# Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study

## TL;DR

High blood levels of PCSK9 may protect against Alzheimer's disease, but only in people without the APOE ε4 gene variant.

## Contribution

This study shows that PCSK9's effect on Alzheimer's risk depends on APOE genotype, suggesting personalized treatment approaches.

## Key findings

- High plasma PCSK9 levels are linked to lower Alzheimer's risk in APOE ε4 noncarriers.
- PCSK9 genotypes associated with low levels increase Alzheimer's risk only in APOE ε4 noncarriers.
- Findings were validated using the ADNI study and CSF biomarkers.

## Abstract

Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an APOE genotype dependent manner.

We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all‐cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on APOE ε4 status. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate some of the main findings.

Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; p = 0.01) in APOE ε4 noncarriers; in contrast, PCSK9 levels were not significantly associated with AD risk in APOE ε4 carriers, after adjusting for common confounders, lipid profile, and lipid treatment. Using the three SNPs (rs502576, rs529787, rs676297) of the PCSK9 gene associated with PCSK9 levels in blood, we consistently found that the genotypes, which determine a low concentration of PCSK9, were associated with AD risk only in APOE ε4 noncarriers. These findings were validated by the ADNI study, which showed that the PCSK9 genotypes were associated with AD risk and with the AD biomarker—a low concentration of Aβ42 in CSF, only in APOE ε4 noncarriers.

Our study suggests that high blood PCSK9 levels are protective against AD risk in APOE ε4 noncarriers, potentially through mechanisms related to lipid metabolism. The findings may highlight the importance of considering APOE genotype when prescribing the drugs targeting PCSK9.

Both apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are involved in lipid metabolism. While PCSK9 inhibitors are commonly used to treat cardiovascular disease (CVD), the potential impact of PCSK9 on Alzheimer's disease (AD) risk, particularly in the context of APOE genotype, remains unclear. Our findings suggest that low plasma levels of PCSK9 and genetic variants associated with reduced PCSK9 expression are linked to an increased risk of AD, but only in individuals without the APOE ε4 allele. This association was not observed in APOE ε4 carriers. Although genotypes associated with low PCSK9 levels are relatively uncommon, clinicians may need to exercise caution when prescribing PCSK9 inhibitors to hyperlipidemic patients who are APOE ε4 noncarriers and have naturally low PCSK9 levels. In such cases, alternative lipid‐lowering therapies might be considered to avoid potentially increasing AD risk.

Why does this paper matter?∘As population ages, multiple systemetic diseases like hyperlipidemia, CVD, and AD often co‐exist in the older persons. However, it is largely understudied on how these geriatric diseases and their treatments impact on each other. PCSK9 inhibitors are a class of antilipidemic medications used for CVD. Our findings offer insights into the interactive effects of APOE genotypes and PCSK9 for AD. Since those patients who are APOE ɛ4 noncarriers and at the same time have a low level of blood PCSK9 may have a high AD risk, other antilipidemic medications, instead of those targeting PCSK9, should be used to treat hyperlipidemia for the patients.

Why does this paper matter?

As population ages, multiple systemetic diseases like hyperlipidemia, CVD, and AD often co‐exist in the older persons. However, it is largely understudied on how these geriatric diseases and their treatments impact on each other. PCSK9 inhibitors are a class of antilipidemic medications used for CVD. Our findings offer insights into the interactive effects of APOE genotypes and PCSK9 for AD. Since those patients who are APOE ɛ4 noncarriers and at the same time have a low level of blood PCSK9 may have a high AD risk, other antilipidemic medications, instead of those targeting PCSK9, should be used to treat hyperlipidemia for the patients.