Springer2024047Alzheimer'sRoom4

SUBMIT

Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Mielke MM, et al. Alzheimers Dement. 2024;20:8216-8224. Palmqvist S, et al. Alzheimers Dement. 2025;21(7):e70535.

Answer

5. Use the arrow buttons to navigate.

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.

Cognitive assessment score (MoCA)

How to use

Symptoms Shows increased irritability, is more self-focused, and has become less socially activeReports anxiety and occasional forgetfulnessReasons for referral Referred to the memory service by her primary care provider, who is concerned that her symptoms may be indicative of ADImaging results Magnetic resonance imaging (MRI) adequate for ageMedical evaluation Evaluation with psychologist finds no significant abnormalitiesMoCA: 27/30 (normal)MMSE 25/30 (normal)CSF biomarker test results Aβ42: 540 (↓)Aβ42:Aβ40: 0.066 (↓)t-tau: 400 (normal)p-tau181: 45 (normal)

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

May 10, 2025

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.

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 EXPERT COMMENTARY

Date of test

Markedly elevated

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Question

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Blood p-tau217

You are evaluating a patient referred to your specialist memory clinic. After the initial consultation, you explain that a full diagnostic workup, including neuropsychological testing, imaging, and biomarkers, typically takes around 3 months.

BACK TO EXPERT COMMENTARY

A 71-year-old man is referred to your neurology clinic for evaluation of progressive memory difficulties over the past 18 months. He occasionally has word-finding difficulties and mild executive deficits but remains independent in all activities of daily living.

Fiona is an 80-year-old woman with a history of type 2 diabetes, osteoarthritis, and atrial fibrillation. She leads a fulfilling life and is particularly proud of her family, which includes her children and grandchildren. Fiona was recently diagnosed with MCI by her primary care physician following concerns raised during a routine checkup. Despite the diagnosis, she functions independently at home and can still drive a car. Her family is eager for her to undergo a more comprehensive memory assessment and have brought her to the clinic to explore the underlying causes of her cognitive changes and determine whether any treatments might be appropriate.

Clue 1: Adam’s clinical profile

Hypertension and CKD

BACK TO ESCAPE ROOM

The patient becomes frustrated, asks you to skip everything and “just take one blood test that explains everything.”

Fiona expresses hesitation about proceeding with further diagnostic workup. She shares,“At my age, I’m not sure I want to go through a bunch of tests. I don’t feel that bad, and I don’t want to be treated like I’m sick. I want to keep my driver’s license.”

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His past medical history includes well-controlled hypertension, no history of seizures, stroke, or anticoagulation therapy. The patient’s CSF biomarker tests indicate that he has decreased Aβ42:Aβ40 ratio and elevated p-tau181, supporting a diagnosis of MCI due to early-stage AD.

Cummings J, et al.J Prev Alzheimers Dis. 2023;10:362-377. Foley KE, et al. Front Aging Neurosci. 2024;16:1412006. Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

CONTINUE TO QUESTION

Markedly reduced

Her daughter voices a different view:“We just want to understand what’s happening and make sure Mom gets the best care possible. If there’s anything we can do now, we’d rather know than wait.”

BACK TO BACKGROUND

The patient and his family are keen to start amyloid-targeting therapy. As his neurologist, you need to determine which investigations are required to assess safety, inclusion, and exclusion criteria before initiating treatment.

You have reached the end of Room 4: neurologist office

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Diagnose vascular MCI, recommend lifestyle interventions, and treat underlying cardiovascular diseases 2 Diagnose MCI due to early-stage AD and discuss the possibility of an amyloid-targeting therapy 3 Diagnose subjective cognitive impairment (SCI), recommend lifestyle changes, and organize follow-up and monitoring 4 Tell Ebba that her symptoms are part of healthy aging 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Blood plasma Aẞ42:Aẞ40 ratio

Welcome to the neurologist escape room with Professor Dorota Religa.

Name: Ebba Age: 79 years old Sex: Female

Current situation

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Initiate a discussion about starting an amyloid-targeting therapy, including its potential benefits and risks 2 Inform Adam that he is not eligible for amyloid-targeting therapy due to his APOE genotype 3 Begin treatment with an amyloid-targeting therapy; schedule monitoring with MRI and amyloid PET in 1 year 4 Conduct amyloid PET imaging to confirm his eligibility for treatment 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

BEGIN

Baker et al.JAMA. 2025;e2512923. Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Dubois B, et al. JAMA Neurol. 2024;81:1304-1311. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

Clue 3: Adam’s biomarker test results

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 “Your family would really like you to be investigated further. They just want the best for you” 2 “We have some potential treatment options now, but we can only offer them if the diagnosis is confirmed with biomarkers” 3 “I’d like to understand more about what’s causing your symptoms. Would you be open to talking through what further tests could tell us?” 4 “There are treatments that may improve your memory, and doing more tests could help us decide if you’re a candidate” 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Family perspective

A 68-year-old woman is referred to your memory clinic with a 1-year history of progressive memory loss and occasional disorientation.

Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150. Vigneswaran S, et al. Alzheimers Dement. 2025;21:e70375.

Her Montreal Cognitive Assessment (MoCA) score is 21/30. There is no significant vascular history, and routine blood work and head computed tomography (CT) are unremarkable.

CONTINUE TO ESCAPE QUESTION 1

BACK TO CLUE 1

Annual wellness examination

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THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Presenting reason

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Current symptoms

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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”.

Retired accountant

CONTINUE TO CLUE 3

Family history

BACK TO ESCAPE QUESTION 2

Social history

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

Medical history

Aβ42

• 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

t-tau

Clue 4: meet Fiona and her family

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

LEFT column APOE genotyping ε3/ε4MRI One microhemorrageNo superficial siderosis

Cano A, et al.EBioMedicine. 2024;108:105345. Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Mielke MM, et al. Alzheimers Dement. 2024;20:8216-8224. Palmqvist S, et al. Alzheimers Dement. 2025;21:e70535. Palmqvist S, et al. Nature Med. 2025;31:2036-2043.

LEFT column Reasons for referral Referred to the memory clinic by his primary care provider due to symptoms of mild cognitive impairment (MCI) and suspected ADSocial and family history Active physical education teacher and volleyball coachMarried RIGHT column Medical history Basic memory workup in primary careMini-Mental State Examination (MMSE): 24/30Current symptoms Short-term and episodic memory lossForgetting people’s names and has become dependent on writing down informationFamily members report that he seems more irritable

p-tau

>599 ng/L

Vitals

Current medications

Question 2 background

NfL

<404 ng/L

Which of the following biomarkers would you test for to support an early diagnosis of AD in this setting? (required)

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

CSF biomarker

Name: Adam Age: 76 years old Sex: Male

0.05

<56.3 ng/L

Question 1

Atri A, et al.Alzheimers Dement. 2025;21:e14333. O’Brien K, et al.Alzheimers Dement. 2024;21:e14200.

Result

683

<1850 ng/L

Normal value

533

Aβ42:Aβ40 ratio

Medical history

Menu WITHIN EACH SECTION, USE THE BUTTONS TO NAVIGATE. Title Baseline question Neurologist 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

2,130

Clue 2: Ebba’s clinical profile and test results

>0.068

Looking at Ebba’s clinical profile and biomarker test results in Clue 2, what should you do next? (required)

Escape question 2

A 65-year-old woman is being evaluated in a memory clinic for progressive cognitive decline.

Based on Adam’s test results in Clue 3, what would be the most appropriate course of action? (required)

Escape question 3

Her CSF results show decreased Aβ42 and a low Aβ42:Aβ40 ratio.

How would you approach a conversation with Fiona about further diagnostic workup in the specialist setting? (required)

CONTINUE TO HOW TO USE

Escape question 4

Key takeaways

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 The patient's decreased Aβ42:Aβ40 ratio has higher diagnostic accuracy for AD compared to the Aβ42 result alone 2 These results are not consistent with AD, as Aβ42 should be increased rather than decreased 3 This CSF profile is not consistent with amyloid pathology 4 These findings must be confirmed using amyloid PET to corroborate the finding of amyloid pathology 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Baseline question

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

TYPE YOUR ANSWER IN THE FIELD PROVIDED

What test(s) would you select to assess safety inclusion and exclusion criteria before initiating an amyloid-targeting therapy in AD in this patient?

Hotspot 1

Atri A, et al. Alzheimers Dement. 2025;21:e14333. Largent EA, et al. Neurology. 2023;100:1010-1019. O’Brien K, et al. Alzheimers Dement. 2024;21:e14200. Ralman-Filipiak A, et al. Alzheimer Dis Assoc Disord. 2023;37:274-281.

Hotspot 2

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Amyloid PET 2 Blood p-tau217 3 Tau PET 4 Apolipoprotein E4 (APOE4) genotyping and MRI 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Hotspot 3

Hotspot 4

Escape door

Invalid response. Please type in a number value.

Question 3 background

Congratulations on completing the escape room!

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.

SUBMIT

Room 4: Neurologist office

PREPARING THE MULTIDISCIPLINARY CARE TEAM

Based on Adam’s information in Clue 1, what is the next best step to confirm a diagnosis of AD? (required)

Based on biomarker testing and clinical evaluation, Adam has been diagnosed with MCI due to early-stage AD. He is initiated on donepezil, starting at 5 mg and titrated to 10 mg daily. Adam has expressed interest in starting an amyloid-targeting therapy; therefore, he is referred for APOE genotyping and brain MRI to assess eligibility and baseline risk prior to initiating treatment. The results from his tests are provided below:

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

Escape question 1

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Q5-only styles Start of question set 1 Initiate a full cognitive workup, including CSF biomarkers or amyloid PET 2 Conduct blood-based biomarker testing for plasma p-tau217 3 Order APOE genotyping; if negative for APOE4, no further investigation is needed 4 Schedule a follow-up visit in 1 year for further testing 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

The clinical team is considering further investigations to support a diagnosis of early-stage Alzheimer’s disease (AD).

Prof Dorota Religa on the utility of biomarkers for AD diagnosis

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

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.

100%

Prof Dorota Religa on using biomarkers for treatment selection and monitoring

Question 1 background

Prof Dorota Religa on the interpretation of AD biomarkers

Prof Dorota Religa on shared decision-making

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

CONTINUE TO ESCAPE QUESTION 3

BACK TO CLUE 3

CONTINUE TO CLUE 4

Hansson O, et al. Alzheimers Res Ther. 2019;11:34. Janelidze S, et al. Ann Clin Transl Neurol. 2016;3:154-165.

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CONTINUE TO ESCAPE QUESTION 4

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CONTINUE TO KEY TAKEAWAYS

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CONTINUE

BACK TO KEY TAKEAWAYS

GlossaryAβ, beta-amyloid AD, Alzheimer’s disease APOE, apolipoprotein E gene ARIA, amyloid-related imaging abnormalities ATN, amyloid/tau/neurodegeneration CSF, cerebrospinal fluid CT, computed tomography DMT, disease-modifying therapy IWG, International Working Group MCI, mild cognitive impairment MMSE, Mini-Mental State Examination MoCA, Montreal Cognitive Assessment MRI, magnetic resonance imaging NfL, neurofilament light p-tau, phosphorylated tau PET, positron emission tomography SCI, subjective cognitive impairment t-tau, total tau

Question 4 background

Question 2

Question 3

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

SUBMIT

Positron emission tomography (PET) scanning is not currently available in your clinic.

SUBMIT

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Cerebrospinal fluid (CSF) neurofilament light chain (NfL) 2 Blood Aβ42:Aβ40 ratio, p-tau217 3 CSF Aβ42, Aβ42:Aβ40 ratio, t-tau, p-tau 4 Structural magnetic resonance imaging (MRI) of the brain 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

SUBMIT

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

How should these findings be interpreted in the context of amyloid pathology? (required)

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA

CLAIM CREDITS

In specialist settings, the diagnosis of AD should be supported by biomarkers to improve diagnostic accuracy and confidence.CSF biomarkers (Aβ42, Aβ42:Aβ40 ratio, t-tau, and p-tau) and amyloid PET imaging are the gold-standard, validated tools for confirming the presence of AD pathology and supporting a biological diagnosis.Blood-based biomarkers are rapidly emerging and starting to be implemented in clinical pathways. While not yet universally adopted, they show strong potential for both triage and diagnostic support, particularly when used with defined cutoffs.Biomarkers now play a central role in identifying patients eligible for amyloid-targeting therapies, such as donanemab and lecanemab, which can help to slow disease progression. Confirmation of amyloid pathology is required for treatment initiation, making timely and accurate biomarker testing essential.Biomarkers are also increasingly important for treatment safety and monitoring with amyloid-targeting therapies, including establishing baseline risk (e.g., ARIA risk with APOE4 genotype and baseline MRI) and identifying potential safety concerns during treatment (serial MRI to detect ARIA).As the landscape of AD and treatment evolves, it is critical to integrate biomarker testing within a shared decision-making framework. Patients and care partners should be engaged in meaningful discussions about the benefits, limitations, and implications of biomarker testing and potential treatment options.

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

CONTINUE TO THE ESCAPE ROOM

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How would you respond to support the patient’s understanding and engagement in the diagnostic process? (required)

Question 4

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 "I understand your concerns, but a reliable diagnosis requires multiple pieces of information. Blood-based biomarkers cannot give us the full picture on their own” 2 “You should speak to your family before making any decisions about stopping the workup” 3 "I understand your concerns, but there is a high chance you can receive an amyloid-targeting therapy that can slow disease progression, so we should continue with the full diagnostic workup” 4 “I understand your concerns, but since you've already started the process, we have to finish it” 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

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Room 4: Neurologist office

Hotspot 3

Question 1 rationale Auto-expanding background box The most established fluid biomarkers for early AD in memory clinics are classical CSF biomarkers, including Aβ42, Aβ42:Aβ40 ratio, t‑tau, and p‑tau. These biomarkers reflect amyloid and tau pathology and are incorporated into the amyloid/tau/neurodegeneration (ATN) research framework. While blood-based biomarkers (e.g., plasma p‑tau217, p‑tau181 or p‑tau217:Aβ42 ratio) are promising tools that can support early diagnosis and triage of patients, they require further validation before they can be widely used for diagnosis in most clinical settings. Alzheimer's Association guidelines state that in memory clinic settings, blood-based biomarker tests with ≥90% sensitivity and ≥75% specificity can be used as a triaging test and tests with ≥90% sensitivity and specificity can serve as a substitute for amyloid PET imaging or CSF in patients with cognitive impairment. However, these tests should only be used as part of a full diagnostic workup and should not replace comprehensive clinical evaluation. Despite growing guideline support and recent regulatory approvals, the clinical implementation of blood-based biomarkers for AD requires validation within local populations, including the establishment of population-specific cutoffs to ensure diagnostic accuracy. CSF NfL is more indicative of general neurodegeneration, and MRI can help exclude other causes but lacks specificity for early AD. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 2 How should these findings be interpreted in the context of amyloid pathology? (required) SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON 1The patient's decreased Aβ42:Aβ40 ratio has higher diagnostic accuracy for AD compared to the Aβ42 result alone2These results are not consistent with AD, as Aβ42 should be increased rather than decreased3This CSF profile is not consistent with amyloid pathology4These findings must be confirmed using amyloid PET to corroborate the finding of amyloid pathology5Unsure Centered Submit Button SUBMIT Feedback box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Question 2 rationale Auto-expanding background box The current clinical consensus supports using the CSF Aβ42:Aβ40 ratio when evaluating amyloid pathology. This ratio adjusts for individual differences in total amyloid production and reduces the impact of variation in pre-analytical handling, offering greater diagnostic accuracy than Aβ42 levels alone. The patient’s decreased Aβ42 level combined with a low Aβ42:Aβ40 ratio indicates the presence of amyloid pathology and supports a diagnosis of AD. Aβ42 levels are typically decreased in the CSF due to deposition of amyloid plaques in the brain. Therefore, reduced rather than elevated Aβ42 supports the presence of amyloid pathology. CSF biomarkers remain an essential part of the diagnostic process in memory clinics. Amyloid PET imaging can also identify amyloid pathology; however, it is not required to confirm findings from CSF, as the two methods show strong concordance. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 3 rationale Auto-expanding background box While CSF biomarkers (e.g., Aβ42:Aβ40 ratio) or amyloid PET are required to confirm amyloid pathology before initiation of amyloid-targeting therapies, they are not the only tools required to determine treatment eligibility. In this case, the patient already has confirmed amyloid pathology via CSF, therefore additional amyloid PET imaging is not required. Additional evaluations, including genetic and neuroimaging assessments, are critical to fulfill patient safety criteria. APOE4 genotyping aids in risk stratification because carriers (especially homozygotes) are at increased risk of amyloid-related imaging abnormalities (ARIA). The risk of ARIA should be carefully considered when making decisions about starting treatment and the intensity of monitoring needed. It is important to note that in some regions (e.g., EU), patients who are homozygous for APOE4 are ineligible for treatment with amyloid-targeting therapies. A baseline brain MRI is essential for identifying exclusion criteria (e.g., pre-existing microhemorrhages or significant vascular pathology). Brain MRI also plays a key role in ongoing safety monitoring, with serial MRIs required throughout treatment, particularly during dose-escalation phases. Blood p‑tau217 is emerging as a promising biomarker that reflects underlying AD pathology, but it can not currently be used to assess eligibility for amyloid-targeting therapies. 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 4: neurologist 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 rationale Auto-expanding background box This response reflects advanced clinical communication skills and shared decision-making. It acknowledges the patient’s frustration, while calmly explaining that no single biomarker currently provides a definitive diagnosis of AD. Instead, a comprehensive approach is needed, combining clinical assessment, imaging, cognitive testing, and biomarkers to reach a solid and accurate diagnosis. Blood-based biomarkers are promising tools, but further validation is required before they can be used as standalone diagnostic tools in most clinical settings. Explaining this helps maintain trust and supports patient engagement. The other options fail to respect patient autonomy, may foster false hope around treatment, or may inappropriately shift responsibility to family members. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Title Question 4 Question text How would you respond to support the patient’s understanding and engagement in the diagnostic process? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1"I understand your concerns, but a reliable diagnosis requires multiple pieces of information. Blood-based biomarkers cannot give us the full picture on their own”2“You should speak to your family before making any decisions about stopping the workup”3"I understand your concerns, but there is a high chance you can receive an amyloid-targeting therapy that can slow disease progression, so we should continue with the full diagnostic workup”4“I understand your concerns, but since you've already started the process, we have to finish it”5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Clue Title Clue 3: Adam’s biomarker test results Based on biomarker testing and clinical evaluation, Adam has been diagnosed with MCI due to early-stage AD. He is initiated on donepezil, starting at 5 mg and titrated to 10 mg daily. Adam has expressed interest in starting an amyloid-targeting therapy; therefore, he is referred for APOE genotyping and brain MRI to assess eligibility and baseline risk prior to initiating treatment. The results from his tests are provided below: CSF biomarker results table CSF biomarkerResultNormal value Aβ42:Aβ40 ratio 0.05 >0.068 Aβ42 683 >599 ng/L t-tau 533 <404 ng/L p-tau 91 <56.3 ng/L NfL 2,130 <1850 ng/L APOE genotyping ε3/ε4MRI One microhemorrageNo superficial siderosisTAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

Question 4 background You are evaluating a patient referred to your specialist memory clinic. After the initial consultation, you explain that a full diagnostic workup, including neuropsychological testing, imaging, and biomarkers, typically takes around 3 months. The patient becomes frustrated, asks you to skip everything and “just take one blood test that explains everything.” TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 4

Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150. Vigneswaran S, et al. Alzheimers Dement. 2025;21:e70375.

Title Escape question 2 Question text Looking at Ebba’s clinical profile and biomarker test results in Clue 2, what should you do next? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Diagnose vascular MCI, recommend lifestyle interventions, and treat underlying cardiovascular diseases2Diagnose MCI due to early-stage AD and discuss the possibility of an amyloid-targeting therapy3Diagnose subjective cognitive impairment (SCI), recommend lifestyle changes, and organize follow-up and monitoring4Tell Ebba that her symptoms are part of healthy aging5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 1

Atri A, et al. Alzheimers Dement. 2025;21:e14333. O’Brien K, et al. Alzheimers Dement . 2024;21:e14200.

Title Key takeaways Bullet Box In specialist settings, the diagnosis of AD should be supported by biomarkers to improve diagnostic accuracy and confidence.CSF biomarkers (Aβ42, Aβ42:Aβ40 ratio, t-tau, and p-tau) and amyloid PET imaging are the gold-standard, validated tools for confirming the presence of AD pathology and supporting a biological diagnosis.Blood-based biomarkers are rapidly emerging and starting to be implemented in clinical pathways. While not yet universally adopted, they show strong potential for both triage and diagnostic support, particularly when used with defined cutoffs.Biomarkers now play a central role in identifying patients eligible for amyloid-targeting therapies, such as donanemab and lecanemab, which can help to slow disease progression. Confirmation of amyloid pathology is required for treatment initiation, making timely and accurate biomarker testing essential.Biomarkers are also increasingly important for treatment safety and monitoring with amyloid-targeting therapies, including establishing baseline risk (e.g., ARIA risk with APOE4 genotype and baseline MRI) and identifying potential safety concerns during treatment (serial MRI to detect ARIA).As the landscape of AD and treatment evolves, it is critical to integrate biomarker testing within a shared decision-making framework. Patients and care partners should be engaged in meaningful discussions about the benefits, limitations, and implications of biomarker testing and potential treatment options. Next Button Box TAP THE “NEXT” BUTTON TO CONTINUE

Question 2 background A 65-year-old woman is being evaluated in a memory clinic for progressive cognitive decline. A memory specialist has diagnosed her with mild AD. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 2

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

Title Question 3 Question text What test(s) would you select to assess safety inclusion and exclusion criteria before initiating an amyloid-targeting therapy in AD in this patient? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Amyloid PET2Blood p-tau2173Tau PET4Apolipoprotein E4 (APOE4) genotyping and MRI5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 2

Question 3 background A 71-year-old man is referred to your neurology clinic for evaluation of progressive memory difficulties over the past 18 months. He occasionally has word-finding difficulties and mild executive deficits but remains independent in all activities of daily living. His past medical history includes well-controlled hypertension, no history of seizures, stroke, or anticoagulation therapy. The patient’s CSF biomarker tests indicate that he has decreased Aβ42:Aβ40 ratio and elevated p-tau181, supporting a diagnosis of MCI due to early-stage AD. The patient and his family are keen to start amyloid-targeting therapy. As his neurologist, you need to determine which investigations are required to assess safety, inclusion, and exclusion criteria before initiating treatment. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 3

Escape Door

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA PREPARING THE MULTIDISCIPLINARY CARE TEAM Welcome to the neurologist escape room with Professor Dorota Religa. 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.

Escape door

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 Which of the following biomarkers would you test for to support an early diagnosis of AD in this setting? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Cerebrospinal fluid (CSF) neurofilament light chain (NfL)2Blood Aβ42:Aβ40 ratio, p-tau2173CSF Aβ42, Aβ42:Aβ40 ratio, t-tau, p-tau4Structural magnetic resonance imaging (MRI) of the brain5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

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Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Mielke MM, et al. Alzheimers Dement. 2024;20:8216-8224. Palmqvist S, et al. Alzheimers Dement. 2025;21(7):e70535.

Clue 2: Ebba’s clinical profile and test results ✅ Centered patient card clipboard top abi image Name:Ebba Age: 79 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Symptoms Shows increased irritability, is more self-focused, and has become less socially activeReports anxiety and occasional forgetfulnessReasons for referral Referred to the memory service by her primary care provider, who is concerned that her symptoms may be indicative of ADImaging results Magnetic resonance imaging (MRI) adequate for ageMedical evaluation Evaluation with psychologist finds no significant abnormalitiesMoCA: 27/30 (normal)MMSE 25/30 (normal)CSF biomarker test results Aβ42: 540 (↓)Aβ42:Aβ40: 0.066 (↓)t-tau: 400 (normal)p-tau181: 45 (normal)

Question 1 background A 68-year-old woman is referred to your memory clinic with a 1-year history of progressive memory loss and occasional disorientation. Her Montreal Cognitive Assessment (MoCA) score is 21/30. There is no significant vascular history, and routine blood work and head computed tomography (CT) are unremarkable. The clinical team is considering further investigations to support a diagnosis of early-stage Alzheimer’s disease (AD). Positron emission tomography (PET) scanning is not currently available in your clinic. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 1

Hotspot 2: Expert commentary

Clue 1: Adam’s clinical profile ✅ Centered patient card clipboard top abi image Name:Adam Age: 76 years old Sex: Male ✅ Unified grey background for patient chart content Left-column bullets Reasons for referral Referred to the memory clinic by his primary care provider due to symptoms of mild cognitive impairment (MCI) and suspected ADSocial and family history Active physical education teacher and volleyball coachMarriedMedical history Basic memory workup in primary careMini-Mental State Examination (MMSE): 24/30Current symptoms Short-term and episodic memory lossForgetting people’s names and has become dependent on writing down informationFamily members report that he seems more irritable Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

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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 1 Question text Based on Adam’s information in Clue 1, what is the next best step to confirm a diagnosis of AD? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Initiate a full cognitive workup, including CSF biomarkers or amyloid PET2Conduct blood-based biomarker testing for plasma p-tau2173Order APOE genotyping; if negative for APOE4, no further investigation is needed 4Schedule a follow-up visit in 1 year for further testing5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 3: Expert commentary

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Escape question 1 rationale Auto-expanding background box Adam’s clinical history and cognitive testing indicate MCI, warranting further diagnostic evaluation. A full specialist cognitive workup is appropriate, including CSF biomarkers (such as Aβ42, Aβ42:Aβ40 ratio, t‑tau, and p‑tau) or amyloid PET imaging where available. Plasma p‑tau217 is currently the most accurate and well-established blood-based biomarker. However, blood-based biomarkers are not yet routinely used for diagnosis in most memory clinics, and further validation is needed in diverse populations. Population-appropriate cutoffs must be established for clinicians to understand how best to incorporate blood-based biomarkers into local diagnostic pathways. As a result, testing with CSF or PET is typically required to confirm a diagnosis of AD. APOE genotyping is not recommended as a first-line diagnostic tool. Delaying assessment risks missing the opportunity for early diagnosis, care planning, and access to disease-modifying therapies (DMTs). Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 2

Hotspot 4: Expert commentary

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“Your family would really like you to be investigated further. They just want the best for you”2“We have some potential treatment options now, but we can only offer them if the diagnosis is confirmed with biomarkers”3“I’d like to understand more about what’s causing your symptoms. Would you be open to talking through what further tests could tell us?”4“There are treatments that may improve your memory, and doing more tests could help us decide if you’re a candidate”5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 2 rationale Auto-expanding background box Although Ebba is currently at the SCI stage clinically, her abnormal CSF biomarker profile (reduced Aβ42 and Aβ42:Aβ40 ratio and normal t-tau and p-tau181) is consistent with an increased risk of AD. The International Working Group (IWG) recommendations state that it is essential to interpret biomarker results in the context of clinical evaluation and symptoms, and an AD diagnosis and management plan should be based on the combination of both biological evidence and cognitive symptoms. At this stage, it is appropriate to recommend lifestyle changes aimed at reducing risk factors and to organize structured follow-up monitoring, ideally within a brain health clinic setting. This approach allows for comprehensive risk factor management and timely re-evaluation. While her biomarker results raise the possibility of early-stage AD, she does not yet meet the criteria for MCI, which is typically required for diagnosis of prodromal AD and for eligibility to receive an amyloid-targeting therapy. These discussions may become more relevant at her follow-up, particularly if further cognitive decline is detected. It is important not to dismiss her concerns as normal aging, given Ebba’s abnormal biomarkers. Early intervention and monitoring are key to supporting brain health and preparing for potential progression. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 3

Hansson O, et al. Alzheimers Res Ther. 2019;11:34. Janelidze S, et al. Ann Clin Transl Neurol. 2016;3:154-165.

Escape question 3 rationale Auto-expanding background box Adam is eligible for amyloid-targeting therapy with lecanemab or donanemab based on his confirmed amyloid pathology via CSF testing. His APOE ε3/ε4 genotype increases his risk of ARIA but does not exclude him from treatment. Therefore, the most appropriate next step is to initiate a shared decision-making discussion with Adam. This conversation should include the potential benefits and risks of treatment, particularly his increased ARIA risk and the requirements for safety monitoring with MRI if he chooses to proceed. Starting an amyloid-targeting therapy immediately without this discussion would be inappropriate. Moreover, waiting a full year to perform MRI monitoring is not aligned with current recommendations, which advise MRI screening at baseline and at regular intervals during treatment to detect ARIA early, especially in APOE ε4 carriers. Ordering an amyloid PET scan to confirm eligibility is unnecessary, as his CSF already confirms amyloid positivity. However, amyloid PET can be used to monitor treatment response to amyloid-targeting therapy if Adam decides to start treatment. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 4

Hotspot 1: Expert commentary

Title Escape question 3 Question text Based on Adam’s test results in Clue 3, what would be the most appropriate course of action? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Initiate a discussion about starting an amyloid-targeting therapy, including its potential benefits and risks2Inform Adam that he is not eligible for amyloid-targeting therapy due to his APOE genotype 3Begin treatment with an amyloid-targeting therapy; schedule monitoring with MRI and amyloid PET in 1 year4Conduct amyloid PET imaging to confirm his eligibility for treatment5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 4 rationale Auto-expanding background box Desire for biomarker testing among older adults and care partners is usually high. However, when there are hesitations, the most appropriate way to approach this conversation is through a collaborative and empathetic dialog that respects the patient’s autonomy, while providing clear clinical reasoning. Inviting the patient to consider whether they would like more information or to explore further testing signals that the decision is theirs and not something being imposed. This type of invitation supports autonomy by positioning the patient as an active participant in their care. It allows them to weigh the value of further testing in the context of their own goals, concerns, and preferences. Although involving care partners in the process is important, focusing on the family’s wishes or presenting biomarker testing as a requirement for treatment can undermine trust or make the patient feel sidelined. Suggesting that treatment will improve Fiona’s memory may raise unrealistic expectations, especially when a diagnosis and treatment eligibility have not yet been confirmed. Instruction Box TAP THE “NEXT” BUTTON FOR KEY TAKEAWAYS

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Clue Title Clue 4: meet Fiona and her family Fiona description Fiona is an 80-year-old woman with a history of type 2 diabetes, osteoarthritis, and atrial fibrillation. She leads a fulfilling life and is particularly proud of her family, which includes her children and grandchildren. Fiona was recently diagnosed with MCI by her primary care physician following concerns raised during a routine checkup. Despite the diagnosis, she functions independently at home and can still drive a car. Her family is eager for her to undergo a more comprehensive memory assessment and have brought her to the clinic to explore the underlying causes of her cognitive changes and determine whether any treatments might be appropriate. TWO BOXES (Current Situation + Family Perspective) Current Situation SAME font size as your original title Current situation SAME font size as your original body text Fiona expresses hesitation about proceeding with further diagnostic workup. She shares, “At my age, I’m not sure I want to go through a bunch of tests. I don’t feel that bad, and I don’t want to be treated like I’m sick. I want to keep my driver’s license.” Family Perspective SAME title font Family perspective SAME body font Her daughter voices a different view: “We just want to understand what’s happening and make sure Mom gets the best care possible. If there’s anything we can do now, we’d rather know than wait.”

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