Anchoring Alzheimer’s Disease Along an Amyloid Timeline

By Makoto Ishii, MD, PhD

Assistant Professor, Department of Neurology, Peter O’Donnell Jr. Brain Institute, Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center

SYNOPSIS: In 601 individuals from Wisconsin-based cohorts with amyloid-beta and tau positron emission tomography scans, the magnitude and topographical spread of tau pathology increased with longer duration of amyloid-beta positivity, and the cognitive decline was steepest in those with the longest duration of amyloid-beta positivity and elevated entorhinal tau.

SOURCE: Cody KA, Langhough RE, Zammit MD, et al. Characterizing the brain tau and cognitive decline along the amyloid timeline in Alzheimer’s disease. Brain 2024:147;2144-2157.

The amyloid cascade hypothesis of Alzheimer’s disease postulates that the deposition of amyloid-beta in the brain is a critical initial step that results in several downstream pathological events, including the aggregation of hyper-phosphorylated tau proteins, synaptic dysfunction, neuronal loss, cognitive impairment, and, eventually, dementia. Supporting the amyloid cascade hypothesis, recent Phase III clinical trials found that treatment with monoclonal antibodies against amyloid-beta resulted in modest but significant decline in the clinical progression in those with mild cognitive impairment (MCI) or mild stages of dementia caused by Alzheimer’s disease.

Interestingly, the monoclonal antibodies were most effective in those with a low burden of tau pathology. This suggests an important therapeutic window exists when amyloid-beta pathology has accumulated but before the development of significant tau pathology. Therefore, understanding the temporal relation between amyloid-beta and tau pathology would be critical for prognosticating and identifying patients who may receive the most benefit from anti-amyloid therapies.

Cody and colleagues examined this temporal relation between amyloid-beta and tau pathology in a well-characterized cohort of 601 individuals from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center. Each study participant had undergone amyloid-beta positron emission tomography (PET) by 11C-Pittsburgh compound B (PiB), tau PET by 18F-MK-6420, and longitudinal neuropsychological assessments. Notably, this cohort was comprised primarily of cognitively unimpaired individuals (89.4%) with an additional 8.0% with MCI and 2.7% with dementia.

By using their previously established sample iterative local approximation (SILA) algorithm, the study authors were able to estimate the onset age of amyloid-beta positivity from the cortical PiB distribution volume ratio. They then were able to construct an amyloid timeline by estimating an individual’s duration of amyloid-beta positivity at the time of tau PET imaging by subtracting the SILA-estimated onset age of amyloid-beta positivity from the age at the time of the tau PET.

Using this model, the authors found that for each decade of amyloid-beta positivity, tau had “spread” or progressed following the neurofibrillary tangle (NFT) tau or Braak stages. On average, tau pathology was first detectable in the entorhinal cortex (Braak stage I) approximately 6.2 (95% confidence interval, 4.5-7.8) years after the onset of amyloid-beta.

Tau progression beyond the medial temporal lobes (Braak stages IV-VI) was associated with cognitive impairment and was found to occur, on average, > 10 years after onset of amyloid-beta positivity or 10.5 years to Braak stage III, 11.4 years to Braak stage IV, 19.2 years to Braak stage V, and more than 25 years to Braak stage VI. Furthermore, an interactive effect of amyloid-beta and tau pathology in cognitively unimpaired individuals was seen where individuals with both longer duration of amyloid-beta positivity and tau positivity in the entorhinal cortex had the most pronounced decline in cognition.

COMMENTARY

This study by Cody and colleagues provides further support that amyloid-beta pathology precedes and, over time, can drive the tau accumulation during the transition period from the asymptomatic preclinical to symptomatic stages of Alzheimer’s disease. Furthermore, the tau PET findings are consistent with the earlier neuropathological studies conducted by Braak and Braak, where a topographical “spread” of tau was seen with clinical progression.

Strengths of this study include the use of a well-characterized cohort with longitudinal neuropsychological assessments and both amyloid-beta and tau PET scans. Additionally, it should be noted that by using the SILA algorithm, the authors were able to construct an amyloid timeline and overcome the need for prolonged longitudinal PET studies, which would have been very costly and timely.

Despite the many strengths of this study, there are several caveats and limitations. First, the use of the SILA algorithm and constructing a model is a limitation. The authors created a longitudinal timeline based on cross-sectional data. Longitudinal amyloid and tau assessments would be needed to validate the model and verify the study findings.

There also are inherent limitations with both amyloid-beta and tau PET, including spatial resolution and limited sensitivity. Additionally, the model did not incorporate important contributing factors, such as apolipoprotein E genotype status. Furthermore, the cohort was predominantly cognitively unimpaired and, thus, the findings from more advanced stages may be less reliable. Finally, the cohort was comprised of primarily highly educated, non-Hispanic white individuals. Therefore, verification and replication in other cohorts will be needed.

Despite any limitations, this study highlights the need to examine Alzheimer’s disease, particularly amyloid-beta and tau pathology, beyond a dichotomous positive or negative status and to pay particular attention to the magnitude and duration of exposure. As we move toward preventive and early intervention strategies, it is important to identify critical therapeutic windows, since not all interventions may be appropriate or effective at all stages of Alzheimer’s disease.

For example, based on the results from this study, there appears to be a period of around 10 years from the onset of amyloid-beta pathology to when tau deposits in the entorhinal cortex and the development of cognitive decline. Therefore, it would be reasonable to hypothesize that any anti-amyloid intervention would have the most benefit for individuals who are in this critical time window, and, as the disease progresses further, anti-amyloid therapies likely will be less effective.

We now are closer to the day when patients know not only their Alzheimer’s pathology status but where they are on the Alzheimer’s disease continuum, enabling one to have important information about their potential clinical trajectory and to better identify when to intervene with anti-amyloid and other yet-to-be-discovered therapies.