Comorbidity

1. Comorbidity Alzheimer’s disease (AD)

2. Pre-existing medical conditions related to Alzheimer’s disease Adapted from: Jiang et al. Curr Alzheimer Res 2013;10(8):852–867

3. Modifiable lifestyle factors related to Alzheimer’s disease (+) (-) Light-to-moderate (-) Excessive (+) (-) (-) Late-life (-) Mid-life (+) Adapted from: Jiang et al. Curr Alzheimer Res 2013;10(8):852–867

4. 78.6% of patients have >1 comorbidity1 Cumulative rates of comorbidities in patients with dementia Rates of multimorbidity in patients with dementia1 • A retrospective analysis of a UK health record database included 4,999 patients with dementia1 • The most frequent comorbidities in patients with dementia were:1 • Cardiovascular-related conditions (13.4–53.4%) • Chronic pain (33.5%) • Depression (23.5%) • Hearing loss (22.3%) • Constipation (14.2%) • Diabetes (14.0%) • The rates of multimorbidity – the presence of two or more chronic health conditions – was striking: 78.6% of patients with dementia suffered with >1 medical comorbidity1 UK=United Kingdom 1. Browne et al. BMJ Open 2017;7:e012546

5. The comorbidity burden of Alzheimer’s disease Comorbidity in patients with AD compared with control group1 Rates of diabetes, osteoporosis, depression, and cerebrovascular disease are increased in patients with AD1 *** ** *** *** ** **p≤0.01, ***p<0.001 AD=Alzheimer’s disease; COPD=chronic obstructive pulmonary disease 1. Wang et al. J Alzheimers Dis 2018;63(2):773–781

6. Costs associated with the comorbidities of AD • An American study found that treating the comorbidities of people with dementia generated $4,134 greater healthcare costs, in 2002 US dollars, compared with the costs of treating age-matched control cases1 • The increase in costs were attributed to higher usage of inpatient and skilled-nursing facilities1 • Better treatment and care of patients with AD could, therefore, reduce the costs of comorbid illness1 and reduce the burden on society • A retrospective analysis of a UK health record database found a correlation between the number of comorbidities and healthcare resource use2 • Compared with patients with AD and 2–3 comorbidities, patients with ≥6 comorbidities:2 • This would translate to a cost difference of £5,100 per person over 3 years (based on UK 2013 costs)2 68% higher prescription rate 62% higher hospitalisation rate 31% higher primary care consultation rate The comorbidities of AD add to the costs of treating an already burdensome disease1,2 AD=Alzheimer’s disease; UK=United Kingdom; US=United States 1. Hill et al. Neurology 2002;58(1):62–70; 2. Browne et al. BMJ Open 2017;7:e012546

7. The psychiatric comorbidities of Alzheimer’s disease

8. The psychiatric comorbidities of dementia • Although AD is considered to be a cognitive disorder, almost all patients develop neuropsychiatric symptoms as the disease progresses1,2 • Apathy, depression, and agitation are common neuropsychiatric disturbances observed in patients with dementia2 • The neuropsychiatric symptoms of dementia add to the burden of the disease – increasing morbidity and disability, and adding to the burden placed on caregivers2 Frequency of NPI disturbances in patients with and without dementia2 AD=Alzheimer’s disease; NPI=Neuropsychiatric Inventory 1. Lyketsos et al. Alz Dement 2011;7(5):532–539; 2. Lyketsos et al. Am J Psychiatry 2000;157:708–714

9. Depression and Alzheimer’s disease 48% • Depression has long been linked with dementia and AD, with prevalence estimates 25–75%1 • One meta-analysis, which included 20,892 patients with dementia across 57 studies, estimated a pooled prevalence of depression of 32% in patients with mild cognitive impairment2 • Another meta-analysis, including 63 studies, estimated the prevalence of depression in patients with AD to be as high as 48%3 • In the general population, the global prevalence of depression is estimated to be 4.4%4 – thus, the prevalence of depression in patients with AD is as high as 10 times that of the general population3,4 • There has been a great deal of research into the underlying pathology of depression in dementia, including studies investigating the importance of serotonin, brain imaging approaches, and genetic analyses1 The potential shared pathology of depression and dementia1 The endocrinology of depression may hasten degenerative processes Dementia Depression Vascular changes in dementia may be a risk factor for depression AD=Alzheimer’s disease 1. Li et al. Biomed Res Int 2014; 927804; 2. Ismail et al. JAMA Psychiatry 2017;74(1):58–67;3. Chi et al. Curr Alzheimer Res 2015;12(2):189–198; 4. Ferrari et al. PLoS One 2013;8(7):e69637

10. Anxiety and Alzheimer’s disease 70% • Symptoms of anxiety are common in patients with AD, symptoms can include fear, apprehension, irritability, ease to anger, agitation, restlessness, suspiciousness, and paranoia1,2 • In a study of 523 community-dwelling patients with AD:2 • Anxiety symptoms occurred in 70% of patients • Anxiety symptoms were significantly correlated with impairments in activities of daily living, and with other behavioural disturbances, including wandering, sexual misconduct, hallucinations, verbal threats, and physical abuse • Anxiety was commonly seen with depression; 54% of the sample showed symptoms of both • In a study that examined the characteristics of dementia combined with GAD, some differences were discerned:3 • GAD was more common among men with dementia than women with dementia (68% vs 33%, p<0.05) • Patients with dementia and GAD reported more severe worry (on the PSWQ-A scale) than those without GAD, but no differences on the categories of worries • The most common topics of worry were for their own health, and the health of their family • GAD was less common among patients with greater levels of cognitive impairment A better understanding of the characteristics of anxiety in dementia would allow patients to be treated in a more tailored fashion3 AD=Alzheimer’s disease; GAD=generalised anxiety disorder; PSWQ-A=Penn State Worry Questionnaire – Abbreviated 1. Seignourel et al. ClinPsychol Rev 2008;28(7):1071–1082; 2. Teri et al. J Gerontol A Biol Sci Med Sci 1999;54(7):M348–352;3. Calleo et al. Am J Alzheimers Dis Other Demen 2011;26(6):492–497

11. Agitation and Alzheimer’s disease 60–80% • The presence of agitation in patients with AD is associated with reduced quality of life for patients, earlier placement in a care home, and with earlier death1-3 • Agitation is a common symptom of AD; estimates of the prevalence of agitation in AD range as high as: • 60% amongst community-based patients with AD4 • 80% amongst patients with AD in residential care settings5 • For a long time, there was a lack of a consensus definition of agitation6 • In 2015, the IPA published a provisional definition of agitation, which it is hoped will advance the development of treatment options for patients with AD and agitation; the definition includes:6 • Excessive motor activity (e.g., pacing) • Verbal aggression (e.g., shouting) • Physical aggression (e.g., kicking) AD=Alzheimer’s disease; IPA=International Psychogeriatric Association 1. Peters et al. Am J Psychiatry 2015;172(5):460–465; 2. Banerjee et al. J Neurol Neurosurg Psychiatry 2006;77(2):146–148;3. Knapp et al. BMJ Open 2016;6(11):e013591; 4. Borsje et al. Int Psychogeriatr 2015;27(3):385–405; 5. Selbæk et al. J Am Med Dir Assoc 2013;14(3):161–169; 6. Cummings et al. Int Psychogeriatr 2015;27(1):7–17

12. Bipolar disorder, schizophrenia, and Alzheimer’s disease • Schizophrenia is a disorder characterised by the positive symptoms of hallucination and delusion, and the negative symptoms that represent loss of normal function1 • Although somewhat controversial, schizophrenia in mid-life has been associated with the development of AD in later life2,3 • A meta-analysis of 6 studies concluded that schizophrenia increased the risk of developing dementia by 2.3 times (p<0.01)4 • It has been suggested that certain psychiatric disorders and AD are associated with shared risk factors2,3 – meaning that an individual at risk of developing schizophrenia might be at a greater risk of developing dementia, and vice versa • Bipolar disorders (BD) bridge the diagnoses of schizophrenia and depression, and are characterised by periods of mania and periods of depression1 • One study of Taiwanese patients with bipolar disorder showed those individuals had a 5.6 times greater risk of developing dementia than control individuals5 • The possibility that bipolar disorder and AD share common underlying pathology has been studied, including the link between circulating Aβ levels and cognitive decline in patients with BD, and the role of neuroinflammation in both conditions2 AD=Alzheimer’s disease; BD=bipolar disorder 1. APA. DSM-5. 2013; 2. Garcez et al. An Acad Bras Cienc 2015;87(2 Suppl):1461–1473; 3. Zilkens et al. CurrAlz Res 2014;11:681–693; 4. Cai & Huang. Neurosci Dis Treat 2018;14:2047–2055;5. Chen et al. JAMDA 2015;16:504–508

13. Sleep disturbances and Alzheimer’s disease 65.7% • Sleep disturbances are commonly seen in patients with AD, and can include insomnia, arousal at night, and breathing disorders1-3 • One study included 63 patients with AD and 54 age-matched control individuals and compared performance on indices of cognitive ability and sleep quality:4 • Sleep latency was negatively correlated with measures of cognitive functioning, whilst sleep duration and efficiency were positively correlated with measures of cognitive function • Treatment of sleep disturbances in patients with dementia may, the authors suggest, improve a patient’s cognitive abilities Prevalence of sleep disturbances in patients with AD2 Clinical assessment of sleep disorders in patients with dementia should always include screening for secondary causes, medication side effects, and specific sleep disorders3 REM=rapid eye movement 1. Brzecka et al. Front Neurosci 2018;12:330; 2. Guarnieri et al. Dement GeriatrCognDisord 2012;33(1):50–58;3. Cipriani et al. Psychogeriatrics 2015;15(1):65–74; 4. Shin et al. J ClinNeurol 2014;10(3):203–209

14. The impact of the psychiatric comorbidities of Alzheimer’s disease • AD places a burden on caregivers, and as the disease advances, patients with AD become more dependent on others – physically and mentally:1 • The majority of patients with dementia are cared for at home, by a partner or other family member • Often, the caregiver is themselves elderly, and their ability to cope may be limited • The financial impact of caring for someone with dementia includes medical/care fees, and lost earnings The level of caregiver distress significantly increases with increasing number, and severity, of neuropsychiatric symptoms in patients with dementia (both p<0.001)2,3 • In one study that tracked cognitive decline in patients with AD over 6 years:4 • Baseline psychosis appeared to be linked to lower baseline cognition • Greater baseline psychosis or depression predicted greater cognitive decline across the study • Changes on indices of agitation/aggression were linked to the patient’s level of dependence The level of neuropsychiatric burden in patients with AD negatively affects the prognosis – a greater psychiatric symptom burden predicts a worse disease course2 AD=Alzheimer’s disease 1. Georges et al. Int J Geriatr Psychiatry 2008;23(5):546–551; 2. Mukherjee et al. Dement GeriatrCogn Dis Extra 2017;7(3):354-365; 3. Küçükgüçlü. Am J Alzheimers Dis Other Demen 2017;32(4):200–206; 4. Zahodne et al. Am J Geriatr Psychiatry 2015;23(2):130–140

15. The physical comorbidities of Alzheimer’s disease

16. The physical comorbidities of Alzheimer’s disease Odds of dementia-associated chronic comorbidities in men and women ≥65 years old1 Men Women Individuals with dementia have a significantly greater number of comorbidities than those without dementia1 CI=confidence interval; OR=adds ratio 1. Poblador-Plou et al. BMC Psychiatry 2014;14:84

17. Vascular disease and Alzheimer’s disease • The association between dementia and vascular disease risk has been investigated using data from the large-scale ARIC study2 • The study followed individuals over 20 years and tracked differences in brain amyloid deposition2 • It was found that a cumulative number of vascular risk factorsa was associated with an increase in brain amyloid deposition2 • The results suggest that exposure to vascular risk factors also constitutes a risk for dementia2 • Whilst more research is needed, the case in favour of risk factor management and appropriate counselling to promote vascular brain health is now clear3 The shared risks of vascular disease and AD1 • Genetic risks • APOE gene (apolipoprotein E) • MTHFR (methylenetetrahydrofolate reductase) • Medical risk factors • Hyper/hypotension • High cholesterol • Diabetes • Lifestyle/behavioural/environmental risk factors • Obesity • Lack of exercise and poor physical fitness • Smoking • Major depressive disorder • Fungal pathogens • Exposure to air pollution aRisk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dl; AD=Alzheimer’s disease; ARIC=atherosclerosis risk in communities 1. Santos et al. Alzheimers Dement (Amst) 2017;7:69–87; 2. Gottesman et al. JAMA 2017;317(14):1443–1450; 3. Breitner & Galasko. NeurolClinPract 2015;5(3):190–192

18. Cardiovascular disease and Alzheimer’s disease Risk factors for CVD and dementia1 • Many of the risk factors associated with CVD are thought to also increase the risk of cognitive decline in older people, and potentially the risk of AD1 • Because CVD risk increases with age, it has been suggested that the cognitive decline seen in patients with dementia leads to worsening self care, and a greater risk of CVD2 • In one study, patients with dementia were found to be at a greater risk of cerebrovascular disease (OR: men, 1.63; women, 1.57)3 • More research into the links between atherosclerotic and neurodegenerative disease may provide avenues for prevention and treatment in the future3 Lipids Inflammation Hypertension Lack of antioxidantvitamins Apolipoprotein E genotype Excessivealcoholintake Type 2diabetes Risk of dementia CVD=cardiovascular disease; OR=odds ratio 1. Stampfer. J Intern Med 2006;260(3):211–223;2. Stewart. J Neurol Neurosurg Psychiatry 1998;65:143–147;3. Poblador-Plou et al. BMC Psychiatry 2014;14:84

19. Thyroid function and Alzheimer’s disease • Dementia and thyroid dysfunction are both conditions that become more prevalent with advancing age1 • The function of the thyroid gland is controlled by hormones released from the brain2 • One theory holds that the neurodegeneration of AD leads to a decrease in the amount of TRH from the pituitary, causing low levels of TSH hormone, and a subsequent reduction in the levels of thyroid hormones in the circulation1,2 • However, in an analysis of the Framingham study data, low and high levels of circulating thyroid hormones were linked to an increased risk of AD – but only in women3 Normal control of thyroid function and possible links with AD1,2 Hypothalamus - TRH AD - Pituitary gland - TSH Thyroid gland T3 Calcitonin T4 AD=Alzheimer’s disease; TRH=thyroid releasing hormone; TSH=thyroid stimulating hormone 1. Tan & Vasan. J Alzheimers Dis 2009;16(3):503–507; 2. Medscape. Hypothyroidism. https://emedicine.medscape.com/article/122393-overview; 3. Tan et al. Arch Intern Med 2008;168(14):1514–1520

20. Diabetes and Alzheimer’s disease • A meta-analysis of 19 studies has shown that diabetes increases the risk of developing AD, and the risk of mild cognitive impairment1 • Thus, AD and diabetes may share risk factors, including overlapping metabolic risk factors1 • However, it has been suggested that, whilst under-nutrition is a problem in patients with dementia, some patients may develop preferences for sweet foods, or snack foods, which heighten their risk of developing diabetes2,3 Given the progressive and life-long nature of diabetes and dementia, and the fact that the prevalence of both conditions is increasing, healthcare systems need to prepare for patients with comorbid AD and diabetes2 AD=Alzheimer’s disease 1. Cheng et al. Intern Med J 2012;42(5):484–491;2. Scrutton & Brancati. Dementia and comorbidities. Ensuring parity of care. 2016;3. Ikeda et al. J NeurolNeurosurg Psychiatry 2002;73(4):371–376

21. Osteoporosis and Alzheimer’s disease • AD is considered to be a risk factor for the development of osteoperosis1 • Patients with AD commonly have lower bone-mineral density in certain areas – lower density can be a risk factor for fractures1,2 • In one study, which followed 264 patients with dementia and a control group of 1,098 individuals without dementia over a 3-year period, dementia was associated with a two-times greater risk of hip fracture (hazard ratio: 1.9, p<0.05)3 • Given the high incidence of comorbidity, patients with AD should be treated with prophylactic interventions aimed at preventing osteoporosis and fractures4 Although a large body of evidence now links osteoporosis and dementia, more research is needed to understand the connection, and potentially inform future treatments5 AD=Alzheimer’s disease 1. Chen & Lo. Tzu Chi Med J 2017;29(3):138–142; 2. Zhao et al. Scientific World Journal 2012; 2012: 872173; 3. Wang et al. BMC Neurol 2014; 14: 175; 4. Bednarski et al. MEDtube Sci 2014;(2)1:32–38;5. Downey et al. World J Orthop 2017;8(5):412–423

22. Urinary tract infections and Alzheimer’s disease • UTIs are a common infection seen in older individuals, including patients with dementia but are avoidable with the use of good care practices and hygiene1,2 • UTIs can cause a sudden-onset confusion or delirium in older patients; symptoms that can be mistaken for those of dementia3 • A retrospective analysis examined the prevalence of undiagnosed conditions in 265 patients with dementia:4 • 96 patients (36%) had an undiagnosed medical condition • 37 patients (14%) had bacteriuria – indicative of a risk of UTIs Percent of patients hospitalised for UTI2 *** Patients hospitalised for UTI (%) ***p<0.001 UTI=urinary tract infection 1. Scrutton & Brancati. Dementia and comorbidities. Ensuring parity of care. 2016; 2. Sampson et al. Br J Psychiatry 2009;195(1):61–66;3. Alzheimer’s Society. Urinary tract infections (UTIs) and dementia. Factsheet 528LP; 4. Hodgson et al. Alzheimer Dis AssocDisord 2011;25(2):109–115

23. Glaucoma and Alzheimer’s disease • A retrospective, population-based, case-control study was conducted using a Taiwanese health database to test whether glaucoma may be an early, non-memory manifestation of AD1 • Between 2000–2011, a total of 1,351 patients with AD were identified, who were compared against 5,329 control individuals1 • Patients with AD had a higher rate of glaucoma diagnosis than the control individuals – 7.9% versus 5.3%, p<0.0011 • Additionally, the risk of AD was greater in patients with glaucoma compared with controls, with an odds ratio of 1.51 Many lines of evidence point to a pathology shared by glaucoma and AD, leading some to consider glaucoma to be a non-memory manifestation of AD1-3 AD=Alzheimer’s disease 1. Lai et al. IntPsychogeriatr 2017;29(9):1535–1541; 2. Mancino et al. CurrNeuropharmacol 2018;16(7):971–977;3. Cesareo et al. Front Neurosci 2015;9:479

24. Seizures, epilepsy, and Alzheimer’s disease • Several lines of evidence point to a higher risk of seizures in patients with AD1-3 • One study pooled data from 10 clinical trials, including 3,078 patients, and found a significantly greater incidence of seizures in patients with poorer baseline cognition scores, as assessed by the MMSE, hazard ratio: 2.792 • Another study, that used the US Nationwide Inpatient Sample (NIS) 1999–2008, found that patients with AD were three times as likely to have seizures, odds ratio: 3.073 • However, the relationship is complicated – new-onset epilepsy in the elderly may well present with cognitive dysfunction, which may be incorrectly diagnosed as dementia1,4 • When seizures appear as a late feature of AD, there is a greater chance that the seizures are a result of the pathology underlying dementia; however, when they present as an early feature, there is a increased likelihood that the symptoms of dementia are a consequence of the epilepsy, or its therapy1 AD=Alzheimer’s disease; MMSE=mini–mental state examination 1. Abou-Khalil. Epilepsy Curr 2010;10(2):36–37; 2. Irizarry et al. Arch Neurol 2012;69(3):368–372;3. Sherzai et al. Epilepsy Behav 2014;36:53–56; 4. Høgh et al. Neurology 2002;58(2):298–301

25. Clinical guidelines and older patients with dementia • There are many clinical guidelines for the management of AD and dementia1 • A meta-analysis aimed to investigate how many of the available guidelines address the comorbidity burden commonly observed in older patients with dementia1 • Out of the total of 22 clinical guidelines that were included for analysis:1 • 20 (91%) addressed issues of treatment for older patients • 5 (23%) classified older patients by age • 13 (60%) addressed issues of comorbidity • 7 (32%) reported recommendations for patients with several comorbid conditions The majority of current clinical guidelines on dementia do not adequately address the issues of comorbidities in older patients – new guidelines are needed that address this knowledge gap1 AD=Alzheimer’s disease 1. Damiani et al. ClinInterv Aging 2014;9:1399–1407

26. While dementia is often viewed as an isolated condition, this patient group suffer from a high prevalence of comorbid medical conditions, with a number of conditions appearing to be ‘significantly associated’ with dementia Scrutton & Brancati. Dementia and Comorbidities. Ensuring Parity of Care. 2016