Many of us (myself, included) would prefer to keep our wits about us and avoid the development of dementia at all costs. Some behaviors include not smoking, staying social, and keeping blood lipids in check. But which lipids are we talking about?

Some research alludes that very high lipid levels may raise the risk of developing dementia and Alzheimer’s Disease while other studies suggest that high LDL (“lousy”) cholesterol or maybe triglycerides may be protective against dementia. Meanwhile, high levels of HDL (healthy) cholesterol which was considered protective may potentially have a negative impact.

The link between serum lipids and the development of dementia is as clear as mud. Betsy Mills, PhD, Assistant Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation agrees, "This is an incredibly complex area, and there really isn't a clear consensus on this subject because different lipid classes reflect different things,".

Mills notes, "It depends on what lipids you're measuring, what you're using to measure those lipids, what age the person is, and multiple other factors,".

According to Mills, separating the factors and possible ways for a link between lipids and risk for dementia requires understanding the way lipids act in a healthy brain, the effect of brain lipid dysregulation, and the interactions between cholesterol in the central nervous system versus the rest of the body.

Not Just Amyloid

Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida believes lipids and their role in risk for AD have been bypassed.

Most recognize that amyloid is at the root of AD, which is true in familial AD. "It's been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that's not clear at all."

He believes that because aducanumab has limited efficacy in treating amyloid plaques, there are other factors beyond amyloid affecting the risk for AD. Scientists like Scott are also noting the role of inflammation and lipids. Research from his lab suggests that cholesterol promotes the creation of amyloid through inflammation and inflammation in turn drives amyloid.

Invasion of Lipids

The brain is rich in lipids according to Mills and "any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions."

Healthy lipid regulation is needed for a healthy brain. Hansen notes that the initial description of AD a century ago notes that AD is a disease linked with altered brain lipids.

Hansen mentioned the “lipid invasion model” as a means of explaining dysregulation in lipids. This belief suggests that AD is influenced by alternate lipids that get to the brain due to damage of the blood-brain barrier (BBB).

Hansen claims that brain cholesterol and body cholesterol are separate. "The brain produces its own cholesterol and keeps tight control of it."

Cholesterol from food does not enter the brain under normal conditions. “Each pool of cholesterol — in the brain and the periphery — has its distinct regulatory mechanisms, target cells, and transport mechanisms.", according to Hansen.

The BBB becomes permeable if compromised, letting LDL cholesterol into the brain. The brains lipoproteins then shuttle this cholesterol which allows absorption by neurons. As a result, neuronal amyloid levels increase, eventually leading to the development of amyloid-b plaques. It is also involved in tau phosphorylation, which are key features of AD.

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Hansen. Then the brain's own lipoproteins transport the invading cholesterol, allowing it to absorbed by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are important components of AD pathology.

According to Hansen, high cholesterol levels and other fats have been located in amyloid plaques. In addition, research on brains of AD patients have identified BBB damage.

Risk factors including aging, brain trauma, high blood pressure, stress, poor sleep, smoking, excess alcohol, obesity, diabetes and APOE genotype impact risk of BBB in addition to AD, based on the lipid invasion model paper cited by Hansen

Which Came First?

Mills notes the link between brain and heart health is strong. Risk factors such as diabetes, hypertension, high cholesterol and obesity also raise the risk for dementia, especially vascular dementia.

A lipid profile that is atherogenic leads to hardening of the arteries with reduced blood flow to the brain. This stresses the brain, which may result in inflammation and pathology.

Hansen also adds that cholesterol alone has an important role in inflammation. “In the periphery, it is "part of an integral response to tissue damage and infection".

Once cholesterol is made into astrocytes in the brain, it is shuttled to neurons throughout the APOE protein, which affects the balance of brain cholesterol, according to Mills. Individuals who have the ε4 allele of APOE usually have damaged transport and storage of brain lipids compared to the other APOE variants.

Individuals with APOE4 are at higher risk for late-onset AD, according to Hansen. However, APOE2 has a protective effect. Most people are in between with APOE3.

Inflammation in the brain is driven higher when the uptake of “invading cholesterol” occurs in the brain. Amyloid as well as neuroinflammatory cytokines are made and a vicious cycle starts: Cholesterol releases cytokines and cytokines produce cholesterol. Hansen believes the BBB permeability lets inflammatory cytokines in from other parts of the body, which invade the brain thus raising inflammation.

Mills adds, "We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it's a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It's probably a combination, but it's unclear at this point."

Plasma vs CSF Lipids

Mills goes on to explain that particles of HDL in the brain are not the same as those in the periphery. "In the CNS, you have 'HDL-like particles,' which are similar in size and composition [to HDL in the periphery] but aren't the same particles." HDL-like lipoproteins are made by the brain’s astrocytes and other glial glands and located in cerebrospinal fluid (CSF).

Peripheral dyslipidemia can be a risk factor for cardiovascular disease. In the brain, Mills states, it can be an indication that there is active damage going on, depending on which compartment you're looking at."

She goes on to say that blood lipid levels and brain CSF lipids are quite different. Research suggests that HDL in the CSF acts similarly to plasma HDL but shows up at 100-fold lower amounts when compared to plasma HDL and has unusual combinations of alternate proteins.

Lipid evaluation studies indicate these lipids get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated." 

Cholesterol in the brain has to be transported from glial cells to neurons and disruptions in this movement can impact overall brain balance. As the brain system is separate from the periphery system, monitoring plasma lipids is more likely going to suggest cardiovascular risk. Alterations in CSF lipids are "more indicative of alteration in lipid homeostasis in the brain.", according to Mills.

What you can do to reduce your risk of AD:

·         Know your family history. Ask your parents, aunts, uncles, and other family members about any known history of AD.

·         Don’t smoke and avoid secondhand smoke. Smokers and those exposed to cigarette smoke have higher rates of dementia according to research. 2

·         Manage blood pressure to prevent strokes. The BBB may be damaged due to stroke. 3

·         Avoid traumatic brain injuries such as concussions or falls. These raise the risk of dementia.4

·         Limit alcohol consumption. Alcohol passes the BBB and damages brain tissue over time. 5

·         Stay social! We need social interaction daily. Research shows that older individuals with strong social connections have lower rates of AD. 6

Lisa Andrews, MEd, RD, LD

References:

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

2.      Zhou S, Wang K. Childhood Secondhand Smoke Exposure and Risk of Dementia, Alzheimer's Disease and Stroke in Adulthood: A Prospective Cohort Study. J Prev Alzheimers Dis. 2021;8(3):345-350. doi: 10.14283/jpad.2021.10. PMID: 34101793.

3.      Rost NS, Brodtmann A, Pase MP, van Veluw SJ, Biffi A, Duering M, Hinman JD, Dichgans M. Post-Stroke Cognitive Impairment and Dementia. Circ Res. 2022 Apr 15;130(8):1252-1271. doi: 10.1161/CIRCRESAHA.122.319951. Epub 2022 Apr 14. PMID: 35420911.

4.      Brett BL, Gardner RC, Godbout J, Dams-O'Connor K, Keene CD. Traumatic Brain Injury and Risk of Neurodegenerative Disorder. Biol Psychiatry. 2022 Mar 1;91(5):498-507. doi: 10.1016/j.biopsych.2021.05.025. Epub 2021 Jun 2. PMID: 34364650; PMCID: PMC8636548.

5.      Zhang YR, Xu W, Zhang W, Wang HF, Ou YN, Qu Y, Shen XN, Chen SD, Wu KM, Zhao QH, Zhang HN, Sun L, Dong Q, Tan L, Feng L, Zhang C, Evangelou E, Smith AD, Yu JT. Modifiable risk factors for incident dementia and cognitive impairment: An umbrella review of evidence. J Affect Disord. 2022 Oct 1;314:160-167. doi: 10.1016/j.jad.2022.07.008. Epub 2022 Jul 19. PMID: 35863541.

6.    Joshi P, Hendrie K, Jester DJ, Dasarathy D, Lavretsky H, Ku BS, Leutwyler H, Torous J, Jeste DV, Tampi RR. Social connections as determinants of cognitive health and as targets for social interventions in persons with or at risk of Alzheimer's disease and related disorders: a scoping review. Int Psychogeriatr. 2023 Nov 23:1-27. doi: 10.1017/S1041610223000923. Epub ahead of print. PMID: 37994532.