Discussion

In this prospective cohort study of 94 184 individuals from the Danish general population, low adherence to national dietary guidelines was associated with an atherogenic plasma lipid profile and with increased risk of non-Alzheimer's dementia, an association that did not appear to be present in individuals treated with lipid-lowering therapy. These findings are novel and may be clinically important as they suggest that non-Alzheimer's dementia can potentially be prevented by well-established interventions such as adhering to national dietary guidelines and by lipid-lowering treatment.

To our knowledge this is the first study to show an association between low adherence to dietary guidelines and increased risk of non-Alzheimer's dementia in Denmark as well as globally. Previous cross-sectional or prospective studies investigating the association between diet and risk of dementia have primarily observed an association between a healthy diet and less cognitive decline or a lower risk of Alzheimer's disease (Féart et al., Reference Féart, Samieri, Rondeau, Amieva, Portet, Dartigues, Scarmeas and Barberger-Gateau2009; Morris et al., Reference Morris, Tangney, Wang, Sacks, Bennett and Aggarwal2015; Haring et al., Reference Haring, Wu, Mossavar-Rahmani, Snetselaar, Brunner, Wallace, Neuhouser and Wassertheil-Smoller2016; Van Den Brink et al., Reference Van Den Brink, Brouwer-Brolsma, Berendsen and Van De Rest2019). These studies often focused on single nutrients or foods, did not adjust for all known risk factors and did not take APOE genotype into account (Cao et al., Reference Cao, Tan, Wang, Jiang, Zhu, Lu, Tan and Yu2016; Van Den Brink et al., Reference Van Den Brink, Brouwer-Brolsma, Berendsen and Van De Rest2019; Barbaresko et al., Reference Barbaresko, Lellmann, Schmidt, Lehmann, Amini, Egert, Schlesinger and Nöthlings2020; Limongi et al., Reference Limongi, Siviero, Bozanic, Noale, Veronese and Maggi2020; Zhang et al., Reference Zhang, Greenwood, Risch, Bunce, Hardie and Cade2021). Evidence of an association with all-cause dementia has been inconsistent (Wu and Sun, Reference Wu and Sun2017; Akbaraly et al., Reference Akbaraly, Singh-Manoux, Dugravot, Brunner, Kivimäki and Sabia2019; Van Den Brink et al., Reference Van Den Brink, Brouwer-Brolsma, Berendsen and Van De Rest2019; McKenzie et al., Reference McKenzie, Harris, Peters, Webster and Woodward2021), and findings on vascular dementia are sparse (Perez et al., Reference Perez, Heim, Sherzai, Jaceldo-Siegl and Sherzai2012). Randomised controlled trials including dietary interventions show results in favour of a healthy diet with higher cognition, however, with no measures on hard endpoints such as Alzheimer's disease or vascular dementia (Martínez-Lapiscina et al., Reference Martínez-Lapiscina, Clavero, Toledo, Estruch, Salas-Salvadó, San Julián, Sanchez-Tainta, Ros, Valls-Pedret and Martinez-Gonzalez2013; Valls-Pedret et al., Reference Valls-Pedret, Sala-Vila, Serra-Mir, Corella, De La Torre, Martínez-González, Martínez-Lapiscina, Fitó, Pérez-Heras, Salas-Salvadó, Estruch and Ros2015). Non-Alzheimer's dementia is a dementia subtype associated with cardiovascular risk factors; the present findings on low adherence to dietary guidelines and non-Alzheimer's dementia firmly support that diet may play an important role in vascular health including cerebrovascular health and dementia with vascular pathology. The World Health Organization states that a ‘healthy and balanced diet should be recommended to all adults’, as it has the potential to prevent cognitive decline both directly and through other potential risk factors or diseases (WHO Guidelines, 2019).

During the past few years dietary research has changed from focusing on the role of single nutrients or food items to the role of dietary patterns like the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) or the Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diet (Pistollato et al., Reference Pistollato, Iglesias, Ruiz, Aparicio, Crespo, Lopez, Manna, Giampieri and Battino2018). Previous studies have frequently investigated these specific diets and their associations with dementia, which are all characterised by a high intake of vegetables, fruits and unsaturated fats with modest amounts of alcohol and animal foods. In general, observational studies have found that these diets are associated with lower risk of Alzheimer's disease and less cognitive decline (Van Den Brink et al., Reference Van Den Brink, Brouwer-Brolsma, Berendsen and Van De Rest2019). The current study did not use one of these established methods to characterise dietary patterns, however, the dietary assessment focused on very similar aspects with only minor discrepancies.

Dietary risk is one of the leading causes of attributable deaths in the Global Burden of Disease 2019 report, and diet quality is the fifth leading risk factor for disability mainly due to cardiovascular disease, diabetes, kidney diseases and neoplasms (Abbafati et al., Reference Abbafati, Abbas, Abbasi-Kangevari, Abd-Allah, Abdelalim, Abdollahi, Abdollahpour, Abegaz, Abolhassani, Aboyans, Abreu, Abrigo, Abualhasan, Abu-Raddad, Abushouk, Adabi, Adekanmbi, Adeoye, Adetokunboh, Adham, Advani, Afshin, Agarwal, Aghamir, Agrawal, Ahmad, Ahmadi, Ahmadi, Ahmadieh, Ahmed, Akalu, Akinyemi, Akinyemiju, Akombi, Akunna, Alahdab, Al-Aly, Alam, Alam, Alam, Alanezi, Alanzi, Alemu, Alhabib, Ali, Ali, Alicandro, Alinia, Alipour, Alizade, Aljunid, Alla, Allebeck, Almasi-Hashiani, Al-Mekhlafi, Alonso, Altirkawi, Amini-Rarani, Amiri, Amugsi, Ancuceanu, Anderlini, Anderson, Andrei, Andrei, Angus, Anjomshoa, Ansari, Ansari-Moghaddam, Antonazzo, Antonio, Antony, Antriyandarti, Anvari, Anwer, Appiah, Arabloo, Arab-Zozani, Aravkin, Ariani, Armoon, Ärnlöv, Arzani, Asadi-Aliabadi, Asadi-Pooya, Ashbaugh, Assmus, Atafar, Atnafu, Atout, Ausloos, Ausloos, Ayala Quintanilla, Ayano, Ayanore, Azari, Azarian, Azene, Badawi, Badiye, Bahrami, Bakhshaei, Bakhtiari, Bakkannavar, Baldasseroni, Ball, Ballew, Balzi, Banach, Banerjee, Bante, Baraki, Barker-Collo, Bärnighausen, Barrero, Barthelemy, Barua, Basu, Baune, Bayati, Becker, Bedi, Beghi, Béjot, Bell, Bennitt, Bensenor, Berhe, Berman, Bhagavathula, Bhageerathy, Bhala, Bhandari, Bhattacharyya, Bhutta, Bijani, Bikbov, Bin Sayeed, Biondi, Birihane, Bisignano, Biswas, Bitew, Bohlouli, Bohluli, Boon-Dooley, Borges, Borzì, Borzouei, Bosetti, Boufous, Braithwaite, Brauer, Breitborde, Breitner, Brenner, Briant, Briko, Briko, Britton, Bryazka, Bumgarner, Burkart, Burnett, Burugina Nagaraja, Butt, Caetano Dos Santos, Cahill, Cámera, Campos-Nonato, Cárdenas, Carreras, Carrero, Carvalho, Castaldelli-Maia, Castañeda-Orjuela, Castelpietra, Castro, Causey, Cederroth, Cercy, Cerin, Chandan, Chang, Charlson, Chattu, Chaturvedi, Cherbuin, Chimed-Ochir, Cho, Choi, Christensen, Chu, Chung, Chung, Cicuttini, Ciobanu, Cirillo, Classen, Cohen, Compton, Cooper, Costa, Cousin, Cowden, Cross, Cruz, Dahlawi, Damasceno, Damiani, Dandona, Dandona, Dangel, Danielsson, Dargan, Darwesh, Daryani, Das, Das Gupta Rajat, das Neves, Dávila-Cervantes, Davitoiu, De Leo, Degenhardt, DeLang, Dellavalle, Demeke, Demoz, Demsie, Denova-Gutiérrez, Dervenis, Dhungana, Dianatinasab, Dias da Silva, Diaz, Dibaji Forooshani, Djalalinia, Do, Dokova, Dorostkar, Doshmangir, Driscoll, Duncan, Duraes, Eagan, Edvardsson, El Nahas, El Sayed, El Tantawi, Elbarazi, Elgendy, El-Jaafary, Elyazar, Emmons-Bell, Erskine, Eskandarieh, Esmaeilnejad, Esteghamati, Estep, Etemadi, Etisso, Fanzo, Farahmand, Fareed, Faridnia, Farioli, Faro, Faruque, Farzadfar, Fattahi, Fazlzadeh, Feigin, Feldman, Fereshtehnejad, Fernandes, Ferrara, Ferrari, Ferreira, Filip, Fischer, Fisher, Flor, Foigt, Folayan, Fomenkov, Force, Foroutan, Franklin, Freitas, Fu, Fukumoto, Furtado, Gad, Gakidou, Gallus, Garcia-Basteiro, Gardner, Geberemariyam, Ayalew Gebreslassie, Geremew, Gershberg Hayoon, Gething, Ghadimi, Ghadiri, Ghaffarifar, Ghafourifard, Ghamari, Ghashghaee, Ghiasvand, Ghith, Gholamian, Ghosh, Gill, Ginindza, Giussani, Gnedovskaya E, Goharinezhad, Gopalani, Gorini, Goudarzi, Goulart, Greaves, Grivna, Grosso, Gubari, Gugnani, Guimarães, Guled, Guo, Guo, Gupta Rajeev, Gupta, Haddock, Hafezi-Nejad, Hafiz, Haj-Mirzaian Arvin, Haj-Mirzaian Arya, Hall, Halvaei, Hamadeh, Hamidi, Hammer, Hankey, Haririan, Haro, Hasaballah, Hasan, Hasanpoor, Hashi, Hassanipour, Hassankhani, Havmoeller, Hay, Hayat, Heidari, Heidari-Soureshjani, Henrikson, Herbert, Herteliu, Heydarpour, Hird, Hoek, Holla, Hoogar, Hosgood, Hossain, Hosseini, Hosseinzadeh, Hostiuc, Hostiuc, Househ, Hsairi, Hsieh, Hu, Hu, Huda, Humayun, Huynh, Hwang, Iannucci, Ibitoye, Ikeda, Ikuta, Ilesanmi, Ilic, Ilic, Inbaraj, Ippolito, Iqbal, Irvani, Irvine, Islam, Islam, Iso, Ivers, Iwu, Iwu, Iyamu, Jaafari, Jacobsen, Jafari, Jafarinia, Jahani, Jakovljevic, Jalilian, James, Janjani, Javaheri, Javidnia, Jeemon, Jenabi, Jha, Jha, Ji, Johansson, John, John-Akinola, Johnson, Jonas, Joukar, Jozwiak, Jürisson, Kabir, Kabir, Kalani, Kalani, Kalankesh, Kalhor, Kanchan, Kapoor, Matin, Karch, Karim, Kassa, Katikireddi, Kayode, Kazemi Karyani, Keiyoro, Keller, Kemmer, Kendrick, Khalid, Khammarnia, Khan, Khan, Khatab, Khater, Khatib, Khayamzadeh, Khazaei, Kieling, Kim, Kimokoti, Kisa, Kisa, Kivimäki, Knibbs, Knudsen, Kocarnik, Kochhar, Kopec, Korshunov, Koul, Koyanagi, Kraemer, Krishan, Krohn, Kromhout, Kuate Defo, Kumar, Kumar, Kurmi, Kusuma, La Vecchia, Lacey, Lal, Lalloo, Lallukka, Lami, Landires, Lang, Langan, Larsson, Lasrado, Lauriola, Lazarus, Lee, Lee, Legrand, Leigh, Leonardi, Lescinsky, Leung, Levi, Li, Lim, Linn, Shiwei, Simin, Liu, Lo, Lopez, Lopez, Lopukhov, Lorkowski, Lotufo, Lu, Lugo, Maddison, Mahasha, Mahdavi, Mahmoudi, Majeed, Maleki, Maleki, Malekzadeh, Malta, Mamun, Manda, Manguerra, Mansour-Ghanaei, Mansouri, Mansournia, Mantilla Herrera, Maravilla, Marks, Martin, Martini, Martins-Melo, Masaka, Masoumi, Mathur, Matsushita, Maulik, McAlinden, McGrath, McKee, Mehndiratta, Mehri, Mehta, Memish, Mendoza, Menezes, Mengesha, Mereke, Mereta, Meretoja, Meretoja, Mestrovic, Miazgowski, Miazgowski, Michalek, Miller, Mills, Mini, Miri, Mirica, Mirrakhimov, Mirzaei, Mirzaei, Mirzaei, Mirzaei-Alavijeh, Misganaw, Mithra, Moazen, Mohammad, Mohammad, Mohammad Gholi Mezerji, Mohammadian-Hafshejani, Mohammadifard, Mohammadpourhodki, Mohammed, Mohammed, Mohammed, Mohammed, Mokdad, Molokhia, Monasta, Mooney, Moradi, Moradi, Moradi-Lakeh, Moradzadeh, Moraga, Morawska, Morgado-Da-Costa, Morrison, Mosapour, Mosser, Mouodi, Mousavi, Khaneghah, Mueller, Mukhopadhyay, Mullany, Musa, Muthupandian, Nabhan, Naderi, Nagarajan, Nagel, Naghavi, Naghshtabrizi, Naimzada, Najafi, Nangia, Nansseu, Naserbakht, Nayak, Negoi, Ngunjiri, Nguyen, Nguyen, Nguyen, Nigatu, Nikbakhsh, Nixon, Nnaji, Nomura, Norrving, Noubiap, Nowak, Nunez-Samudio, Oancea, Odell, Ogbo, Oh, Okunga, Oladnabi, Olagunju, Olusanya, Olusanya, Omer, Ong, Onwujekwe, Orpana, Ortiz, Osarenotor, Osei, Ostroff, Otoiu, Otstavnov, Otstavnov, Øverland, Owolabi, Mahesh, Padubidri, Palladino, Panda-Jonas, Pandey, Parry, Pasovic, Pasupula, Patel, Pathak, Patten, Patton, Toroudi, Peden, Pennini, Pepito, Peprah, Pereira, Pesudovs, Pham, Phillips, Piccinelli, Pilz, Piradov, Pirsaheb, Plass, Polinder, Polkinghorne, Pond, Postma, Pourjafar, Pourmalek, Poznañska, Prada, Prakash, Pribadi, Pupillo, Syed, Rabiee, Rabiee, Radfar, Rafiee, Raggi, Rahman, Rajabpour-Sanati, Rajati, Rakovac, Ram, Ramezanzadeh, Ranabhat, Rao, Rao, Rashedi, Rathi, Rawaf, Rawaf, Rawal, Rawassizadeh, Rawat, Razo, Redford, Reiner, Reitsma, Remuzzi, Renjith, Renzaho, Resnikoff, Rezaei Negar, Rezaei Nima, Rezapour, Rhinehart, Riahi, Ribeiro, Ribeiro, Rickard, Rivera, Roberts, Rodríguez-Ramírez, Roever, Ronfani, Room, Roshandel, Roth, Rothenbacher, Rubagotti, Rwegerera, Sabour, Sachdev, Saddik, Sadeghi, Sadeghi, Saeedi, Saeedi Moghaddam, Safari, Safi, Safiri, Sagar, Sahebkar, Sajadi, Salam, Salamati, Salem, Salem, Salimzadeh, Salman, Salomon, Samad, Samadi Kafil, Sambala, Samy, Sanabria, Sánchez-Pimienta, Santomauro, Santos, Santos, Santric-Milicevic, Saraswathy, Sarmiento-Suárez, Sarrafzadegan, Sartorius, Sarveazad, Sathian, Sathish, Sattin, Saxena, Schaeffer, Schiavolin, Schlaich, Schmidt, Schutte, Schwebel, Schwendicke, Senbeta, Senthilkumaran, Sepanlou, Serdar, Serre, Shadid, Shafaat, Shahabi, Shaheen, Shaikh, Shalash, Shams-Beyranvand, Shamsizadeh, Sharafi, Sheikh, Sheikhtaheri, Shibuya, Shield, Shigematsu, Shin, Shin, Shiri, Shirkoohi, Shuval, Siabani, Sierpinski, Sigfusdottir, Sigurvinsdottir, Silva, Simpson, Singh, Singh, Skiadaresi, Skou, Skryabin, Smith, Soheili, Soltani, Soofi, Sorensen, Soriano, Sorrie, Soshnikov, Soyiri, Spencer, Spotin, Sreeramareddy, Srinivasan, Stanaway, Stein, Stein, Steiner, Stockfelt, Stokes, Straif, Stubbs, Sufiyan, Suleria, Suliankatchi Abdulkader, Sulo, Sultan, Tabarés-Seisdedos, Tabb, Tabuchi, Taherkhani, Tajdini, Takahashi, Takala, Tamiru, Taveira, Tehrani-Banihashemi, Temsah, Tesema, Tessema, Thurston, Titova, Tohidinik, Tonelli, Topor-Madry, Topouzis, Torre, Touvier, Tovani-Palone, Tran, Travillian, Tsatsakis, Tudor Car, Tyrovolas, Uddin, Umeokonkwo, Unnikrishnan, Upadhyay, Vacante, Valdez, van Donkelaar, Vasankari, Vasseghian, Veisani, Venketasubramanian, Violante, Vlassov, Vollset, Vos, Vukovic, Waheed, Wallin, Wang, Wang, Watson, Wei, Wei, Weintraub, Weiss, Werdecker, West, Westerman, Whisnant, Whiteford, Wiens, Wolfe, Wozniak, Wu, Wu, Wulf Hanson, Xu, Xu, Yadgir, Yahyazadeh Jabbari, Yamagishi, Yaminfirooz, Yano, Yaya, Yazdi-Feyzabadi, Yeheyis, Yilgwan, Yilma, Yip, Yonemoto, Younis, Younker, Yousefi, Yousefi, Yousefinezhadi, Yousuf, Yu, Yusefzadeh, Moghadam, Zamani, Zamanian, Zandian, Zastrozhin, Zhang, Zhang, Zhao, Zhao, Zhao, Zheng, Zhou, Ziapour, Zimsen, Lim and Murray2020). In addition, our study suggests an increased risk of non-Alzheimer's dementia by non-adherence to dietary guidelines. Interestingly, a study published in 2020 found that current diets in most countries worldwide are too unhealthy and that national dietary guidelines should be reformed and better implemented (Springmann et al., Reference Springmann, Spajic, Clark, Poore, Herforth, Webb, Rayner and Scarborough2020). The study showed that dietary changes as those recommended by dietary guidelines could be associated with substantially reduced premature mortality (Springmann et al., Reference Springmann, Spajic, Clark, Poore, Herforth, Webb, Rayner and Scarborough2020). This would be by following the Mediterranean diet, the DASH, the MIND diet or more specifically by increasing consumption of healthy foods such as fruits, vegetables and legumes; reducing consumption of unhealthy foods, such as sugar, unrefined grains, salt, highly processed foods and red meat and choosing unsaturated fats rather than saturated fats (Willett et al., Reference Willett, Rockström, Loken, Springmann, Lang, Vermeulen, Garnett, Tilman, DeClerck, Wood, Jonell, Clark, Gordon, Fanzo, Hawkes, Zurayk, Rivera, De Vries, Majele Sibanda, Afshin, Chaudhary, Herrero, Agustina, Branca, Lartey, Fan, Crona, Fox, Bignet, Troell, Lindahl, Singh, Cornell, Srinath Reddy, Narain, Nishtar and Murray2019). There are numerous ways of implementing food-based dietary guidelines e.g. by updating policies to incentivise better adherence to dietary guidelines for instance by investment in health promotion campaigns and programmes, regulation of agricultural strategies, changes in consumer behaviour, educating families on healthy diets and taxation of unhealthy food items (Sassi et al., Reference Sassi, Belloni, Mirelman, Suhrcke, Thomas, Salti, Vellakkal, Visaruthvong, Popkin and Nugent2018; Willett et al., Reference Willett, Rockström, Loken, Springmann, Lang, Vermeulen, Garnett, Tilman, DeClerck, Wood, Jonell, Clark, Gordon, Fanzo, Hawkes, Zurayk, Rivera, De Vries, Majele Sibanda, Afshin, Chaudhary, Herrero, Agustina, Branca, Lartey, Fan, Crona, Fox, Bignet, Troell, Lindahl, Singh, Cornell, Srinath Reddy, Narain, Nishtar and Murray2019; Springmann et al., Reference Springmann, Spajic, Clark, Poore, Herforth, Webb, Rayner and Scarborough2020). Furthermore, as this study shows a clear clustering of unfavourable cardiovascular risk factors in individuals with low adherence to dietary guidelines the potential to target health strategies towards specific subpopulations is evident. Moreover, updating national food-based dietary guidelines could be beneficial for meeting global sustainability goals (Springmann et al., Reference Springmann, Spajic, Clark, Poore, Herforth, Webb, Rayner and Scarborough2020) in line with the EAT Lancet Commission and the United Nations Sustainable Development Goals 2030 Agenda (United Nations; Willett et al., Reference Willett, Rockström, Loken, Springmann, Lang, Vermeulen, Garnett, Tilman, DeClerck, Wood, Jonell, Clark, Gordon, Fanzo, Hawkes, Zurayk, Rivera, De Vries, Majele Sibanda, Afshin, Chaudhary, Herrero, Agustina, Branca, Lartey, Fan, Crona, Fox, Bignet, Troell, Lindahl, Singh, Cornell, Srinath Reddy, Narain, Nishtar and Murray2019). Adopting a sustainable diet rich in plant-based foods, low in animal source foods and highly processed foods would not only benefit human health but also the environment (Willett et al., Reference Willett, Rockström, Loken, Springmann, Lang, Vermeulen, Garnett, Tilman, DeClerck, Wood, Jonell, Clark, Gordon, Fanzo, Hawkes, Zurayk, Rivera, De Vries, Majele Sibanda, Afshin, Chaudhary, Herrero, Agustina, Branca, Lartey, Fan, Crona, Fox, Bignet, Troell, Lindahl, Singh, Cornell, Srinath Reddy, Narain, Nishtar and Murray2019). A huge potential for prevention exists, unfortunately, it is not currently met. More attention towards effective dietary strategies to reduce disease and mortality risk is imperative.

A plausible mechanism for our findings could be that non-Alzheimer's dementia and atherosclerotic cardiovascular disease share pathogenesis through atherosclerosis. In this study, individuals with low adherence to dietary guidelines were characterised by an atherogenic lipid profile with high levels of LDL cholesterol, non-HDL cholesterol and plasma triglycerides as a marker of triglyceride-rich lipoproteins, all causally related to atherosclerotic cardiovascular disease (Nordestgaard and Varbo, Reference Nordestgaard and Varbo2014; Ference et al., Reference Ference, Ginsberg, Graham, Ray, Packard, Bruckert, Hegele, Krauss, Raal, Schunkert, Watt, Borén, Fazio, Horton, Masana, Nicholls, Nordestgaard, Van De Sluis, Taskinen, Tokgözoǧlu, Landmesser, Laufs, Wiklund, Stock, Chapman and Catapano2017; Mach et al., Reference Mach, Baigent, Catapano, Koskinas, Casula, Badimon, Chapman, De Backer, Delgado, Ference, Graham, Halliday, Landmesser, Mihaylova, Pedersen, Riccardi, Richter, Sabatine, Taskinen, Tokgozoglu, Wiklund, Mueller, Drexel, Aboyans, Corsini, Doehner, Farnier, Gigante, Kayikcioglu, Krstacic, Lambrinou, Lewis, Masip, Moulin, Petersen, Petronio, Piepoli, Pinto, Raber, Ray, Reiner, Riesen, Roffi, Schmid, Shlyakhto, Simpson, Stroes, Sudano, Tselepis, Viigimaa, Vindis, Vonbank, Vrablik, Vrsalovic, Gomez, Collet, Windecker, Dean, Fitzsimons, Gale, Grobbee, Halvorsen, Hindricks, Iung, Jüni, Katus, Leclercq, Lettino, Merkely, Sousa-Uva, Touyz, Nibouche, Zelveian, Siostrzonek, Najafov, Van De Borne, Pojskic, Postadzhiyan, Kypris, Spinar, Larsen, Eldin, Strandberg, Ferrières, Agladze, Laufs, Rallidis, Bajnok, Gudjonsson, Maher, Henkin, Gulizia, Mussagaliyeva, Bajraktari, Kerimkulova, Latkovskis, Hamoui, Slapikas, Visser, Dingli, Ivanov, Boskovic, Nazzi, Visseren, Mitevska, Retterstøl, Jankowski, Fontes-Carvalho, Gaita, Ezhov, Foscoli, Giga, Pella, Fras, De Isla, Hagström, Lehmann, Abid, Ozdogan, Mitchenko and Patel2020). This lipid profile is most probably caused by primarily using saturated fat, eating more fast food, eating more sweets and fewer fruits and vegetables. Consistent evidence from genetic studies, prospective cohort studies, Mendelian randomisation studies and randomised controlled trials demonstrate that LDL causes atherosclerotic cardiovascular disease (Ference et al., Reference Ference, Ginsberg, Graham, Ray, Packard, Bruckert, Hegele, Krauss, Raal, Schunkert, Watt, Borén, Fazio, Horton, Masana, Nicholls, Nordestgaard, Van De Sluis, Taskinen, Tokgözoǧlu, Landmesser, Laufs, Wiklund, Stock, Chapman and Catapano2017). LDL is the most abundant atherogenic lipoprotein in plasma and a key deliverer of cholesterol to the arterial wall (Borén et al., Reference Borén, John Chapman, Krauss, Packard, Bentzon, Binder, Daemen, Demer, Hegele, Nicholls, Nordestgaard, Watts, Bruckert, Fazio, Ference, Graham, Horton, Landmesser, Laufs, Masana, Pasterkamp, Raal, Ray, Schunkert, Taskinen, van de Sluis, Wiklund, Tokgozoglu, Catapano and Ginsberg2020). The likelihood of LDLs being kept inside the arterial intima leading to the establishment of atherosclerotic plaques advances when concentrations of circulating LDL particles increase (Skålén et al., Reference Skålén, Gustafsson, Knutsen Rydberg, Hultén, Wiklund, Innerarity and Boren2002). Retention and subsequent modification of the LDL particle can elicit inflammatory processes and oxidative changes which influence the rate of plaque growth and the tendency to plaque disruption (Borén et al., Reference Borén, John Chapman, Krauss, Packard, Bentzon, Binder, Daemen, Demer, Hegele, Nicholls, Nordestgaard, Watts, Bruckert, Fazio, Ference, Graham, Horton, Landmesser, Laufs, Masana, Pasterkamp, Raal, Ray, Schunkert, Taskinen, van de Sluis, Wiklund, Tokgozoglu, Catapano and Ginsberg2020). Furthermore, due to their cholesterol content, triglyceride-rich lipoproteins are causally associated with atherosclerotic cardiovascular disease, as shown repeatedly in observational and genetic studies (Nordestgaard and Varbo, Reference Nordestgaard and Varbo2014; Hegele et al., Reference Hegele, Borén, Ginsberg, Arca, Averna, Binder, Calabresi, Chapman, Cuchel, von Eckardstein, Frikke-Schmidt, Gaudet, Hovingh, Kronenberg, Lütjohann, Parhofer, Raal, Ray, Remaley, Stock, Stroes, Tokgözoğlu, Catapano, von Eckardstein and Rohrer2020). When triglyceride concentrations are mild to moderately elevated (2–10 mmol/L), triglyceride-rich lipoproteins are sufficiently small to go through the arterial wall and therefore prone to preferential entrapment, and consequently accumulation causing atherosclerosis (Nordestgaard and Varbo, Reference Nordestgaard and Varbo2014). Our findings are supported by a recent report showing an association between moderate hypertriglyceridaemia and increased risk of non-Alzheimer's dementia in the general population (Nordestgaard et al., Reference Nordestgaard, Christoffersen, Afzal, Nordestgaard, Tybjærg-Hansen and Frikke-Schmidt2021). Importantly, in the present study we also show that the increasingly higher risk of non-Alzheimer's dementia with non-adherence to dietary guidelines was not observed in individuals on lipid-lowering therapy, indirectly suggesting that statins potentially may be used to prevent non-Alzheimer's dementia. Due to the observational nature of our study, these findings need to be tested in a randomised controlled trial before any conclusion on treatment benefits can be drawn. Other possible mechanisms for the present findings include the hypothesised effects of oxidative stress and neuroinflammation on risk of dementia (Kinney et al., Reference Kinney, Bemiller, Murtishaw, Leisgang, Salazar and Lamb2018; Luo et al., Reference Luo, Mills, le Cessie, Noordam and van Heemst2020). Several risk factors including cardiovascular factors and metabolic diseases such as diabetes, often caused by unhealthy diets, are correlated with an immune response, also in the brain (Kinney et al., Reference Kinney, Bemiller, Murtishaw, Leisgang, Salazar and Lamb2018). Systemic inflammation can lead to damage of the blood–brain barrier (BBB) which allows entry of immune cells into the brain. Moreover, impaired integrity of the BBB and thus increased BBB permeability can lead to excessive activation of microglial cells, which as a result release proinflammatory and reactive oxygen species.

Limitations of our study include the assessment of diet which was self-reported. Diets often change over time secondary to medications, influences from surroundings or diagnosis of a medical condition. However, when we analysed a subset of individuals who both participated at baseline and at follow-up examinations and fulfilled the FFQ at both visits, we found that the majority of individuals remained in the same group of adherence to dietary guidelines. Only a small fraction (<1%) changed dietary adherence group from either high to low or low to high. This indicates that our dietary instrument is a valid exposure over time. The FFQ did not take all national dietary advice into account, as for instance intake of dietary fibre or portion sizes, which therefore prevents us from investigating the impacts of macronutrients or adjusting for energy intake. However, the included questions have previously shown to be a sufficient proxy for an individual's dietary habits (Ewers et al., Reference Ewers, Marott, Schnohr, Nordestgaard and Marckmann2021). Furthermore, a previous Danish study compared an extensive FFQ of 198 items with a short FFQ, like the one in this study (Toft et al., Reference Toft, Kristoffersen, Lau, Borch-Johnsen and Jørgensen2007). They found that the short FFQ reflected dietary quality adequately and could be used as a tool to classify dietary patterns. Whether a change in adherence to dietary guidelines either to the better or worse was associated with Alzheimer's disease or non-Alzheimer's dementia could not be determined due to a limited number of cases in the subset. This important issue warrants further investigation in future prospective studies with repeated assessment of diet during follow-up. Non-response bias cannot be excluded, as individuals who did not respond to the FFQ, and thus excluded from this study, were less healthy and had lower socioeconomic status than those who did respond. This could limit the generalisability of the study. Study participants were white and from an ethnically homogenous population, which may also limit the generalisability of our findings. However, since the Danish national dietary guidelines are similar to guidelines of other countries, we would expect that our findings apply to other populations (Wilson et al., Reference Wilson, Polonsky, Miedema, Khera, Kosinski and Kuvin2019; Mach et al., Reference Mach, Baigent, Catapano, Koskinas, Casula, Badimon, Chapman, De Backer, Delgado, Ference, Graham, Halliday, Landmesser, Mihaylova, Pedersen, Riccardi, Richter, Sabatine, Taskinen, Tokgozoglu, Wiklund, Mueller, Drexel, Aboyans, Corsini, Doehner, Farnier, Gigante, Kayikcioglu, Krstacic, Lambrinou, Lewis, Masip, Moulin, Petersen, Petronio, Piepoli, Pinto, Raber, Ray, Reiner, Riesen, Roffi, Schmid, Shlyakhto, Simpson, Stroes, Sudano, Tselepis, Viigimaa, Vindis, Vonbank, Vrablik, Vrsalovic, Gomez, Collet, Windecker, Dean, Fitzsimons, Gale, Grobbee, Halvorsen, Hindricks, Iung, Jüni, Katus, Leclercq, Lettino, Merkely, Sousa-Uva, Touyz, Nibouche, Zelveian, Siostrzonek, Najafov, Van De Borne, Pojskic, Postadzhiyan, Kypris, Spinar, Larsen, Eldin, Strandberg, Ferrières, Agladze, Laufs, Rallidis, Bajnok, Gudjonsson, Maher, Henkin, Gulizia, Mussagaliyeva, Bajraktari, Kerimkulova, Latkovskis, Hamoui, Slapikas, Visser, Dingli, Ivanov, Boskovic, Nazzi, Visseren, Mitevska, Retterstøl, Jankowski, Fontes-Carvalho, Gaita, Ezhov, Foscoli, Giga, Pella, Fras, De Isla, Hagström, Lehmann, Abid, Ozdogan, Mitchenko and Patel2020). Finally, our findings for those treated with lipid-lowering therapy need to be confirmed in independent studies, preferably in randomised controlled trials. Strengths of the present study are addressed in the online Supplementary materials.

Low adherence to national dietary guidelines is associated with an atherogenic lipid profile and with an increased risk of non-Alzheimer's dementia – the subtype of dementia with a high frequency of vascular risk factors. The present study suggests that implementation of national dietary guidelines associated with an anti-atherogenic lipid profile could be of importance for prevention of non-Alzheimer's dementia and for improved cognitive health in the general population.