A study by the team of Prof. Kristel Sleegers (VIB-UAntwerp), published in Acta Neuropathologica, has offered new insights into the genetic factors that drive Alzheimer’s disease. Using samples from the Leuven Brain Collection, the researchers linked certain genes not only to hallmark features like tau tangles and amyloid plaques but also to other, less understood brain changes.

Alzheimer’s disease (AD), the most common cause of dementia, has a strong genetic basis, with heritability estimates ranging from 60% to 80%. While hallmark features like tau tangles and amyloid beta (Aβ) plaques are well-known, other co-morbid brain changes often complicate the disease’s progression. The lab of Prof. Kristel Sleegers at the VIB-UAntwerp Center for Molecular Neurology focuses on genetic studies to identify early therapeutic targets and risk genes for AD.

In their recent study, the scientists analyzed DNA from 325 individuals aged 50 or older, whose brain tissue is preserved in the Leuven Brain Collection. They identified 75 genetic variants associated with AD through low-coverage whole-genome sequencing and compared these data to the brain’s pathological changes, including tau tangles, amyloid plaques, and other lesions.

Key findings
One key discovery is a genetic variant in the APH1B gene, which directly influences the formation of tau tangles. These disrupt the brain cell structure and function, leading to the progressive cognitive decline seen in AD.

Another important finding involves the APOE gene, already well known for its role in the disease. This study confirmed its link to amyloid plaque formation but also showed its involvement in granulovacuolar degeneration—a form of cell damage tied to programmed cell death.

The team also uncovered connections between lesser-known genes and Alzheimer’s-related abnormalities. For instance, the BIN1 gene was linked to α-synuclein deposits, a feature of Parkinson’s disease and dementia with Lewy bodies, and TPCN1 was associated with TDP-43 inclusions, which can worsen symptoms.

First author Celeste Laureyssen explains: “Alzheimer’s is not a one-size-fits-all disease. Our work shows that specific genes influence different aspects of brain pathology, taking us closer to understanding the full complexity of the disease. ”

The Leuven Brain Collection
This research relied on the Leuven Brain Collection, a unique biobank of human brain tissue. The collection includes samples from individuals diagnosed with AD, people with early brain changes but no symptoms, and healthy controls. Its diversity allowed researchers to uncover genetic influences on a wide range of brain changes, not just the traditional features of Alzheimer’s.

Prof. Kristel Sleegers emphasizes the value of this resource: “Access to such a well-documented collection is invaluable. It provides a direct view into the molecular underpinnings of neurodegeneration, helping us understand why specific pathological changes occur in AD.”

These findings underscore the complexity of Alzheimer’s disease and highlight the importance of studying genetic variations in relation to specific pathological features. By moving beyond a one-size-fits-all approach, scientists can better understand how different biological processes converge to drive cognitive decline. Unraveling these genetic links could eventually lead to targeted therapies that address the diverse ways the disease manifests in individuals.

Funding
The research (team) was supported by the UAntwerp, VIB, the Fund for Scientific Research Flanders, KU-Leuven Onderzoeksraad, BrightFocus, and the Alzheimer Association USA.

Full bibliographic information
Published on 09/12/2024 by VIB
About: Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia
Authors: Laureyssen, et al.
Publication: Acta Neuropathologica, 2024
DOI: 10.1007/s00401-024-02815-w