Summary: Higher levels of LDL cholesterol are associated with an increased risk of early-onset Alzheimer’s disease, both in people with and without the well-known APOE E4 genetic risk. The study also identifies a possible new genetic contributor: rare coding variants in the APOB gene. These findings suggest LDL cholesterol could be an independent risk factor for early-onset dementia.
Source: Veterans Affairs Research Communications
Researchers from the Atlanta Veterans Affairs Medical Center and Emory University report a connection between elevated LDL cholesterol and early-onset Alzheimer’s disease, shedding light on potential biological and genetic contributors to the condition.
Dr. Thomas Wingo, lead author of the study, notes that the data indicate LDL cholesterol may play a causal role in the development of Alzheimer’s disease. The full report was published in the May 28, 2019 issue of JAMA Neurology.
“The central question is whether blood cholesterol levels influence Alzheimer’s risk,” says Wingo. “Previous evidence was inconclusive. Our findings support the possibility that LDL cholesterol contributes directly to disease risk, which could prompt a reevaluation of LDL targets if further studies confirm causality.”
Elevated cholesterol has been linked previously to higher Alzheimer’s risk later in life, and part of that association has been attributed to genetic factors that influence cholesterol metabolism. The strongest known genetic risk factor for Alzheimer’s is the APOE E4 variant, which is also associated with higher circulating cholesterol, especially low-density lipoprotein (LDL). LDL is commonly called “bad cholesterol” because high levels can lead to arterial plaque buildup.
Late-onset Alzheimer’s, the more common form of the disease, has been linked to cholesterol in prior work. Less was known about whether cholesterol levels influence early-onset Alzheimer’s, the less frequent form that appears before age 65. Early-onset cases make up about 10% of all Alzheimer’s diagnoses and are often driven by inherited genetic variants.
Known high-impact genetic causes of early-onset Alzheimer’s include mutations in APP, PSEN1, and PSEN2. APOE E4 is also a risk factor in early-onset disease, but together these known variants account for only a portion of early-onset cases, leaving many unexplained.
To explore the role of cholesterol and to search for additional genetic contributors, the researchers sequenced target regions of the genome in 2,125 individuals, including 654 people with early-onset Alzheimer’s and 1,471 control participants. They also measured plasma cholesterol—including LDL—in frozen blood samples from 267 participants.
The analysis confirmed that APOE E4 accounts for roughly 10% of early-onset Alzheimer’s risk, similar to estimates for late-onset disease. Known pathogenic mutations in APP, PSEN1, and PSEN2 were present in about 3% of early-onset cases in the study cohort.
Importantly, the researchers found that higher LDL cholesterol levels were associated with increased odds of having early-onset Alzheimer’s, even after excluding or adjusting for individuals who carry the APOE E4 variant. This suggests LDL cholesterol could be an independent risk factor, not solely a marker driven by APOE genotype. The study did not find a significant association between HDL (high-density lipoprotein) cholesterol and early-onset Alzheimer’s, and observed only a very small association with triglyceride levels.
In addition to the cholesterol findings, the study identified an enrichment of rare coding variants in the APOB gene among early-onset Alzheimer’s cases. APOB encodes apolipoprotein B, a key protein involved in lipid transport and the main protein component of LDL particles. The presence of rare APOB variants in more cases than controls supports a potential genetic link between lipid metabolism and Alzheimer’s risk. However, the association between LDL-C and early-onset Alzheimer’s was not fully explained by either APOE or APOB variation, indicating that other genes and pathways also contribute to risk.
While these results strengthen the evidence that LDL cholesterol and lipid-related genes play roles in early-onset Alzheimer’s pathogenesis, the authors caution that further work is needed to establish causality and to understand mechanisms. Early-onset Alzheimer’s is relatively uncommon, which makes assembling large, well-characterized cohorts for genetic study more challenging. Larger studies and functional experiments will be important to confirm these observations and to determine whether lowering LDL cholesterol could reduce early-onset Alzheimer’s risk.
Source:
Veterans Affairs Research Communications
Media Contacts:
Gregory Kendall – Veterans Affairs Research Communications
Image Source:
The image is credited as public domain.
Original Research: Closed access
“Association of Early-Onset Alzheimer Disease With Elevated Low-density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB.” Thomas S. Wingo et al., JAMA Neurology. DOI: 10.1001/jamaneurol.2019.0648
Abstract (summary)
The study examined whether circulating cholesterol levels are associated with early-onset Alzheimer’s disease (EOAD) and sought genetic variants that might underlie this relationship. Direct plasma cholesterol measures were analyzed in 267 samples, and targeted sequencing of APOB, APP, PSEN1, PSEN2, and APOE was performed in 2,125 cases and controls recruited from Alzheimer’s Disease Research Centers. After adjusting for APOE E4 status, EOAD cases had higher total cholesterol, LDL-C, and ApoB compared with controls. Rare coding variants in APOB were significantly more frequent in EOAD cases. The results highlight LDL-C and APOB as contributors to EOAD risk and underscore the need for further research into lipid-related mechanisms in Alzheimer’s disease.