A recent investigation into Alzheimer’s disease has harnessed the power of multiple biomarkers, shedding light on novel genetic pathways and gender-specific distinctions. This breakthrough promises enhanced early diagnosis and a deeper comprehension of Alzheimer’s.
Dementia, a category encompassing conditions like Alzheimer’s disease, afflicts approximately 1.8 million individuals in Germany. Despite its prevalence, the precise etiology of this ailment remains elusive, although it is widely acknowledged that genetics plays a pivotal role in its onset. Historically, most research endeavors aimed at identifying new Alzheimer’s-associated genes have relied on a methodology known as the “case-control design.”
According to Prof. Dr. Lars Bertram, the director of the Lübeck Interdisciplinary Platform for Genome Analysis at the University of Lübeck and the lead researcher of the study, this conventional and somewhat simplistic analytical approach has disregarded a trove of clinical data that could be invaluable in uncovering new disease mechanisms. In their latest exploration, which involved nearly 1,000 subjects, the researchers adopted a different approach by amalgamating data from six distinct Alzheimer’s biomarkers. This innovative strategy enabled them to chart the disease’s progression with greater precision during subsequent genetic analyses.
One notable finding pointed to diminished expression of GRIN2D, a receptor responsible for processing the brain messenger glutamate, in Alzheimer’s disease and other neuropsychiatric disorders. According to Bertram, this likely leads to a disruption in synaptic function, which are the connections through which nerve cells in the brain communicate.
Genetic Pathways and Gender Disparities in Alzheimer’s
The amalgamation of Alzheimer’s biomarkers facilitated additional downstream analyses that would have been unattainable using traditional study designs. Dr. Alexander Neumann from the Erasmus University Medical Center in Rotterdam, the study’s lead author, emphasized the importance of mediation analyses, a statistical method that reveals potential causal links between the examined biomarkers and the disease. These analyses unveiled the existence of at least two primary pathways implicated in Alzheimer’s disease.
One pathway operates through the influence of amyloid and tau proteins, a well-established association mediated by the Alzheimer’s risk gene APOE. The second pathway is predominantly influenced by the immune system’s response, driven in part by the effects of genes like TMEM106B and CHI3L1, which play roles in cellular component transport and the regulation of inflammatory responses.
Furthermore, the analysis of the X chromosome, which determines biological sex, as well as genome-wide analyses categorized by gender, offered fresh insights into the hitherto unexplained disparities in Alzheimer’s disease prevalence between men and women. Dr. Olena Ohlei, the second first author of the study from the Lübeck Interdisciplinary Platform for Genome Analytics, highlighted that certain genes appear to have measurable effects on Alzheimer’s biomarkers exclusively in either men or women. Some findings even suggest contradictory effects, indicating that specific genes elevate Alzheimer’s risk in women while reducing it in men, and vice versa.
Further investigations are required to elucidate this phenomenon.
Advancing Alzheimer’s Understanding and Diagnosis
In essence, this groundbreaking study opens new avenues for comprehending the underpinnings of Alzheimer’s disease. Prof. Dr. Lars Bertram summarized the findings by stating that the multivariate approach, which combines the analysis of multiple biomarkers, holds the potential to enhance Alzheimer’s diagnosis or perhaps even enable early detection. However, these results must first undergo validation in independent studies, as is customary in scientific research.
Reference: “Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning” by Alexander Neumann, Olena Ohlei, Fahri Küçükali, Isabelle J. Bos, Jigyasha Timsina, Stephanie Vos, Dmitry Prokopenko, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Philip Scheltens, Charlotte E. Teunissen, Sebastiaan Engelborghs, Giovanni B. Frisoni, Oliver Blin, Jill C. Richardson, Régis Bordet, Alberto Lleó, Daniel Alcolea, Julius Popp, Thomas W. Marsh, Priyanka Gorijala, Christopher Clark, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Christine Van Broeckhoven, Rudolph E. Tanzi, Mara ten Kate, Christina M. Lill, Frederik Barkhof, Carlos Cruchaga, Simon Lovestone, Johannes Streffer, Henrik Zetterberg, Pieter Jelle Visser, Kristel Sleegers, Lars Bertram and EMIF-AD & ADNI study group, 4 October 2023, Genome Medicine.
DOI: 10.1186/s13073-023-01233-z
This study was generously funded by the European Research Council.
Table of Contents
Frequently Asked Questions (FAQs) about Alzheimer’s Genetics
What is the main discovery in this Alzheimer’s disease study?
The study reveals new genetic pathways associated with Alzheimer’s disease, emphasizing the role of multiple biomarkers and uncovering gender-specific differences.
How does this study contribute to Alzheimer’s understanding?
By combining various Alzheimer’s biomarkers, the study enables more accurate downstream genetic analyses and highlights two main pathways linked to the disease: one involving amyloid and tau proteins and another mediated by the immune system.
What is the significance of reduced GRIN2D expression?
Reduced GRIN2D expression suggests impaired synaptic function, affecting how nerve cells in the brain communicate, which is a crucial aspect of Alzheimer’s disease.
How does this study address gender differences in Alzheimer’s?
The research investigates gender differences by analyzing the X chromosome and genome-wide data, revealing that certain genes impact Alzheimer’s biomarkers differently in men and women, providing valuable insights into the disease’s prevalence disparities.
Can the findings improve Alzheimer’s diagnosis?
The study suggests that a multivariate approach, analyzing multiple biomarkers, could enhance Alzheimer’s diagnosis and potentially enable earlier detection, but further validation in independent studies is required.
More about Alzheimer’s Genetics
- Genome Medicine Study
- European Research Council
- Alzheimer’s Association
- University of Lübeck
- Erasmus University Medical Center
- APOE Gene
- TMEM106B Gene
- CHI3L1 Gene
