Omegas and Alzheimer's: Women with dementia have less unsaturated fat in their blood - what could this mean

A study by a team from King's College London and Queen Mary University of London was published in Alzheimer's & Dementia: in a large cohort of 841 participants (Alzheimer's disease, mild cognitive impairment and healthy controls), detailed plasma lipidomics was conducted and significant gender differences were found. In women with Alzheimer's disease, the level of unsaturated lipids (including molecules with omega fatty acids) was significantly lower, and saturated lipids were higher than in healthy women; this was not the case in men. The authors emphasize that this is not about "good" and "bad" fats in the everyday sense, but about the fine biochemistry of membranes and lipid transport, which may be differently associated with the risk and course of the disease in women and men.

Background of the study

Alzheimer's disease disproportionately affects women: approximately two-thirds of those living with dementia are female. However, "female" characteristics of risk and course have long been underestimated in research and clinical trials, although data indicate differences not only in prevalence but also in clinical presentation, rate of decline, and time of diagnosis. Today, the consensus is that, in addition to age, differences are influenced by biological factors (hormonal status, lipid metabolism, genetics), as well as social and behavioral aspects, so gender must be taken into account when designing studies and prevention programs.

Lipids are key to the neurobiology of Alzheimer's: neuronal and synaptic membranes, myelin, receptor rafts and microglial function depend on the precise composition of phospholipids, sphingolipids and cholesterol; their dysregulation accompanies aging and neurodegeneration. Lipidomic studies on brain tissue and plasma increasingly show a "reorganization" of the lipid landscape in AD, and mechanical changes in lipid rafts can disrupt signaling pathways and the clearance of pathological proteins. Against this background, systemic lipidomics of blood has become a convenient "window" into brain metabolism and lipid transport, including the transport of docosahexaenoic acid (DHA) and other omega-3s, critical for membrane fluidity and synaptic function.

Genetic risk factors include APOE ε4, which is closely associated with lipid transport and amyloid utilization; increasing evidence suggests that its impact may differ in women and men. For example, in longitudinal cohorts, the association of ε4 with tau accumulation in women was stronger, but there are also studies that question the universality of the “accelerated” female scenario - the field is actively being refined. There is only one conclusion: sex differences in lipid metabolism, APOE carriage and their interactions are not a minor detail, but an important moderator of risk and biomarkers that should be included in analyses in advance.

On the applied side, the question of nutrition and omega-3 is relevant. DHA is a structural lipid of the brain, and peri- and postmenopause are accompanied by changes in lipid status; at the same time, the results of omega-3 supplements in non-selective groups give mixed results: from zero effects to moderate benefits in subgroups. Therefore, the trend is shifting to the personalization of trials - selection by gender and initial lipidomics (deficiency of highly unsaturated lipids), which is logical against the background of recent data on the reduction of unsaturated lipid levels specifically in women with asthma. This approach increases the chance of seeing an effect where it is biologically expected, and not "washing it out" in heterogeneous samples.

How was this tested?

The researchers took plasma samples from people with confirmed Alzheimer’s disease, MCI, and cognitively intact controls and analyzed hundreds of individual lipids by mass spectrometry (a panel of several major families, from phospholipids to sphingolipids and triacylglycerols). In addition to comparing individual molecules, they used network analysis of lipid “modules” and mediation tests to assess whether the observed associations were explained by bypasses via cholesterol/LDL/apoB. Crucially, the key signals specific to women (deficiency in highly unsaturated phospholipids and excess in saturated ones) were not mediated by classic lipid markers of cholesterol transport.

Main findings

• Women with asthma: ↓ lipid families with highly unsaturated fatty acids (often DHA/EPA-like “omegas”), ↑ saturated lipids; differences are significant at the level of individual molecules and modules.
• Men: no comparable changes were found between patients and healthy controls, suggesting a sex-specific biology of the disease.
• Not via “regular” cholesterol: the effects of unsaturated phospholipids on AD risk/status were not mediated via LDL/apoB/total cholesterol.
• Scale: The analysis covered hundreds of lipid species in the same platform, with emphasis on both the family and single molecule levels.

Why is this important?

Lipids are the foundation for neuronal membranes, synapses, myelin, and microglial function; it has long been clear that lipid metabolism and genes regulating it (e.g., APOE) are involved in the pathogenesis of Alzheimer's. The new work adds a key detail: in women, systemic "mirrors" of lipid status (blood) are shifted specifically toward a deficiency of unsaturated lipids, which are critical for membrane fluidity, neuroinflammation, and clearance of protein aggregates. This may help explain why women get sick more often and/or get sicker, and suggests gender stratification in future preventive and therapeutic studies (including nutritional interventions).

This is an observational blood study, not an interventional trial of supplements. The association "less omegas in the blood ↔ higher risk/severity of the disease" does not equal causality. The authors directly state that the findings are a reason for targeted RCTs, not a recommendation to "immediately take fish oil for everyone." Moreover, previous RCTs of omega-3, "mixed" by gender and stage, gave ambiguous results on cognitive outcomes - perhaps precisely because of the lack of gender-biomarker selection.

What this might mean in practice

• Potential target audience for future RCTs: women with low levels of unsaturated lipids in the blood (determined by a lipidomics panel) at the stages of premorbid complaints or MCI.
• What interventions are logical to check:
  • dietary - cold sea fish 2-3 times a week, Mediterranean/Atlantic diet;
  • supplementation of DHA/EPA (doses/forms will be selected by the RCT design);
  • combined strategies (diet + exercise + control of vascular factors), but with stratification by gender and lipidomics.
• What markers to monitor: plasma lipid panels, neurofilaments (NfL), GFAP, p-tau (as surrogates for neurodegeneration/neuroinflammation) - adjusted for gender.

Where does this fit in with previous science?

• Even in preclinical and postmortem studies, shifts in the brain lipidome in AD were found; review articles emphasize the role of phospholipids, sphingolipids, cholesterol, and lipid droplets in microglia. What is new is a clear sexual asymmetry in the blood of a large clinical set.
• The same school had previously reported a link between unsaturated fatty acids and Alzheimer's pathology; the current publication confirms the line on "omegas" as a vulnerable spot and places an emphasis on women.

Restrictions

• Cross-sectional design: unsaturated lipid deficiency cannot be said to precede disease. Longitudinal data are needed.
• Ethnic heterogeneity and generalizability: Independent experts call for testing the effect in more diverse populations.
• Nutrition vs. Metabolism: Low Blood Omega Levels Not Just a Sign of Not Eating Enough, but Also Altered Lipid Utilization/Transport in Disease and Postmenopause. Mechanistic Studies Needed.

What will science do next?

• Randomized clinical trials where recruitment by gender and baseline lipidomics are built into the design (women with low levels of unsaturated lipids). Endpoints are cognition, functional scales, blood and cerebrospinal fluid biomarkers.
• Longitudinal cohorts from middle age to old age to understand when women begin to experience decline in unsaturated lipids and how this relates to hormonal status.
• Mechanistic work: how exactly does highly unsaturated phospholipid deficiency affect microglia, synapses, myelin, and Aβ/tau clearance?

Research source: Wretlind A. et al. Lipid profiling reveals unsaturated lipid reduction in women with Alzheimer's disease. Alzheimer's & Dementia, August 20, 2025. https://doi.org/10.1002/alz.70512