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Summary in Thirty Seconds
Alzheimer’s Disease (AD) is often misdiagnosed, and much research has been devoted to developing a valid and reliable means of using biomarkers to diagnose this most common neurodegenerative disease.
Amyloid beta and tau, protein markers of AD, can be measured through PET scans and CSF spinal taps, but these tests are costly, uncomfortable, and time-consuming.
Blood-based biomarkers (BBMs) hold promise for fast, convenient, and simple means to diagnose AD, and BBMs (particularly multiple measures) show good diagnostic accuracy.
Biologic changes related to AD can arise as long as 20 years before clinical symptoms manifest; thus, using BBMs to screen for AD holds promise as a way to discover who needs early intervention.
Clinical trials for AD compounds have frequently failed for many reasons including inconsistent diagnosis; targeting symptoms, not causes; and starting treatment too late in the disease process. Using biomarkers—particularly BBMs—may help address these issues and slow or stop the rising prevalence of AD.
Alzheimer’s Disease Diagnosis
Alzheimer’s Disease (AD) is the most common neurodegenerative disease, accounting for approximately 75% of all dementia cases and affecting about 1 in every 9 Americans over 65.[1] Before the early 2000s, AD could only be definitively diagnosed post-mortem.[2] Even though huge advances have been made in AD diagnosis, approximately 25-30% of people currently going to a specialized dementia clinic are incorrectly given an AD diagnosis.[3] In primary care settings, the diagnostic problem is worse. Between 50% and 70% of symptomatic patients with AD are missed or incorrectly diagnosed in primary care, because cognitive screening is not done, and accessible, rapid, cost-effective, and accurate diagnostic tools do not exist.[4] Thus, tremendous effort has gone into developing valid and reliable diagnostic tests—particularly those that can detect pre-symptomatic disease.[5]In this regard, AD biomarker tests have been developed to measure amyloid beta (Aβ) and tau levels in cerebrospinal fluid (CSF) and through specialized PET scans.[6] These biomarker measures currently form the “gold standard” for AD diagnosis.[7]
ATN Classification Diagnosis
The Alzheimer’s Association describes a “symptom agnostic” AD diagnostic system based on amyloidosis, tauopathy, and neurodegeneration (ATN), using CSF and PET biomarker evaluation.[8] A fourth letter “X” has recently been added to denote novel biomarkers currently being explored or yet to be discovered.[9] Studies using this ATN classification method have shown strong relationships with cognitive functioning tests both diagnostically and longitudinally.[10],[11]
AD Pre-clinical Changes
A challenge in diagnosis relates to timing, with patients most often being seen only after clinical AD symptoms arise. However, pre-clinical AD changes may begin as early as 20 years before clinical (most typically short-term memory/rapid forgetting) signs appear.[12] These pre-clinical changes involve biochemical alterations followed by cellular deterioration. The existence of these “silent” and slow-developing pre-clinical changes emphasizes the importance of biomarker testing (screening) conducted many years, if not decades before cognitive symptoms manifest. Such screening is particularly important in people who have genetic predispositions (most notably, APOEε4 alleles[13]) for AD. Widespread simple and inexpensive biomarker testing/screening would help identify at-risk and pre-clinical patients, allowing for earlier interventions and better preventative steps than are currently being taken.
Blood-based Biomarkers
While brain biomarker levels can be accurately measured using PET and CSF, these tests are costly, time-consuming, not easily accessible, and invasive.[14] Brain Aβ and tau proteins cross into the bloodstream at very diluted levels,[15] and methods have been developed to detect these minute levels in blood plasma using immunoassays or quantitative mass spectrometry.[16] Blood-based biomarkers (BBMs) currently include the following three measures (amongst others):
Amyloid biomarkers: 1) Amyloid precursor protein; 2) Aβ peptides; 3) Aβ oligomers. Accumulation of Aβ fibrils and oligomers into Aβ plaques is a neuropathologic hallmark of AD.[17] The ratio of plasma Aβ42/Aβ40 has shown good diagnostic/predictive utility.[18]
Tau biomarkers: 1) Total tau; 2) phosphorylated tau (p-tau). Tau is the major constituent of neurofibrillary tangles, which are the second significant neuropathological marker of AD. Longitudinal studies report increased p-tau levels in the brain paralleling Aβ pathology, linking these two changes.[19]
Neuronal damage biomarkers: Neurofilament light chain protein (NfL) is found in all neurodegenerative diseases, making it less specific as a measure for AD;[20] thus, while not holding diagnostic utility, NfL levels may be useful for monitoring disease progression.[21]
Blood-based Biomarker Diagnostic Accuracy and Utility
A systematic review of 76 articles assessing the diagnostic accuracy of BBMs[22] found that biomarker panels showed better accuracy than individual marker tests in disease detection, with a plasma Aβ42/40 ratio used in combination with age, APOEε4 status, and gender providing strong results. For BBMs alone, a combination of plasma Aβ42/40, p-tau 217, and p-tau181 had high diagnostic validity, while NfL provided utility for measuring disease progression. With advances in BBMs and research to establish their validity, ATN(X) classifications can be determined through BBMs more easily and economically than PET or CSF measures.[23] The Alzheimer’s Association states that while BBMs are already being incorporated into and improving clinical trials, more research needs to take place using BBMs in clinical practice before BBMs can be commonly used in community settings.[24]
AD Clinical Trial Failures
Without an accurate diagnosis, AD treatments can neither be developed nor administered, and myriad biotechs are working to develop AD compounds, particularly given estimates of over 7 million people with AD in the US alone by 2030.[25] A 2022 review of all AD clinical trials since 2004 found a 98% failure rate.[26] A compelling case can be made that the failure of these clinical trials is multivariate, including the following three factors: 1) failing to recognize the heterogeneity of AD in diagnosis and/or including non-AD participants;[27] 2) not addressing the root cause of the disease (including genetic factors)[28]; 3) not starting treatment early enough—only after clinical changes manifest (although some trials of amyloid-clearing monoclonal antibodies starting pre-clinically have failed to show significant results[29]). Clinical trials have begun incorporating biomarkers (including BBMs) along with cognitive performance to not only diagnose AD for trial inclusion, but also as trial endpoints to maximize statistical power while lowering cost and inconvenience to trial participants.[30]
The Future of Blood-based Biomarkers
The Alzheimer’s Association states that BBMs are “very likely to revolutionize the diagnostic work-up of AD in the future.”[31] The development of simple and inexpensive, but accurate, BBMs is leading to their prospective diagnostic use in the pre-clinical stages of AD when cellular changes begin in otherwise cognitively healthy people.[32] Fine-tuning and implementing BBMs indicating early neuropathological signs will also allow pharmacologic interventions to begin that will slow, if not prevent the neuronal damage that is the hallmark of AD. In these ways, widespread use of BBMs for screening, diagnosis, and progression monitoring will help hinder (if not halt) the ongoing rise in AD being seen as advances in healthcare are leading to longer lifespans.
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