For an older adult with progressive memory loss, which blood tests are recommended to evaluate for Alzheimer’s disease?

Blood Tests for Alzheimer's Disease in Progressive Memory Loss

Blood-based biomarkers for Alzheimer's disease are not yet validated as standalone diagnostic tests and must be confirmed with CSF analysis or amyloid PET imaging before making definitive treatment decisions, though they show promise as screening tools in specialized memory clinic settings. 1, 2

Current Clinical Role of Blood Biomarkers

Blood tests for Alzheimer's disease should only be ordered after completing a comprehensive workup that excludes reversible causes of cognitive decline, including thyroid dysfunction, vitamin B12 deficiency, medication effects, depression, and structural brain lesions. 1, 2

In specialized memory clinics, the following blood biomarkers have demonstrated clinical utility as part of the diagnostic algorithm:

Phosphorylated Tau (p-tau)

• P-tau181, p-tau217, and p-tau231 show the highest diagnostic accuracy for distinguishing Alzheimer's disease from other neurodegenerative disorders. 1, 2
• P-tau can differentiate AD dementia from frontotemporal dementia, Lewy body dementia, and vascular dementia with superior performance compared to other blood markers. 1
• These markers can detect AD pathology in patients with mild cognitive impairment and predict progression to dementia. 1

Plasma Aβ42/Aβ40 Ratio

• Reflects cerebral amyloid plaque deposition but requires highly precise assays due to significant analytical variability. 1, 2
• Used primarily in a triaging pathway to identify patients who need confirmatory CSF or PET testing. 2

Glial Fibrillary Acidic Protein (GFAP)

• Indicates amyloid-associated reactive astrogliosis and serves as an early marker of AD pathology. 1, 2

Neurofilament Light Chain (NfL)

• Reflects neurodegeneration but lacks disease specificity for Alzheimer's disease—elevated in multiple neurodegenerative conditions. 1, 2
• Most useful for ruling out non-degenerative causes of cognitive impairment. 2

Diagnostic Performance Standards

For triaging use (deciding who needs CSF/PET confirmation):

• Blood tests must achieve sensitivity ≥90% and specificity ≥85%. 2
• A negative blood test reliably rules out amyloid pathology in most patients, avoiding invasive testing. 2

For confirmatory use (making treatment decisions):

• Assays must reach specificity ≥90% to prevent false-positive diagnoses that could lead to inappropriate disease-modifying therapy. 2
• Positive blood test results require second-line confirmation with CSF or amyloid PET before initiating anti-amyloid therapies like lecanemab or donanemab. 2

Recommended Diagnostic Algorithm

Step 1: Patient Selection

• Test only patients ≥55 years old with objective cognitive impairment documented by standardized testing (e.g., MoCA, MMSE) or reliable informant report of decline. 2
• Complete basic laboratory evaluation (CBC, comprehensive metabolic panel, TSH, vitamin B12, folate) and structural brain imaging (MRI or CT) first. 1, 2

Step 2: Blood Biomarker Testing

• Order plasma p-tau (preferably p-tau217 or p-tau181) as the primary blood biomarker due to highest diagnostic accuracy. 1, 2
• Consider adding plasma Aβ42/Aβ40 ratio and GFAP to improve diagnostic confidence. 1, 2
• Ensure blood collection follows standardized pre-analytical protocols (specific collection tubes, processing times, storage conditions) as analytical variability significantly affects results. 1, 2

Step 3: Result Interpretation

• Negative p-tau and Aβ42/Aβ40: AD pathology unlikely; consider alternative diagnoses. 1, 2
• Positive p-tau and/or Aβ42/Aβ40: High likelihood of AD pathology but requires CSF analysis (Aβ42/Aβ40, p-tau181, total tau) or amyloid PET for confirmation before diagnosis or treatment. 1, 2
• Indeterminate results: Proceed directly to CSF or PET imaging. 2

Step 4: Confirmatory Testing

• CSF biomarkers (preferred in most cases): Reduced Aβ42/Aβ40 ratio with elevated p-tau and total tau confirms AD pathology. 3, 4
• Amyloid PET imaging: Positive scan confirms cerebral amyloid deposition with high specificity. 3
• Confirmation is mandatory before initiating disease-modifying anti-amyloid therapies. 2, 3

Critical Limitations and Pitfalls

Do not use blood tests alone to diagnose Alzheimer's disease or initiate treatment. The risk of false-positive results leading to inappropriate therapy with potentially serious side effects (ARIA-E, ARIA-H from anti-amyloid antibodies) is unacceptable without confirmatory testing. 2, 5

Common pitfalls to avoid:

• Ordering blood biomarkers without first excluding reversible causes of cognitive impairment (thyroid disease, B12 deficiency, medication effects, depression). 1, 2
• Interpreting positive blood tests as definitive AD diagnosis without CSF or PET confirmation. 1, 2
• Using blood tests in asymptomatic individuals or those with subjective cognitive complaints only—not validated in these populations. 1
• Failing to use clinical-grade assays with demonstrated analytical precision—research assays are not appropriate for clinical decision-making. 1, 2
• Ignoring pre-analytical variables (collection method, processing time, storage) that significantly affect biomarker concentrations. 1, 2

Primary Care Considerations

Blood biomarkers are not yet validated for use in primary care settings. 1 The lower prevalence of neurodegenerative disease in primary care compared to specialty clinics means positive predictive value is substantially reduced, increasing false-positive risk. 1

If considering blood biomarker testing in primary care:

• Refer patients with positive results to specialized memory clinics for comprehensive evaluation and confirmatory testing. 1
• Do not initiate disease-modifying therapies based on blood test results alone. 2

Future Directions

Ongoing research priorities include prospective validation in diverse real-world populations, establishment of standardized cut-points for different clinical contexts, and determination of whether blood biomarker algorithms can perform non-inferior to CSF/PET in specific scenarios. 1 Until these studies are completed, blood biomarkers should be used only as screening tools requiring confirmatory testing in specialized settings. 1, 2