Midlife Triglyceride Levels Predict Later Risk of Amyloid and Tau Pathology

High fasting triglyceride levels in midlife are associated with increased risk of amyloid β and tau pathology in the brain 20 years later, according to research published in the January 2 issue of Neurology. Increased levels of medium and large low-density lipoprotein (LDL) subfractions also may be risk factors for amyloid β pathology, said the researchers.

“Even though our results were not robust regarding all amyloid β measures, our findings, together with previous studies, may indicate that triglycerides are associated with early amyloid β accumulation and [that] cholesterol is associated with later stages of the predementia phase of Alzheimer’s disease,” said Katarina Nägga, MD, PhD, Associate Professor of Clinical Memory Research at Lund University in Sweden, and colleagues.

Katarina Nägga, MD, PhD

Patients Were Recruited From a Longitudinal Study

In 2016, researchers conducting a cross-sectional study in healthy elderly participants found an association between higher triglyceride levels and amyloid β PET. The following year, two longitudinal studies suggested that an increased number of midlife vascular risk factors and midlife dyslipidemia were associated with brain amyloid deposition, as measured with PET.

Dr. Nägga and colleagues sought to examine the association between midlife lipid levels and brain amyloid 20 years later in people who were asymptomatic at baseline and cognitively normal at follow-up. They also aimed to determine whether lipoprotein subfractions are associated with Alzheimer’s disease pathology.

In 2009, the investigators recruited participants from the longitudinal, population-based Malmö Diet and Cancer Study (MDCS) cardiovascular cohort. In that study, baseline examinations, including fasted triglyceride, cholesterol, and high-density lipoprotein (HDL) measurements, occurred between 1991 and 1994. LDL was calculated using the Friedewald formula. Follow-up took place between 2007 and 2012.

Participants who were eligible for Dr. Nägga’s study were older than 60, had a Mini-Mental State Examination score of 27 points or greater, and were without subjective cognitive impairment. People with a history of transient ischemic attack or stroke, severe neurologic or psychiatric disease, dementia, or mild cognitive impairment were excluded.

The investigators enrolled 361 patients into their study. Participants underwent cognitive testing, brain MRI, and lumbar puncture between 2010 and 2015. Dr. Nägga and colleagues measured brain amyloid β using [¹⁸F] flutemetamol PET in 134 patients. They also examined308 participants for white matter lesions using 3T MRI.

Large HDL Had a Protective Effect

In all, 318 participants were included in the analysis. Mean age was 54 at baseline and 73 at entry into Dr. Nägga’s study. Approximately 60% of participants were women. At follow-up, 23% of the population had an abnormal CSF amyloid β level, and 16% had amyloid and tau pathology.

After adjustments for age, sex, APOE ε4, education, and vascular risk factors, the odds ratio (OR) of abnormal CSF amyloid β was 1.34 among participants with high triglyceride levels at midlife. The OR of an abnormal ratio of amyloid β to phosphorylated tau was 1.46 among participants with high triglyceride levels at midlife.

Furthermore, triglycerides were associated with abnormal amyloid β PET measurements in multivariable regression models, but the association was attenuated in the fully adjusted model. Lipid levels were not associated with white matter lesion volume.

Medium and large LDL were associated with an approximately doubled risk of abnormal amyloid β PET in multivariable regression models. Large HDL decreased the risk of amyloid β pathology by about 75%. Small HDL and very small LDL were not associated with increased risk in the fully adjusted model.

A Possible Basis for Intervention Trials

One potential limitation of the current study is that its participants were healthier than the majority of participants who presented for reexamination in MDCS, said the authors. This difference introduced possible selection bias and might have caused an underestimation of the associations identified. Nevertheless, the sample size of the present study was larger than those of previous studies examining lipids and brain amyloid β.

“If our finding that increased triglyceride levels in midlife lead to an increase in abnormal amyloid β accumulation can be reproduced in larger cohorts, it would be of great interest to initiate intervention trials with triglyceride-lowering therapies in midlife and study potential long-term reductions in amyloid β as the main outcome,” said Dr. Nägga and colleagues. “If such treatments can decrease the risk of developing Alzheimer’s disease pathology, this could lead to significant health improvements for millions of people.”

—Erik Greb

Suggested Reading

Nägga K, Gustavsson AM, Stomrud E, et al. Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later. Neurology. 2018;90(1):e73-e81.