27th April 2025, A/Prof Chee L Khoo
We recently looked at the LDL-C levels needed to stabilise plaque progression and the LDL-C levels needed to cause plaque regression. Plaque stabilisation and regression leads to reduction in cardiovascular events. Dyslipidaemia (especially LDL-C) is also associated with cognitive impairment and dementia and reducing those numbers with statin therapy reduces the risk. The data is conflicting and because of that we are not sure what our targets should be for brain health or whether we can go too low.
The development of CVD complications is relatively short (in the realm of few years) and typically, outcome studies are of 2-3 years duration. There are defined entities with coronary artery disease (ACS, PCI, CABG or death from CAD). There is lots of data out there connecting LDL-C with ASCVD. With brain health though, the development of cognitive impairment and dementia takes 10-20 years to develop and thence, studies take a lot longer to complete. The “complications” of cerebral diseases are less defined – cognitive impairment, vascular dementia, non-vascular dementia and Alzheimer’s Dementia or Alzheimer’s Dementia Related Diseases (ADRD). There are also many confounding factors that are hard to tease out. Hence, data linking LDL-C with brain health is rather sparse, mostly observational and more conflicting
With those caveats in mind, in determining the association of LDL-C with brain health, there are 3 questions we needed answers to:
Q1. Is LDL-C associated with cognitive impairment?
Prior observational studies have been hampered by different study populations, different cutoff points of total cholesterol for categorisation, different studies using different lipid fractions and varying methods for capturing dementia cases and controlling for confounding. Earlier studies were of shorter duration but we have recent published data spanning >20 years of follow up.
Hyperlipidaemia in midlife is a risk factor for late onset Alzheimers Disease (AD) in prospective epidemiological studies (1) and associations of higher LDL-C with increased cerebral β-amyloid load have also been observed in autopsy and in vivo imaging studies (2,3).
There are studies which showed association between total cholesterol and risk of dementia appears to vary with age at measurement (mid-life [<65 years] or later life [≥65 years]) and follow-up duration (4-9).
Iwagami M, et al. (2021) studied a large cohort of people > 40 years old from the UK Clinical Practice Research Datalink (CPRD) (10). 1 853 954 people whose lipid readings was measured back in 1992 had follow up data for 2 decades. Overall, they found we a modest positive association between LDL-C and dementia (adjusted relative risk of 1.03 per 1.0 mmol/L increase). The RR were higher in people < 65 yo when first measured compared with those > 65 years old.
Yet, Ferguson E, et al (2023) did not find an association between LDL-C and dementia when they looked at 184, 367 participants > 55 years old from the US Kaiser Permanente Northern California health plan database (11).
Beydoun M, et al followed up 1600 and 1345 patients > 50 years old for 25 years to examine for dementia and mild cognitive impairment respectively (12). They found that participants with incident dementia had a higher first-visit TC compared with participants who remained free of dementia and MCI ().
Thus, it would seem that LDL-C is associated with a higher risk of dementia and cognitive impairment although less so in people over the age of 50-55 years old if high cholesterol was first diagnosed. I guess, it is a question of the burden of disease. Those diagnosed at a younger age (before ageing sets in), probably have high cholesterol from a young age while those diagnosed later have high cholesterol only when ageing sets in.
Q2. If the answer to Q1 is yes, will reducing LDL-C lead to reduction in cognitive impairment?
Seemingly straight forward question to ask but not that straight forward. In Beydon M et al study, statin users had a two- to threefold lower risk of developing dementia (HR=0.41), but not mild cognitive impairment MCI (12). In fact, a high total cholesterol at baseline was associated with low MCI risk.
In the Ferguson E, et al study, while they did not find an overall association between LDL-C and dementia, they did find that there was a higher risk for Alzheimer’s Dementia and related dementia (ADRD) in patients with higher LDL-C taking statins (11). Perhaps, there is a threshold which prompted patients to be on statins and LDL-C levels above that threshold is related to higher dementia risks. These compounding factors are always problematic in observational studies.
Williams D, et al. (2019) conducted a Mendelian randomisation analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen) (13). While they all reduced cardiovascular risk, lowering LDL-C by targeting these genetic defects did not affect AD risk. According to the authors, this may signify the absence of a substantial role of primary hypercholesterolemia in AD aetiology.
Q3. If reducing LDL-C helps, what are the thresholds for benefit (and/or harm)?
Lee YB, et al. explored the association between cholesterol levels and dementia risk according to the presence of diabetes and statin use in a population-based longitudinal cohort study, the Korean National Health Insurance Service datasets (2002–2017) (14). 6,883,494 underwent health examinations and data on lipid levels and dementia were available. The mean duration of follow up was 8.3 years.
In statin non-users with or without diabetes, the hazards of all-cause dementia were highest for those in the lowest quartile or quintile of LDL-C level (< 2.4 mmol/L), showing an inverted J-shaped relationship. It was noted, though, that patients in the lowest quartile/quintile were more likely to be current smokers and heavy drinkers and had a higher prevalence of ASCVD at baseline.
Among statin users with or without diabetes, an increase in LDL-C was associated with an increase in hazards of all-cause dementia. In statin users with diabetes, even very low LDL-C level was not associated with an increased risk of all-cause dementia.
In a most recent study also by Lee MW et al (2025) they retrospectively analysed data from 11 university hospitals (15). The data was used to compare individuals with LDL-C levels below 1.8 mmol/L with those with levels above 3.4 mmol/L, resulting in a primary analysis cohort of 108 980 matched patients. Secondary analyses further examined LDL-C thresholds below 1.4 mmol/L and the influence of statin use.
The LDL-C levels below 1.8 mmol/L were associated with a 26% reduction in the risk of all-cause dementia and a 28% reduction in the risk of ADRD, compared with levels above 3.4 mmol/L. For LDL-C levels below 1.4 mmol/L, there was an 18% risk reduction for both outcomes. Among those with LDL-C <1.8 mmol/L, statin use was associated with a 13% reduction in all-cause dementia risk and a 12% decrease in ADRD risk compared with non-users.
There were concerns that extremely low blood cholesterol levels can impair neuronal homeostasis. However, cerebral cholesterol is primarily produced locally, and cerebral cholesterol levels may be independent of plasma levels (16,17). It’s reassuring that a Mendelian randomisation study in those with proprotein convertase subtilisin-kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-CoA reductase genetic variations and recent randomised controlled trials of ezetimibe and anti-PCSK9 monoclonal antibodies indicated that very low LDL-C level does not increase the incidence of neurocognitive adverse events (18-20).
In summary, there is evidence suggesting that LDL-C is associated with higher risk of dementia especially if the elevated LDL-C is present from a younger age (<50-55 yo). It would appear that it is worth treating LDL-C to reduce the risk of dementia especially in patients with diabetes. Further, according to a recent study by MW Lee (2025), we need to get the LDL-C below 1.8 mmol/L to see benefit. In this study, there were no increase in the risk of harm if the LDL-C was lower than this. This is despite an early study which found that in patients with LDL-C < 2.4 mmol/L but not on statins, there seems to be an increase in the risk of dementia. This may be due to that group of patients having a higher rate of ASCVD and smoking.
References:
1. Meng X-F, Yu J-T, Wang H-F, et al. Midlife vascular risk factors and the risk of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 2014; 42: 1295–1310.
2. Matsuzaki T, Sasaki K, Hata J, et al. Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama study. Neurology 2011; 77: 1068–1075
3. Reed B, Villeneuve S, Mack W, et al. Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol 2014; 71: 195–200.
4. WHO. Risk reduction of cognitive decline and dementia: WHO guidelines World Health Organization, Geneva, 2019
5. Prince, M, Albanese, E, Guerchet, M, et al. World Alzheimer Report 2014. Dementia and risk reduction: an analysis of protective and modifiable factors Alzheimer’s Disease International, London, 2014
6. Anstey, KJ, Lipnicki, DM, Low, LF. Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis Am J Geriatr Psychiatry. 2008; 16:343-354
7. Shepardson, NE, Shankar, GM, Selkoe, DJ. Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies Arch Neurol. 2011; 68:1239-1244
8. Anstey, KJ, Ashby-Mitchell, K, Peters, R. Updating the evidence on the association between serum cholesterol and risk of late-life dementia: review and meta-analysis J Alzheimers Dis.
9. Hersi, M, Irvine, B, Gupta, P, et al. Risk factors associated with the onset and progression of Alzheimer’s disease: a systematic review of the evidence Neurotoxicology. 2017; 61:143-187
10. Iwagami, Masao et al. Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort study. The Lancet Healthy Longevity, Volume 2, Issue 8, e498 – e506
11. Ferguson EL, Zimmerman SC, Jiang C, et al. Low- and High-Density Lipoprotein Cholesterol and Dementia Risk Over 17 Years of Follow-up Among Members of a Large Health Care Plan. Neurology. 2023 Nov 21;101(21):e2172-e2184.
12. Beydoun MA, Beason-Held LL, Kitner-Triolo MH et al. Statins and serum cholesterol’s associations with incident dementia and mild cognitive impairment. J Epidemiol Community Health. 2011 Nov;65(11):949-57.
13. Williams DM, Finan C, Schmidt AF, Burgess S, Hingorani AD. Lipid lowering and Alzheimer disease risk: A mendelian randomization study. Ann Neurol. 2020 Jan;87(1):30-39.
14. Lee, YB., Kim, M.Y., Han, K. et al. Association between cholesterol levels and dementia risk according to the presence of diabetes and statin use: a nationwide cohort study. Sci Rep 12, 19383 (2022).
15. Lee M, Lee KJ, Kim J, Lee DY, et al. Low-density lipoprotein cholesterol levels and risk of incident dementia: a distributed network analysis using common data models. J Neurol Neurosurg Psychiatry. 2025 Apr 1:jnnp-2024-334708.
16. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 2001;12:105–112
17. Lane RM, Farlow MR. Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer’s disease. J. Lipid Res. 2005;46:949–968
18. Giugliano RP, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: A prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390:1962–197
19. Benn M, Nordestgaard BG, Frikke-Schmidt R, Tybjaerg-Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer’s disease and Parkinson’s disease: Mendelian randomisation study. BMJ. 2017;357:j1648 20. Giugliano RP, et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol: A prespecified analysis of the IMPROVE-IT trial. JAMA Cardiol. 2017;2:547–555