ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
BrianR
Senior Contributor
Senior Contributor
Posts: 206
Joined: Tue Oct 02, 2018 12:32 pm
Location: Southeastern Michigan

ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby BrianR » Fri May 10, 2019 8:26 am

ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change [Paywalled]
Yashashwi Pokharel, Farah Mouhanna, Vijay Nambi, Salim S. Virani, Ron Hoogeveen, Alvaro Alonso, Gerardo Heiss, Josef Coresh, Thomas Mosley, Rebecca F. Gottesman, Christie M. Ballantyne, Melinda C. Power
Neurology May 2019, DOI: 10.1212/WNL.0000000000007574


Objective
To examine the association of specific lipoproteins/inflammatory enzyme with cognitive change.

Methods
We examined the association of apolipoprotein B (ApoB), small-dense low-density lipoprotein cholesterol (sdLDL-C), lipoprotein (a) (Lp[a]), and lipoprotein-associated phospholipase A2 (LpPLA2) activity with 15-year change in Delayed Word Recall Test, Digit Symbol Substitution Test (DSST), Word Fluency Test (WFT), and overall summary score in 9,350 participants in the Atherosclerosis Risk in Communities study. We assessed interaction by race, sex, education, APOE e4 status, and statin use. We also addressed questions of informative missingness, the role of stroke, and the influence of fasting status.

Results
The mean (SD) age was 63.4 (5.7) years; 56.4% were women and 17.4% were black. We observed faster cognitive decline on DSST and global z scores with every 10-mg/dL higher sdLDL-C level (D DSST z score, −0.010; 95% confidence interval [CI] −0.017, −0.002 and D global z score, −0.011; −0.021, −0.001) and the highest vs the lowest ApoB quintiles (D DSST z score, −0.092; −0.0164, −0.019 and D global z score, −0.101; −0.200, −0.002). Association for the ApoB quintiles with D global z score (−0.10) was comparable with that of having 1 APOE e4 allele (−0.11). Higher Lp(a) was associated with slower decline in DSST, WFT, and global z scores. LpPLA2 activity was not associated with cognitive change. Results were similar in sensitivity analyses. The associations of sdLDL-C or Lp(a) on cognitive change were more pronounced in statin users.

Conclusions
Optimal control of atherogenic lipoproteins such as ApoB and sdLDL-C in midlife for cardiovascular health may also benefit late-life cognitive health. Evidence of cognitive decline is a requirement for dementia diagnosis,1 and it is well-established that cognitive decline accelerates in the years prior to a dementia diagnosis.2 Thus, this period, where cognitive change is occurring but cognition is not impaired, may represent a potential therapeutic window for interventions.3 Stroke,4 subclinical atherosclerosis,5 and traditional cardiovascular risk factors,6–9 including elevated total cholesterol and low-density lipoprotein cholesterol (LDL-C),6,10–13 are all associated with increased risk for cognitive decline, attesting to the importance of vascular health for late-life cognitive health. However, the mechanisms underlying the link between cardiovascular health and late-life cognition, as well as ideal treatment of vascular risk factors for the preservation of cognition, remain unclear.

Consideration of biomarkers linked to atherosclerosis and cardiovascular health may yield additional insight. Apolipoprotein B (ApoB) reflects total atherogenic lipoprotein particles including and beyond explained by LDL-C.14 Lipoprotein (a) (Lp[a]) has been implicated by Mendelian randomization studies to be in the causal pathway for atherosclerotic cardiovascular disease.15 Small dense LDL-C (sdLDL-C) is a measure of the cholesterol content in small dense low-density lipoproteins that likely have enhanced atherogenic potential.16,17 Lipoprotein-associated phospholipase A2 (LpPLA2) is an enzyme transported by lipoproteins and secreted by inflammatory cells in atherosclerotic plaques.18 These lipoproteins and enzymes may be involved in subclinical and overt brain injury leading to cognitive change through a variety of mechanisms, including enhancing atherosclerosis, thrombosis, inflammation, microvascular dysfunction, and hypoperfusion.14,19–22 However, the existing data on the association between these biomarkers and cognition show conflicting results and are constrained by smaller sample sizes and case-control or cross-sectional designs.23–31 Thus, the purpose of this study was to examine the associations of baseline levels of ApoB, sdLDL-C, Lp(a), and LpPLA2 activity with 15-year change in cognitive function in the Atherosclerosis Risk in Communities (RIC)

Glossary
ApoB = apolipoprotein B; ARIC = Atherosclerosis Risk in Communities; CI = confidence interval; DSST = Digit-Symbol Substitution Test; DWRT = Delayed Word Recall Test; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); LpPLA2 = lipoprotein-associated phospholipase A2; sdLDL-C = small dense low-density lipoprotein cholesterol; WFT = Word Fluency Test.

...

Discussion
Using a biracial, large, prospective cohort study, we showed that higher levels of ApoB as well as sdLDL-C were associated with greater cognitive decline, primarily in executive function, over 15 years. Analysis using quintile and linear terms to assess for nonlinear relationships indicated that the association between ApoB and cognitive change may be limited to those with high ApoB levels, whereas the association with sdLDL-C appears linear. Conversely, higher Lp(a) levels were associated with slower cognitive decline in semantic fluency.
...

BrianR
Senior Contributor
Senior Contributor
Posts: 206
Joined: Tue Oct 02, 2018 12:32 pm
Location: Southeastern Michigan

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby BrianR » Fri May 10, 2019 9:20 am

An apropos insight for this group into relative risk:
To contextualize, the observed strength of association of the highest quintile of ApoB with 15-year change in global z score (i.e., −0.10) was almost comparable to 15-year change in global z score seen with the presence of 1 APOE e4 allele (i.e., −0.11), a known risk factor for Alzheimer disease.

mike
Senior Contributor
Senior Contributor
Posts: 664
Joined: Fri Mar 09, 2018 4:55 pm
Location: CA - Sonoma County

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby mike » Fri May 10, 2019 11:13 am

The associations of sdLDL-C or Lp(a) on cognitive change were more pronounced in statin users.


What was the association with out the statin? My cholesterol sucks, but If I don't take a statin, does the risk diminish significantly, or only a little...?
Sonoma Mike
4/4

User avatar
Julie G
Mod
Mod
Posts: 8526
Joined: Sat Oct 26, 2013 6:36 pm

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby Julie G » Fri May 10, 2019 2:50 pm

Great find, Brian, and very relevant for us! This certainly pours cold water on the "higher the better" cholesterol/cognition theory and points to a more nuanced picture... which most of us suspected.
What was the association with out the statin? My cholesterol sucks, but If I don't take a statin, does the risk diminish significantly, or only a little...?

My guess is that in those who take statins, higher ApoB and sdLDL would hasten cognitive decline; whereas higher Lp(a) would provide greater protection. Is that how others are reading it? I would love to find full-text to learn more.

BrianR
Senior Contributor
Senior Contributor
Posts: 206
Joined: Tue Oct 02, 2018 12:32 pm
Location: Southeastern Michigan

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby BrianR » Fri May 10, 2019 3:57 pm

mike wrote:
The associations of sdLDL-C or Lp(a) on cognitive change were more pronounced in statin users.


What was the association with out the statin? My cholesterol sucks, but If I don't take a statin, does the risk diminish significantly, or only a little...?


The association of sdLDL-C and cognitive decline was amplified in persons using statins. While we cannot rule out chance, this most likely reflects unmeasured confounding. People with higher sdLDL-C are more likely to be treated with statins (14.5% vs 11.5% in people with sdLDL-C ≥50 mg/dL vs those with <50 mg/dL in our study), as they have increased propensity to atherosclerosis and perhaps a longer lifetime exposure to higher cholesterol levels. This finding requires additional confirmation; it should not be used to justify ceasing or not starting statin use for cardiovascular benefits.

and, fwiw:
Figure 2 Effect Modification.png

(I believe "visit 4" refers to specific timing in ARIC study.)
You do not have the required permissions to view the files attached to this post.

mike
Senior Contributor
Senior Contributor
Posts: 664
Joined: Fri Mar 09, 2018 4:55 pm
Location: CA - Sonoma County

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby mike » Fri May 10, 2019 4:07 pm

So if I'm reading graph A correctly, the non-statin users actually improved in some cases... I would certainly say there is a huge difference between Nonusers and Users. Global Z score for non-user at highest dose was same as statin user lowest dose...I think.
Statin.PNG
You do not have the required permissions to view the files attached to this post.
Sonoma Mike
4/4

BrianR
Senior Contributor
Senior Contributor
Posts: 206
Joined: Tue Oct 02, 2018 12:32 pm
Location: Southeastern Michigan

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby BrianR » Fri May 10, 2019 4:12 pm

I'd follow the authors' inclination to wait for a better study regarding the statin/non-statin effects before making any changes to a statin regimen. (As usual with AD, lots of intriguing notions, far fewer well proven conclusions.)

User avatar
MarcR
Mod
Mod
Posts: 1739
Joined: Wed Mar 05, 2014 8:28 pm
Location: Camas, Washington, US

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby MarcR » Sat May 11, 2019 3:47 pm

Julie G wrote:This certainly pours cold water on the "higher the better" cholesterol/cognition theory
Straw man? I recall more nuance than "higher the better". We have discussed the weakness of the lipid hypothesis at length and have identified high-powered studies which note that mortality rates decline as LDL cholesterol rises in populations not beset by insulin resistance, metabolic syndrome, and Type 2 diabetes. We have also reviewed compelling evidence supporting the ratio of triglycerides to HDL as a much stronger predictor of CVD and mortality than LDL.

From the tables, average triglycerides were 150, and average HDL-C was 50. Even though they offered an oblique nod to the ratio ...
Excessive LDL-C is the major component of ApoB and sdLDL-C and high triglycerides and low high-density lipoprotein levels are common in people with elevated sdLDL-C
... they failed to examine it directly.

This particular study included many sick people - average BMI 29, half had hypertension, and 18% had full-blown diabetes. I'm sure the results are applicable to those of us afflicted similarly; however, I continue to enjoy vigor and well-being while hewing to these targets:

TG/HDL < 1
Overall cholesterol >200
Normal BMI (~23)
Normal BP (<120/80)

In my 40s I was even sicker than the average ARIC participant (TG/HDL = 10; BMI = 32). I healed by ignoring conventional nutritional and clinical wisdom, and I stay well today - 10 years later - by continuing to avoid processed foods and by continuing to emphasize high quality foods loaded with saturated fat like grass fed beef, butter, and cheese, pastured eggs, and high-fat yogurt.
I would love to find full-text to learn more.
A little birdie told me that searching sci-hub.tw for the paper's DOI (10.1212/WNL.0000000000007574) might help.

User avatar
Julie G
Mod
Mod
Posts: 8526
Joined: Sat Oct 26, 2013 6:36 pm

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby Julie G » Sat May 11, 2019 7:09 pm

Straw man? I recall more nuance than "higher the better".

Only a "straw man" if you take half of my sentence and disregard the part specifically about nuance... which most of us suspected. ;)

FWIW, I was able to get my hands on full text and agree with much of your assessment. This was definitely an unhealthy population. The strongest correlation was between sdLDL and cognition which fits beautifully with our majority understanding as sdLDL rises with worsened glycemic markers, high Tgs, etc. I also found it very encouraging that the lowest quartile for sdLDL was 28-40mg/dl.
A little birdie told me that searching sci-hub.tw for the paper's DOI (10.1212/WNL.0000000000007574) might help.

Thank you! I had previously plugged in the title and not the DOI. Your helpful hint is much appreciated.

Matisse
Contributor
Contributor
Posts: 53
Joined: Sun May 04, 2014 4:44 pm

Re: ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Postby Matisse » Sun May 12, 2019 1:17 pm

I have Walk in Lab NMR results and I'm not sure where small dense LDL (sdLDL) is on it. I see LDL-P and small LDL and LDL size but no where does it say sdLDL. Can someone help me out please?


Return to “Science and Research”

Who is online

Users browsing this forum: No registered users and 10 guests