Scientists on 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 serious role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism, and microglial function in AD,” the authors wrote in a paper published within the journal Nature Genetics on Monday.

Using gene-based burden evaluation rather than the more common genome-wide association studies (GWAS), the researchers found a powerful link between rare, damaging variants in ATP8B4 and ABCA1 with AD risk, and a signal in ADAM10, in addition to rare-variant burden within the genes RIN3, CLU, ZCWPW1 and ACE, in line with GenEngNews.

Damaging mutations in  ATP8B4 — an ATPase enzyme — occur in 3.6% of early-onset patients, 3.1% of late-onset patients, and a pair of.1% of people without dementia, the study found.

“We discover that missense mutations [in  ATP8B4 ] associate with the next increased risk (1.6-fold increased risk in early-onset AD cases in comparison with non-carriers) in comparison with truncating mutations (1.2-fold), which suggests that the deleterious effects could also be as a consequence of gain-of-function missense mutations.” senior creator, Henne Holstege, an assistant professor of clinical genetics at VU said, reported GenEngNews.

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

“Here, truncating mutations associate with the next risk of AD (4.7-fold increase) in comparison with 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 outcomes showed that the mutations occur in just 0.23% of early-onset patients, 0.05% of late-onset patients, and 0.02% of people without dementia.

“Carrying a harmful variant is related to 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.”

Quite a few studies in favor notwithstanding, the β-amyloid theory of AD is hotly debated on account of the dearth of effectiveness of AD drugs that focus on β-amyloid deposition or degradation.

Nonetheless, the recent success of amyloid-clearing agents similar to Aducanumab or Lecanemab might change the views.

“Early treatment with Aducanumab or Lecanemab could be very necessary for effectivity,” Holstege suggested. “Moreover, the sector must concentrate 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 build up to disease-associated levels.”

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

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