical tracer uptake (frontal and parietal cortex) Clinical interpretation Positive amyloid PET scan, indicating the presence of significant β-amyloid plaque deposition. These findings are consistent with an underlying AD process Instruction TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 3

Question 3 rationale Auto-expanding background box Initiation of amyloid-targeting therapy requires confirmation of amyloid pathology via PET or CSF analysis. This ensures that the treatment is appropriate and aligned with the underlying disease process. Psychiatric comorbidities should not delay appropriate diagnostic workup. Even though (APOE) ε4 is a genetic risk factor for AD, it is not diagnostic and is not sufficient on its own to justify treatment with an amyloid-targeting therapy. While structural MRI showing hippocampal atrophy may support a neurodegenerative process, it is not specific to amyloid pathology and cannot replace biomarker confirmation. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Clue Title Clue 4: Patient dialogue Miguel is a 68-year-old patient with MCI and a history of generalized anxiety disorder. He is feeling very anxious after receiving the results of his CSF biomarker tests, which show a decreased Aβ42:Aβ40 ratio and elevated p-tau181, findings consistent with AD pathology. His daughter, Eve, has been reading about amyloid-targeting therapies and is concerned about their potential side effects. Abigail image + quote Left: image and name Miguel Right: quote text “I’ve seen the results, but I still don’t really understand what they mean for me. I feel overwhelmed and scared about starting treatment. I’m not sure I want to go down a path that might just make me more anxious.” Eve section (photo right, text left) Right: image and name Eve Left: quote text “Now that we know the results point to Alzheimer’s, I just want to help him do the right thing. But the more I read about these new therapies, the more worried I get, especially about the side effects. With how anxious he already is, I’m scared that starting treatment might do more harm than good.” Instruction TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 4

Title Question 3 Question text Which of the following pieces of evidence would you use to justify treatment initiation? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Apolipoprotein E (APOE ε4) positivity2Structural MRI showing hippocampal atrophy3PET or CSF evidence showing amyloid pathology4Completion of psychotherapy5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 2

TAP THE “NEXT” BUTTON FOR CLUE 4

Escape question 1 rationale Auto-expanding background box Lynda has both affective (recurrent depression) and cognitive symptoms, including abnormal psychometric test results (MMSE and Clock Drawing Tests). However, because her CSF neurodegeneration biomarkers (Aβ42 and p‑tau181) are both in line with AD, this diagnosis is the most likely explanation of her recent cognitive deterioration. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 2

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 Recurrent depression and memory issuesPresenting to the clinic to see her biomarker test resultsSocial history Previously worked as an office worker, retired 3 years agoHas a daughter, who accompanies her to appointmentsMedical history Recurrent depression for the past 5 yearsMini-Mental State Examination (MMSE) 23/30 pointsClock-Drawing-Test abnormal (Shulman score 3)Biomarker test results Decreased CSF Aβ42Elevated CSF p-tau181 Right-column bullets Current medications Fluoxetine 40 mg once daily (QD)Current symptoms Lynda reports being more forgetful lately; however, she thinks this is normal for her ageHer daughter reports that she keeps forgetting to take her antidepressant medication. She has also missed a recent medication review Instruction TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 1

Hotspot 2: Expert commentary

Escape Door

TAP THE “NEXT” BUTTON FOR CLUE 2

Hotspot 1: Expert commentary

TAP THE “NEXT” BUTTON FOR CLUE 1

Escape question 4 rationale Auto-expanding background box In the context of a patient who is anxious about their biomarker results and a care partner who is concerned about the potential side effects of treatment, the best next step is to engage in shared decision-making. This involves taking time to explain the implications of the biomarker results, explore the patient’s values, address both the patient’s and care partner’s concerns, and clearly outline the available treatment options, including their risks and benefits, in simple and easy-to-understand language. Recommending an amyloid-targeting therapy without discussion ignores the patient’s preferences and concerns, while avoiding discussions about treatment may increase anxiety and delay appropriate care that could slow disease progression. While care partners play an important role, the patient should remain the primary decision-maker unless they lack capacity. Instruction Box TAP THE “NEXT” BUTTON FOR KEY TAKEAWAYS

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.

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Title Question 1 Question text As the assessing clinician, how would you use these biomarker findings to guide your diagnosis? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1The CSF results are suggestive but not definitive; arrange amyloid-PET imaging to further evaluate amyloid deposition2Consider the findings nonspecific to AD and attribute cognitive symptoms primarily to depression, deferring further dementia workup3The CSF profile supports AD pathology, increasing confidence that the cognitive impairment reflects early-stage AD rather than depression4Treat the abnormalities as age-related changes, repeat cognitive testing in one year, and monitor for progression5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 3: Expert commentary

TAP THE “NEXT” BUTTON FOR CLUE 3

Question 3 background Your 74-year-old patient with cognitive symptoms and comorbid depression wants to start an amyloid-targeting therapy. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 3

Question 1 background A 73-year-old patient presents to your clinic with depressive symptoms and memory difficulties over the past year. Neuropsychological testing confirms mild cognitive impairment (MCI). CSF analysis shows decreased Aβ42 and elevated p-tau181. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 1

Question 1 rationale Auto-expanding background box A decreased Aβ42 and elevated p‑tau181 profile is consistent with amyloid and tau pathology, supporting a diagnosis of early-stage AD. This biomarker pattern is especially helpful in patients presenting with depression and MCI, where cognitive symptoms could otherwise be attributed to psychiatric causes. Biomarker evidence helps distinguish early-stage AD from primary psychiatric disorders. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Hotspot 4: Expert commentary

Room 2: Psychiatrist office

TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 3

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA PREPARING THE MULTIDISCIPLINARY CARE TEAM Welcome to the psychiatrist escape room with Professor Robert Perneczky. 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.

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.

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

Menu WITHIN EACH SECTION, USE THE BUTTONS TO NAVIGATE. Title Baseline question Psychiatrist office Hotspot 1 Background Question 1 Expert commentary Clue 1 Hotspot 2 Background 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

Title Escape question 1 Question text Referring to Clue 1, what is the most likely diagnosis based on Lynda’s clinical profile? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Major depressive disorder2Frontotemporal dementia3Early-stage AD4Normal aging5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 3 rationale Auto-expanding background box Barbara has early-stage AD based on her symptoms, the results of her psychometric tests, and a positive amyloid PET scan. Although she is eligible for amyloid-targeting therapy based on her PET scan results, APOE genotyping must be performed before treatment initiation to make an informed decision about her risk of amyloid-related imaging abnormalities (ARIA), possible treatment-related adverse events associated with amyloid-targeting therapies such as donanemab and lecanemab. The risk of ARIA increases with the number of APOE ε4 alleles the patient carries, and APOE ε4 homozygotes have a higher incidence of symptomatic and serious ARIA compared to non-carriers and heterozygotes. The risk of ARIA should be carefully considered before starting treatment, and patients should be thoroughly educated about their individual risk. A baseline brain MRI is also required before initiating treatment to establish risk, as well as serial MRIs over the course of treatment to monitor for ARIA. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 4

Question 2 rationale Auto-expanding background box An elevated plasma p‑tau217 suggests underlying AD pathology. However, blood-based biomarkers are not yet definitive diagnostic tools on their own. They should be interpreted in the context of clinical presentation and possibly confirmed with more specific tests, such as CSF biomarker testing or positron emission tomography (PET) imaging. This is especially important in patients with psychiatric comorbidities (e.g., anxiety, depression), where cognitive symptoms may be multifactorial. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Title Escape question 4 Question text Based on the information in Clue 4, what is the best next step? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Start an amyloid-targeting therapy immediately to delay further progression2Explore the patient’s values and clearly explain the benefits and risks of available treatment options3Defer to the Eve’s decision because she is the primary care partner4Focus on reassurance rather than discussing treatment to help ease Miguel and Eve’s anxiety5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Brickman AM, et al. Alzheimers Dement. 2021;17(8):1353-1364. Mielke MM, et al. Alzheimers Dement. 2024;20(11):8216-8224. Thijssen EH, et al. Lancet Neurol. 2021;20(9):739-752.

Cummings J, et al. J Prev Alzheimers Dis. 2023;10(3):362-377. Frederiksen KS, et al. Alzheimers Res Ther. 2025;17:116. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12(5):100150.

Title Escape question 3 Question text Based on Barbara’s PET scan results in Clue 3, what would you do? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Start an amyloid-targeting therapy immediately2Perform APOE genotyping before starting an amyloid-targeting therapy3Wait for symptom progression before initiating an amyloid-targeting therapy4Refer for psychotherapy5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

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