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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss that leads to mild cognitive impairment (MCI) and, eventually, dementia. , AD may be categorized as late onset (affecting individuals older than 60-65 years) or early onset (affecting younger individuals). Disease-specific biomarkers, including imaging biomarkers and fluid biomarkers, may be used to diagnose AD in individuals with clinically identified cognitive impairment and may also be used in staging and treatment decision-making. Laboratory tests may also be used to rule out other possible treatable causes of cognitive impairment (eg, thyroid disease, vitamin B12 deficiency) and to assess for familial causes of early-onset AD. ,
Quick Answers for Clinicians
In recent years, the diagnosis of Alzheimer’s disease (AD) has moved from a clinical diagnosis only confirmable by autopsy to a biological diagnosis through the use of imaging and fluid biomarkers. Clinical findings are used to diagnose cognitive impairment or dementia (syndrome), whereas specific fluid or imaging biomarkers are used to establish neuropathology and thus the diagnosis of AD. Both fluid and imaging biomarkers detect the same underlying AD pathophysiologic processes (eg, beta [β]-amyloid proteinopathy); however, the results of imaging and fluid biomarker tests are not interchangeable. The use of imaging and fluid biomarkers for diagnosis, prognosis, and staging varies by biomarker. Refer to the Fluid Biomarkers section for more information.
Several fluid biomarker tests have demonstrated sufficient accuracy for use in the diagnosis of Alzheimer’s disease (AD). These biomarkers reflect early beta (β)-amyloid and/or tau pathophysiologic processes and are considered “core” biomarkers of AD (refer to the Biomarker Categorization section). Some cerebrospinal fluid (CSF) Aβ42/40, CSF p-tau181/Aβ42, CSF t-tau/Aβ42, and “accurate” plasma p-tau217 assays can be diagnostic of AD. The Alzheimer’s Association defines an “accurate” test as one with “accuracy that is equivalent to approved CSF assays in detecting abnormal amyloid (positron emission tomography [PET]) in the intended use population.” Refer to the Fluid Biomarkers section for more information.
New therapeutics (eg, lecanemab, donanemab) that directly target beta-amyloid protein have recently been approved for the treatment of Alzheimer’s disease (AD). , , Because these therapeutics are directed toward a biological target (amyloid protein), patients must demonstrate evidence of that biology to qualify for treatment, and such evidence may be provided with fluid biomarker testing. Additionally, fluid biomarkers may be useful for staging, prognosis, and as indicators of biological treatment effect. Refer to the Fluid Biomarkers section for more information. Other laboratory testing, namely APOE genotyping, may be useful in treatment decision-making because the risk of amyloid-related imaging abnormalities is much greater in individuals homozygous for the APOE e4 allele. Therefore, screening for APOE is recommended on the FDA labels for lecanemab and donanemab to inform risk management , , ; refer to the APOE Testing section for additional detail.
The same fluid biomarker tests may be used in both early-onset and late-onset Alzheimer's disease (AD); refer to the Fluid Biomarkers section. However, genetic tests for late-onset AD are different from those used for early-onset AD. Late-onset familial AD is thought to involve a number of susceptibility genes, , most prominently the APOE gene, whereas early-onset AD has been associated with APP, PSEN1, and PSEN2. Refer to the Molecular Genetic Tests section for more information.
No. In addition to its role in Alzheimer's disease (AD), the APOE gene has been implicated in cardiovascular disease. In AD, heterozygosity or homozygosity for the e4 allele is associated with an increased risk of late-onset AD. In cardiovascular disease, homozygosity for the APOE e2 allele is associated with the development of hyperlipoproteinemia type III, and homozygosity for the e4 allele is associated with increased plasma cholesterol. Thus, APOE tests for AD susceptibility and cardiovascular disease risk are not interchangeable because these tests focus on the identification of APOE variants in the appropriate disease context.
Indications for Testing
Laboratory testing for AD is appropriate in individuals with symptoms of MCI or dementia. , , The Alzheimer’s Association recommends against laboratory testing in individuals who do not exhibit cognitive impairment, unless testing is performed as part of a research study.
Laboratory Testing
Fluid Biomarkers
Biomarkers in AD may be either imaging biomarkers or fluid biomarkers. Fluid biomarkers include cerebrospinal fluid (CSF) and plasma analytes.
Biomarker Categorization
Imaging and fluid biomarkers of AD are categorized as core biomarkers, nonspecific process biomarkers, or copathology biomarkers based on underlying pathophysiologic processes. Core biomarkers are those that are directly related to AD pathophysiology (ie, related to beta [β]-amyloid or tau). Nonspecific biomarkers are markers of pathophysiologic processes that are involved in AD but are non-AD specific, such as general neuronal inflammation. Finally, markers of copathology are indicative of other disease processes, such as infarction, that are not directly related to AD.
Fluid Biomarker Tests
Fluid biomarker testing is an ongoing area of research, and fluid biomarker tests, particularly blood tests, are being increasingly incorporated into clinical practice. Clinical judgment is recommended when interpreting and applying fluid biomarker test results.
The following table presents fluid biomarkers that are being used or considered in clinical practice, although this is not a comprehensive list and additional markers are currently in development.
Molecular Genetic Tests
APOE Testing
APOE testing is recommended if treatment with monoclonal antibodies (eg, lecanemab, donanemab) is being considered because of the risk of amyloid-related imaging abnormalities (ARIAs) in individuals who are homozygous for the APOE e4 variant. , ,
APOE testing is also useful in risk assessment and may be useful for genetic counseling purposes. The APOE e4 variant has been robustly associated with the development of late-onset familial AD, whereas the APOE e2 allele is associated with decreased AD risk. , Thus, APOE testing may be used to support the diagnosis of AD in symptomatic individuals. , Although heterozygosity or homozygosity for the APOE e4 allele is associated with an increased risk of developing AD, APOE testing is not sufficiently sensitive or specific for use in predicting disease development. Lack of the APOE e4 allele does not rule out a diagnosis of AD.
Genetic Testing for Early-Onset Alzheimer’s Disease
Identifying a familial cause of early-onset AD is useful for genetic counseling purposes and may facilitate discussions of prognosis. Recommended approaches to identify a pathogenic variant include a targeted multigene panel or genomic testing (ie, exome sequencing, exome array, or genome sequencing). Single-gene testing is generally not recommended unless a known familial variant exists. Multigene panels should include “causative” genes for early-onset familial AD and may include genes associated with the development of other neurodegenerative disorders with overlapping symptoms (eg, Parkinson disease). The specific genes included on multigene panels, and the methodologies used, vary by laboratory. Genomic testing is reasonable if a multigene panel fails to identify a causative variant.
Pathogenic variants in the APP, PSEN1, and PSEN2 genes are associated with the development of 60-80% of early-onset familial AD cases. The presence of a causative variant in one of these genes supports the diagnosis of MCI or dementia due to AD. , Predictive testing for asymptomatic adults with a history of early-onset familial AD is possible if the pathogenic APP, PSEN1, or PSEN2 variant is known; if such testing is being considered, genetic counseling is recommended. Predictive testing is not recommended in children.
It is likely that other AD-causative variants remain to be identified. Of note, the clinical presentation of early-onset familial AD overlaps with the clinical presentation of frontotemporal dementia, which has been linked to pathogenic variants in the C9orf72, GRN, and MAPT genes.
ARUP Laboratory Tests
Quantitative Electrochemiluminescent Immunoassay (ECLIA)
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
Massively Parallel Sequencing
References
-
GeneReviews - Alzheimer Disease Overview
Bird TD. Alzheimer disease overview. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews. University of Washington, Seattle. Updated Dec 2018; accessed Aug 2024.
-
21514250
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263‐269.
-
38934362
Jack CR Jr, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimers Dement. Published Jun 2024; accessed Aug 2024.
-
Leqembi package insert
Food and Drug Administration. LEQEMBI (lecanemab) package insert. Revised Jul 2023; accessed Aug 2024.
-
Kisunla package insert
Food and Drug Administration. KISUNLA (donanemab) package insert. Revised Jul 2024; accessed Aug 2024.
-
21514249
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):270‐279.