Clinical Geriatrics - Reviews
Published: 2022-12-19

The intricate connection between depression and dementia as a major challenge for clinicians

Former-MD c/o ASLTO4-Ivrea Hospital, Turin, Italy
Techint Industrial Corporation, Milan, Italy
aging depression dementia risk factor antidepressant agents


With the aging of the population over the world, clinicians are called to confront more and more with depression and dementia due to Alzheimer’s disease/other neurodegenerative types and vascular dementia. Depression and dementia raise widespread concerns due to their negative consequences on physical functions, quality of life and mortality in the elderly, associated to undesirable effects on caregivers and society. Growing evidence from population studies indicates that latelife depression (LLD) often accompanies dementia through its stages of severity, but also it is a major risk factor for development of later dementia, or again it can be configured as prodromal manifestation of dementia. Although the nature of the relationship between the two mental disorders is unclear and results of research are heterogeneous, many scholars point out that currently depression is underdiagnosed and -treated by clinicians and speculate that an appropriate diagnosis, monitoring and treatment (using antidepressants and/or other pharmacological/ non-pharmacological regimes) could be of benefit for elderly, regardless of the severity of cognitive decline or even in subjects with adequate cognitive abilities. The authors of this paper, describe and reflect about some problematic characteristics of the relationship between LLD and dementia, taking into consideration epidemiological, pathophysiological and clinical aspects. In their opinion, a conceptual organization of the think around the role plays by depression in dementia could be of some utility to optimize clinical practice.


Population aging is a global phenomenon that is accompanied by a dramatic rise of persons suffering for two main disabling disorders, as depression (major depression and subsyndromal symptomatic depression) and dementia, especially due to Alzheimer’s disease (AD) and that due to vascular causes (VaD) 1-5. Prevalence of late-life depression (LLD), typically defined as depression or depressive symptoms after age 60 6, varies among different studies and populations from 8.5 to 14.5% 7-9. Prevalence of dementia currently ranges from 5 to 8% with an estimated growing trend, worldwide 10. Each of the two illnesses, by itself, is associated with dangerous consequences due to serious adverse effects on health and well-being of the elderly, as disability and impairment of quality of life (QOL) 11,12. Both disorders are strongly implicated to contribute to development of physical illnesses as cardiovascular disease, and are burdened with an excess of mortality due to comorbidity 13-17. The role of depression as independent risk factor for suicide in the elderly deserves particular interest between scholars due to its elevated prevalence and dramatic force 18,19. In addition, LLD and dementia have often negative repercussions on psychological and functional abilities of caregivers 20,21. Finally, they raise a number of problems for society and health policies, such as an excess of health care services utilization 15,22 and considerable costs for family informal care 23.

When LLD and dementia co-exist, a not rare occurrence 1, the entity of respective undesirable effects worsens, due to a set of factors as exacerbation of cognitive and functional impairment, increasing behavioural disturbances related to dementia, early increased mortality, early patient admission in care and assistance institutions, increased health costs in a context of limited resources, increased depression on families and caregivers 15,24-28. Co-existence of depression and dementia make the differential diagnosis between the first and second a challenging, for clinicians 29. Not only, but an emerging concern is that while the second seems to be more considered, the first is to be often overlooked in the clinical practice 2,15,30. Currently, despite depressed elderly patients, regardless the cognitive status, can respond to anti-depressant medication 31, major depression and subsyndromal symptomatic depression continue to be still underdiagnosed and treated, above all in persons living with dementia (PWD), and a not negligible heterogeneity of management persists 2,32,33. Likely, undertreatment of depression symptoms in older adults with dementia is due to lack of consistent diagnostic criteria to assess depression in the context of cognitive impairment that characterized dementia 32,34.

In this complex scenario, the purpose of authors of this paper is to describe and reflect about the entity and some problematic characteristics of the relationship between LLD and dementia. This, in the assumption that the current heterogeneity of practical approaches, with some degree of carelessness for depression can benefit from a conceptual organization that takes its cue from a series of key questions and possible answers.


Prevalence studies of depression in PWD have provided heterogeneous results largely depending by different diagnostic criteria, methodology and the source of the sample. Depression occurs until 20-30% of PWD, and is even higher in patients with VaD and dementia with Lewy bodies 35. In a recent meta-analysis, including 55 studies with a total of more than 13,000 older adults with dementia the prevalence of major depression was 15.9% in all causes of dementia, 14.8% in AD and 24.7% in subjects with VaD 36. Scholars conclude their paper by stating that depression is common among PWD, and the estimated prevalence of depression in dementia varies with the types of dementia and dementia criteria (NINCDS-ADRDA, DSM III, DSM IV). They add that is likely that difference of prevalence of depression between AD and VaD is due to direct relationship between cerebrovascular disease pathology and the risk of developing depression. Rubin et al. (2001) 37 underlined that depression is common among patients with mild and moderate AD dementia type, but is less common in severe dementia. Depression is also often found in individuals with mild cognitive impairment (MCI), with an estimated prevalence of 32% 38. A large prospective US cohort study presents robust evidence that MCI as well as dementia were both associated with significantly higher rates of depression compared with those with normal cognition 39.


Growing evidence indicates that depression exposes individuals to subsequent dementia.

Meta-analysis studies and several reviews have suggested that the presence of depression increases to a two or more times the risk of later dementia 40-44. In a nationwide cohort study carried out by Holmquist et al. (2020) 45 from 1964 to 2016 in Swedish inhabitants aged ≥ 50 years, the odds risk (OR) of dementia subsequent to depression was 10-20 times in the first 6 months after diagnosis of depression (adjusted OR 15.20, 95% CI 11.85-19.50; p < 0.001), and was higher for individuals with severe depression compared with those with mild depression, while a stronger association was seen with VaD; furthermore, the risk of dementia after the first year decreased more or less rapidly, but was still evident 20 years after the diagnosis of depression (aOR 1.58, 95% CI 1.27-1.98; p < 0.001). In a prospective study of over 5,500 subjects with normal cognition and 2,500 subjects with MCI at 30 US Alzheimer’s Disease Centers, Steenland et al. (2012) 46 found that at base line depression was associated in normal individuals as well as in individuals with MCI; a diagnosis of depression within 2 years, but not past depression, was a strong relative risk (RR = 2.35; 95% CI 1.93-3.08) for progression for normal to MCI versus never depressed, and a borderline-significant risk for progression from MCI to AD. More recently, Wang et al. (2021) 47 in a nationwide population-based cohort study (n = 939,099 individuals aged 66 years who participated in the South Korea-National Screening Program between 2009 and 2013) found that depressive symptoms, recent depressive disorder and subjective cognition decline (SCD) independently increased dementia incidence with adjusted hazard ratio (aHR) of 1.286 (95% CI: 1.255-1.318), 1.697 (95% CI: 1.621-1.776), and 1.748 (95% CI: 689-1.808) respectively. Results of this study well demonstrate that depressive symptoms and depressive disorder are relevant risk factors for dementia. In addition, scholars showed that co-occurrence of depression and SCD have an additive effect on the risk of dementia.


The coexistence between AD dementia and depression is an intricate event that raises a number of problems, doubts or questions that directly or indirectly, passing through epidemiology and pathophysiology, involve clinical practice. In particular, some major questions emerge: what is the nature of the relationship between the two clinical entity, in other terms is LLD a risk factor or early sign or prodromal event or also a progression enhancer of dementia? What are major implications on clinical practice of relationship? Do antidepressant treatments in LLD have any effect on improving cognition, also?

The possible answers to these questions are considered in the following sub-paragraphs.


From an epidemiological perspective, currently is unclear if depression is a risk factor for dementia or a prodromal symptom of cognitive decline or an early manifestation of dementia or also a component that accelerates and worsens the clinical course of dementia 32,40. Results of quantitative population studies illustrated in “Dementia risk in people with a history of depression” paragraph support the hypothesis of depression as a risk factor or symptom predicting the onset of AD dementia. In addition to these studies the role of depression as possible risk factor for subsequent dementia and cognitive decline found sufficient evidence in a review of case-control and prospected studies carried out by Jorm (2000) 48. Jorm reviewed the literature in relation to six hypotheses that might explain an association: (1) depression treatments are a risk factor for dementia; (2) dementia and depression share common risk factors; (3) depression is a prodrome of dementia; (4) depression is an early reaction to cognitive decline; (5) depression affects the threshold for manifesting dementia, and (6) depression is a causal factor in dementia. In its paper author affirms that while the first hypothesis is the most probable, further research is needed to examine the others. In a review and meta-analysis, and meta-regression analysis including case-control studies and cohort studies, Ownby et al. (2006) 41 – with the aim to determine the relationship between the interval length between diagnosis of depression and AD, and the risk for developing AD – found that the length of the interval between the diagnoses of depression and AD was positively associated with an increased risk of developing AD in later life. Authors conclude claiming that this finding is in accordance with the hypothesis that depression is a risk factor for AD rather than a prodrome. It is also in accordance with the results of Green et al. (THE MIRAGE study, 2003) 49. This study, including 1,953 subjects with AD and 2,093 subjects without AD, showed existence of an association between depression symptoms and AD with adjusted odds ratio of 2.13 (95% CI 1.71-2.67) 49. A noteworthy point is that a divergence of results emerges: if develop of AD symptoms is within a year of the depression symptoms, thus depression represent an early symptom of AD; if instead depression symptoms occur decades before the onset of AD, this fact suggest that depression is a risk factor for later development of AD. Finally, Li G. et al. (2011) 50, in a community-based prospective research of 3,410 participants initially without dementia aged ≥ 65 years, confirmed previous observations of an association between LLD and increased risk of developing dementia, and supplied evidence that LLD may be an early manifestation of dementia rather than increasing risk for dementia.


Common pathophysiological process and neurobiological mechanisms contributing to an increased risk of depression and dementia could explain the association between the two 51,52. This interpretation suggests the existence of a relationship between depression and neurodegenerative changes of AD mediated by brain vascular-ischemic lesions. There is a growing evidence to support existence of a common primary etiological mechanism between depression and neurodegenerative brain lesions 53, including hippocampal atrophy, hypothalamic-pituitary-adrenal axis dysregulation, inflammation and activation of microglia, decrease of nerve growth factors, modifications in the serotoninergic and noradrenergic system, and cerebrovascular changes 54. For their part, Aznar and Knudsen (2011) 55 explain the co-morbidity suggesting the existence of common neurodegenerative cascade behind depression and AD. In addition, recently Monereo-Sánchez et al. (2021) 56 provide evidence of a genetic overlap between dementia and depression. Common etiological mechanisms between depression and neurodegenerative pathologies make plausible the hypothesis of an accelerating effect of depressive symptoms in progression of symptoms of AD. Figure 1 illustrates predominant pathways linking depression as a risk factor for the onset of dementia 40.


As already mentioned, clinicians have to deal with a series of problems arising from the complex and debated link between the two mental disorders. Below are the main critical aspects.


Research on depression and risk of develop dementia have led to results such as to emphasize the importance of strategy of closely monitoring early-life depression and LLD for subsequent dementia 40. The key concept being this recommendation is that depression, considered as a main risk factor for dementia, can be captured and successfully treated before dementia develops. The elimination of depression is estimated to produce a 4% reduction in dementia incidence on the population level, exceeding the estimated effects of other disorders as hypertension (2%), diabetes (1.2%), obesity (0.8%), and physical inactivity (2.6%) 54,57. Currently, the treatment and management of depression in the elderly at risk of- or with cognitive decline goes through two strategies in order to improve depressive symptoms and to prevent cognitive impairment. The first approach is the use of antidepressant drugs (ADDs), the second is an integration of ADDs with other types of pharmacological and non-pharmacological interventions, all in any case with procognitive intent.

A problem that precedes the treatment is the diagnostic difficulty of depression in the elderly with neurocognitive symptoms. There is agreement among many experts on two point 32 : (i) that the existence of depression in patients undermines the neuropsychological assessment (Fig. 2, box 1), and (ii) that in early dementia depression symptoms can be masked by a prevalent somatic symptomatology, such as anorexia, weight loss, psychomotor retardation and daily mood fluctuation, while in advanced dementia it is masked by behavioral symptoms, such as agitation and aggression and sleep-wake cycle reversal (Fig. 2, box 2). If this “masking” is an obstacle for clinicians, it must be emphasized that help can come by using of appropriate rating scales, such as Cornell Scale for Depression in Dementia (CSDD) and information provided by the relatives (Fig. 2, box 2).


ADDs that are more frequently prescribed to treat LLD in subjects with or without cognitive impairment are selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), drugs that tend to be better tolerated than others. Due to pro-cognitive and synergistic effects when utilized with cholinesterase inhibitors (ChEIs) a preference is reserved by some scholars to drugs having dual/multi-modal effects (venlafaxine/desvenlafaxine, duloxetine, mirtazapine, vortioxetine and tianeptine 32 (Fig. 2, box 3). Potential mechanisms of antidepressant treatment on AD pathology includes molecular effects on neurogenesis, amyloid-ß burden, tau pathology and inflammation 54,58-61 (Fig. 3). These procognitive effects of ADDs would justify treatment of depressed patients also to prevent or mitigate the development of later dementia.

ADDs when correctly prescribed – taking in account some factors, including the type and daily dose of drug, the length of the treatment, side effects and potential interactions with other drugs – may to be of benefit for depressed patients improving depressive symptoms in conjunction with QOL and physical functional status – two dimensions notoriously compromised during clinical course of depressive disorder 11. In addition, depression requires an adequate treatment when co-exists with AD/VaD to improve functional status and QOL already compromised by neurodegenerative and/or vascular lesions 62. Finally, ADDs act mitigating the conversion of MCI to dementia and the subsequent progression through the stages of severity of dementia 63-65.

The neuro-pathophysiological substrate linking LLD and dementia as described in subparagraph “Pathophysiology” supports the hypothesis that the benefit of ADDs in cognition is due to their action on pathophysiological processes and molecular circuits related to dementia 53,55,56,66,67.

This hypothetical link does not always seem to be confirmed by population studies. If there is evidence of substantial positive effects of ADDs on cognition (see above) 63-65, conversely there are studies founding that cognitive symptoms persisted after depression treatment 68,69 or this treatment have modest positive effects on some cognitive functions, such as divided attention, executive function, immediate memory, processing speed, recent memory 70.


Pharmacological therapy for depression in PWD is recommended by guidelines with some variations. For example, NICE-guidelines (2018) 71 suggest of not offer ADDs to manage mild to moderate depression in people living with mild to moderate dementia, unless these drugs are indicated for a pre-existing severe mental health problem. The World Health Organization emphasizes that in PWD with moderate or severe depression, use of SSRIs may be considered. In case of non-response after at least 3 weeks, they should preferably be referred to a mental health specialist for further assessment and management 72.

In summary, the overall picture resulting by scientific literature is heterogenous and inconclusive with respect to this specific aspect. More recently a panel of 37 expert physicians in neurodegenerative diseases formulated key messages for clinicians with indications for antidepressant treatment in patients with depression and with or without associated cognitive impairment 32 (Fig. 2). Byers and Yaffe (2011) 40, already a decade earlier, had point out that it is critically important to determine if treatment of depression alone or combined with other regimes would delay or prevent dementia.


About effects of antidepressants on mortality, Enache et al. (2016) 73 in a population study including more that 20,000 memory clinic patients showed that use of antidepressants during prodromal dementia stages may reduce mortality in dementia and specifically in AD. Su et al. (2019) 74 in a population-based cohort study (25,890 cases between antidepressant users and non-users) found that antidepressant treatment showed significant protective effects in all-cause mortality, by reducing it by 4%. Most classes of antidepressants were effective, especially with longer treatment duration or higher dosage.


An alternative strategy to improving the course of cognitive decline in older adults using antidepressants is an approach that combines these drugs with other regimes of pharmacological and non-pharmacological interventions as physical activity and psychological interventions 40, including cognitive behavioural therapy, reminiscence therapy, multi-sensory stimulation, animal-assisted therapy, exercise, stimulation-oriented treatment (recreational or pleasurable activities), or improvements to a living situation 75,76. A pilot study carried out by Pelton et al. (2008) 77 suggest that addition of a ChEI (donezepil) following antidepressant treatment in elderly with depression and cognitive impairment may improve cognition, but further studies with larger randomized placebo-controlled trial are needed. Finally, scholars shown that the use of antidepressants (such as sertraline, citalopram, venlafaxine) combined with multivitamins, vitamin E, alpha-lipoic acid, omega-3 and coenzyme Q in association to diet and physical exercise not only protracted cognitive decline for 24 months but even improved cognition, especially memory and frontal lobe functions 78.


Even if the nature of the association between depression and AD dementia is unclear and the link is complex to interpret, there is evidence that antidepressant treatment (pharmacological, behavioral or other regimes) is a rational approach in elderly subjects with a diagnosis of depression and different degrees of severity of cognitive decline, from a normal condition to MCI to dementia state 32,40. Of particular relevance is that LLD is recognized a major risk factor for subsequent dementia 79 or prodromal symptom of dementia and it is plausible that antidepressant therapy, due to its neuroprotective effects could delay or mitigate the cognitive decline 32,40. In this way, a considerable fraction of dementia cases could be prevented.

However, to date the discussion between scholars is open with studies leading to heterogenous results and conclusions. In other terms, the evidence regarding the efficacy of these agents in PWD or at risk of dementia remains conflicting. The obvious consequence is that a halo of uncertainty revolves around this topic. In clinical practice, there is a hesitation of the clinicians to recognize symptomatic depression as a target for prevention and treatment of AD dementia 54.

In conclusion, net of the above difficulties, it emerges that undertreatment of depression in dementia currently persists, also if UK scholars shown that prescribing of appropriate antidepressant drugs in PWD appears to be increasing over the years 80. In any case, the intricate relationship between the two late-life disorders requires further studies.

Conflict of interest statement

The Authors declare no conflict of interest.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

The Authors contributed equally to the work.

Ethical consideration

Not applicable.

Figures and tables

Figure 1.Pathways through which depression can promote the onset of dementia. Each of the pathways, indicated in different colors, can contribute to cognitive decline (from Byers, Yaffe, 2012, mod) 40.

Figure 2.Key messages from expert physicians in neurodegenerative disease (from Agüera-Ortiz et al., 2021 [Delphi consensus], mod.) 32.

Figure 3.Molecular mechanisms and neuroprotective effects of antidepressant drugs (from Byer, Yaffe, 2012; Dafsari, Jessen, 2020; Banasr, Duman, 2007; Malberg, Schechter, 2005; Sheline et al., 2014, mod.) 40,54,58-60.


  1. Korczyn AD, Halperin I. Depression and dementia. J Neurol Sci. 2009; 283:139-142. DOI
  2. Gottfries CG. Late life depression. Eur Arch Psychiatry Clin Neurosci. 2001; 251:II57-II61. DOI
  3. Moussavi S, Chatterji S, Verdes E. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007; 370:851-858. DOI
  4. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022; 7:e105-e125. DOI
  5. WHO. Dementia.Publisher Full Text
  6. Espinoza R, Kaufman AH. Diagnosis and treatment of late-life depression. Psychiatric Times. 2014; 31:18. Publisher Full Text
  7. Copeland JR, Beekman AT, Braam AW. Depression among older people in Europe: the EURODEP studies. World psychiatry. 2004; 3:45-49.
  8. Chi I, Yip PS, Chiu HF. Prevalence of depression and its correlates in Hong Kong’s Chinese older adults. Am J Geriatr Psychiatry. 2005; 13:409-416. DOI
  9. Steffens DC, Fisher GG, Langa KM. Prevalence of depression among older Americans: the aging, demographics and memory study. Int Psychogeriatr. 2009; 21:879-888. DOI
  10. Prince M, Bryce R, Albanese E. The global prevalence of dementia: a systematic review and meta-analysis. Alzheimers Dement. 2013; 9:63-75.e2. DOI
  11. Chachamovich E, Fleck M, Laidlaw K. Impact of major depression and subsyndromal symptoms on quality of life and attitudes toward aging in an international sample of older adults. Gerontologist. 2008; 48:593-602. DOI
  12. Whitehouse PJ, Rabins PV. Quality of life and dementia. Alzheimer Dis Assoc Disord. 1992; 6:135-137. DOI
  13. Schulz R, Beach SR, Ives DG. Association between depression and mortality in older adults: the Cardiovascular Health Study. Arch Int Med. 2000; 160:1761-1768. DOI
  14. Beekman AT, Deeg DJ, Braam AW. Consequences of major and minor depression in later life: a study of disability, well-being and service utilization. Psychol Med. 1997; 27:1397-1409. DOI
  15. Reynolds CF, Kupfer DJ. Depression and aging: a look to the future. Psychiatr Serv. 1999; 50:1167-1172. DOI
  16. van Dijk PT, Dippel DW, Habbema JD. Survival of patients with dementia. J Am Geriatr Soc. 1991; 39:603-610. DOI
  17. Bonaiuto S, Mele M, Galluzzo L. Survival and dementia: a 7-year follow-up of an Italian elderly population. Arch Gerontol Geriatr. 1995; 20:105-113. DOI
  18. Fernandez-Rodrigues V, Sanchez-Carro Y, Lagunas LN. Risk factors for suicidal behavior in late-life depression: a systematic review. World J Psychiatry. 2022; 12:187-203. DOI
  19. Juurlink DN, Herrmann N, Szalai JP. Medical illness and the risk of suicide in the elderly. Arch Intern Med. 2004; 164:1179-1184. DOI
  20. Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci. 2003; 58:249-265. DOI
  21. Fonareva I, Oken BS. Physiological and functional consequences of caregiving for relatives with dementia. Int Psychogeriatr. 2014; 26:725-747. DOI
  22. Chung S-D, Liu S-P, Sheu J-J. Increased healthcare service utilizations for patients with dementia: a population-based study. PLoS One. 2014; 9:e105789. DOI
  23. Wimo A, Guerchet M, Ali GC. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement. 2017; 13:1-7. DOI
  24. Curran EM, Loi S. Depression and dementia. Med J Aust. 2013; 199:S40-S44. DOI
  25. Fiske A, Wetherell JL, Gatz M. Depression in older adults. Annu Rev Clin Psychol. 2009; 5:363-389. DOI
  26. Doraiswamy PM, Khan ZM, Donahue RM. The spectrum of quality-of-life impairments in recurrent geriatric depression. J Gerontol A Biol Sci Med Sci. 2002; 57:M134-M137. DOI
  27. Albert SM, Jacobs DM, Sano M. Longitudinal study of quality of life in people with advanced Alzheimer’s disease. Am J Geriatr Psychiatry. 2001; 9:160-168. DOI
  28. Covinsky KE, Newcomer R, Fox P. Patient and caregiver characteristics associated with depression in caregivers of patients with dementia. J Gen Intern Med. 2003; 18:1006-1014. DOI
  29. Liguori C, Pierantozzi M, Chiaravalloti A. When cognitive decline and depression coexist in the elderly: CSF biomarkers analysis can differentiate Alzheimer’s disease from late-life depression. Front Aging Neurosci. 2018; 10:38. DOI
  30. Kok RM, Reynolds CF. Management of depression in older adults: a review. JAMA. 2017; 317:2114-2122. DOI
  31. Reynolds CF, Lebowitz BD, Schneider LS. The NIH consensus development conference on the diagnosis and treatment of depression in late life: an overview. Psychopharmacol Bull. 1993; 29:83-85.
  32. Agüera-Ortiz L, García-Ramos R, Grandas Pérez FJ. Depression in Alzheimer’s disease: a Delphi consensus on etiology, risk factors, and clinical management. Front Psychiatry. 2021; 12:638651. DOI
  33. VanItallie TB. Subsyndromal depression in the elderly: underdiagnosed and undertreated. Metabolism. 2005; 54(5):39-44. DOI
  34. Goodarzi Z, Mele B, Guo S. Guidelines for dementia or Parkinson’s disease with depression or anxiety: a systematic review. BMC Neurol. 2016; 16:244. DOI
  35. Enache D, Winblad B, Aarsland D. Depression in dementia: epidemiology, mechanisms, and treatment. Curr Opin Psychiatry. 2011; 24:461-472. DOI
  36. Asmer MS, Kirkham J, Newton H. Meta-analysis of the prevalence of major depressive disorder among older adults with dementia. J Clin Psychiatry. 2018; 79:17r11772. DOI
  37. Rubin EH, Veiel LL, Kinscherf DA. Clinically significant depressive symptoms and very mild to mild dementia of the Alzheimer type. Int J Geriatr Psychiatry. 2001; 16:694-701. DOI
  38. Ismail Z, Elbayoumi H, Fischer CE. Prevalence of depression in patients with mild cognitive impairment: a systematic review and meta-analysis. JAMA Psychiatry. 2017; 74:58-67. DOI
  39. Snowden MB, Atkins DC, Steinman LE. Longitudinal association of dementia and depression. Am J Geriatr Psychiatry. 2015; 23:897-905. DOI
  40. Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011; 7:323-331. DOI
  41. Ownby RL, Crocco E, Acevedo A. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006; 63:530-538. DOI
  42. Jorm AF. History of depression as a risk factor for dementia: an updated review. Aust N Z J Psychiatry. 2001; 35:776-781. DOI
  43. Diniz BS, Butters MA, Albert SM. 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
  44. Andreasen P, Lönnroos E, von Euler-Chelpin MC. Prevalence of depression among older adults with dementia living in low- and middle-income countries: a cross-sectional study. Eur J Public Health. 2014; 24:40-44. DOI
  45. Holmquist S, Nordström A, Nordström P. The association of depression with subsequent dementia diagnosis: a Swedish nationwide cohort study from 1964 to 2016. PloS Med. 2020; 17:e1003016. DOI
  46. Steenland K, Karnes C, Seals R. Late-life depression as a risk factor for mild cognitive impairment or Alzheimer’s disease in 30 US Alzheimer’s disease centers. J Alzheimers Dis. 2012; 31:265-275. Publisher Full Text
  47. Wang SM, Han KD, Kim NY. Late-life depression, subjective cognitive decline, and their additive risk in incidence of dementia: a nationwide longitudinal study. PloS One. 2021; 16:e0254639. DOI
  48. Jorm AF. Is depression a risk factor for dementia or cognitive decline? A review. Gerontology. 2000; 46:219-227. DOI
  49. Green RC, Cupples LA, Kurz A. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch Neurol. 2003; 60:753-759. DOI
  50. Li G, Wang LY, Shofer JB. 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
  51. Richard E, Reitz C, Honig LH. Late-life depression, mild cognitive impairment, and dementia. JAMA Neurol. 2013; 70:383-389. DOI
  52. Alexopoulos GS. Vascular disease, depression, and dementia. J Am Geriatr Soc. 2003; 51:1178-1180. DOI
  53. Rashidi-Ranjbar N, Miranda D, Butters MA. Evidence for structural and functional alterations of frontal-executive and corticolimbic circuits in late-life depression and relationship to mild cognitive impairment and dementia: a systematic review. Front Neurosci. 2020; 14:253. DOI
  54. Dafsari FS, Jessen F. Depression-an underrecognized target for prevention of dementia in Alzheimer’s disease. Transl Psychiatry. 2020; 10:160. DOI
  55. Aznar S, Knudsen GM. Depression and Alzheimer’s disease: is stress the initiating factor in a common neuropathological cascade?. J Alzheimers Dis. 2011; 23:177-193. DOI
  56. Monereo-Sánchez J, Schram MT, Frei O. Genetic overlap between Alzheimer’s disease and depression mapped into the brain. Front Neurosci. 2021; 15:653130. DOI
  57. Livingston G, Sommerlad A, Orgeta V. Dementia prevention, intervention, and care. Lancet. 2017; 390:2673-2734. DOI
  58. Banasr M, Duman RS. Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets. 2007; 6:311-320. DOI
  59. Malberg JE, Schechter LE. Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs. Curr Pharm Des. 2005; 11:145-155. DOI
  60. Sheline YI, West T, Yarasheski K. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014; 6:236re4. DOI
  61. Caraci F, Copani A, Nicoletti F. Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur J Pharmacol. 2010; 626:64-71. DOI
  62. Winter Y, Korchounov A, Zhukova TV. Depression in elderly patients with Alzheimer dementia or vascular dementia and its influence on their quality of life. J Neurosci Rural Pract. 2011; 2:27-32. DOI
  63. Mourao RJ, Mansur G, Malloy-Diniz LF. Depressive symptoms increase the risk of progression to dementia in subjects with mild cognitive impairment: systematic review and meta-analysis. Int J Geriatr Psychiatry. 2016; 31:905-911. DOI
  64. Doraiswamy PM, Krishnan KR, Oxman T. Does antidepressant therapy improve cognition in elderly depressed patients?. J Gerontol A Biol Sci Med Sci. 2003; 58:M1137-M1144. DOI
  65. Herrera-Guzmán I, Gudayol-Ferré E, Herrera-Guzmán D. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res. 2009; 43:855-863. DOI
  66. Hashioka S, McGeer PL, Monji A. Anti-inflammatory effects of antidepressants: possibilities for preventives against Alzheimer’s disease. Cent Nerv Syst Agents Med Chem. 2009; 9:12-19. DOI
  67. Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 2004; 45:104-114. DOI
  68. Nebes RD, Pollock BG, Houck PR. Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine. J Psychiatr Res. 2003; 37:99-108. DOI
  69. Devanand DP, Pelton GH, Marston K. Sertraline treatment of elderly patients with depression and cognitive impairment. Int J Geriatr Psychiatry. 2003; 18:123-130. DOI
  70. Prado CE, Watt S, Crowe SF. A meta-analysis of the effects of antidepressants on cognitive functioning in depressed and non-depressed samples. Neuropsychol Rev. 2018; 28:32-72. DOI
  71. NICE. Dementia: assessment, management and support for people living with dementia and their carers.Publisher Full Text
  72. Dua T, Barbui C, Clark N. Evidence-based guidelines for mental, neurological, and substance use disorders in low- and middle-income countries: summary of WHO recommendations. PLoS Med. 2011; 8:e1001122. DOI
  73. Enache D, Fereshtehnejad SM, Kåreholt I. Antidepressants and mortality risk in a dementia cohort: data from SveDem, the Swedish Dementia Registry. Acta Psychiatr Scand. 2016; 134:430-440. Publisher Full Text
  74. Su JA, Chang CC, Wang HM. Antidepressant treatment and mortality risk in patients with dementia and depression: a nationwide population cohort study in Taiwan. Ther Adv Chronic Dis. 2019; 10DOI
  75. Burke AD, Goldfarb D, Bollam P. Diagnosing and treating depression in patients with Alzheimer’s disease. Neurol Ther. 2019; 8:325-350. DOI
  76. Goodarzi Z, Mele B, Guo S. Guidelines for dementia or Parkinson’s disease with depression or anxiety: a systematic review. BMC Neurol. 2016; 16:244. DOI
  77. Pelton GH, Harper OL, Tabert MH. Randomized double-blind placebo-controlled donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive impairment: a pilot study. Int J Geriatr Psychiatry. 2008; 23:670-676. DOI
  78. Bragin V, Chemodanova M, Dzhafarova N. Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am J Alzheimers Dis Other Demen. 2005; 20:21-26. DOI
  79. Livingston G, Huntley J, Sommerlad A. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020; 396:413-446. DOI
  80. Donegan K, Fox N, Black N. Trends in diagnosis and treatment for people with dementia in the UK from 2005 to 2015: a longitudinal retrospective cohort study. Lancet Public Health. 2017; 2:e149-e156. DOI


Flavio Ronchetto

Former-MD c/o ASLTO4-Ivrea Hospital, Turin, Italy

Martina Ronchetto

Techint Industrial Corporation, Milan, Italy



How to Cite

Ronchetto, F. and Ronchetto, M. 2022. The intricate connection between depression and dementia as a major challenge for clinicians. JOURNAL OF GERONTOLOGY AND GERIATRICS. 71, 2 (Dec. 2022), 77-86. DOI:
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