Midlife dyslipidaemia as a modifiable risk factor for later-life dementia
Authors: Makoto Ishii
Journal: The Lancet Healthy Longevity (2021)

Since the risk of developing dementia increases with age and the number of older individuals continues to grow worldwide, the prevalence of dementia is predicted to increase substantially unless effective prevention strategies are developed.12021 Alzheimer's disease facts and figures.Alzheimers Dement. 2021; 17: 327-406Crossref PubMed Scopus (72) Google Scholar Interestingly, in the USA and many countries in western Europe, age-specific incidence of dementia has been stable or declining in recent birth cohorts, suggesting that improvements in modifiable risk factors, such as education, health care, and lifestyle, might decrease the risk of developing dementia.2Wu YT Beiser AS Breteler MMB et al.The changing prevalence and incidence of dementia over time—current evidence.Nat Rev Neurol. 2017; 13: 327-339Crossref PubMed Scopus (233) Google Scholar The Lancet Commission on dementia prevention, intervention, and care reported in 2020 that there was sufficiently strong evidence to identify 12 risk factors that, if appropriately modified, might prevent or delay up to 40% of dementia cases.3Livingston G Huntley J Sommerlad A et al.Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.Lancet. 2020; 396: 413-446Summary Full Text Full Text PDF PubMed Scopus (516) Google Scholar The list included several risk factors that can impact cardiovascular health, such as obesity, diabetes, hypertension, and smoking.3Livingston G Huntley J Sommerlad A et al.Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.Lancet. 2020; 396: 413-446Summary Full Text Full Text PDF PubMed Scopus (516) Google Scholar Conspicuously missing from the list was dyslipidaemia. Although dyslipidaemia has been established as a risk factor for cardiovascular disease, the evidence supporting dyslipidaemia as a dementia risk factor has been conflicting and inconclusive.4Peters R Peters J Booth A Anstey KJ Trajectory of blood pressure, body-mass index, cholesterol and incident dementia: systematic review.Br J Psychiatry. 2020; 216: 16-28Crossref PubMed Scopus (14) Google Scholar In The Lancet Healthy Longevity, Masao Iwagami and colleagues5Iwagami M Qizilbash N Gregson J et al.Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort study.Lancet Healthy Longev. 2021; (published onlineJuly 23.)https://doi.org/10.1016/S2666-7568(21)00150-1Summary Full Text Full Text PDF Scopus (2) Google Scholar examine the association between blood lipid levels and the development of dementia using data obtained from the UK Clinical Practice Research Datalink (CPRD), which represents nearly 7% of the UK population. An impressively large number of individuals (aged ≥40 years; median age 59 years, IQR 50–69) with baseline blood lipid levels (1 853 954 individuals with total cholesterol, 1 133 366 individuals with high-density lipoprotein [HDL] cholesterol, 1 201 656 individuals with triglyceride, and 953 635 individuals with calculated low-density lipoprotein [LDL] cholesterol) and a relatively long follow-up time (median 7·4 years, IQR 4·6–10·4; maximum 23 years) were analysed. After adjusting for age and sex, LDL cholesterol was not associated with dementia risk (rate ratio [RR] per 1-SD higher LDL cholesterol levels 0·99, 95% CI 0·97–1·00). However, after adjusting for additional potential confounders, such as socioeconomic status, ethnicity, body-mass index, comorbidites, and prescriptions, higher LDL cholesterol levels were modestly associated with increased dementia risk (adjusted RR 1·05, 95% CI 1·03–1·06). Further subgroup analyses found that the adjusted RR was highest in people who were younger than 65 years at baseline with 10 or more years of follow-up (1·17, 1·08–1·27). Classification of non-vascular dementia into subtypes yielded overall similar results, with the highest adjusted RR for Alzheimer's disease in people younger than 65 years with 10 or more years of follow-up (1·30, 1·14–1·48). The association between total cholesterol and dementia showed a similar pattern to that of LDL cholesterol but was weaker, with the strongest association in people younger than 65 years with 10 or more years of follow-up (adjusted RR 1·08, 1·03–1·12). For triglycerides and HDL cholesterol, there were weak or no associations with dementia. Based on these findings, Iwagami and colleagues conclude that LDL cholesterol is likely to be the main driver in the positive association between cholesterol and dementia.5Iwagami M Qizilbash N Gregson J et al.Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort study.Lancet Healthy Longev. 2021; (published onlineJuly 23.)https://doi.org/10.1016/S2666-7568(21)00150-1Summary Full Text Full Text PDF Scopus (2) Google Scholar Additionally, they noted that the highest adjusted RR was found in the midlife group (<65 years), with a long duration of follow-up, whereas short-term follow-up or measurement in later life might result in an absent or inverse association. The importance of age at the time of lipid measurement and follow-up length is consistent with several other studies that investigated the association between cardiovascular factors and later-life dementia risk. For example, midlife obesity is a risk factor for later-life dementia, presumably in large part by causing cerebrovascular damage over time, while later-life weight loss is positively associated with dementia, which might be due to the dementia pathology directly affecting brain regions that regulate bodyweight, such as the hypothalamus.6Ishii M Iadecola C Metabolic and non-cognitive manifestations of Alzheimer's disease: the hypothalamus as both culprit and target of pathology.Cell Metab. 2015; 22: 761-776Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 7Kiliaan AJ Arnoldussen IAC Gustafson DR Adipokines: a link between obesity and dementia?.Lancet Neurol. 2014; 13: 913-923Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar Major strengths of this study include the large number of study participants and the careful consideration of several confounding factors. Although the study was well designed overall, there are some notable limitations. First, dementia was classified using diagnostic codes. Misclassification could affect the results of this study, as the incidence of dementia and, particularly the various dementia subtypes, was relatively low compared with the large number of participants in the study. Another limitation is the lack of genotyping of the APOEε4 allele, which can strongly affect dementia risk and cholesterol transport. Although Iwagami and colleagues attempted to address this with a simulation study,5Iwagami M Qizilbash N Gregson J et al.Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort study.Lancet Healthy Longev. 2021; (published onlineJuly 23.)https://doi.org/10.1016/S2666-7568(21)00150-1Summary Full Text Full Text PDF Scopus (2) Google Scholar the true effects of APOEε4 genotype cannot be ascertained from this simulation. Other lipoproteins, including apolipoprotein B, which might also be contributing factors to the development of dementia,8Wingo TS Cutler DJ Wingo AP et al.Association of early-onset Alzheimer disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB.JAMA Neurol. 2019; 76: 809-817Crossref PubMed Scopus (41) Google Scholar were similarly not measured or genotyped. Finally, this study was done entirely in the UK, and it is unclear if the findings would be generalisable to other populations. Despite these limitations, this study should be commended for being one of the largest to investigate the association between blood lipids and later-life dementia. The data from this study support midlife LDL cholesterol as being one of the modifiable risk factors for later-life dementia. However, the association was modest, and it is possible that LDL cholesterol is a marker for another related factor with a more direct causal role. Therefore, whether statins or similar LDL cholesterol lowering therapies will be beneficial for preventing later-life dementia remains unclear. Finally, as cardiovascular risk factors are consistently found to be significantly associated with dementia, this raises the intriguing possibility that other factors associated with cardiovascular disease and lipid metabolism, such as the adipocyte hormone (adipokine) leptin, might contribute to the development of later-life dementia.9McGuire MJ Ishii M Leptin dysfunction and Alzheimer's disease: evidence from cellular, animal, and human studies.Cell Mol Neurobiol. 2016; 36: 203-217Crossref PubMed Scopus (50) Google Scholar Future longitudinal studies investigating novel factors associated with cardiovascular disease, including lipoproteins and adipokines, might lead to new prevention strategies against later-life dementia. MI is supported by funding from the National Institutes of Health ( R01AG070868 , K08AG051179 ), Alzheimer's Association ( AARG-20-681013 ), BrightFocus Foundation ( A2020363S , A2015485S ), and American Federation for Aging Research. MI owns stock in Regeneron Pharmaceuticals. This work was supported by a grant from the National Institutes of Health R01AG070868 . Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort studyLDL cholesterol measured in mid-life (<65 years) is modestly associated with dementia risk more than 10 years later. LDL cholesterol should be added to the list of modifiable risk factors for dementia. Full-Text PDF Open Access