The key to assessing Alzheimer’s disease treatments? Test them in Parkinson’s disease patients.
David Dai was the lead author on this study, and was the writer of this brief. David is a MD/PhD student in Eddie Lee's lab. He is interested in understanding the mechanisms underlying neurodegenerative diseases.
or technically,
ADNC-RS, a clinical-genetic risk score, predicts Alzheimer’s pathology in autopsy-confirmed Parkinson’s disease and Dementia with Lewy bodies
[See Original Abstract on Pubmed]
Authors of the study: David L Dai, Thomas F Tropea, John L Robinson, Eunran Suh, Howard Hurtig, Daniel Weintraub, Vivianna Van Deerlin, Edward B Lee, John Q Trojanowski, Alice S Chen-Plotkin
In a world full of uncertainty, the only thing we can be sure of is that time will go on. And with time, unfortunately, comes disease. Age is the greatest risk factor for neurodegenerativebrain diseases characterized by the progressive loss of neurons over time. diseases which are characterized by the progressive loss of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Three of the most common neurodegenerativebrain diseases characterized by the progressive loss of neurons over time. diseases are AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, Parkinson’s disease, and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms.. Together they affect more than 6 million Americans, and that number is expected to reach over 9.8 million by 2030. To effectively diagnose and treat these diseases, it is vital to develop tools that can accurately predict who will develop disease. However, efforts to predict disease development, especially in AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, have largely been unsuccessful, despite advancements in our understanding of the genetic risk factors for AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease.
In all three diseases, abnormal proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregate, injure brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells, and lead to neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles death, resulting in the symptoms that patients experience -- loss of memory, cognition, and movement. Doctors do their best to diagnose patients, but diagnoses are not confirmed until after patients die, when their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are autopsied, and the presence of abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates confirms which disease the patients experienced during life. In AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, these abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called amyloid-beta plaques (Aβ) and tau neurofibrillary tangles. In Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms., these proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called Lewy bodies. Because of their similarities, Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. are both included in a group of diseases called Lewy body diseases (LBD).
Although AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s and LBD are traditionally thought of as separate diseases, patients with LBD often have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. 50-80% of patients with a primary diagnosis of LBD also exhibit Aβ and tau proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates at autopsy-- hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Up to 40% of patients with a primary diagnosis of Parkinson’s have enough Aβ and tau aggregates in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. for a secondary diagnosis of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. As only 10% of people age 65 and older have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease in the United States, it may not just be a coincidence that Parkinson’s patients commonly also have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Patients with Parkinson’s or dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. may actually be at increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease. This is important for clinicians to recognize when caring for LBD patients!
Taking advantage of LBD patients’ increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks, David Dai and the Chen-Plotkin Lab at the University of Pennsylvania asked: Can we predict which Parkinson’s/dementia with Lewy Bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. patients are likely to develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks using known AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s genetic risk factors? They gathered various demographic and genetic variables that could impact AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s development and used a machine learning approach to identify the specific factors important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status.
They found that using only 4 pieces of information (age of onset and 3 pieces of genetic information), they could predict AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status to a modest degree. They transformed this information into a risk score, called the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change – Risk Score, that provides a continuous assessment of individuals’ risk for developing the hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. A continuous risk score is useful because it reflects individuals’ incremental differences in disease development likelihood and allows researchers to set specific, numerical thresholds when predicting which patients are likely or unlikely to develop disease. They checked the effectiveness of their risk score in two additional groups and achieved comparable results. These additional validation steps were important because they showed that the risk score worked not only in the population that was used to build it but also in two other, unrelated groups. In other words, by showing that the risk score succeeded in three distinct groups, the researchers demonstrated that the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change -- Risk Score is a tool that could be successfully used in the general population.
These results have important scientific and clinical implications! By studying how the model made successful predictions, the scientists found that not all genetic information is equal when it comes to predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in Parkinson’s/dementia with Lewy body patients. They identified three genetic locations that were particularly important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in this group of individuals. They hope that further investigation will reveal why these locations are so crucial for the model’s predictions. If they are found to increase the development of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks in Parkinson’s and dementia with Lewy body patients, then treatments can be designed to block these genetic locations’ functions and maybe prevent AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease development in this subset of patients!
Given that the toxic proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates Aβ and tau accumulate in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. decades before patients develop symptoms, the medical community is trying to remove the aggregates as early as possible in the disease development process. However, this is extremely difficult because we don’t know who will develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s, and we don’t know if removing the aggregates even helps patients! This new risk score could help solve that problem. On average, patients receive clinical diagnoses of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s at ~80 years old, while Parkinson’s patients receive their diagnoses at ~60 years old. That means, using this risk score, we may be able to identify future AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s patients at least a decade before they develop symptoms, allowing us to first assess the effectiveness of Aβ and tau targeting treatments in a group of patients with increased risk of developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. If those treatments are proven to work, we may finally be able to slow the progression of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease!
In all three diseases, abnormal proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregate, injure brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells, and lead to neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles death, resulting in the symptoms that patients experience -- loss of memory, cognition, and movement. Doctors do their best to diagnose patients, but diagnoses are not confirmed until after patients die, when their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are autopsied, and the presence of abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates confirms which disease the patients experienced during life. In AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, these abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called amyloid-beta plaques (Aβ) and tau neurofibrillary tangles. In Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms., these proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called Lewy bodies. Because of their similarities, Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. are both included in a group of diseases called Lewy body diseases (LBD).
Although AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s and LBD are traditionally thought of as separate diseases, patients with LBD often have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. 50-80% of patients with a primary diagnosis of LBD also exhibit Aβ and tau proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates at autopsy-- hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Up to 40% of patients with a primary diagnosis of Parkinson’s have enough Aβ and tau aggregates in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. for a secondary diagnosis of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. As only 10% of people age 65 and older have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease in the United States, it may not just be a coincidence that Parkinson’s patients commonly also have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Patients with Parkinson’s or dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. may actually be at increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease. This is important for clinicians to recognize when caring for LBD patients!
Taking advantage of LBD patients’ increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks, David Dai and the Chen-Plotkin Lab at the University of Pennsylvania asked: Can we predict which Parkinson’s/dementia with Lewy Bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. patients are likely to develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks using known AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s genetic risk factors? They gathered various demographic and genetic variables that could impact AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s development and used a machine learning approach to identify the specific factors important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status.
They found that using only 4 pieces of information (age of onset and 3 pieces of genetic information), they could predict AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status to a modest degree. They transformed this information into a risk score, called the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change – Risk Score, that provides a continuous assessment of individuals’ risk for developing the hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. A continuous risk score is useful because it reflects individuals’ incremental differences in disease development likelihood and allows researchers to set specific, numerical thresholds when predicting which patients are likely or unlikely to develop disease. They checked the effectiveness of their risk score in two additional groups and achieved comparable results. These additional validation steps were important because they showed that the risk score worked not only in the population that was used to build it but also in two other, unrelated groups. In other words, by showing that the risk score succeeded in three distinct groups, the researchers demonstrated that the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change -- Risk Score is a tool that could be successfully used in the general population.
These results have important scientific and clinical implications! By studying how the model made successful predictions, the scientists found that not all genetic information is equal when it comes to predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in Parkinson’s/dementia with Lewy body patients. They identified three genetic locations that were particularly important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in this group of individuals. They hope that further investigation will reveal why these locations are so crucial for the model’s predictions. If they are found to increase the development of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks in Parkinson’s and dementia with Lewy body patients, then treatments can be designed to block these genetic locations’ functions and maybe prevent AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease development in this subset of patients!
Given that the toxic proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates Aβ and tau accumulate in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. decades before patients develop symptoms, the medical community is trying to remove the aggregates as early as possible in the disease development process. However, this is extremely difficult because we don’t know who will develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s, and we don’t know if removing the aggregates even helps patients! This new risk score could help solve that problem. On average, patients receive clinical diagnoses of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s at ~80 years old, while Parkinson’s patients receive their diagnoses at ~60 years old. That means, using this risk score, we may be able to identify future AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s patients at least a decade before they develop symptoms, allowing us to first assess the effectiveness of Aβ and tau targeting treatments in a group of patients with increased risk of developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. If those treatments are proven to work, we may finally be able to slow the progression of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease!
Citations:
Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement 2020;16(3):391+. You can find the report here.
Parkinson’s Foundation. Statistics. Parkinson’s Foundation. 2019 September 19. You can read the article here.