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Study Finds Multiple Rare, Damaging Genetic Variants That Increase Alzheimer’s Risk

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

“Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism, and microglial function in AD,” the authors wrote in a paper published in the journal Nature Genetics on Monday.

Using gene-based burden analysis in place of the more common genome-wide association studies (GWAS), the researchers found a strong link between rare, damaging variants in ATP8B4 and ABCA1 with AD risk, and a signal in ADAM10, as well as rare-variant burden in the genes RIN3, CLU, ZCWPW1 and ACE, according to GenEngNews.

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

“We find that missense mutations [in  ATP8B4 ] associate with a higher increased risk (1.6-fold increased risk in early-onset AD cases compared to non-carriers) compared to truncating mutations (1.2-fold), which suggests that the deleterious effects may be due to gain-of-function missense mutations.” senior author, Henne Holstege, an assistant professor of clinical genetics at VU said, reported GenEngNews.

Coming to gene variation in ABCA1, the study found that mutations in the gene occur in 1.5% of early-onset patients, 1.1% of late-onset patients, and 0.52% of individuals without dementia.

“Here, truncating mutations associate with a higher risk of AD (4.7-fold increase) compared to missense mutations (2.7-fold), which suggests that damaging or losing protein function underlies the observed increased risk,” Holstege noted.

As for variants in ADAM10, the results showed that the mutations occur in only 0.23% of early-onset patients, 0.05% of late-onset patients, and 0.02% of individuals without dementia.

“Carrying a damaging variant is associated with a 9-fold increased risk of AD,” Holstege commented. “These variants include protein truncating and missense variants, suggesting that losing protein function or protein impairment underlies the increased risk.”

Numerous studies in favor notwithstanding, the β-amyloid theory of AD is hotly debated on account of the lack of effectiveness of AD drugs that target β-amyloid deposition or degradation.

However, the recent success of amyloid-clearing agents such as Aducanumab or Lecanemab might change the views.

“Early treatment with Aducanumab or Lecanemab may be very important for effectivity,” Holstege suggested. “Additionally, the field needs to focus on generating treatments that ‘correct’ or support the endogenous mechanisms involved in protein processing and clearance. When applied to at-risk individuals before the onset of disease such agents may prevent a load of amyloid or other aggregating proteins to accumulate to disease-associated levels.”

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

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

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