22 April 2022
In rare cases, Alzheimer’s disease results from a genetic mutation and is inherited from one generation to the next. In such cases, the disease usually hits much earlier in life, affecting people in their forties or fifties, or sometimes even earlier. A research team led by prof. Lucía Chávez-Gutiérrez (VIB-KU Leuven) has now uncovered a direct relationship between changes in the amyloid-beta fragments that accumulate in the brain tissue of Alzheimer’s patients, and the age at which symptoms first arise. The researchers hope we can use these insights not only to predict but eventually also to delay disease onset.
When do Alzheimer’s symptoms first appear?
In most cases, Alzheimer’s disease is not inherited and starts to manifest after the age of 65. In rare cases, however, Alzheimer’s can be passed on in families and typically this so-called familial form also manifests much earlier in life, affecting people in their forties or fifties, or sometimes even already in their twenties or thirties. The 2014 award-winning drama Still Alice tells the story of one such family affected by early onset Alzheimer's.
Although this so-called familial form of the disease is rare in the perspective of the total patient group, researchers have already identified close to 400 different mutations in families affected with early-onset Alzheimer’s around the globe.
Alzheimer’s-disease-causing mutations can all be traced back to the same small set of genes encoding the molecular machinery that generates amyloid beta fragments in the brain. The accumulation of longer amyloid-beta fragments starts years before symptoms appear.
“Interestingly, the age at which clinical symptoms first manifest is relatively consistent within families and between carriers of the same mutations, but differs markedly between mutations,” says prof. Lucía Chávez-Gutiérrez of the VIB-KU Leuven Center for Brain & Disease Research. Her lab studies the molecular bases of Alzheimer’s disease.
“It is important to understand the mechanisms by which some mutations cause symptoms to manifest decades earlier than others,” she says. “Not only because of the practical importance for families affected by familial Alzheimer’s, but also to understand how we could conceive to halt or at least delay disease.”
A linear correlation
Chávez-Gutiérrez’ team analyzed the amyloid-beta fragments generated by 25 different mutations discovered in families presenting with Alzheimer’s symptoms at ages varying from 25 to 60 years.
“We found that changes in the molecular composition of amyloid-beta correlated linearly with the age at disease onset,” says dr. Dieter Petit, a recently graduated PhD student in the lab. “Clearly, longer amyloid-beta fragments are more abundantly present in mutant amyloid-beta profiles linked to earlier symptom onsets.”
“In collaboration with our clinical partners, we were also able to use this linear correlation for the experimental assessment of age at disease onset of mutations for which there had been limited family history or a complex clinical picture,” adds Sara Gutiérrez Fernández, another PhD student closely involved in the study.
From biochemistry to therapy?
While the study involves mutations linked to rare familial forms of Alzheimer’s; all Alzheimer’s cases are characterized by amyloid-beta deposition in the brain, and clearly common pathways eventually result in the development of the same collection of symptoms.
Chávez-Gutiérrez: “Our ultimate question is: can we shift the molecular composition of brain amyloid profiles in such a way that we can delay symptom onset? This is a fundamental question, that we cannot answer in a definitive way today, but our results do support exploring the therapeutic potential of compounds that could tweak amyloid-beta production with the aim of generating shorter fragments.”
She stresses that even today, being able to predict the age of disease onset based on amyloid-beta profiles, could be really helpful in clinical settings: “Information on how a certain mutation affects amyloid processing, together with the clinical picture of a patient, can help us determine whether the mutation is indeed causative. We have already been able to clarify this for multiple mutations, which means families can receive adequate genetic counseling and gain access to clinical trials.”
Aβ profiles generated by Alzheimer’s disease-causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset
Petit, Gutiérrez Fernández et al. Mol Psychiatry 2022
This work was supported by the Belgian Foundation for Alzheimer Research (Stichting Alzheimer Onderzoek). Both Dieter Petit and Sara Gutiérrez Fernández are FWO doctoral fellows.