Periodic Reporting for period 2 - TAU-NOW (Tau Pathology in Alzheimer’s disease: Spreading and Resilience)
Reporting period: 2022-10-01 to 2024-03-31
What is the problem being addressed and why is it important for society?
Alzheimer’s disease (AD) poses a major societal challenge, as currently 40 million people worldwide are diagnosed with this condition and there is treatment possibilities are currently limited. As a consequence of the aging society, prevalence estimates indicate that the number of individuals with AD will be doubled by 2040. This projected increase will have profound socio-economic consequences, and dementia has therefore been denoted a public health priority by the World Health Organization. AD is neuropathologically characterized by cerebral plaques containing aggregates of various amyloid-β (Aβ) peptides and neurofibrillary tangles containing hyperphosphorylated and aggregated tau. Both Aβ and tau pathology can now also be quantified during life using positron emission tomography (PET). These AD pathological hallmarks are associated with gradual neurodegeneration of the brain, leading to cognitive deficits and ultimately dementia. AD is characterized by a long preclinical stage in which accumulation of Aβ and tau occurs, while cognitive performance and brain structure remain largely preserved. The estimated time interval between the initial deposition of AD pathology in the neocortex and the emergence of symptoms is 15-20 years, highlighting a considerable window of opportunity to intervene in the relatively healthy brain.
Over the past decades, Aβ pathology has received a tremendous amount of interest from academia and industry. This has resulted in major improvements in the early and differential diagnosis of AD. However, the associations between Aβ pathology (especially regionally) and neurodegeneration as well as cognition are modest at best. Moreover, despite some recent successful phase III clinical trials targeting the physiological pathways that lead to aggregation of Aβ, the observed clinical benefits were modest and adverse advents occurred frequently. The limited risk/benefit ratio stresses the need for further diversification of the drug portfolio. Tau pathology is a promising drug target because neuropathological, in vitro and animal studies have provided strong evidence for a causal role of tau in the breakdown of synaptic integrity, degeneration of neurons and glial cells and cognitive impairment. Among many mechanisms of action, I envision two tau-targeted treatment options to be potentially effective in halting or slowing down the progression of AD: 1) preventing the spreading of pathological tau, and 2) boosting brain and cognitive resilience against tau pathology. These two processes are currently insufficiently understood, especially in living humans. Since only a few years, tau pathology can be visualized and quantified in vivo using PET ligands that bind with high affinity and specificity to the tau aggregates formed in AD. I have access to a large multicenter dataset with longitudinal tau PET, enabling investigations into the evolution of tau pathology during AD progression. The ability to map tau longitudinally in humans, with great anatomical detail, offers tremendous opportunities. Especially since available in vitro and animal models do not adequately reflect the pathophysiology and pathogenesis of sporadic AD.
What are the overall objectives?
TAU-NOW uniquely utilizes longitudinal tau PET in conjunction with functional and structural magnetic resonance imaging (MRI), biofluid and cognitive data, to investigate mechanisms of tau spread and brain and cognitive resilience in individuals with early to clinically advanced AD. This is a first step towards development of tau-targeted drugs to prevent disease progression of AD. The following objectives flow from this ambition:
A. Identify modifiers of tau spreading: There is great inter-individual variability in the rate of disease progression. Identifying genetic and molecular factors that slow spreading of tau pathology is of utmost importance for our understanding of AD pathogenesis and could reveal novel drug targets and pathways for intervention.
B. Detect determinants of brain and cognitive resilience to tau pathology: Some individuals can withstand severe tau load with only limited brain atrophy or cognitive loss, while in others relatively little tau pathology results in severe atrophy and cognitive deficits. Unravelling why some individuals are more resilient to tau pathology than others may provide leads to discover drug-targets and help refine the prognosis in individuals with AD.
C. Determine the prognostic value of tau spreading and resilience for predicting change in cognition and brain atrophy over time: Clinicians are currently not able to provide an accurate prognosis of disease progression in AD to patients and caregivers. TAU-NOW will fulfil this significant unmet need, by improving the accuracy of prognostic information informed by tau spreading and resilience to tau. This will also provide important information about downstream effects of tau pathology, and allows the assessment of the impact of therapeutic strategies aimed at decelerating tau spread or boosting resilience. Finally, the ability to select a group of “fast-progressors” will allow more efficient screening of potential drug candidates (i.e. shorter duration and fewer persons needed), thereby facilitating proof-of-concept studies for drug efficacy.
Alzheimer’s disease (AD) poses a major societal challenge, as currently 40 million people worldwide are diagnosed with this condition and there is treatment possibilities are currently limited. As a consequence of the aging society, prevalence estimates indicate that the number of individuals with AD will be doubled by 2040. This projected increase will have profound socio-economic consequences, and dementia has therefore been denoted a public health priority by the World Health Organization. AD is neuropathologically characterized by cerebral plaques containing aggregates of various amyloid-β (Aβ) peptides and neurofibrillary tangles containing hyperphosphorylated and aggregated tau. Both Aβ and tau pathology can now also be quantified during life using positron emission tomography (PET). These AD pathological hallmarks are associated with gradual neurodegeneration of the brain, leading to cognitive deficits and ultimately dementia. AD is characterized by a long preclinical stage in which accumulation of Aβ and tau occurs, while cognitive performance and brain structure remain largely preserved. The estimated time interval between the initial deposition of AD pathology in the neocortex and the emergence of symptoms is 15-20 years, highlighting a considerable window of opportunity to intervene in the relatively healthy brain.
Over the past decades, Aβ pathology has received a tremendous amount of interest from academia and industry. This has resulted in major improvements in the early and differential diagnosis of AD. However, the associations between Aβ pathology (especially regionally) and neurodegeneration as well as cognition are modest at best. Moreover, despite some recent successful phase III clinical trials targeting the physiological pathways that lead to aggregation of Aβ, the observed clinical benefits were modest and adverse advents occurred frequently. The limited risk/benefit ratio stresses the need for further diversification of the drug portfolio. Tau pathology is a promising drug target because neuropathological, in vitro and animal studies have provided strong evidence for a causal role of tau in the breakdown of synaptic integrity, degeneration of neurons and glial cells and cognitive impairment. Among many mechanisms of action, I envision two tau-targeted treatment options to be potentially effective in halting or slowing down the progression of AD: 1) preventing the spreading of pathological tau, and 2) boosting brain and cognitive resilience against tau pathology. These two processes are currently insufficiently understood, especially in living humans. Since only a few years, tau pathology can be visualized and quantified in vivo using PET ligands that bind with high affinity and specificity to the tau aggregates formed in AD. I have access to a large multicenter dataset with longitudinal tau PET, enabling investigations into the evolution of tau pathology during AD progression. The ability to map tau longitudinally in humans, with great anatomical detail, offers tremendous opportunities. Especially since available in vitro and animal models do not adequately reflect the pathophysiology and pathogenesis of sporadic AD.
What are the overall objectives?
TAU-NOW uniquely utilizes longitudinal tau PET in conjunction with functional and structural magnetic resonance imaging (MRI), biofluid and cognitive data, to investigate mechanisms of tau spread and brain and cognitive resilience in individuals with early to clinically advanced AD. This is a first step towards development of tau-targeted drugs to prevent disease progression of AD. The following objectives flow from this ambition:
A. Identify modifiers of tau spreading: There is great inter-individual variability in the rate of disease progression. Identifying genetic and molecular factors that slow spreading of tau pathology is of utmost importance for our understanding of AD pathogenesis and could reveal novel drug targets and pathways for intervention.
B. Detect determinants of brain and cognitive resilience to tau pathology: Some individuals can withstand severe tau load with only limited brain atrophy or cognitive loss, while in others relatively little tau pathology results in severe atrophy and cognitive deficits. Unravelling why some individuals are more resilient to tau pathology than others may provide leads to discover drug-targets and help refine the prognosis in individuals with AD.
C. Determine the prognostic value of tau spreading and resilience for predicting change in cognition and brain atrophy over time: Clinicians are currently not able to provide an accurate prognosis of disease progression in AD to patients and caregivers. TAU-NOW will fulfil this significant unmet need, by improving the accuracy of prognostic information informed by tau spreading and resilience to tau. This will also provide important information about downstream effects of tau pathology, and allows the assessment of the impact of therapeutic strategies aimed at decelerating tau spread or boosting resilience. Finally, the ability to select a group of “fast-progressors” will allow more efficient screening of potential drug candidates (i.e. shorter duration and fewer persons needed), thereby facilitating proof-of-concept studies for drug efficacy.
Aim A: Identify modifiers of tau spreading.
- Paper led by ERC stg funded post-doctoral researcher Colin Groot (PI as shared senior author) in Brain [PMID: 36084009] showed that increased phosphorylation of tau in cerebrospinal fluid predicts future accumulation of tau aggregates as measured by PET;
- Paper co-led by the PI and published in Alzheimer’s and Dementia [PMID: 34060233] showed that the genetic variant BIN1 is associated with faster spreading of tau pathology;
- Two papers with prominent involvement of the PI on biological (p-tau, amyloid, connectivity), demographic (age, sex) and vascular modifiers of tau spreading published in Nature Communications [PMID: 36333294], Brain [PMID: 33439987] and Brain [PMID: 37721482].
Aim B. Detect determinants of resilience to tau pathology.
- Manuscript on demographic, genetic and imaging markers of resilience to tau pathology with the PI as senior author is published at Brain [PMID: 36967222];
- Manuscript on biological determinants of resilience to tau pathology is close to submission.
Aim C. Determine the prognostic value of tau spreading and resilience for predicting change in cognition and brain atrophy over time.
- Paper led by the PI and published in Nature Medicine [PMID: 36357681] showed that the combination of amyloid and tau PET is highly predictive for development of future symptoms in initially cognitively healthy individuals;
- Paper led by the PI and published in JAMA Neurology [PMID: 34180956] showed that tau PET holds strong prognostic value across the Alzheimer’s disease clinical continuum.
- Paper on how the degree of resilience against tau pathology impact rates of future cognitive decline (PI as senior author) is published at Brain [PMID: 36967222]
- Manuscript on baseline and longitudinal tau PET levels as predictors of future cognitive decline is close to submission
- Manuscript directly comparing tau PET vs plasma p-tau217 levels as predictors of future cognitive decline is in preparation.
- Paper led by ERC stg funded post-doctoral researcher Colin Groot (PI as shared senior author) in Brain [PMID: 36084009] showed that increased phosphorylation of tau in cerebrospinal fluid predicts future accumulation of tau aggregates as measured by PET;
- Paper co-led by the PI and published in Alzheimer’s and Dementia [PMID: 34060233] showed that the genetic variant BIN1 is associated with faster spreading of tau pathology;
- Two papers with prominent involvement of the PI on biological (p-tau, amyloid, connectivity), demographic (age, sex) and vascular modifiers of tau spreading published in Nature Communications [PMID: 36333294], Brain [PMID: 33439987] and Brain [PMID: 37721482].
Aim B. Detect determinants of resilience to tau pathology.
- Manuscript on demographic, genetic and imaging markers of resilience to tau pathology with the PI as senior author is published at Brain [PMID: 36967222];
- Manuscript on biological determinants of resilience to tau pathology is close to submission.
Aim C. Determine the prognostic value of tau spreading and resilience for predicting change in cognition and brain atrophy over time.
- Paper led by the PI and published in Nature Medicine [PMID: 36357681] showed that the combination of amyloid and tau PET is highly predictive for development of future symptoms in initially cognitively healthy individuals;
- Paper led by the PI and published in JAMA Neurology [PMID: 34180956] showed that tau PET holds strong prognostic value across the Alzheimer’s disease clinical continuum.
- Paper on how the degree of resilience against tau pathology impact rates of future cognitive decline (PI as senior author) is published at Brain [PMID: 36967222]
- Manuscript on baseline and longitudinal tau PET levels as predictors of future cognitive decline is close to submission
- Manuscript directly comparing tau PET vs plasma p-tau217 levels as predictors of future cognitive decline is in preparation.
Several project have made a significant impact on the field and have influenced our thinking about the disease. A good example is our paper published in Nature Medicine [PMID: 36357681] showing that the combination of amyloid and tau PET is highly predictive for development of future symptoms in initially cognitively healthy individuals. There is active debate in the field what abnormal biomarkers mean in cognitively unimpaired individuals. Our data supports the NIA-AA criteria-based classification of A+T+ cognitively unimpaired individuals as “preclinical AD”. To consider A+T+ merely as risk factor, and not manifest disease, may be an underestimation of its malignancy. We have also made great progress on understanding the modifiers of tau spreading throughout the brain, and have identified several demographic (younger age and female sex), biological (soluble p-tau, functional connectivity), genetic (BIN1) and vascular (micro bleeds) factors that promote tau spreading.
The next projects will specifically focus on better understanding the biological mechanisms underlying tau spreading and resilience against tau pathology. We will do this using imaging techniques to map brain pathologies and functional changes, molecular markers to identify particular proteins and genetic analysis to discover new genetic pathways associated with tau spreading and resilience against tau pathology.
The next projects will specifically focus on better understanding the biological mechanisms underlying tau spreading and resilience against tau pathology. We will do this using imaging techniques to map brain pathologies and functional changes, molecular markers to identify particular proteins and genetic analysis to discover new genetic pathways associated with tau spreading and resilience against tau pathology.