What biomarkers and medications are used to diagnose and treat Alzheimer's disease?

Biomarkers for Alzheimer's Disease Diagnosis

The core biomarkers for diagnosing Alzheimer's disease are CSF amyloid-beta 42/40 ratio and phosphorylated tau (p-tau), with amyloid PET imaging reserved for cases where diagnostic uncertainty persists after CSF testing. 1, 2

Diagnostic Biomarker Hierarchy

Core 1 Biomarkers (Establish AD Diagnosis)

CSF biomarkers are the primary diagnostic tool when clinical evaluation and structural imaging leave diagnostic uncertainty. 1, 3

• CSF Aβ42/Aβ40 ratio is more specific than absolute Aβ42 values alone for detecting cerebral amyloid pathology 3
• CSF phosphorylated tau (p-tau181, p-tau217, p-tau231) and total tau reflect neurofibrillary tangles and neuronal injury specific to AD 1, 3
• These biomarkers are sensitive and specific for AD neuropathologic changes (neuritic plaques and tau tangles) 1
• Abnormal Core 1 biomarkers are sufficient to establish AD diagnosis and guide treatment decisions, including eligibility for disease-modifying therapies 1, 3, 4

When to Order CSF Biomarkers

Use CSF testing in the following scenarios 1:

• Diagnostic uncertainty remains after comprehensive clinical evaluation and structural brain imaging
• Very early clinical stages (early MCI) where high diagnostic confidence is needed
• Atypical clinical presentations or syndromes
• Required before initiating disease-modifying therapies to confirm amyloid-beta pathology 1

Amyloid PET Imaging

Amyloid PET should only be obtained when diagnostic uncertainty persists after structural imaging, FDG PET (if performed), and/or CSF biomarkers. 1, 3

• Confirms or excludes cerebral amyloid pathology with high specificity 3
• More expensive and less accessible than CSF testing 1
• Follow appropriate use criteria published by professional societies 1

Core 2 Biomarkers (Staging and Prognosis)

Tau PET and specific CSF/plasma tau species provide prognostic information about disease stage and predict rate of cognitive decline, but are not required for diagnosis. 5

• Used for biological staging (Stages A through D based on extent of tau pathology) 5
• When both Core 1 and Core 2 biomarkers are positive, likelihood of MCI progressing to dementia is high 5
• Most valuable when integrated with Core 1 biomarkers and clinical assessment 5

Blood-Based Biomarkers (Emerging)

Plasma phosphorylated tau (especially p-tau217) shows high accuracy in specialized memory clinics but currently requires confirmation with CSF or PET in clinical practice. 1

Current Status and Limitations

• Plasma p-tau can differentiate AD dementia from other neurodegenerative diseases, detect AD pathology in MCI, and predict AD dementia development 1
• Blood biomarkers should only be used in symptomatic patients at specialist clinics with established thresholds 1
• Results must be confirmed with CSF or PET whenever possible 1
• Additional validation needed before use as stand-alone diagnostic markers 1
• Not yet recommended for routine use in primary care settings 1

Research Priorities for Blood Biomarkers

The field requires 1:

• Prospective validation in diverse real-world populations using predefined cut-offs
• Studies comparing blood biomarkers to CSF/PET to determine if they can serve as stand-alone tests or only as gatekeepers
• Better understanding of longitudinal variability and impact of medical comorbidities

Structural and Functional Imaging

Required Baseline Imaging

MRI is the preferred structural imaging modality, with CT as an alternative if MRI is contraindicated. 2

• Excludes non-AD conditions (tumors, subdural hematomas, normal pressure hydrocephalus) 2
• Identifies regional atrophy patterns characteristic of AD 2
• Assesses vascular cognitive impairment contribution 2

FDG PET (Optional)

FDG PET can be obtained when diagnostic uncertainty persists after structural imaging, particularly in early MCI or atypical presentations. 1

• Shows characteristic temporoparietal hypometabolism in AD 1
• Avoid in severe dementia with global impairments, as it will show diffuse hypometabolism regardless of cause 1
• SPECT may be considered when FDG PET is unavailable 1

Biomarker Interpretation Framework

High Likelihood of AD

• Both amyloid biomarkers (PET or CSF) AND neuronal injury markers (tau, structural MRI, FDG PET) are positive 1, 3
• Provides highest probability that cognitive symptoms are due to AD pathology 3

Intermediate Likelihood

• One biomarker category positive, the other untested or conflicting results 1, 5

Low Likelihood of AD

• Both amyloid and neuronal injury biomarkers are absent 1, 5

Critical Caveats

Always interpret biomarker results in context of clinical presentation, age, risk profile, and possibility of multiple pathologies. 1

• Biomarkers are adjuncts to, not substitutes for, thorough clinical evaluation 1
• Age-related increases in brain amyloid and tau pathology occur even without clinical symptoms 1
• Pretest probability significantly affects interpretation 1
• High inter-individual variability exists in decline rates among biomarker-positive individuals 5

Medications for Alzheimer's Disease

Cholinesterase Inhibitors

Donepezil is FDA-approved for mild to severe Alzheimer's disease dementia. 6

• Initiated at 5 mg daily for 28 days, then increased to 10 mg daily 6
• 23 mg daily dose available for moderate to severe AD, providing additional benefit over 10 mg 6
• Improves cognitive performance (ADAS-cog) and global function (CIBIC-plus) compared to placebo 6
• Treatment effects abate within 6 weeks of discontinuation 6

NMDA Receptor Antagonists

Memantine is FDA-approved for moderate to severe Alzheimer's disease dementia. 7

Disease-Modifying Therapies

Confirmation of amyloid-beta pathology via CSF or PET is required before initiating disease-modifying anti-amyloid therapies. 1, 3