Study finds multiple rare, harmful genetic variants that increase Alzheimer’s risk

Researchers at the Vrije University (VU) in Amsterdam have identified rare deleterious genetic variants that increase the risk of Alzheimer’s disease (AD).

“Our findings provide further evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism, and microbe dynamics in AD,” the authors wrote in an article published Monday in the journal Nature Genetics.

Using gene-based strain analysis instead of the more common genome-wide association studies (GWAS), the researchers found strong associations between rare, deleterious variants in ATP8B4 and ABCA1 with AD risk, and markers in ADAM10, as well as rarity. – variant burden in the genes RIN3, CLU, ZCWPW1 and ACE, according to GenEngNews.

Damage mutations in ATP8B4 — ATPase enzyme occur in 3.6% of early-onset patients, 3.1% of late-onset patients, and 2.1% of individuals without dementia, according to the study.

“We find these mutations [in  ATP8B4 ] associate with a greater increased risk (1.6-fold increased risk in early-onset AD cases compared to non-carriers) compared with truncation mutations (1.2-fold), suggesting that deleterious effects may result from loss-of-function -activity. mutations.” Senior author Henne Holstege, assistant professor of clinical genetics at VU said, reported GenEngNews.

When it comes to gene variation in ABCA1, mutations in the gene were found to occur in 1.5% of early-onset patients, 1.1% of late-onset patients, and 0.52% of individuals without dementia.

“Here, truncating mutations are associated with a higher risk of AD (4.7-fold increase) compared to missense mutations (2.7-fold), suggesting that damage or loss of protein function underlies the observed increased risk,” said Holstege .

Regarding variants in ADAM10, the results showed that the mutations occur only in 0.23% of early-onset patients, 0.05% of late-onset patients, and 0.02% of non-demented individuals.

“Carrying a deleterious variant is associated with a 9-fold increased risk of AD,” Holstege said. “These variants include protein truncation and missense variants, which suggest that loss of protein function or protein degradation underlies the increased risk.”

Despite numerous studies in its favor, the β-amyloid theory of AD is hotly debated due to the lack of efficacy of AD drugs targeting β-amyloid deposition or degradation.

However, the recent success of amyloid-clearing drugs such as Aducanumab or Lecanemab could change opinions.

“Early treatment with Aducanumab or Lecanemab can be very important for success,” suggested Holstege. “Additionally, the field needs to focus on creating therapies that ‘correct’ or support the endogenous mechanisms involved in protein processing and clearance.” When used in at-risk individuals before the onset of disease, such drugs can prevent a lot of amyloid or other aggregated proteins from accumulating to disease-related levels.

Holstege believes that larger studies with international collaborations will help uncover more genes associated with a high risk of AD.

Nevertheless, the results of this study will help open up opportunities to better understand and treat AD in patients.

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