The number of people living with dementia and Alzheimer's disease is growing rapidly, making dementia one of the biggest challenges for this century. Many studies have indicated that depression plays an important role in development of dementia, including Alzheimer's disease; depression, especially, during the late life may either increase the risk of dementia or even being its prodromal stage. Despite a notably large number of carried observational studies and/or clinical trials, the association between the late life depression and dementia remains, due to the complexity of their relationship, still unclear. Moreover, during past two decades multiple other (non-)modifiable risk and possibly protective factors such as the hypertension, social engagement, obesity, level of education or physical (in)activity have been identified and their relationship with the risk for development of dementia and Alzheimer's disease has been extensively studied. It has been proposed that to understand mechanisms of dementia and Alzheimer's disease pathogeneses require their multifactorial nature represented by these multiple factors to be considered. In this review, we first summarize the recent literature findings on roles of the late life depression and the other known (non-)modifiable risk and possibly protective factors in development of dementia and Alzheimer's disease. Then, we provide evidences supporting hypotheses that (i) depressive syndromes in late life may indicate the prodromal stage of dementia (Alzheimer's disease) and, (ii) the interplay among the multiple (non-)modifiable risk and protective factors should be considered to gain a better understanding of dementia and Alzheimer's disease pathogeneses. We also discuss the evidences of recently established interventions considered to prevent or delay the prodromes of dementia and provide the prospective future directions in prevention and treatment of dementia and Alzheimer's disease using both the single-domain and multidomain interventions.

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University 12108 Prague Czech Republic

Drážní revize s r o Místecká 1120 103 70300 Ostrava Vitkovice Czech Republic

Institute of Physics Czech Academy of Sciences 18221 Prague Czech Republic

See more in PubMed

Steenman M., Lande G. Cardiac aging and heart disease in humans. Biophys. Rev. 2017;9:131–137. doi: 10.1007/s12551-017-0255-9. PubMed DOI PMC

Weir H.K., Anderson R.N., Coleman-King S.M., Soman A., Thompson T.D., Hong Y., Moller B., Leadbetter S. Heart disease and cancer deaths—Trends and projections in the United States, 1969–2020. Prev. Chronic. Dis. 2016;13:E157. doi: 10.5888/pcd13.160211. PubMed DOI PMC

Laidlaw K., Pachana N.A. Aging, mental health, and demographic change: Challenges for psychotherapists. Prof. Psychol. Res. Pract. 2009;40:601–608. doi: 10.1037/a0017215. DOI

Mirowski J., Ross C.E. Age and depression. J. Health Soc. Behav. 1992;33:187–205. doi: 10.2307/2137349. PubMed DOI

Vink D., Aartsen M.J., Comijs H.C., Heymans M.W., Penninx B.W.J.H., Stek M.L., Deeg D.J.H., Beekman A.T.F. Onset of anxiety and depression in the aging population: Comparison of risk factors in a 9-year prospective study. Am. J. Geriatr. Psychiatry. 2009;17:642–652. doi: 10.1097/JGP.0b013e3181a65228. PubMed DOI

Djernes J.K. Prevalence and predictors of depression in populations of elderly: A review. Acta Psychiatr. Scand. 2006;113:372–387. doi: 10.1111/j.1600-0447.2006.00770.x. PubMed DOI

Diniz B.S., Butters M.A., Albert S.M., Dew M.A., Reynolds C.F. Late-life depression and risk of vascular dementia and Alzheimer’s disease: Systematic review and meta-analysis of community-based cohort studies. Br. J. Psychiatry. 2013;202:329–335. doi: 10.1192/bjp.bp.112.118307. PubMed DOI PMC

Steffens D.S. Late-life depression and the prodromes of dementia. JAMA Psychiatry. 2017;74:673–674. doi: 10.1001/jamapsychiatry.2017.0658. PubMed DOI

Kokmen E., Beard C.M., Chandra V., Offord K.P., Schoenberg B.S., Ballard D.J. Critical risk factors for Alzheimer’s disease: A population-based case-control study. Neurology. 1991;41:1393–1397. doi: 10.1212/WNL.41.9.1393. PubMed DOI

Herbert J., Lucassen P.J. Depression as a risk factor for Alzheimer’s disease: Genes, steroids, cytokines and neurogenesis—What do we need to know? Front. Neuroendocrinol. 2016;41:153–171. doi: 10.1016/j.yfrne.2015.12.001. PubMed DOI

Alzheimer’s Association 2020 Alzheimer’s Disease Facts and Figures. [(accessed on 1 January 2020)]; Available online: https://www.alz.org/alzheimers-dementia/facts-figures.

Alzheimer’s Disease International World Alzheimer’s report 2019 Attitudes to Dementia. [(accessed on 3 September 2019)]; Available online: https://www.alz.co.uk/research/world-report-2019.

Stampfer M.J. Cardiovascular disease and Alzheimer’s disease: Common links. J. Intern. Med. 2006;260:211–223. doi: 10.1111/j.1365-2796.2006.01687.x. PubMed DOI

de Brujin R.F.A.G., Ikram M.A. Cardiovascular risk factors and future risk of Alzheimer’s disease. BMC Med. 2014;12:130. doi: 10.1186/s12916-014-0130-5. PubMed DOI PMC

Profenno L.A., Porsteinsson A.P., Fareone V. Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol. Psychiatry. 2010;67:505–512. doi: 10.1016/j.biopsych.2009.02.013. PubMed DOI

Livingston G., Sommerlad A., Orgeta V., Costafreda S.G., Huntley J., Ames D., Ballard C., Banerjee S., Burns A., Cohen-Mansfield J., et al. Dementia prevention, intervention, and care. Lancet. 2017;390:2673–2734. doi: 10.1016/S0140-6736(17)31363-6. PubMed DOI

Craik F.I.M., Bialystok E., Freedman M. Delaying the onset of Alzheimer disease. Neurology. 2010;75:1725–1729. doi: 10.1212/WNL.0b013e3181fc2a1c. PubMed DOI PMC

Rasmussen J., Langerman H. Alzheimer’s disease—Why we need early stage diagnosis. Degener. Neurol. Neuromuscul. Dis. 2019;9:123–130. doi: 10.2147/DNND.S228939. PubMed DOI PMC

Brookmeyer R., Abdalla N., Kawas C.H., Corrada M.M. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2018;14:121–129. doi: 10.1016/j.jalz.2017.10.009. PubMed DOI PMC

Almeida O.P., Hankey G.J., Yeap B.B., Golledge J., Flicker L. Depression as a modifiable factor to decrease the risk of dementia. Transl. Psychiatry. 2017;7:e1117. doi: 10.1038/tp.2017.90. PubMed DOI PMC

Kivipelto M., Mangialasche F., Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer’s disease. Nat. Rev. Neurol. 2018;14:653–666. doi: 10.1038/s41582-018-0070-3. PubMed DOI

Mortimer J.A., Stern Y. Physical exercise and activity may be important in reducing dementia risk at any age. Neurology. 2019;92:1–2. doi: 10.1212/WNL.0000000000006935. PubMed DOI

Bott N.T., Hall A., Madero E.N., Glenn J.M., Fuseya N., Gills J.L., Gray M. Face-to-face and digital multidomain lifestyle interventions to enhance cognitive reserve and reduce risk of Alzheimer’s disease and related dementias: A review of completed and prospective studies. Nutrients. 2019;11:2258. doi: 10.3390/nu11092258. PubMed DOI PMC

Munn Z., Peters M.D.J., Stern C., Tufanaru C., McArthur A., Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med. Res. Methodol. 2018;18:143. doi: 10.1186/s12874-018-0611-x. PubMed DOI PMC

Tricco A.C., Lillie E., Zarin W., O’Brien K.K., Levac D., Moher D., Peters M.D.J., Horsley T., Weeks L., Hempel S., et al. PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann. Intern. Med. 2018;169:467–473. doi: 10.7326/M18-0850. PubMed DOI

van Wanrooij L.L., Borsboom D., Moll van Charante E.P., van Gool W.A. A network approach on the relation between apathy and depression symptoms with dementia and functional disability. Int. Psychogeriatr. 2019;31:1655–1663. doi: 10.1017/S1041610218002387. PubMed DOI

Balsis S., Carpenter B.D., Storandt M. Personality change precedes clinical diagnosis of dementia of the Alzheimer’s type. J. Gerontol. B Psychol. Sci. Soc. Sci. 2005;60:P98–P101. doi: 10.1093/geronb/60.2.P98. PubMed DOI

Reise S.P., Wallet N.G. Item response theory and clinical measurement. Annu. Rev. Clin. Psychol. 2009;5:27–48. doi: 10.1146/annurev.clinpsy.032408.153553. PubMed DOI

Barnes D.E., Alexopoulos G.S., Lopez O.L., Williamson J.D., Yaffe K. Depressive symptoms, vascular disease, and mild cognitive impairment. Arch. Gen. Psychiatry. 2006;63:273–279. doi: 10.1001/archpsyc.63.3.273. PubMed DOI

Johnson D.K., Watts A.S., Chapin B.A., Anderson R., Burns J.M. Neuropsychiatric profiles in dementia. Alzheimer Dis. Assoc. Disord. 2011;25:326–332. doi: 10.1097/WAD.0b013e31820d89b6. PubMed DOI PMC

Leoutsakos J.-M.S., Forrester S.N., Corcoran C.D., Norton M.C., Rabins P.V., Steinberg M.I., Tschanz J.T., Lyketsos C.G. Latent classes of course in Alzheimer’s disease and predictors: The Cache county dementia progression study. Int. J. Geriatr. Psychiatry. 2015;30:824–832. doi: 10.1002/gps.4221. PubMed DOI PMC

Gatz J.L., Tyas S.L., John P., Montgomery P. Do depressive symptoms predict Alzheimer’s disease and dementia? J. Gerontol. A Biol. Sci. Med. Sci. 2005;60:744–747. doi: 10.1093/gerona/60.6.744. PubMed DOI

Olaya B., Moneta M.V., Miret M., Ayuso-Mateos J.L., Haro J.M. Course of depression and cognitive decline at 3-years follow-up: The role of age of onset. Psychol. Aging. 2019;34:475–485. doi: 10.1037/pag0000354. PubMed DOI

Geerlings M.I., Bouter L.M., Schoevers R.A., Beekman A.T.F., Jonker C., Deeg D.J.J., Tilburg W.V., Ader H.J., Schmand B. Depression and risk of cognitive decline and Alzheimer’s disease: Results of two prospective community-based studies in The Netherlands. Br. J. Psychiatry. 2000;176:568–575. doi: 10.1192/bjp.176.6.568. PubMed DOI

Xia M., Yang L., Sun G., Qi S., Li B. Mechanism of depression as a risk factor in the development of Alzheimer’s disease: The function of AQP4 and the glymphatic system. Psychopharmacology. 2017;234:365–379. doi: 10.1007/s00213-016-4473-9. PubMed DOI

Burke S.L., Cadet T., Alcide A., O’Driscoll J., Maramaldi P. Psychosocial risk factors and Alzheimer’s disease: The associative effect of depression, sleep disturbance, and anxiety. Aging Ment. Health. 2017;22:1–8. doi: 10.1080/13607863.2017.1387760. PubMed DOI PMC

Migliorelli R., Teson A., Sabe L., Petracchi M., Leiguarda R., Starkstein S.E. Prevalence and correlates of dysthymia and major depression among patients with Alzheimer’s disease. Am. J. Psychiatry. 1995;152:37–44. doi: 10.1176/ajp.152.1.37. PubMed DOI

Barca M.L., Persson K., Eldholm R., Benth J.S., Kersten H. Trajectories of depressive symptoms and their relationship to the progression of dementia. J. Affect. Disord. 2017;222:146–152. doi: 10.1016/j.jad.2017.07.008. PubMed DOI

Enache D., Winblad B., Aarsland D. Depression in dementia: Epidemiology, mechanisms, and treatment. Curr. Opin. Psychiatry. 2011;24:461–472. doi: 10.1097/YCO.0b013e32834bb9d4. PubMed DOI

Kaup A.R., Byers A.L., Falvey C., Simonsick E.M., Satterfield S. Trajectories of depressive symptoms in older adults and risk of dementia. JAMA Psychiatry. 2016;73:525–531. doi: 10.1001/jamapsychiatry.2016.0004. PubMed DOI PMC

Ownby R.L., Crocco E., Acevedo A., John V., Loewenstein D. Depression and risk for Alzheimer’s disease: Systematic review, Meta-analysis, and Meta-regression analysis. Arch. Gen. Psychiatry. 2006;63:530–538. doi: 10.1001/archpsyc.63.5.530. PubMed DOI PMC

Tapainen V., Hartikainen S., Taipale H., Tiihonen J., Tolppanen A.-M. Hospital-treated mental and behavioral disorders and risk of Alzheimer’s disease: A nationwide nested case-control study. Eur. Psychiatry. 2017;43:92–98. doi: 10.1016/j.eurpsy.2017.02.486. PubMed DOI

Becker J.T., Chang Y.F., Lopez O.L., Dew M.A., Sweet R.A., Barnes D., Yaffe K., Young K., Kuller L., Reynolds III C.F. Depressed mood is not a risk factor for incident dementia in a community-based cohort. Am. J. Geriatr. Psychiatry. 2009;17:653–663. doi: 10.1097/JGP.0b013e3181aad1fe. PubMed DOI PMC

Brommelhoff J.A. Depression as a risk factor or prodromal feature for dementia? Findings in a population-based sample of Swedish twins. Psychol. Aging. 2009;24:373–384. doi: 10.1037/a0015713. PubMed DOI PMC

Valkanova V., Ebmeier K.P., Allan C.L. Depression is linked to dementia in older adults. Practioner. 2017;261:11–15. doi: 10.1037/a0015713. PubMed DOI

Saczynski J.S., Beiser A., Seshadri-Auerbach S., Wolf P.A., Au R. Depressive symptoms and risk of dementia. Neurology. 2010;75:35–41. doi: 10.1212/WNL.0b013e3181e62138. PubMed DOI PMC

Li G., Wang L.Y., Shofer J.B., Thompson M.L., Peskind E.R., McCormick W., Bowen J.D., Crane P.K., Larson E.B. Temporal relationship between depression and dementia: Findings from a large community-based 15-year follow-up study. Arch. Gen. Psychiatry. 2011;68:970–977. doi: 10.1001/archgenpsychiatry.2011.86. PubMed DOI PMC

Amieva H., Goff M.L., Millet X., Orgogozo J.M., Pérès K., Barberger-Gateau P., Jacqmin-Gadda H., Dartigues J.F. Prodromal Alzheimer’s disease: Successive emergence of the clinical symptoms. Ann. Neurol. 2008;64:492–498. doi: 10.1002/ana.21509. PubMed DOI

Singh-Manoux A., Dugravot A., Fournier A., Abell J., Ebmeier K., Kivimaki M., Sabia S. Trajectories of depressive symptoms before diagnosis of dementia: A 28-year follow-up study. JAMA Psychiatry. 2017;74:712–718. doi: 10.1001/jamapsychiatry.2017.0660. PubMed DOI PMC

Pierce A.L., Kawas C.H. Dementia in the oldest old: Beyond the Alzheimer’s disease. PLoS Med. 2017;14:e1002263. doi: 10.1371/journal.pmed.1002263. PubMed DOI PMC

Ritchie K., Lovestone S. The dementias. Lancet. 2002;360:1759–1766. doi: 10.1016/S0140-6736(02)11667-9. PubMed DOI

Kivipelto M., Rovio S., Ngandu T., Kåreholt I., Eskelinen M., Winblad B., Hachinsku V., Cedazo-Minguez A., Soininen H., Tuomilehto J., et al. Apolipoprotein E 4 magnifies lifestyle risks for dementia: A population-based study. J. Cell. Mol. Med. 2008;12:2762–2771. doi: 10.1111/j.1582-4934.2008.00296.x. PubMed DOI PMC

Solomon A., Turunen H., Ngandu T., Peltonen M., Levälahti E., Helisalmi S., Antikainen R., Backman L., Hanninen T., Jula A. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: A subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462–470. doi: 10.1001/jamaneurol.2017.4365. PubMed DOI PMC

van der Lee S.J., Wolters F., Ikram M.K., Hofman A., Ikram M.A., Amin N., Dujin C.M.V. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: A community-based cohort study. Lancet Neurol. 2018;17:434–444. doi: 10.1016/S1474-4422(18)30053-X. PubMed DOI

Licher S., Ahmad S., Karamujić-Čomić H., Voortman T., Leeing M.J.G., Ikram M.A., Ikram M.K. Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nat. Med. 2019;25:1364–1369. doi: 10.1038/s41591-019-0547-7. PubMed DOI PMC

Burke S.L., Maramaldi P., Cadet T., Kukull W. Association between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer’s disease: Dementia. Int. Psychogeriatr. 2016;28:1409–1424. doi: 10.1017/S1041610216000405. PubMed DOI PMC

Rasmussen K.L., Tybjaer-Hansen A., Nordestgaard B.G., Frikke-Schmidt R. Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals. Alzheimers Dement. 2018;14:71–80. doi: 10.1016/j.jalz.2017.05.006. PubMed DOI

Johnson E.C.B., Dammer E.B., Duong D.M., Ping L., Zhou M., Yin L., Higginbotha L.A., Guajardo A., White B., Troncoso J.C., et al. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat. Med. 2020;26:769–780. doi: 10.1038/s41591-020-0815-6. PubMed DOI PMC

Farrer L.A., Cupples L.A., Haines J.L. Effects of age, sex, the ethnicity on association between Apolipoprotein E genotype and Alzheimer disease. JAMA. 1997;278:1349–1356. doi: 10.1001/jama.1997.03550160069041. PubMed DOI

Waring S.C., Rocca W.A., Petersen R.C., O’Brein P.C., Tangalos E.G., Kokmen E. Postmenopausal estrogen replacement therapy and risk of AD: A population-based study. Neurology. 1999;52:956–970. doi: 10.1212/WNL.52.5.965. PubMed DOI

Imtiaz B., Tuppurainen M., Rikkonen T., Kivipelto M., Soininen H., Kroger H., Tolppanen A.-M. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology. 2017;88:1062–1068. doi: 10.1212/WNL.0000000000003696. PubMed DOI PMC

Savolainen-Peltonen H., Rahkola-Soisalo P., Hoti F., Vattulainen P., Gissler M., Ylikorkala O., Mikkola T.S. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: Nationwide case-control study. BMJ. 2019;364:1665. doi: 10.1136/bmj.l665. PubMed DOI PMC

Shao H., Breitner J.C.S., Whitmer R.A., Wang J., Hayden K., Wengreen H., Corcoran C., Tschanz J., Norton M., Munger R., et al. Hormone therapy and Alzheimer disease dementia. Neurology. 2012;79:1846–1852. doi: 10.1212/WNL.0b013e318271f823. PubMed DOI PMC

Lv W., Du N., Liu Y., Fan X., Wang Y., Jia X., Hou X., Wang B. Low testosterone level and risk of Alzheimer’s disease in the elderly men: Systematic review and meta-analysis. Mol. Neurobiol. 2016;53:2679–2684. doi: 10.1007/s12035-015-9315-y. PubMed DOI

Ford A.H., Yeap B.B., Flicker L., Hankey G.J., Chubb S.A.P., Golledge J., Almeida O.P. Sex hormones and incident dementia in older men: The health in men study. Psychoneuroendocrinology. 2018;98:139–147. doi: 10.1016/j.psyneuen.2018.08.013. PubMed DOI

Carcaillon L., Brailly-Tabard S., Ancelin M.-L., Tzourio C., Foubert-Samier A., Dartigues J.-F., Guiochon-Mantel A., Scarabin P.-Y. Low testosterone and the risk of dementia in elderly men: Impact of age and education. Alzheimers Dement. 2013;10:S306–S310. doi: 10.1016/j.jalz.2013.06.006. PubMed DOI

Alivisatos A.P., Chun M., Church G.M., Greenspan R.J., Roukes M.L., Yuste R. The Brain Activity Map Project and the Challenge of Functional Connectomics. Neuron. 2012;74:970–974. doi: 10.1016/j.neuron.2012.06.006. PubMed DOI PMC

Stachiv I., Gan L., Kuo C.-Y., Sittner P., Sevecek O. Mass Spectrometry of Heavy Analytes and Large Biological Aggregates by Monitoring Changes in the Quality Factor of Nanomechanical Resonators in Air. ACS Sens. 2020;5:2128–2135. doi: 10.1021/acssensors.0c00756. PubMed DOI

Winblad B., Amouyel P., Andrieu S., Ballard C., Brayne C., Brodaty H., Cedazo-Minguez A., Dubois B., Edvardsson D., Feldman H., et al. Defeating Alzheimer’s disease and other dementias: A priority for European science and society. Lancet Neurol. 2016;15:455–532. doi: 10.1016/S1474-4422(16)00062-4. PubMed DOI

Pike C.J. Sex and the development of Alzheimer’s disease. J. Neurosci. Res. 2017;95:671–680. doi: 10.1002/jnr.23827. PubMed DOI PMC

Wahjoepramono E.J., Asih P.R., Aniwiyanti V., Taddei K., Dhaliwal S.S., Fuller S.J., Foster J., Carruthers M., Verdile G., Sohrabi R.H., et al. The effects of testosterone supplementation on cognitive functioning in older men. CNS Neurol. Disord. Drug Targets. 2016;15:337–343. doi: 10.2174/1871527315666151110125704. PubMed DOI PMC

Bennett S., Thomas A.J. Depression and dementia: Cause, consequence or coincidence? Maturitas. 2014;79:184–190. doi: 10.1016/j.maturitas.2014.05.009. PubMed DOI

Gimson A., Schlosser M., Huntley J.D., Marchant N.L. Support for midlife anxiety diagnosis as an independent risk factor for dementia: A systematic review. BMJ Open. 2018;8:e019399. doi: 10.1136/bmjopen-2017-019399. PubMed DOI PMC

Shalev D., Arbuckle M.R. Metabolism and memory: Obesity, diabetes and dementia. Biol. Psychiatry. 2017;82:e81–e83. doi: 10.1016/j.biopsych.2017.09.025. PubMed DOI PMC

Xu W.L., Atti A.R., Gatz M., Pedersen N.L., Johansson B., Fratiglioni L. Midlife overweight and obesity increase late-life depression risk: A population-based twin study. Neurology. 2011;76:1568–1574. doi: 10.1212/WNL.0b013e3182190d09. PubMed DOI PMC

Albanese E., Launer L.J., Egger M., Prince M.J., Giannakopoulos P., Wolters J.F., Egan K. Body mass index in midlife and dementia: Systematic review and meta-regression analysis of 589,649 men and women followed in longitudinal studies. Alzheimers Dement. 2017;8:165–178. doi: 10.1016/j.dadm.2017.05.007. PubMed DOI PMC

Kivimaki M., Luukkonen R., Batty G.D., Ferrie J.E., Pentti J., Nyberg S.T., Shipley M.J., Alfredsson L., Fransson E.I., Goldberg M., et al. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement. 2018;14:601–609. doi: 10.1016/j.jalz.2017.09.016. PubMed DOI PMC

Floud S., Simpson R.F., Balkwill A., Brown A., Goodill A., Gallacher J., Sudlow C., Harris P., Hofman A., Parish S., et al. Body mass index, diet, physical inactivity, and the incidence of dementia in 1 million UK women. Neurology. 2020;94:e123–e132. doi: 10.1212/WNL.0000000000008779. PubMed DOI PMC

Lazar M.A. How obesity causes diabetes: Not a tall tale. Science. 2005;307:373–375. doi: 10.1126/science.1104342. PubMed DOI

Gonzales-Reyes R.E., Aliev G., Avila-Rodrigues M., Barreto G.E. Alterations in glucose metabolism on cognition: A possible link between diabetes and dementia. Curr. Pharm. Des. 2016;22:812–818. doi: 10.2174/1381612822666151209152013. PubMed DOI

Fan Y.-C., Hsu J.-L., Tung H.-Y., Chou C.-C., Bai C.-H. Increased dementia risk predominantly in diabetes mellitus rather than in hypertension or hyperlipidemia: A population-based cohort study. Alzheimers Res. Ther. 2017;9:7. doi: 10.1186/s13195-017-0236-z. PubMed DOI PMC

Avgerinos K.L., Kalaitzidas G., Malli A., Kalaitzoglou D., Myserlis P.G., Lioutas V.-A. Internasal insulin in Alzheimer’s dementia or mild cognitive impairment: A systematic review. J. Neurol. 2018;265:1497–1510. doi: 10.1007/s00415-018-8768-0. PubMed DOI PMC

Emdin C.A., Rothwell H.P.M., Salimi-Khorshidi F.G., Kiran D.A., Conrad N., Callender T., Mehta Z., Pendlebury S.T., Anderson S.G., Mohseni H., et al. Blood pressure and risk of vascular dementia: Evidence from 4.3 million adults and a cohort study of TIA and stroke. Stroke. 2016;47:1429–1435. doi: 10.1161/STROKEAHA.116.012658. PubMed DOI PMC

Nagai M., Hoshide S., Kairo K. Hypertension and dementia. Am. J. Hypertens. 2010;23:116–124. doi: 10.1038/ajh.2009.212. PubMed DOI

Janelidze S. Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci. Rep. 2016;6:26801. doi: 10.1038/srep26801. PubMed DOI PMC

Walker K.A., Sharrett A.R., Wu A., Schneider A.L.C., Albert M., Lutsey P.L., Bandeen-Roche K., Coresh J., Gross A.L., Windham B.G., et al. Association of midlife to late-life blood pressure patterns with incident dementia. JAMA. 2019;322:535–545. doi: 10.1001/jama.2019.10575. PubMed DOI PMC

Corrada M.M., Hayden K.M., Paganini-Hill A., Bullain S.S., de Moss J., Aguirre C., Brookmeyer R., Kawas H.C. Age of onset of hypertension and risk of dementia in the oldest-old: The 90+ study. Alzheimers Dement. 2017;13:103–110. doi: 10.1016/j.jalz.2016.09.007. PubMed DOI PMC

Gilsanz P., Mayeda E.R., Glymour M.M., Quesenberry C.P., Mungas D.M., DeCarli C., Dean A., Whitmer A.R. Female sex, early-onset hypertension, and risk of dementia. Neurology. 2017;89:1–8. doi: 10.1212/WNL.0000000000004602. PubMed DOI PMC

Murray M.D., Hendrie H.C., Lane K.A., Zheng M., Ambuehl R., Li S., Unverzagt W.F., Callahan M.C., Gao S. Antihypertensive medication and dementia risk in older adult African Americans with hypertension: A prospective cohort study. J. Gen. Intern. Med. 2018;33:455–462. doi: 10.1007/s11606-017-4281-x. PubMed DOI PMC

Smith E.E., Schneider J.A., Wardlaw J.M., Greenberg S.M. Cerebral microinfarcts: The invisible lesions. Lancet Neurol. 2012;11:272–282. doi: 10.1016/S1474-4422(11)70307-6. PubMed DOI PMC

Igase M., Kohara K., Miki T. The association between hypertension and dementia in elderly. Int. J. Hypertens. 2012;2012:320648. doi: 10.1155/2012/320648. PubMed DOI PMC

Iadecola C. Hypertension and dementia. Hypertension. 2014;64:3–5. doi: 10.1161/HYPERTENSIONAHA.114.03040. PubMed DOI PMC

Turana Y., Tengkawan J., Chia Y.C., Hoshide S., Shin J., Chen C.-H., Buranakitjaroen P., Nailes J., Park S., Siddique S., et al. Hypertension and dementia: A comprehensive review from the HOPE Asia network. J. Clin. Hypertens. 2019;21:1091–1098. doi: 10.1111/jch.13558. PubMed DOI PMC

Perrotta M., Lembo G., Carnevale D. Hypertension and dementia: Epidemiological and experimental evidence revealing a detrimental relationship. Int. J. Mol. Sci. 2016;17:347. doi: 10.3390/ijms17030347. PubMed DOI PMC

Skoog I., Börjesson-Hanson A., Kern S., Johansson L., Falk H., Sigstrom R., Ostling S. Decreasing prevalence of dementia in 85-years olds examined 22 years apart: The influence of education and stroke. Sci. Rep. 2017;7:6136. doi: 10.1038/s41598-017-05022-8. PubMed DOI PMC

Xu W., Tan L., Wang H.-F., Tan M.-S., Tan L., Li J.-Q., Zhao Q.-F., Yu J.-T. Education and risk of dementia: Dose-response meta-analysis of prospective cohort studies. Mol. Neurobiol. 2016;53:3113–3123. doi: 10.1007/s12035-015-9211-5. PubMed DOI

Nguyen T.T., Tchetgen E.J.T., Kawachi I., Gilman S.E., Walter S., Liu Y.S., Manly J.J., Glymour M.M. Instrumental variable approaches to identifying the casual effect of educational attainment on dementia risk. Ann. Epidemiol. 2016;26:71–76. doi: 10.1016/j.annepidem.2015.10.006. PubMed DOI PMC

Then F.S., Luck T., Angermeyer M.C., Riedel-Heller R.G. Education as protector against dementia, but what exactly do we mean by education? Age Ageing. 2016;45:523–528. doi: 10.1093/ageing/afw049. PubMed DOI

Matthews F.E., Arthur A., Barnes L., Bond J., Jagger C., Robinson L., Brayne C. and on behalf of the Medical Research Council Cognitive Function and Ageing Collaboration. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: Results of the Cognitive Function and Ageing Study I and II. Lancet. 2013;382:1405–1412. doi: 10.1016/S0140-6736(13)61570-6. PubMed DOI PMC

Iacono D., Zandi P., Gross M., Markesbery W.R., Pletnikova O., Rudow G., Troncoso C.J. APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: Findings from the Nun Study. Oncotarget. 2015;6:14082–14091. doi: 10.18632/oncotarget.4118. PubMed DOI PMC

Wang H.-X., Gustafson D.R., Kivipelto M., Pedersen N.L., Skoog I., Windblad B., Fratiglioni L. Education halves the risk of dementia due to apolipoprotein ε4 allele: A collaborative study from Swedish brain power initiative. Neurobiol. Aging. 2012;33:1007. doi: 10.1016/j.neurobiolaging.2011.10.003. PubMed DOI

Appiah D., Baumgartner R.N. The influence of education and Apoliprotein ε4 on mortality in community-dwelling elderly men and women. J. Aging Res. 2018;2018:6037058. doi: 10.1155/2018/6037058. PubMed DOI PMC

Zhou Z., Wang P., Fang Y. Social engagement and its change are associated with dementia risk among Chinese older adults: A longitudinal study. Sci. Rep. 2018;8:1551. doi: 10.1038/s41598-017-17879-w. PubMed DOI PMC

Saito T., Murata C., Saito M., Takeda T., Kondo K. Influence of social relationship domains and their combinations on incident dementia: A prospective cohort study. J. Epidemiol. Community Health. 2018;72:7–12. doi: 10.1136/jech-2017-209811. PubMed DOI PMC

Khondoker M., Rafnsson S.B., Morris S., Orrell M., Steptoe A. Positive and negative experiences of social support and risk of dementia in later life: An investigation using the English longitudinal study of ageing. J. Alzheimers Dis. 2017;58:99–108. doi: 10.3233/JAD-161160. PubMed DOI PMC

Kuiper J.S., Zuidersma M., Oude-Voshaar R.C., Zuidema S.U., van den Heuvel E.R., Stolk P.R., Smidt N. Social relationships and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies. Ageing Res. Rev. 2015;22:39–57. doi: 10.1016/j.arr.2015.04.006. PubMed DOI

Penninkilampi R., Casey A.-N., Sigh M.F., Brodaty H. The association between social engagement, loneliness, and risk of dementia: A systematic review and meta-analysis. J. Alzheimers Dis. 2018;66:1619–1633. doi: 10.3233/JAD-180439. PubMed DOI

Salinas J., Beiser A., Himali J., Satizabal C.L., Aparicio H.J., Weinstein G., Mateen J.F., Berkman F.L., Rosand J., Seshadri S. Associations between social relationship measures, serum brain-derived neurotrophic factor, and risk of stroke and dementia. Alzheimers Dement. 2017;3:229–237. doi: 10.1016/j.trci.2017.03.001. PubMed DOI PMC

Murata C., Saito T., Saito M., Kondo K. The association between social support and incident dementia: A 10-year follow-up study in Japan. Int. J. Environ. Res. Public Health. 2019;16:239. doi: 10.3390/ijerph16020239. PubMed DOI PMC

Nithianantharajah J., Hannan A.J. The neurobiology of brain and cognitive reserve: Mental and physical activity as modulators of brain disorders. Prog. Neurobiol. 2009;89:369–382. doi: 10.1016/j.pneurobio.2009.10.001. PubMed DOI

Bisht K., Sharma K., Tremblaya M.-E. Chronic stress as a risk factor for Alzheimer’s disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress. Neurobiol. Stress. 2018;9:9–21. doi: 10.1016/j.ynstr.2018.05.003. PubMed DOI PMC

D’Orsi E., Xavier A.J., Rafnsson S.B., Steptoe A., Hogervorst E., Orrell M. Is use of the internet in midlife associated with lower dementia incidence? Results from the England longitudinal study of aging. Aging Ment. Health. 2018;22:1525–1533. doi: 10.1080/13607863.2017.1360840. PubMed DOI PMC

Xu W., Wang H., Tan C., LI J., Tan L., Yu J.-T. Alcohol consumption and dementia risk: A dose–response meta-analysis of prospective studies. Eur. J. Epidemiol. 2017;32:31–42. doi: 10.1007/s10654-017-0225-3. PubMed DOI

Sabia S., Fayosse A., Dumurgier J., Dugravot A., Akbaraly T., Britton A., Kivimaki M., Singh-Manoux A. Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study. BMJ. 2018;362:k2927. doi: 10.1136/bmj.k2927. PubMed DOI PMC

Ormstad H., Rosness T.A., Bergem A.L.M., Bjertness E., Strand B.-H. Alcohol consumption in the elderly and risk of dementia related death—A Norwegian prospective study with a 17-year follow-up. Int. J. Neurosci. 2006;126:135–144. doi: 10.3109/00207454.2014.997876. PubMed DOI

Hu M., Corkill R. Population studies highlight an increased risk of dementia in both dependent and non-dependent drinkers. J. Neurol. 2019;266:790–792. doi: 10.1007/s00415-019-09192-5. PubMed DOI

Dikalov S., Itani H., Richmond B., Arslanbaeva L., Vergeade A., Jamshedur-Rahman S.M., Boutaud O., Blackwell T., Massion P.P., Harrison G.D., et al. Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension. Am. J. Physiol. Heart Circ. Physiol. 2019;316:H639–H646. doi: 10.1152/ajpheart.00595.2018. PubMed DOI PMC

Batty G.D., Shipley M.J., Kvaavik E., Russ T., Hamer M., Stamatakis E., Kivimaki M. Biomarker assessment of tobacco smoking exposure and risk of dementia death: Pooling of individual participant data from 14 cohort studies. J. Epidemiol. Community Health. 2018;72:513–515. doi: 10.1136/jech-2017-209922. PubMed DOI

Choi D., Choi S., Park S.M. Effect of smoking cessation on the risk of dementia: A longitudinal study. Ann. Clin. Transl. Neurol. 2018;5:1192–1199. doi: 10.1002/acn3.633. PubMed DOI PMC

Steven S., Frenis K., Oelze M., Kalinovic S., Kuntic M., Bayo-Jimenez T.M., Vujacic-Mirski K., Helmstadter J., Kroller-Schon S., Munzel T., et al. Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease. Oxidative Med. Cell. Longev. 2019;2019:1–26. doi: 10.1155/2019/7092151. PubMed DOI PMC

Elias A., Cummins T., Tyrrell R., Lamb F., Dore V., Bobert W., Rosenfeld J.V., Hopwood M., Villemagne L.V., Rowe C.C. Risk of Alzheimer’s disease in obstructive sleep apnea syndrome: Amyloid-β and Tau imaging. J. Alzheimers Dis. 2018;66:733–741. doi: 10.3233/JAD-180640. PubMed DOI

Przybylska-Kuć S., Zakrzewski M., Dybata A., Kicinski P., Dzida G., Myslinski W., Prystupa A., Mosiewicz-Madejska B., Mosiewicz J. Obstructive sleep apnea may increase the risk of Alzheimer’s disease. PLoS ONE. 2019;14:e0221255. doi: 10.1371/journal.pone.0221255. PubMed DOI PMC

Hahn E.A., Wang H.-X., Andel R., Fratiglioni L. A change in sleep pattern may predict Alzheimer disease. Am. J. Geriat. Psychiatry. 2014;22:1262–1271. doi: 10.1016/j.jagp.2013.04.015. PubMed DOI

Liguori C., Mercuri N.B., Nuccetelli M., Izzi F., Cordella A. Obstructive sleep apnea may induce orexinergic system and cerebral β-amyloid metabolism dysregulation: Is it a further proof for Alzheimer’s disease risk? Sleep Med. 2019;56:171–176. doi: 10.1016/j.sleep.2019.01.003. PubMed DOI

Marchand D.G., Postuma R.B., Escudier F., Roy J., Pelletier A., Montplaisir J. How does dementia with Lewy bodies start? Prodromal cognitive changes in REM sleep behavior disorder. Ann. Neurol. 2018;83:1016–1026. doi: 10.1002/ana.25239. PubMed DOI

Alzheimer’s Association Surprising Differences Found in How Sleep Medications Increase Dementia Risk for Some, Protect Others. [(accessed on 15 July 2019)]; Available online: https://www.prnewswire.com/news-releases/surprising-differences-found-in-how-sleep-medications-increase-dementia-risk-for-some-protect-others-300884450.html.

Richards K.C., Goonerante N., Dicicco B., Hanlon A., Moelter S., Onen F., Wang Y., Sawyer A., Weaver T., Lozano A., et al. CPAP Adherence May Slow 1—Year Cognitive Decline in Older Adults with Mild Cognitive Impairment and Apnea. J. Am. Geriatr. Soc. 2019;67:558–564. doi: 10.1111/jgs.15758. PubMed DOI PMC

Weier M., Hall W. The use of cannabinoids in treating dementia. Curr. Neurol. Neurosci. 2017;17:56. doi: 10.1007/s11910-017-0766-6. PubMed DOI

Chiu H.-L., Chu H., Tsai J.-C., Liu D., Chen Y.-R., Yang H.-L., Chou K.-R. The effect of cognitive-based training for healthy older people: A metanalysis of randomized controlled trials. PLoS ONE. 2017;12:e0176742. doi: 10.1371/journal.pone.0176742. PubMed DOI PMC

Rabinovici G.D., Carrillo M.C., Forman M., DeSanti S., Miller D.S., Kozauer N., Petersen C.R., Randolph C., Knopman S.D., Smith E.E., et al. Multi comorbid neuropathologies in the setting of Alzheimer’s disease neuropathology and implications for drug development. Alzheimers Dement. 2017;3:83–91. doi: 10.1016/j.trci.2016.09.002. PubMed DOI PMC

Wang Z., Marseglia A., Shang Y., Dintica C., Patrone C., Xu W. Leisure activity and social integration mitigate the risk of dementia related to cardiometabolic diseases: A population-based longitudinal study. Alzheimers Dement. 2019 doi: 10.1016/j.jalz.2019.09.003. in press. PubMed DOI

Liang J.-H., Xu Y., Lin L., Jia R.-X., Zhang H.-B., Hang L. Comparison of multiple interventions for older adults with Alzheimer disease or mild cognitive impairment. Medicine. 2018;97:e10744. doi: 10.1097/MD.0000000000010744. PubMed DOI PMC

Ngandu T., Lehtisalo J., Solomon A., LevälahtI E., Ahtiluoto S., Antikainen R., Backman L., Hanninen T., Jula A. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controller trial. Lancet. 2015;385:2255–2263. doi: 10.1016/S0140-6736(15)60461-5. PubMed DOI

Moll van Charante E.P., Richard E., Eurelings L.S., van Dalen J.-W., Ligthart S.A., Bussel E.F.V., Hoevenaar-Bol M.P., Vermeulen M., Gool W.A.V. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): A cluster-randomised controlled trial. Lancet. 2016;388:797–805. doi: 10.1016/S0140-6736(16)30950-3. PubMed DOI

Andrieu S., Guyonnet S., Coley N., Cantet C., Bonnefoy M. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial. Lancet. 2017;16:377–389. doi: 10.1016/S1474-4422(17)30040-6. PubMed DOI

Eggink E., Moll van Charante E.P., van Gool W., Richard E. A population perspective on prevention of dementia. J. Clin. Med. 2019;8:834. doi: 10.3390/jcm8060834. PubMed DOI PMC

Leorin C., Stella E., Nugent C., Cleland I., Paggetti C. The value of including people with dementia in the co-design of personalized eHealth technologies. Dement. Geriatr. Cogn. Disord. 2019;47:164–175. doi: 10.1159/000497804. PubMed DOI

Iacono D., Markesbery W.R., Gross M., Pletnikova O., Rudow G., Zandi P., Troncoso J.C. The Nun Study: Clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology. 2009;73:665–673. doi: 10.1212/WNL.0b013e3181b01077. PubMed DOI PMC

Combining Neuropsychological Assessment with Neuroimaging to Distinguish Early-Stage Alzheimer's Disease from Frontotemporal Lobar Degeneration in Non-Western Tonal Native Language-Speaking Individuals Living in Taiwan: A Case Series

Biological mechanisms and possible primary prevention of depression

Neuroinflammation in Alzheimer's Disease

Association Between Obstructive Sleep Apnea, Its Treatment, and Alzheimer's Disease: Systematic Mini-Review