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The journal Alzheimer’s & Dementia published the results of a lipidomics study, which found significant differences in plasma lipids associated with Alzheimer’s disease (AD), but only among women. This study was a post hoc analysis of data from two cohorts, the AddNeuroMed and Dementia Case Register cohorts, both conducted among European populations. A total of 841 participants were involved, including 306 diagnosed with AD, 165 with mild cognitive impairment (MCI), and 370 cognitively healthy people (controls). A lipidomic analysis was performed on plasma samples, including a total of 268 lipids included in the analysis.
This study revealed sex-specific associations with AD, primarily that among women (but not men) with AD, there was a deficit of lipids containing polyunsaturated fatty acids. Specifically, 17 highly unsaturated lipids (those with 5 or more carbon-carbon double bonds) were found in lower amounts (negatively associated with AD) among women with AD, particularly triglycerides, phosphtatidylcholines (PCs), and phosphtatidylethanolamines (PEs). Fifteen lipids were positively associated with AD among women, including saturated or monounsaturated PCs and PEs. While the saturated and monounsaturated lipids were mediated by LDL-C and ApoB, many of the unsaturated lipids were not. The authors note that “the association between highly unsaturated lipids and AD may be linked to the amount of omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), incorporated into the tail ends of these lipids.”
This analysis also observed several other sex-specific associations. For example, lysophosphatidylcholines (LPCs, derived from PCs) were increased among women with AD, a finding previously documented in a smaller metabolomic study. LPCs normally deliver unsaturated lipids such as DHA to the brain, and higher levels suggest an upregulation as a consequence of lower amounts of unsaturated fatty acids available for transport. Interestingly, the group of LPCs was only associated with AD after adjustment for APOE ε4 genotype.
Another notable genetic association was mentioned in this study; many of the lipids associated with AD risk found in this analysis were linked to fatty acid desaturase 2 (FADS2) activity in a previously published genome/lipidome analysis. Polymorphisms in this gene, whose protein is a key enzyme for fatty acid desaturation, have been linked to differences in the level of unsaturated fatty acids in the red blood cell (RBC) membrane, possibly contributing to cognitive decline. This could be reflected in the results of the Framingham offspring study, in which the highest quintile of RBC DHA was associated with a 49% lower risk of AD compared to the lowest, and increasing RBC DHA levels from the lowest to the highest was estimated to provide an additional 4.7 years of life free of AD.
Given that two-thirds of AD cases occur among women, an emphasis on discerning sex-based modifiers is well justified. A 2024 review published in Neuron cites a number of sex-based biological differences that may contribute, such as the loss of ovarian hormones during perimenopause. This possibility is supported by two recent trials; one was a cross-sectional study published in JAMA Neurology, which found that both earlier menopause and later initiation of hormone replacement therapy were associated with greater tau deposition, as measured by positron emission tomography (PET). The second, published in Alzheimer’s Research & Therapy, was an analysis of a large European cohort which found that hormone replacement therapy improved cognition and increased brain volumes (entorhinal and amygdala) among women at high risk, i.e., those carrying an APOE ε4 allele. X chromosome-linked genes have also been implicated in modifying AD risk; for example, the product of the X-linked gene ubiquitin-specific peptidase 11 (USP11) appears to augment pathological tau aggregation and accumulates in tauopathies, but primarily in women, not men. In contrast, the use of bile acid sequestrants was associated with an increase in risk for vascular dementia among men, but not women.
Another possible contributing factor is sex-linked differences in mitochondrial function. In a metabolomics study published in Nature Communications with over 1500 participants, substantial differences were observed between men and women (some of which were more prominent when stratified by APOE ε4 genotype). Fifteen metabolites were associated with AD risk, including valine, glycine, and proline, which may be possible markers for differences in glucogenic/ketogenic energy metabolism, energy homeostasis, and metabolic stress responses. Estrogen has also been associated with a protective effect on mitochondrial function in women, marked by a higher antioxidant enzyme expression and lower levels of hydrogen peroxide and homocysteine. While this may provide an initial resistance to AD, as estrogen levels decline, mitochondrial function may be more susceptible to dysfunction in women. There may also be sex-based differences in the utilization of proteins vs. lipids in men and women; for example, some evidence suggests that women may predominantly utilize lipids as a fuel source in mitochondria, which again points to the role of lipids in AD risk, particularly among women.
Lastly, it’s worth pointing out that in 2024 the Lancet standing commission suggested that nearly half of dementia cases could be eliminated if 14 risk factors (e.g., smoking, hearing loss, etc.) were addressed. This more recent study suggests that polyunsaturated fat intake, particularly among women, may be an important component of prevention.
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