A noticeable deficit of highly unsaturated lipids — including omega-3 fatty acids — found in women with Alzheimer's disease (AD) but not in cognitively healthy women is linked to worse cognition and biomarkers of neurodegeneration and inflammation, new research showed. 

Investigators found no significant difference in lipid profiles in men with AD compared to healthy peers, and the effects of unsaturated phospholipids on AD were not mediated by cholesterol, low-density lipoprotein (LDL), or apolipoprotein B.

“The study reveals that Alzheimer's lipid biology is different between the sexes, opening new avenues for research,” senior author Cristina Legido-Quigley, PhD, from King’s College London, UK, said in a statement. 

“Our study suggests that women should make sure they are getting omega fatty acids in their diet — through fatty fish or via supplements. However, we need clinical trials to determine if shifting the lipid composition can influence the biological trajectory of Alzheimer’s Disease,” Legido-Quigley said. 

The study was published online August 20 in Alzheimer’s & Dementia.

Clear Sex Differences

AD disproportionately affects women, but biological explanations for the disparity remain unclear. Lipids are essential to neuronal membranes, synaptic plasticity, and signaling, and prior metabolomics work has hinted at sex-specific patterns in dementia risk. 

To investigate further, researchers analyzed the lipid profile in plasma samples from 306 men and women with AD: 165 with mild cognitive impairment and 370 cognitively health controls. The mean age of the overall cohort was 76 years. 

In women with AD, lipid families containing highly unsaturated fatty acids were reduced and those containing saturated lipids were increased. Similar lipid associations were not found in men with AD. 

After multiple-testing correction, 32 lipids were associated with AD in women: 17 were highly unsaturated species that were found in lower levels in those with AD, while 15 were more saturated or monounsaturated species that were found at higher levels in those with AD.

“In particular, large, highly unsaturated triglycerides were markedly reduced in affected women, indicating a potential role for dietary supplementation to mitigate AD progression,” the authors reported. 

Causal Link? 

The researchers also found a positive association between highly unsaturated lipids, especially triglycerides, and Mini-Mental State Examination (MMSE) scores. Saturated lipids showed a negative association.

The findings highlight “how decreases in unsaturated lipids directly linked to worsened clinical outcomes such as poorer MMSE test performance,” investigators wrote. 

“When [we] statistically controlled for the particle characteristics, the results indicated that these omega-carrying particles affect the brain through pathways involving omega fatty acid delivery or blood-brain barrier interactions rather than through bad cholesterol-related mechanisms,” Legido-Quigley told Medscape Medical News. 

“This finding could reshape treatment approaches from simply lowering cholesterol numbers to focusing on optimizing the types of lipid particles in the blood,” she said. 

Legido-Quigley cautioned, however, that while this study “helps map out how causation might work if it exists, [we] still need other evidence like a clinical trial to be confident it is truly a factor causing Alzheimer’s disease.” 

AD Lipid Recommendations Premature 

Julia Dudley, head of research at Alzheimer’s Research UK, Cambridge, also cautioned against drawing any firm conclusions regarding causation.

“While this study shows that women with Alzheimer’s had lower levels of some unsaturated fats compared with men, further work is needed. This includes understanding the mechanisms behind this difference and finding out if lifestyle changes, including diet, could have a role. Understanding how the disease works differently in women could help doctors tailor future treatments and health advice,” Dudley said in a statement. 

Heather M. Snyder, PhD, senior vice president of medical and scientific relations, Alzheimer's Association, Chicago, told Medscape Medical News “understanding lipid biology in Alzheimer’s disease is an active area in research.”

The suggestion that lipids may have different roles in the cause and progression of AD based on sex is interesting and needs further study, she said. 

“For example, we need to know more specifically what the differences are, and why the roles are different in men and women. This is the essence of precision medicine,” Snyder said. 

Future studies should also include a study cohort that better reflects the diverse population affected by AD and other dementias. 

Snyder noted that research to date has not elucidated whether AD or another dementia causes the reduced lipid levels in women, or if the depletion causes the disease, or if there is another reason for this association.

“The more we know about how the disease works — and how it differs in various individuals and different groups — the better we will eventually be at diagnosing and treating it in a way that is tailored to each patient,” Snyder said. “However, based on this study, there is no specific recommendation regarding lipids and/or supplements that can be made at this time.”

The research was supported by funding from LundbeckFonden and Alzheimer's Research UK. Legido-Quigley, Snyder and Dudley had no relevant disclosures.