Lipids and Cognitive Decline

We recently reviewed how serum lipids and CSF lipids shouldn’t be treated the same when it comes to preventing dementia. This week we’ll take a look at HDL, triglycerides, and other factors in protecting your precious noggin.

HDL and Triglycerides: Not a Simple Story

The numbers in a lipid profile to be concerned about do not include just total cholesterol and LDL. We recently reviewed an expert’s panel on lipids and brain health. This week we’ll focus on HDL and triglycerides.

We typically think of HDL (healthy cholesterol) as being protective against heart disease and dementia. However, Betsy Mills, PhD, Assistant Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation suggests that HDL in the periphery is "very complicated," and the idea that HDL, as a measure on its own, is "necessarily 'good' isn't particularly informative."

HDL is "extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications." For example, similar to oxidized LDL, oxidized HDL is also "bad," which prevents HDL from its protective function.

Also, the apolipoproteins linked with HDL can impact the function of the HDL. "Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link," Mills said. "It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles." 

As HDL is more complicated than being “good”, monitoring HDL doesn’t give you the full picture. Mills believes this could be why research that infers high HDL levels might not have protective benefits and might even be detrimental. This makes it tricky to evaluate population studies where various subclasses of HDL are not studied in depth.

Mills notes an additional confounding component. A big part of the risk for AD development seems to be associated with the relationships between LDL, HDL, and triglycerides. "When you look at each of these individually, you get a lot of heterogeneity, and it's unclear what's driving what," she said.

The beauty of observational studies is that they offer insights about which of these markers is linked with trends and risks of disease in specific groups versus others.

"For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men," she said. And the triglyceride-to-HDL ratio seems "particularly robust" as a measure of cardiovascular health and risk. 

The understanding of the links with triglycerides can be “tricky” and “confusing” as results differ between studies so often, she notes. "There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different," she said.\

Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, at Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy notes that some studies have suggested that triglycerides may have a protective effect against dementia.

This may be because the brain "runs mostly on energy from burning triglycerides," suggested Naidoo, who is the author of the books Calm Your Mind with Food and This Is Your Brain on Food.

Naidoo also notes that “having higher levels of triglycerides may be linked with having overall healthier behaviors”.

Mills claims that in middle-aged people, having high LDL-C and triglycerides are "often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory.” Things become more murky in older people as there are differences in how people clear some of these compounds, as well as their tissue clearance, transport, and nutrient status.

Currently, for older people, it appears that fluctuations in either direction— too high or too low are an indicator that some dysregulation is happening in the system.

She stressed that, in this "emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets 'off,' as people age." 

What Can Statins Do?

Mills speculated that there may be "neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don't have any clear data whether statins actually directly impact brain cholesterol, since it's a separate pool."

She thinks they could benefit the brain "by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation."

Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida directed to research supporting statins taken at midlife seem to be cardioprotective and may also protect brain health while statins initiated in older age don’t appear to possess the same benefits.

He infers that statins started later in life may not be as helpful because the Blood Brain Barrier (BBB) has been damaged by systemic inflammation in the periphery. Inflammation in the neurons and consequential neuronal destruction are already occurring.

"I think statins aren't going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won't grow back."

Can Diet Changes Help?

Naidoo notes that when assessing neurologic and psychiatric disease, "it's important to think about the 'long game' — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?"

Naidoo’s focus is on nourishing the gut microbiome and decreasing inflammation from a nutritional psychiatry point of view. "A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD." 

She advises a nutrient-dense, anti-inflammatory diet, rich in probiotic foods including kimchi, miso, plain yogurt, and sauerkraut. In addition, "the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health."

Naidoo also suggests extra-virgin olive oil for its health fat. Intake of this fat is linked to lower incidence of AD by way of encouraging autophagy, which she calls "our own process of "cellular cleanup.'"

Naidoo suggests clinicians should advise their patients to "focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction." 

Mills also cites the importance of omega-3-fatty acids including docosahexaenoic acid (DHA) for brain health. "DHA is a major lipid component of neuronal membranes. Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact."

How Can Clinicians Help Their Patients?

Despite the relationship between lipids and dementia, Mills notes it’s not exactly clear what an individual’s lipid levels mean. It’s a complex situation that’s growing and changing, so the clinical application isn’t yet clear.

One suggestion she offers is for clinicians to track lipid levels over time. If you follow a patient and see an increase or decrease [in lipid levels], that can be informative." Looking at ratios of lipids might be more useful than looking only at a change in a single measure. "If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong." 

Lifestyle interventions are certainly advised but medication is a personal clinical decision an individual should make depending on their risk factors and the direction their lipids are going.

Below are some takeaways in reducing risk of dementia.

·         Get a baseline lipid panel and recheck them as needed according to your healthcare provider’s advice.

·         Increase omega-3-fats in your diet with fatty fish twice per week or vegan sources such as chia seeds, flaxseed, or walnuts. Talk to your doctor or dietitian to see if supplements are appropriate.

·         Maintain physical activity to keep your weight, blood pressure, blood sugar, and cholesterol levels in healthy ranges.

·         Reduce ultra-processed foods including fast food, sugary beverages, and high-fat, high-sugar snacks. These have been linked with higher rates of cognitive decline. 2

·         Keep blood sugar in good control if you have insulin resistance, prediabetes or diabetes. Diabetes is an independent risk factor for cognitive decline. 3

·         Include plenty of high-fiber foods in your diet to maintain a healthy gut microbiome, which may impact the brain-gut axix. 4

Lisa Andrews, MEd, RD, LD

References:

1.      Lipids and Dementia: A Complex and Evolving Story | SOMEONE SOMEWHERE (zedie.org)

2.     Gomes Gonçalves N, Vidal Ferreira N, Khandpur N, Martinez Steele E, Bertazzi Levy R, Andrade Lotufo P, Bensenor IM, Caramelli P, Alvim de Matos SM, Marchioni DM, Suemoto CK. Association Between Consumption of Ultraprocessed Foods and Cognitive Decline. JAMA Neurol. 2023 Feb 1;80(2):142-150. doi: 10.1001/jamaneurol.2022.4397. PMID: 36469335; PMCID: PMC9857155.

3.     Pignalosa FC, Desiderio A, Mirra P, Nigro C, Perruolo G, Ulianich L, Formisano P, Beguinot F, Miele C, Napoli R, Fiory F. Diabetes and Cognitive Impairment: A Role for Glucotoxicity and Dopaminergic Dysfunction. Int J Mol Sci. 2021 Nov 16;22(22):12366. doi: 10.3390/ijms222212366. PMID: 34830246; PMCID: PMC8619146.

4.     Barber TM, Kabisch S, Pfeiffer AFH, Weickert MO. The Effects of the Mediterranean Diet on Health and Gut Microbiota. Nutrients. 2023 Apr 29;15(9):2150. doi: 10.3390/nu15092150. PMID: 37432307; PMCID: PMC10180651.