What is the best course of management for an elderly male patient with cognitive decline, high-risk biomarkers for Alzheimer's disease, but negative Amyloid PET (Positron Emission Tomography) Centiloid score, and evidence of small vessel ischemic disease on imaging?

Management of Cognitive Decline with Discordant Biomarkers

This patient should be managed as having Alzheimer's disease with concurrent vascular cognitive impairment, prioritizing aggressive vascular risk factor management and symptomatic treatment with cholinesterase inhibitors, while recognizing that the negative amyloid PET does not exclude AD given the highly elevated CSF p-tau217 and positive CARM score. 1, 2

Understanding the Biomarker Discordance

The critical issue here is the mismatch between positive CSF biomarkers and negative amyloid PET imaging:

• CSF biomarkers show high-risk AD pathology: Beta-amyloid 42 = 28 (abnormally low, <8 is threshold), p-tau217 = 0.281 (elevated, >0.185), and a high-risk ratio of 0.00993 (>0.00738) 3
• Amyloid PET is negative: Centiloid score of -3.3 indicates no significant amyloid deposition 2
• CARM score is 4/4: This indicates high-risk amyloid presence by a different assessment method 1

This discordance occurs because CSF biomarkers can detect earlier stages of amyloid pathology than PET imaging, which typically only becomes positive with intermediate to high amyloid burden (Braak stages ≥IV) 4. The International Working Group notes that CSF Aβ42 can be positive despite negative amyloid PET in early amyloid accumulation 4.

Diagnostic Interpretation

The diagnosis remains Alzheimer's disease with mixed pathology (vascular contribution):

• The combination of abnormal CSF Aβ42/Aβ40 ratio and elevated p-tau217 provides sufficient evidence for AD pathology, even with negative amyloid PET 3
• P-tau217 is highly specific for AD and correlates with neurofibrillary tangles 3
• The presence of small vessel ischemic disease on imaging represents a vascular contribution to cognitive impairment 1
• Cognitive decline from MoCA 29→25 over the documented period confirms progressive impairment 1

The 2025 Alzheimer's Association guidelines emphasize that abnormal Core 1 biomarkers (CSF Aβ42/Aβ40 ratio and phosphorylated tau) are sufficient to establish AD diagnosis and guide treatment decisions 3.

Primary Management Strategy

1. Aggressive Vascular Risk Factor Management

This is the highest priority intervention given the documented small vessel ischemic disease 1:

• Target blood pressure <130/80 mmHg (or individualized based on comorbidities) 1
• Optimize lipid management with statin therapy 1
• Ensure tight glycemic control if diabetic (HbA1c <7%) 1
• Antiplatelet therapy (aspirin 81mg daily) if not contraindicated 1
• Smoking cessation if applicable 1
• Regular aerobic exercise (150 minutes/week moderate intensity) 1

2. Symptomatic Pharmacotherapy

Initiate cholinesterase inhibitor therapy immediately 1:

• Start donepezil 5mg daily, titrate to 10mg after 4-6 weeks if tolerated 1
• Consider memantine addition if progression continues, particularly given the vascular component 1
• Do not delay symptomatic treatment while awaiting additional biomarker testing 1

3. Disease-Modifying Therapy Considerations

Anti-amyloid monoclonal antibodies (lecanemab, donanemab) are NOT appropriate for this patient 1:

• These therapies require positive amyloid PET for eligibility 3
• The negative Centiloid score (-3.3) excludes this patient from current FDA-approved anti-amyloid therapy protocols 2
• Even if amyloid PET were positive, the presence of significant vascular disease and progression beyond MCI may place him outside the therapeutic window 1

Monitoring Protocol

Cognitive Assessment

• Repeat MoCA or similar cognitive testing every 6 months to track disease progression 1
• Consider formal neuropsychological testing annually for more detailed assessment 1

Imaging Surveillance

• Annual brain MRI to assess progression of atrophy and vascular disease burden 1
• Monitor for new infarcts, hemorrhages, or accelerated atrophy 1

Biomarker Reassessment

• Repeat amyloid PET in 12-24 months if clinical progression is rapid or if considering clinical trial enrollment 2
• The 2024 ACR Appropriateness Criteria notes that amyloid PET may become positive over time as pathology accumulates 2
• CSF biomarkers do not need routine repetition once diagnosis is established 3

Critical Pitfalls to Avoid

Do Not Dismiss the Diagnosis Based on Negative Amyloid PET

• A negative amyloid PET significantly reduces but does not completely rule out AD, especially when CSF biomarkers are strongly positive 2
• The Society of Nuclear Medicine guidelines emphasize that amyloid PET is most useful to exclude AD, but a negative scan in the context of positive CSF biomarkers represents early-stage disease 2

Do Not Overlook the Vascular Component

• The mild periventricular white matter changes represent small vessel ischemic disease that independently contributes to cognitive decline 1
• When amyloid and vascular pathology coexist, the 2024 ACR Appropriateness Criteria recommends considering mixed dementia 2
• Vascular risk factor management may have greater impact on slowing progression than in pure AD 1

Do Not Pursue Anti-Amyloid Therapy

• The American College of Physicians explicitly recommends avoiding anti-amyloid therapy in patients beyond the approved disease stage 1
• Negative amyloid PET is an absolute contraindication to lecanemab and donanemab 3

Supportive Care Interventions

Refer to occupational therapy for activities of daily living support to improve quality of life 1:

• Home safety evaluation and modifications 1
• Cognitive rehabilitation strategies 1
• Caregiver education and support 1

Consider referral to clinical trials that do not require positive amyloid PET, such as:

• Trials targeting tau pathology 3
• Trials for mixed dementia or vascular cognitive impairment 2
• Precision medicine protocols that address multiple drivers of cognitive decline 5

Prognosis and Counseling

This patient is at high risk for progression based on:

• Elevated p-tau217 indicating active tau pathology 3
• Documented cognitive decline (MoCA 29→25) 1
• Presence of both AD biomarkers and vascular disease 2

However, the lifetime risk of dementia in biomarker-positive individuals ranges from 5-42%, and some individuals may remain stable for extended periods through compensatory mechanisms 4. The International Working Group emphasizes that cognitively unimpaired individuals with biomarker positivity will not invariably experience subsequent cognitive decline 4.