The widely accepted Amyloid Cascade Hypothesis (Figure 1) indicates that the most effective and meaningful way to treat Alzheimer’s disease (AD) is to reduce amyloid pathology early in the disease course -prior to excessive tau phosphorylation and accumulation, neuronal degeneration, and overt symptoms of dementia.
Figure 1. The Amyloid Cascade Hypothesis
With the simultaneous advancement of early pathology biomarkers along with disease-modifying treatments, it’s an exciting time for the future of AD patients and their loved ones. Recent advances in detecting AD pathology (amyloid beta (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau)) through positron emission tomography (PET) brain imaging and cerebrospinal fluid (CSF) have given us some power in early differential diagnosis; however, these procedures are costly and invasive. In this study by Mattson-Carlgren et al., the utility of a plasma biomarker (easily detected in a minimally invasive and inexpensive blood draw) was validated. It was found that levels of pTau217 in plasma reliably allowed for the estimation of brain Aβ positivity as well as degree of tau pathology. Specificity (0.94) and sensitivity (0.86) for detecting AD pathology was in-line with that of more involved and expensive measures (e.g., PET imaging) and withstood for patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or dementia. Given the results of this study, the authors propose a new algorithm for determining which patients may be best-suited for anti-Aβ immunotherapy -i.e., those with the presence of Aβ pathology but low tau pathology (Figure 2).
Figure 2. Proposed Update to Identifying Anti-Aβ Immunotherapy Candidates
A. Using the current, standard workflow, in order to determine that a patient is a good candidate for disease modifying anti-Aβ immunotherapy (i.e. Aβ + and low tau burden), they must undergo invasive and expensive CSF and/or PET measures of Aβ and tau. B. Under the newly proposed algorithm, both Aβ positivity and tau burden can be reliably estimated via pTau217 plasma levels as measured from inexpensive and minimally invasive blood draw. Only a small subset of patients whose Aβ positivity falls in the grey (unclear) zone and/or who have pTau217 levels indicative of high tau burden need undergo more expensive and invasive PET imaging or spinal tap.
Given the expense and potential safety risk (most notably amyloid-related imaging abnormalities; ARIAS) associated with the emerging, disease-modifying anti-Aβ immunotherapies, utilizing them only in patients for which (and when) they are warranted would be a tremendous advance in the precision treatment of AD. Additionally, adoption of the proposed algorithm is estimated to avoid Aβ PET or CSF measures in 80-85% and tau PET in 57% of individuals and potentially have a cost savings of up to 70%. Results such as these (as well as other emerging cost-effective, non-invasive AD pathology detection strategies such as retinal scans), coupled with the ever-evolving disease modifying treatments, hold promise for a future in which the devastating effects of AD are but a distant memory.
Mattsson-Carlgren N et al. JAMA Neurol. 2024;81(1):69. Abstract.