European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration, Luo J, Thomassen JQ, Bellenguez C, Grenier-Boley B, de Rojas I, Castillo A, Parveen K, Küçükali F, Nicolas A, Peters O, Schneider A, Dichgans M, Rujescu D, Scherbaum N, Jürgen D, Riedel-Heller S, Hausner L, Porcel LM, Düzel E, Grimmer T, Wiltfang J, Heilmann-Heimbach S, Moebus S, Tegos T, Scarmeas N, Clarimon J, Moreno F, Pérez-Tur J, Bullido MJ, Pastor P, Sánchez-Valle R, Álvarez V, Boada M, García-González P, Puerta R, Mir P, Real LM, Piñol-Ripoll G, García-Alberca JM, Royo JL, Rodriguez-Rodriguez E, Soininen H, Kuulasmaa T, de Mendonça A, Mehrabian S, Hort J, Vyhnalek M, van der Lee S, Graff C, Papenberg G, Giedraitis V, Boland A, Bacq-Daian D, Deleuze JF, Nicolas G, Dufouil C, Pasquier F, Hanon O, Debette S, Grünblatt E, Popp J, Benussi L, Galimberti D, Arosio B, Mecocci P, Solfrizzi V, Parnetti L, Squassina A, Tremolizzo L, Borroni B, Nacmias B, Sorbi S, Caffarra P, Seripa D, Rainero I, Daniele A, Masullo C, Spalletta G, Williams J, Amouyel P, Jessen F, Kehoe P, Magda T, Rossi G, Sánchez-Juan P, Sleegers K, Ingelsson M, Andreassen OA, Hiltunen M, Van Duijn C, Sims R, van der Flier W, Ruiz A, Ramirez A, Lambert JC, Frikke-Schmidt R. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease. JAMA Netw Open. 2023 May 1;6(5):e2313734. PubMed.

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  1. This comprehensive genetic study shows that high HDL-cholesterol (HDL-C) concentrations and high systolic blood pressure (SBP) are associated with greater risk of AD. While the detrimental effects of high SBP are well-documented, the paradoxical association between high HDL-C, the so called “good cholesterol,” and AD risk needs more discussion.

    First, although HDL-C has been widely used as a maker for HDL, it does not reflect the complex and dynamic composition, structure, and function of HDL. It has long been recognized that HDL can serve as a double-edged sword, playing both anti-inflammatory and pro-inflammatory roles in cardiovascular disease (Navab et al., 2005). In fact, recent studies have demonstrated a U-shaped relationship between HDL-C and adverse outcomes, with both low and extremely high HDL increasing the risk (Madsen et al., 2017; Huang et al., 2020). 

    Second, although HDL-C concentrations were determined by SNPs in well-known genes, most of those associations were based on only a single time-point measurement, as indicated in the article. The function of HDL can be modified by many lifestyle and environmental factors, independent of genetically determined HDL-C concentrations. It is also unclear whether the effects of any potential epigenetic and/or post-translational modifications were taken into consideration. Further, Richardson et al. reported that almost half of the SNPs were associated with more than one lipid-related trait (Richardson et al., 2020). Although the results on HDL-C were adjusted for LDL and triglycerides in this article, other components of lipoproteins might be involved, due to the complexity and dynamic nature of lipoprotein metabolism.

    Third, as high HDL-C generally correlates inversely with the incidence of cardiovascular disease, the association of high HDL-C with AD could be the result of better cardiovascular health and longevity. The fact that the participants with AD were clearly older (72-83 years) than controls (51-80 years) supports this possibility.

    Finally, the impact of HDL on AD-related processes has been investigated experimentally by genetic manipulation of APOA-I expression. Elevating HDL-C or enhancing HDL function by APOA-I overexpression rescued cognitive function and attenuated neuroinflammation and cerebral amyloid angiopathy (CAA) in AD mice, whereas APOA-I deficiency exacerbated cognitive deficits and CAA in those same mice (Lewis et al., 2010; Lefterov et al., 2010; Oct 2010 news). Notably, while genetic manipulation of apoA-I expression did not affect parenchymal amyloid pathology in earlier studies (Fagan et al., 2004; Lefterov et al., 2010; Lewis et al., 2010), a later study showed that APOA-I deficiency worsened both parenchymal and vascular amyloid deposition in AD mice (Button et al., 2019). Overall, these findings support the benefits of HDL in AD and the widely held belief that “what is good for the heart is also good for the brain.”

    Based on these discussions, the association between high HDL-C and AD risk should be interpreted with caution. In the meantime, these findings underscore the role of HDL in AD and the need for further investigation in this direction.

    References:

    Button EB, Boyce GK, Wilkinson A, Stukas S, Hayat A, Fan J, Wadsworth BJ, Robert J, Martens KM, Wellington CL. ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice. Alzheimers Res Ther. 2019 May 13;11(1):44. PubMed.

    Fagan AM, Christopher E, Taylor JW, Parsadanian M, Spinner M, Watson M, Fryer JD, Wahrle S, Bales KR, Paul SM, Holtzman DM. ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. Am J Pathol. 2004 Oct;165(4):1413-22. PubMed.

    Huang YQ, Liu XC, Lo K, Liu L, Yu YL, Chen CL, Huang JY, Feng YQ, Zhang B. The U Shaped Relationship Between High-Density Lipoprotein Cholesterol and All-Cause or Cause-Specific Mortality in Adult Population. Clin Interv Aging. 2020;15:1883-1896. Epub 2020 Oct 2 PubMed.

    Lefterov I, Fitz NF, Cronican AA, Fogg A, Lefterov P, Kodali R, Wetzel R, Koldamova R. Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice. J Biol Chem. 2010 Nov 19;285(47):36945-57. Epub 2010 Aug 25 PubMed.

    Lewis TL, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, LaDu MJ, Li L. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem. 2010 Nov 19;285(47):36958-68. Epub 2010 Sep 16 PubMed.

    Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017 Aug 21;38(32):2478-2486. PubMed.

    Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Hama S, Hough G, Bachini E, Grijalva VR, Wagner AC, Shaposhnik Z, Fogelman AM. The double jeopardy of HDL. Ann Med. 2005;37(3):173-8. PubMed.

    Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, Holmes MV. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med. 2020 Mar;17(3):e1003062. Epub 2020 Mar 23 PubMed.

    View all comments by Ling Li

  2. The European Alzheimer’s & Dementia Biobank Collaboration employed a mendelian randomization (MR) design to investigate whether single-nucleotide variants in 39,106 participants diagnosed with Alzheimer's disease and 401,577 control participants without AD can identify modifiable risk factors for AD that could serve as intervention targets. The basis of this MR approach lies in the notion that genetic variants randomly assigned at conception help mitigate confounding factors and reverse causation, which are two major limitations of observational studies that often lead to confusion between association and causation.

    The study reveals two associations: higher risk of AD being linked to elevated levels of HDL cholesterol, and increased systolic blood pressure. While the connection between higher systolic blood pressure and greater AD risk is expected, the association between high HDL cholesterol and increased risk might seem surprising. Traditionally, HDL or "good cholesterol," has been regarded as a protective cardiovascular risk factor. However, extensive research in HDL biology over the past two decades has illustrated its complexity and explained why targeting HDL cholesterol is not effective. Unlike LDL, HDL particles exhibit significant variations in size, shape, composition, and function. Moreover, HDL cholesterol does not adequately represent HDL function. HDL particles in the bloodstream predominantly consist of ApoA-I particles, whereas in the brain, they are composed of ApoE (Van Valkenburgh et al., 2021). Notably, genetic variations in ApoA-I did not show any association with the risk of AD in this cohort.

    The initial step in HDL formation involves the interaction of ApoA-I in plasma or ApoE in the brain with ATP-binding cassette 1 (ABCA-1), resulting in the production of small HDL particles that are not yet fully loaded with cholesterol but exhibit high cholesterol efflux activity. These small HDL particles then undergo remodeling through the actions of LCAT, PLTP, CETP, ABCG1, and SR-BI to acquire more cholesterol and form larger, cholesterol-rich particles. Elevated HDL cholesterol levels sometimes may indicate reduced reverse cholesterol transport, as observed in the case of loss-of-function mutations in the SR-BI receptor responsible for HDL liver uptake and cholesterol clearance (Rigotti et al., 1997). Conversely, loss-of-function mutations in ABCA1, responsible for generating small HDL particles, are associated with greater AD risk (Nordestgaard et al., 2015). Small HDL particle concentrations are not captured by measuring HDL cholesterol levels, and they correlate with better measures of cognitive function performance and lower cerebral amyloid accumulation (Martinez et al., 2022). 

    Although it remains unclear whether small HDL particles formed in the periphery can cross into the brain, unlike large HDL particles their concentrations in the bloodstream and the brain are correlated (Martinez et al., 2022). 

    The findings of this study prompt us to question the value of HDL cholesterol and whether reducing HDL cholesterol levels can translate into a lower AD risk. Recent advancements in HDL biology suggest a shift from thinking about HDL cholesterol to focusing on HDL particle numbers and HDL's cholesterol efflux activity. Understanding the mechanisms that promote the formation of small HDL particles in the brain holds promise for research aimed at reducing the risk of AD.

    References:

    Van Valkenburgh J, Meuret C, Martinez AE, Kodancha V, Solomon V, Chen K, Yassine HN. Understanding the Exchange of Systemic HDL Particles Into the Brain and Vascular Cells Has Diagnostic and Therapeutic Implications for Neurodegenerative Diseases. Front Physiol. 2021;12:700847. Epub 2021 Sep 6 PubMed.

    Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12610-5. PubMed.

    Nordestgaard LT, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease. Alzheimers Dement. 2015 Jun 13; PubMed.

    Martinez AE, Weissberger G, Kuklenyik Z, He X, Meuret C, Parekh T, Rees JC, Parks BA, Gardner MS, King SM, Collier TS, Harrington MG, Sweeney MD, Wang X, Zlokovic BV, Joe E, Nation DA, Schneider LS, Chui HC, Barr JR, Han SD, Krauss RM, Yassine HN. The small HDL particle hypothesis of Alzheimer's disease. Alzheimers Dement. 2022 Apr 13; PubMed.

    View all comments by Hussein Yassine

  3. It is great to see this study, which used the largest genomic consortia to date to systematically investigate the causal relationship between modifiable risk factors and Alzheimer’s disease. An additional strength of the study is that it highlighted the potential influence of proxy AD cases when evaluating causal relationships between behavioral risk factors and AD. Findings from this study will inspire the exploration of novel intervention and prevention avenues.

    In addition to established associations between modifiable risk factors and AD (e.g., educational attainment), the authors reported that genetically determined high HDL cholesterol and high systolic blood pressure (SBP) were associated with higher odds of AD. These findings are very interesting. The HDL association, in particular, contrasts previous studies reporting no association, or a protective association, between high HDL cholesterol and AD.

    The finding of a positive causal association between SBP and AD is also interesting, particularly as such a relationship is observed only after adjusting for diastolic blood pressure.

    As the authors highlight, it is crucial to replicate these findings in non-European populations. Additionally, now that large, well-powered GWAS, such as the EADB are available, it would be interesting to investigate any potential medication effects, causal associations with HDL sub-fractions, or causal, nonlinear blood pressure associations.

    View all comments by Petroula Proitsi

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