Molecular Markers of Dementia

FYI -

Pat & Dennis Bender Early Dementia Diagnosis & Prognosis Fund

Dennis & Pat 07-84 $C:\Users\jdenb\AppData\Local\Microsoft\Windows\INetCacheContent.Word\Dennis.jpg$ $C:\Users\jdenb\AppData\Local\Microsoft\Windows\INetCacheContent.Word\DSCN2587.jpg$

J. Dennis Bender

Office, Home & Cell Phone: 859-391-5226

5726 La Jolla Blvd. – Suite 311

La Jolla, CA 92037-7345

Office - 100 Riverside Pl. - Suite 303

Covington, KY 41011-5711

We support the development of improved diagnostic methods for the early detection and diagnosis of MCI, Alzheimer’s, vascular and other dementias, their likely prognosis, and best treatment options. We focus on the development of Bayesian-based, medical-decision-support systems, comparative-effectiveness research, and the better utilization of these for the above. (After incorporating in KY as a 501(c)3 in 2002, we dissolved that entity in favor of a simplified form of two entirely self-financed, private philanthropies utilizing a Vanguard Charitable Trust for making annual-research-grants for early-dementia-detection and its correct differential-diagnosis and likely-prognosis. They will continue on, after I am long gone, either mentally or physically, with annual grants. Scripps Foundation, Profs. Randall Bateman, James Brewer and others will be our fund’s future research grant advisors. KMK Law is our legal advisor and my estate executor is Elizabeth Dunn.

(See: https://www.alz.org/alzheimers-dementia/research_progress/earlier-diagnosis)

This email address is being protected from spambots. You need JavaScript enabled to view it.

www.JDBender.com – EMS/eVTOL & Educational Experimental Aviation Fund (Vanguard Charitable Trust)

www.JDBender.org – Dementia Diagnosis Fund (Vanguard Charitable Trust)

September 13, 2024

A 3D rendering of the human brain.

[vectorfusionart - stock.adobe.co]

“In dementia and neurodegenerative-disease more-generally, specific brain regions and cells are most vulnerable in each disease. This is what leads to the different symptoms and signs across disorders. Since regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would give new insights, and that was the case. In addition to identifying shared and distinct molecular markers, we showed how genetic risk relates to these disease-specific-pathways that are altered in the brain.”

This is why I’ve have spent two-decades and millions on research to develop better diagnostic procedures for identifying the many different forms of dementia, including those frequently of mixed-origin, such as my own MCI.

Study Reveals Shared and Unique Molecular Markers Across Multiple Forms of Dementia

University of California - Los Angeles Health Sciences – Sep. 11, 2024

Researchers have for the first time identified degeneration-associated "molecular-markers" – observable changes in cells and their gene-regulating networks – that are shared by several forms of dementia that affect different regions of the brain. Critically, the UCLA-led research, published in the journal Cell, also identified markers specific to different forms of dementia, and the combined findings represent a potential paradigm shift in the search for causes, treatments and cures.

"This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for development of therapeutics," said senior and corresponding author Daniel Geschwind, MD, PhD, a professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine at UCLA and director of the Institute for Precision Health at UCLA Health.

Previous studies have focused on a single disorder at a time. Called case-control studies, they compared "diseased" cells with normal ones and often just focused on one brain region. But in this research, the scientists also looked at molecular changes across three different forms of dementia that can involve "tau pathology," the accumulation of abnormal tau protein in vulnerable regions that differ across disorders.

They performed single-cell genomic analysis on more than 1 million cells to identify distinct and shared molecular markers in three related conditions: Alzheimer's disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). In addition to validating changes previously observed in AD, they identify dozens of cell types whose changes are shared across multiple dementias and several cell types whose changes in disease were specific to a single disorder, many of which had not been previously identified.

"Different conditions have different patterns of degeneration. We reasoned that comparison across cases from different disorders, in addition to the typical case-control comparison, would be useful to identify shared components of neurodegeneration and to understand cell type-specific changes that underlie all these conditions," Geschwind said, adding that most studies profile only one brain region – typically the frontal lobe.

Daniel Geschwind, MD, PhD, professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine at UCLA and director of the Institute for Precision Health at UCLA Health

Using this study design, the investigators found four genes that marked vulnerable neurons across all three disorders, highlighting pathways that could be used to develop new therapeutic approaches.

First author Jessica Rexach, MD, PhD, an assistant professor in neurology and neurobehavioral genetics at the David Geffen School of Medicine at UCLA, said this work "profoundly shifted" her perspective on the mechanisms underlying disease susceptibility.

"It is remarkable and humbling to have identified several distinct molecular differences that set apart cells from individuals with one form of dementia from those with closely related diseases. Although these disease-specific differences were among the minority of the changes observed in diseased brains, they were strongly linked to heritability. This surprising finding opens new avenues for understanding why and how certain genes influence the risk of developing one brain disease over another closely related condition."

Combined, Alzheimer's, FTD and PSP affect more than 28 million people worldwide. Although Alzheimer's has been studied extensively, there is no cure, and existing, approved medications only slow disease progression. There are few clinical trials available for FTD and PSP.

"We have created an extensive data resource that paves the way for identifying and exploring new therapeutic candidates for neurodegenerative dementias," Rexach said. "We have pinpointed specific molecules that can now be advanced as potential novel regulators of disease in experimental systems – importantly, grounded in primary human disease data. Additionally, we've uncovered unexpected conceptual phenomena that may explain why certain cells exhibit more resilience or vulnerability to disease, and we're eager to investigate these findings further."

The researchers:

Identified unique changes specific to Alzheimer's disease and demonstrated that several findings in Alzheimer's were also observed across the other disorders, identifying targets for therapeutic development.
Found that "cellular resilience programs" – molecular mechanisms that support cells in response to injury – activated or failed differently, when comparing the same cell types across disorders.
Were surprised to discover that each of the three disorders had changes in cells of the primary visual cortex – the area of the brain that processes visual information and which was thought to be unaffected by dementia. In PSP, this discovery revealed previously unknown changes in brain cells called astrocytes.
Identified specific changes in the expression of certain tau-related genes and others in PSP. These appear to correlate with the unique pattern of brain cell degeneration that is observed in PSP.

The authors, who will next begin experiments to validate the causal nature of their findings, anticipate the study will inspire similar cross-disorder research.

"These data show that known risk genes act in specific neuronal and glial states or cell types that differ across related disorders. Moreover, causally associated disease states may be limited to specific cell types and regions," the Cell article concludes. "This underscores the importance of examining multiple brain regions to understand causal disease pathways at the cellular level, which we show provides a clearer picture of shared and disease-specific aspects of resilience and vulnerability to inform the therapeutic roadmap."

Source: University of California - Los Angeles Health Sciences

Journal reference: Rexach, J. E., et al. (2024) Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics. Cell. doi.org/10.1016/j.cell.2024.08.019.

Researchers Uncover Shared Cellular Mechanisms Across Three Major Dementias

Work May Open Pathways to New Therapeutic Targets

September 11, 2024

Researchers have for the first time identified degeneration-associated “molecular markers” – observable changes in cells and their gene-regulating networks – that are shared by several forms of dementia that affect different regions of the brain. Critically, the UCLA-led research, published in the journal Cell, also identified markers specific to different forms of dementia, and the combined findings represent a potential paradigm shift in the search for causes, treatments and cures.

“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for development of therapeutics,” said senior and corresponding author Daniel Geschwind, MD, PhD(Link is external), a professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine(Link is external) at UCLA and director of the Institute for Precision Health at UCLA Health.

Previous studies have focused on a single disorder at a time. Called case-control studies, they compared “diseased” cells with normal ones and often just focused on one brain region. But in this research, the scientists also looked at molecular changes across three different forms of dementia that can involve “tau pathology,” the accumulation of abnormal tau protein in vulnerable regions that differ across disorders.

They performed single-cell genomic analysis on more than 1 million cells to identify distinct and shared molecular markers in three related conditions: Alzheimer’s disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). In addition to validating changes previously observed in AD, they identify dozens of cell types whose changes are shared across multiple dementias and several cell types whose changes in disease were specific to a single disorder, many of which had not been previously identified.

“Different conditions have different patterns of degeneration. We reasoned that comparison across cases from different disorders, in addition to the typical case-control comparison, would be useful to identify shared components of neurodegeneration and to understand cell type-specific changes that underlie all these conditions,” Geschwind said, adding that most studies profile only one brain region – typically the frontal lobe.

“In dementia and neurodegenerative disease more generally, specific brain regions and cells are most vulnerable in each disease. This is what leads to the different symptoms and signs across disorders,” Geschwind said. “Since regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would give new insights, and that was the case. In addition to identifying shared and distinct molecular markers, we showed how genetic risk relates to these disease-specific pathways that are altered in the brain.” Using this study design, the investigators found four genes that marked vulnerable neurons across all three disorders, highlighting pathways that could be used to develop new therapeutic approaches.

First author Jessica Rexach, MD, PhD(Link is external), an assistant professor in neurology and neurobehavioral genetics at the David Geffen School of Medicine(Link is external) at UCLA, said this work “profoundly shifted” her perspective on the mechanisms underlying disease susceptibility.

“It is remarkable and humbling to have identified several distinct molecular differences that set apart cells from individuals with one form of dementia from those with closely related diseases. Although these disease-specific differences were among the minority of the changes observed in diseased brains, they were strongly linked to heritability. This surprising finding opens new avenues for understanding why and how certain genes influence the risk of developing one brain disease over another closely related condition.”

Combined, Alzheimer’s, FTD and PSP affect more than 28 million people worldwide. Although Alzheimer’s has been studied extensively, there is no cure, and existing, approved medications only slow disease progression. There are few clinical trials available for FTD and PSP.

“We have created an extensive data resource that paves the way for identifying and exploring new therapeutic candidates for neurodegenerative dementias,” Rexach said. “We have pinpointed specific molecules that can now be advanced as potential novel regulators of disease in experimental systems – importantly, grounded in primary human disease data. Additionally, we’ve uncovered unexpected conceptual phenomena that may explain why certain cells exhibit more resilience or vulnerability to disease, and we’re eager to investigate these findings further.”

The researchers:

Identified unique changes specific to Alzheimer’s disease and demonstrated that several findings in Alzheimer’s were also observed across the other disorders, identifying targets for therapeutic development.
Found that “cellular resilience programs” – molecular mechanisms that support cells in response to injury – activated or failed differently, when comparing the same cell types across disorders.
Were surprised to discover that each of the three disorders had changes in cells of the primary visual cortex – the area of the brain that processes visual information and which was thought to be unaffected by dementia. In PSP, this discovery revealed previously unknown changes in brain cells called astrocytes.
Identified specific changes in the expression of certain tau-related genes and others in PSP. These appear to correlate with the unique pattern of brain cell degeneration that is observed in PSP.

The authors, who will next begin experiments to validate the causal nature of their findings, anticipate the study will inspire similar cross-disorder research.

“These data show that known risk genes act in specific neuronal and glial states or cell types that differ across related disorders. Moreover, causally associated disease states may be limited to specific cell types and regions,” the Cell article concludes. “This underscores the importance of examining multiple brain regions to understand causal disease pathways at the cellular level, which we show provides a clearer picture of shared and disease-specific aspects of resilience and vulnerability to inform the therapeutic roadmap.”

Authors The full list of authors is published with the Cell article.

Funding Funding for this work was provided by Roche Pharmaceuticals (D.H.G., D.M.), BrightFocus (D.H.G., J.E.R), Rainwater Charitable Foundation (D.H.G. and W.W.S), NIH grants (K08 NS105916 (J.E.R), R01 AG075802 (J.E.R., L.T.G), 5UG3NS104095 (D.H.G)), and John Douglas French Alzheimer’s Foundation (J.E.R.). The UCSF Neurodegenerative Disease Brain Bank is supported by NIH grants AG023501 and AG019724, the Rainwater Charitable Foundation, and the Bluefield Project to Cure bvFTD. The University of Pennsylvania Center for Neurodegenerative Disease Research is supported by NIH grant P01AG066597, P30AG072979 and U19AG062418.

Disclosures Geschwind has received research funding from Hoffman-LaRoche for this project. A full declaration of interests is published with the article.

(D.H.G. has received research funding from Hoffman-LaRoche for this project. D.C. is a full-time employee of F. Hoffmann-La Roche, Basel, Switzerland. During the study period, D.M. was a full-time employee of F. Hoffmann-La Roche, Basel, Switzerland, and is currently a full-time employee of Biogen, Cambridge, MA, USA.)

Article Cell: Cross-disorder and disease-specific pathways in dementia revealed by single cell genomics.

DOI 10.1016/j.cell.2024.08.019

Draft - 9/13/2024 1:55 AM

{Molecular Markers of Dementia}