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Thanks for joining us, both of you.
[00:00:38] Prof. Xiang Gao: Thank you. Thanks for having me.
[00:00:40] Prof. Xinming Xu: Very happy to be here tonight.
[00:00:43] Dr. Sara Schaefer: So Alzheimer's disease and Parkinson's disease have been felt historically to be independent disorders with different pathophysiological underpinnings. What data is already out there to suggest there may be a link between the two? Xiang?
[00:00:59] Prof. Xiang Gao: [00:01:00] Yes. A good question. Some typical pathological signs of Alzheimer's disease, such as beta amyloid tau protein or found also in Parkinson's disease. At the same time, some alpha synuclein could be found in Alzheimer's disease too. Some post mortem study indicated that Parkinson's disease and Alzheimer's disease have some common regional atrophy, amyloid, and a tau deposition.
Also, some image study found cognitive decline can be presented in both diseases. Parkinson's disease, Alzheimer's disease demonstrate similar symptoms in malcognitive impairment, including memory loss, difficulty in problem solving, we call that executive function, and mood [00:02:00] change.
Also, some study suggested That some cognitive decline can be found in very, very early stage of Parkinson's disease.
[00:02:13] Dr. Sara Schaefer: And what about genetic links between the two in previous literature, has that been demonstrated?
[00:02:20] Prof. Xiang Gao: Yes some genetic link between these two diseases, such as some gene coding tau protein also be founded to be associated with Parkinson's disease.
[00:02:35] Dr. Sara Schaefer: So you use the UK biobank in your data collection and analysis, drawing connections between three main prongs, as I understand it, family history of Alzheimer's or dementia, polygenic risk score for Alzheimer's disease, and the presence of Parkinson's disease.
Can you give more details on how you conducted your study?
[00:02:56] Prof. Xiang Gao: In this study, we included around [00:03:00] 480, 000 participants from UK Biobank who are free of Parkinson's disease at the baseline. Also have complete data on the studied exposure variables. We use Cox Proportional-Hazard Model to look at the positive ratio and there are 95 confident interval of family history of Alzheimer's dementia, and for Parkinson's disease risk.
We also conducted some mediation analysis to examine the proportion of the association between family history of Alzheimer's disease and Parkinson's disease that could be mediated by some AD related genetic factors.
[00:03:49] Dr. Sara Schaefer: And what did you find?
[00:03:51] Prof. Xiang Gao: Oh, we found that family history of Alzheimer's disease and dementia was associated with a higher [00:04:00] risk of Parkinson's disease. People with family history of dementia and Alzheimer's disease had around 20 percent higher risk of Parkinson's disease relative to other people. We adjusted for some, well established risk factor for Parkinson's disease, such as age, sex, lifestyle, such as smoking and other potential co founders. And we also found that the association between family history of Alzheimer's dementia and Parkinson's disease. Could be mediated by AD related genetic factor. Those factor account for around 13 percent of the association.
[00:04:49] Dr. Sara Schaefer: And were those the same genetic factors that you mentioned earlier that influenced Tau?
[00:04:57] Prof. Xiang Gao: Even more complicated, more [00:05:00] comprehensive. For this polygenetic risk score, they included all potential genetic factor for Alzheimer's disease.
[00:05:11] Dr. Sara Schaefer: So I've had plenty of patients with a family history of Alzheimer's whom it becomes apparent later. Based on careful history that the diagnosis was incorrect and maybe they had dementia related to Huntington's or Lewy body disease or some other disorder. Historically, it seems like Alzheimer's diagnosis may not have been based on biomarker data as it more often is today, but rather the presence of dementia just led to an Alzheimer's diagnosis by default.
So in your data, the Alzheimer's diagnosis in family members was by patient report and also conflated with any dementia diagnosis, you know, Alzheimer's slash dementia, right? Given this, how much do you think your results reflect true links to [00:06:00] Parkinson's disease associated with Alzheimer's pathology as opposed to dementia in general?
[00:06:07] Prof. Xinming Xu: Yeah, we have to admit that the questionnaire of the self report was not that precise. The lack of clarification in the questionnaire itself will certainly increase the measurement error of this exposure. Family history was identified through the self reported touch screens questionnaire at baseline and the following visits and the participants were asked three questions regarding family history.
Has your father or mother or siblings ever suffer from any of the following diseases, the participants were asked to choose one or more conditions among 12 diseases related to family medical history into sets of illness. Thus the exposure, the self report family history in this study was from participants screening selection.[00:07:00]
So information bias might occur when participants recall their parents or siblings of having Alzheimer's disease when there was no classification regarding AD or dementia with other mixed types of dementia, or even Lewy body dementia in the questionnaire itself. So, therefore, the studies findings might reflect broader dementia related links to PD rather than specific AD PD associations. To make up for it, we conducted some sensitivity analysis. We removed participants who developed dementia during the follow up period because it was possible that PD and certain subtype dementia For example, PD dementia or Lewy body dementia were misdiagnosed.
Finally, we removed participants who had family history of Parkinson's disease to prevent information bias, as there could be errors occurring in recalling the diseases of their parents or siblings and a [00:08:00] lack of clarification regarding AD dementia or with other neurodegenerative diseases. Such as PD, and from this sensitivity analysis, we got a stable results compared to the main analysis.
Besides the sensitivity analysis, we also found that the polygenic risk of AD was associated with Parkinson's disease risk in a dose response manner and the adjusted hR was 1. 1 per 1 unit increment, and ADPRS itself could mediate 30 percent of the association between family history of AD and Parkinson's disease as previously mentioned.
So, to some degree, we are confident in our results. However, future studies should collect detailed data regarding family history of diseases. Especially regarding specific diagnosis, pathology biomarkers to refine our understanding of these two complex disorders.
[00:08:55] Dr. Sara Schaefer: As you point out in your discussion and Xiong, as you pointed out [00:09:00] earlier in this discussion, Parkinson's and Alzheimer's are characterized by predominantly different protein depositions. However, there's a lot of overlap and mixed pathology in patients. Do you think there are common pathways that lead to increased protein aggregation independent of which protein is aggregating?
What common genetic and environmental factors are of the most interest at this time?
[00:09:25] Prof. Xinming Xu: Yeah, as previously mentioned by professor Gao amyloid beta and tau lesions, typical pathological cosigns of AD were also found in PD while Lewy type aggregates containing alpha synuclein could be also found in AD too and postmortem studies also indicated that PD and AD had tau deposition. Recent studies reported common genetic overlaps between these two neurodegenerative diseases, such as MAPD, the gene that could encode tau protein, suggesting that [00:10:00] common genetic factors might partially explain the assert association between family history of AD and PD risk. Also, there's ongoing research into the common pathways that could lead to protein aggregation in these two neurodegenerative diseases.
Although we do not discuss this point in our paper, one hypothesis is that cellular process that normally help to fold proteins correctly or clear misfolded proteins might become impaired. For instance, the ubiquitin proteasome system and autophagy lysosome pathway, which are responsible for degrading damaged or misfolded proteins are often found to be dysfunctional in both Parkinson's disease and Alzheimer's disease.
Understanding the commonalities in protein aggregation pathways could lead to a broader treatment strategy that might be applicable to multiple neurodegenerative diseases. Also family history included information besides genetic susceptibility, like our brain [00:11:00] environments, especially for lifestyle factors such as diet quality and physical activity, which has been previously reported and also there's a lot of research into how environmental factors like toxins and gut microbiota might also influence this disease risk, which this study could not address.
[00:11:21] Dr. Sara Schaefer: So, Xinming, you mentioned this before a little bit. What did you learn from this research about how biobank surveys and data could be optimized in the future to better answer our questions?
[00:11:34] Prof. Xinming Xu: This research highlights the value of large data sets like the UK Biobank in uncovering potential links between these two diseases, large sample size and considerate covariates adjusted in the model enable us to conduct this kind of perspective study. Further, I believe that future comprehensive family history assessments should [00:12:00] include detailed information on who in a pedigree or family tree is afflicted with AD
For example, your inherent risk is different according to the member who had AD in your family, like your mother compared to a distant relative. Furthermore, information on how the diagnosis was established should also be included because it could help us to define a precise measuring instrument regarding family history diseases.
[00:12:28] Dr. Sara Schaefer: Thank you both so much for sharing this paper with us and sharing your thoughts today.
[00:12:34] Prof. Xinming Xu: Thank you for the time. It was pleasure to be here.
[00:12:37] Prof. Xiang Gao: Yeah. Have a good day.
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