Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A (2001) Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population-based study. BMJ 322:1447–1451. https://doi.org/10.1136/bmj.322.7300.1447

Article  CAS  PubMed  PubMed Central  Google Scholar 

Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA (2009) Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord 28:75–80. https://doi.org/10.1159/000231980

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tyrovolas S, Lionis C, Zeimbekis A, Bountziouka V, Micheli M, Katsarou A, Papairakleous N, Metallinos G, Makri K, Polychronopoulos E, Panagiotakos DB (2009) Increased body mass and depressive symptomatology are associated with hypercholesterolemia among elderly individuals: results from the MEDIS study. Lipids Health Dis 8:10. https://doi.org/10.1186/1476-511X-8-10

Article  PubMed  PubMed Central  Google Scholar 

Strekalova T, Evans M, Costa-Nunes J, Bachurin S, Yeritsyan N, Couch Y, Steinbusch HMW, Köhler SE, Lesch KP, Anthony DC (2015) Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet. Brain Behav Immun 48:42–47. https://doi.org/10.1016/j.bbi.2015.02.015

Article  CAS  PubMed  Google Scholar 

Anstey KJ, Ashby-Mitchell K, Peters R (2017) Updating the evidence on the association between serum cholesterol and risk of late-life dementia: review and meta-analysis. J Alzheimers Dis 56:215–228. https://doi.org/10.3233/JAD-160826

Article  PubMed  PubMed Central  Google Scholar 

Livingston G, Huntley J, Liu KY, Costafreda SG, Selbæk G, Alladi S, Ames D, Banerjee S, Burns A, Brayne C, Fox NC, Ferri CP, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Nakasujja N, Rockwood K, Samus Q, Shirai K, Singh-Manoux A, Schneider LS, Walsh S, Yao Y, Sommerlad A, Mukadam N (2024) Dementia prevention, intervention, and care: 2024 report of the lancet standing commission. Lancet 404:572–628. https://doi.org/10.1016/S0140-6736(24)01296-0

Article  PubMed  Google Scholar 

Ariza M, Cuenca N, Mauri M, Jurado MA, Garolera M (2016) Neuropsychological performance of young Familial hypercholesterolemia patients. Eur J Intern Med 34:e29–e31. https://doi.org/10.1016/j.ejim.2016.05.009

Article  PubMed  Google Scholar 

Zambón D, Quintana M, Mata P, Alonso R, Benavent J, Cruz-Sánchez F, Gich J, Pocoví M, Civeira F, Capurro S, Bachman D, Sambamurti K, Nicholas J, Pappolla MA (2010) Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med 123:267–274. https://doi.org/10.1016/j.amjmed.2009.08.015

Article  PubMed  PubMed Central  Google Scholar 

Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ (1990) Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 264:3007–3012. https://doi.org/10.1001/jama.1990.03450230043027

Article  CAS  PubMed  Google Scholar 

Mytilinaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS (2018) Familial hypercholesterolemia: new horizons for diagnosis and effective management. Front Pharmacol 9:707. https://doi.org/10.3389/fphar.2018.00707

Article  CAS  PubMed  PubMed Central  Google Scholar 

Engel DF, de Oliveira J, Lopes JB, Santos DB, Moreira ELG, Farina M, Rodrigues ALS, de Souza Brocardo P, de Bem AF (2016) Is there an association between hypercholesterolemia and depression? Behavioral evidence from the LDLr<Superscript>−/−</Superscript> mouse experimental model. Behav Brain Res 311:31–38. https://doi.org/10.1016/j.bbr.2016.05.029

Article  CAS  PubMed  Google Scholar 

de Oliveira J, Engel DF, De Paula GC, Dos Santos DB, Lopes JB, Farina M, Moreira ELG, de Bem AF (2020) High cholesterol diet exacerbates blood-brain barrier disruption in LDLr<Superscript>−/−</Superscript> mice: impact on cognitive function. J Alzheimers Dis 78:97–115. https://doi.org/10.3233/JAD-200541

Article  CAS  PubMed  PubMed Central  Google Scholar 

de Oliveira J, Moreira ELG, de Bem AF (2024) Beyond cardiovascular risk: implications of familial hypercholesterolemia on cognition and brain function. Ageing Res Rev 93:102149. https://doi.org/10.1016/j.arr.2023.102149

Article  CAS  PubMed  Google Scholar 

de Oliveira J, Moreira ELG, Dos Santos DB, Piermartiri TC, Dutra RC, Pinton S, Tasca CI, Farina M, Prediger RDS, de Bem AF (2014) Increased susceptibility to amyloid-β-induced neurotoxicity in mice lacking the low-density lipoprotein receptor. J Alzheimers Dis 41:43–60. https://doi.org/10.3233/JAD-132228

Article  CAS  PubMed  Google Scholar 

Rodrigues MS, do Nascimento NB, Farias HR, Schons T, Machado AG, Behenck E, Mesquita A, Krolow Bast R, Budni J, Engblom D, de Bem AF, de Oliveira J (2024) Microglia contribute to cognitive decline in hypercholesterolemic LDLr<Superscript>−/−</Superscript> mice. J Neurochem 168:1565–1586. https://doi.org/10.1111/jnc.15952

Article  CAS  PubMed  Google Scholar 

Jahrling JB, Lin AL, DeRosa N, Hussong SA, Van Skike CE, Girotti M, Javors M, Zhao Q, Maslin LA, Asmis R, Galvan V (2018) mTOR drives cerebral blood flow and memory deficits in LDLR<Superscript>−/−</Superscript> mice modeling atherosclerosis and vascular cognitive impairment. J Cereb Blood Flow Metab 38:58–74. https://doi.org/10.1177/0271678X17705973

Article  CAS  PubMed  Google Scholar 

Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226. https://doi.org/10.1016/j.molcel.2008.03.003

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ning J, Clemmons DR (2010) AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol Endocrinol 24:1218–1230. https://doi.org/10.1210/me.2009-0474

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hindupur SK, González A, Hall MN (2015) The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol 7:a019141. https://doi.org/10.1101/cshperspect.a019141

Article  PubMed  PubMed Central  Google Scholar 

Amin S, Lux A, O’Callaghan F (2019) The journey of Metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth. Br J Clin Pharmacol 85:37–46. https://doi.org/10.1111/bcp.13852

Article  CAS  PubMed  Google Scholar 

Du RW, Bu WG (2020) Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-κB–NLRP3 inflammation activation. Exp Brain Res 238:2549–2556. https://doi.org/10.1007/s00221-020-05911-x

Article  CAS  PubMed  Google Scholar 

Rabieipoor S, Zare M, Ettcheto M, Camins A, Javan M (2023) Metformin restores cognitive dysfunction and histopathological deficits in an animal model of sporadic Alzheimer’s disease. Heliyon 9:e17873. https://doi.org/10.1016/j.heliyon.2023.e17873

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kodali M, Attaluri S, Madhu LN, Shuai B, Upadhya R, Gonzalez JJ, Rao X, Shetty AK (2021) Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus. Aging Cell 20:e13277. https://doi.org/10.1111/acel.13277

Article  CAS  PubMed  PubMed Central  Google Scholar 

Seneviratne A, Cave L, Hyde G, Moestrup SK, Carling D, Mason JC, Haskard DO, Boyle JJ (2020) Metformin directly suppresses atherosclerosis in normoglycaemic mice via Haematopoietic AMP-activated protein kinase. Cardiovasc Res 117:1295. https://doi.org/10.1093/cvr/cvaa171

Article  CAS  PubMed Central  Google Scholar 

Farr SA, Roesler E, Niehoff ML, Roby DA, McKee A, Morley JE (2019) Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer’s disease. J Alzheimers Dis 68:1699–1710. https://doi.org/10.3233/JAD-181240

Article  CAS  PubMed