Epidemiology and Burden​

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Epidemiology and Burden​

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Epidemiology and Burden​
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Causes and Underlying biology of AD​
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What causes Alzheimer’s disease?​
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AD has multifactorial etiology and is thought to result from many inter-related components, including genetic and environmental factors. ​

AD is classified according to the age of the person at onset – late-onset (≥65 years; most common form of AD) and early-onset (≤65 years of age).[Jiang et al., 2013] AD can be further classified into familial AD (FAD), which follows a genetically determined inheritance pattern, or sporadic AD, where there is no obvious inheritance pattern.1,4 Familial aggregation (i.e., two or more family members with the disease) is a putative risk for AD.[Winblad et al., 2016] Cases of early-onset familial AD (EOFAD) are now known to be caused by specific mutations in genes located on different chromosomes.2 Examples of modified genes are: the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the presenilin 2 (PSEN2) gene on chromosome 1.2

Genetics are also implicated in the development of sporadic late-onset AD. Natural variations (alleles) of the apolipoprotein E (ApoE) gene, on chromosome 19, influence the susceptibility of an individual to AD.3,4 The ApoE gene has three common alleles – ApoE 2, 3 and 4.[Bendlin et al., 2010] There is an increased risk of developing AD, and at an earlier age of disease onset, in people carrying one or two copies of the ApoE 4 allele.3 However, the ApoE 4 allele does not determine who will develop AD.1 The ApoE 2 allele shows a moderately protective effect against AD.1 Other susceptibility genes include CR1 (complement component receptor 1), PICALM (phosphatidylinositol-binding clathrin assembly protein), CLU (clusterin), TREM2 (triggering receptor expressed on myeloid cells 2), and TOMM40 (translocase of outer mitochondrial membrane 40 homologue).4

Environmental factors can also be implicated in the development of AD. These include exposure to certain chemicals, the presence of pre-existing medical conditions, and individual lifestyle factors.2 These environmental factors are discussed on the following slides.​

  1. Bendlin BB, Carlsson CM, Gleason CE, et al. Midlife predictors of Alzheimer’s disease. Maturitas 2010; 65 (2): 131–137.​
  2. Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10 (8): 852–867.​
  3. Sando SB, Melquist S, Cannon A, et al. APOE 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol 2008; 8: 9.​
  4. Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15 (5): 455–532.​
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Pre-existing medical conditions related to Alzheimer’s disease​
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The slide presents an overview of various pre-existing medical conditions that are associated with AD.​

There is a good body of evidence to support an association between traumatic brain injury (TBI), diabetes, and depression with an increased risk of dementia.1 The pathogenesis of depression and AD, putatively, involve common molecular mechanisms, such as chronic inflammation, and hyperactivation of the hypothalamic–pituitary–adrenal axis.1

Cerebrovascular events (e.g., stroke, cerebral embolism, microinfarct, white matter intensities) are associated with cognitive impairment and/or an increased risk of dementia, potentially caused by direct damage to the brain regions involved in cognitive function, increased β-amyloid (Aβ) deposition (by promoting production and disrupting clearance mechanisms), or an enhanced inflammatory response.1 In contrast, cancer appears to have an inverse relationship with the development of AD, as studies have shown a decreased risk of AD in patients surviving cancer.1 This may be due to the common (often reciprocal) molecular mechanisms involved in cancer and in the development of AD (e.g., factors which regulate apoptosis, and the cell cycle).1

  1. Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10 (8): 852–867.​
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Modifiable lifestyle factors related to Alzheimer’s disease​
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The slide presents an overview of the various modifiable lifestyle factors that are associated with AD.​

There is evidence to suggest that moderate coffee consumption, physical activity, and cognitive activity, all play a preventative role in AD.1 Animal studies have shown that caffeine reduces oxidative stress, inhibits Aβ production, protects against disruptions of the blood–brain barrier, and improves cognitive performance.1 Physical activity can help to maintain normal brain function in the elderly, reducing the risk of developing AD, and there is evidence to suggest that physical activity may also prolong survival in people with AD.1 The protective effect of physical activity may be mediated by factors such as a reduction in Aβ levels, increased cerebral perfusion (blood flow to the brain), enhanced neurogenesis in the brain, and reduced oxidative stress, among other factors.1 Cognitive activity may protect against the progression of AD by preventing the deposition of Aβ and increasing cognitive reserve (i.e., the resilience to neuropathological damage).1

There is a good body of evidence to support an association between smoking and the risk of developing AD, which appears to be influenced by ApoE status (increased risk of AD in ApoE 4 carriers).1

Light-to-moderate alcohol consumption reduces the risk of AD, possibly more so in women than in men, due to effects such as elevated high-density lipoprotein cholesterol, reductions in fibrinogen (and other thrombotic factors), reduced insulin resistance, and improved endothelial function.1 In contrast, excessive alcohol intake has detrimental effects on the brain (possibly due to brain atrophy and to smaller brain volumes, or even due to secondary complications of excessive alcohol intake such as TBI, stroke, etc.), and may predispose people to dementia.1

The relationship between body weight and the risk of AD depends on the age at which the body weight is measured.1 Evidence suggests that a higher body mass index (BMI) or obesity in mid-life is associated with an increased risk of dementia, whereas in late-life an inverse association has been reported.1

  1. Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10 (8): 852–867.​
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Accumulation of Alzheimer’s disease risk factors over time​
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The risk factors and protective factors for the development of AD/dementia accumulate over a lifetime, as shown in this slide.1,2,3

Many risk and protective factors for dementia and AD have been proposed and investigated; the most pronounced risk factors are advancing age and carrying one or two ApoE ε4 alleles.3 The presence of cardiometabolic risk factors, such as hypertension, high cholesterol, and obesity, in young adulthood or in middle life (i.e., <65 years), and not necessarily in later life (i.e., ≥75 years), are associated with an increased risk of dementia and AD.3 Therefore, interventions targeting lifestyle-related cardiovascular risk factors (e.g., unhealthy diet, smoking, alcohol misuse) would be best initiated in young adulthood/middle age, in order to delay the onset of dementia.3 Similarly, engaging in education, physical exercise, and a good level of mental and social activity, from young adulthood, may reduce the risk of developing dementia.3

Psychosocial factors, such as high education and socioeconomic status, high work complexity, rich social network and social engagement, and mentally stimulating activity are considered protective.3 Diet and nutritional factors, such as Mediterranean diet, polyunsaturated fatty acid and fish-related fats, vitamin B6, vitamin B12, and folate, antioxidant vitamins (A, C, E), vitamin D are also considered protective against dementia and AD.3 There is evidence that some drugs, e.g., antihypertensive drugs, statins, hormone replacement therapy, and non-steroidal anti-inflammatory drugs may also be protective.3

  1. Bendlin BB, Carlsson CM, Gleason CE, et al. Midlife predictors of Alzheimer’s disease. Maturitas 2010; 65 (2): 131–137.​
  2. Jiang T, Yu J-T, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10 (8): 852–867.​
  3. Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15 (5): 455–532.​
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Putative risk and protective factors for late-onset dementia and Alzheimer’s disease​
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Many risk and protective factors for dementia and AD have been proposed and investigated; however, the evidence to support the factors listed on this slide is variable, and the relevance of several proposed factors is open to debate.1 The most pronounced risk factors are advancing age and carrying one or two ApoE ε4 alleles.1

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  1. Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15 (5): 455–532.​
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Burden of AD
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Projected increase in the prevalence of Alzheimer’s disease​
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Worldwide, in 2015, an estimated 46.8 million people were living with dementia.5 In the US, in 2016, an estimated 5.2 million people >65 years of age were affected by AD.3 Age is one of the greatest risk factors for the development of late-onset ‘sporadic’ AD, but AD is not a normal part of aging, and old age alone is not sufficient to cause the disease.1 The prevalence of dementia is estimated to double with every 5-year increment in age after 65 years.4

Over the past decades, there has been a shift in the developed world towards higher standards of living, higher standards of healthcare, and lower birth rates. Similar changes are also taking place in the developing world. As a result, more people are living well into old age and, therefore, there are more people suffering from the associated neurodegenerative diseases, such as dementia. Awareness of dementia has risen, both among the general population and the medical community, and the demand for new treatments, and eventually a cure, is also rising.

Since the elderly population is growing, and the prevalence of dementia increases with age, it is logical to assume that the number of dementia cases will also increase. The WHO predicts that the prevalence of dementia will almost double every 20 years, to give a worldwide prevalence of 131.5 million by 2050.5 The rise in dementia cases is predicted to be higher in developing countries than in the developed world,2 possibly due to the fact that the population of older people in developing countries looks set to increase dramatically over the next few decades, and to a greater extent than has been predicted for developed countries.5

 

  1. Alzheimer’s Association. Alzheimer’s Association Report. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12 (4): 459–509.
  2. Ferri CP, Prince M, Brayne C, et al.; Alzheimer’s Disease International. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366 (9503): 2112–2117. 
  3. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 2013; 80 (19): 1778–1783. 
  4. World Health Organization (WHO). Dementia: a public health priority. 2012.
  5. World Health Organization (WHO). World Alzheimer Report 2015. The global impact of dementia. An analysis of prevalence, incidence, cost and trends. 2015.
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Domains of Alzheimer’s disease​
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Three domains of AD feed into overall global function, all of which can increase the burden on caregivers.​

  • Cognitive function – higher mental processes such as memory, reasoning, attention, and language, that facilitate information gathering and processing.​

  • Activities of daily living (ADLs) – the ability to perform everyday tasks such as, washing and dressing, preparing food, shopping, dealing with finances, driving, etc. ​

  • Behavior – the manner in which a person conducts themselves, especially towards others.​

As AD progresses, functioning – the ability to perform ADLs, and to complete complex tasks – becomes increasingly impaired, such that individuals become more dependent on caregivers. Individuals may also develop behavioral and psychological disturbances, which further increase the burden of care.​

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Alzheimer’s disease has a large impact on society​
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AD has a considerable public health impact. In the US, in 2014, AD was listed as the sixth leading cause of death (based on ICD-10, G30 classification) for the total population, after heart disease, malignant neoplasms, chronic lower respiratory diseases, accidents (unintentional injuries), and cerebrovascular diseases.[Kochanek et al., 2016] In individuals over 65 years of age, AD was the fourth leading cause of death in the US, in 2014, after heart disease, malignant neoplasms, cerebrovascular diseases, and chronic lower respiratory diseases.3 In 2000, AD was the eighth leading cause of death in the US, and the sixth leading cause of death in adults aged ≥65 years.4

Data from the National Center for Health Statistics have shown a considerable increase in the number of deaths from AD over the period from 2000 to 2014, whereas the number of deaths from other more treatable causes is decreasing.3,4 The increase noted for AD is thought to be due to changing patterns in the reporting of deaths on death certificates, as well as a rise in the actual number of deaths attributable to AD.1 Data from the Chicago Health and Aging Project (CHAP) estimate that there will be 700,000 deaths among people with AD who are ≥65 years, in the US, in 2016, comprising one-third of all older adult (≥65 years) deaths.5 The number is estimated to rise to 1.6 million by 2050 (43% of all older adult deaths).5

With a growing older population, and the associated expected increase in the number of people developing AD, the impact on healthcare resources and society will be considerable. Three-quarters of people aged ≥80 years with AD will be admitted to a nursing home (compared with 4% of the age-matched general population).2

The cost of AD to the healthcare system, and to families and caregivers, is considerable. The total cost of care in the US for all individuals ≥65 years old who have AD (and other dementias) is estimated to be $236 billion; Medicare/Medicaid is expected to cover almost 70% of the cost.1 More than 15 million Americans provide unpaid care for people with AD and other dementias; these are mainly family members or friends.1 In 2015, this unpaid care amounted to an estimated 18.1 billion hours, valued at $221.3 billion.1

 

  1. Alzheimer’s Association. Alzheimer’s Association Report. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12: 459–509.
  2. Arrighi HM, Neumann PJ, Lieberburg IM, Townsend RJ. Lethality of Alzheimer disease and its impact on nursing home placement. Alzheimer Dis Assoc Disord 2010; 24 (1): 90–95.
  3. Kochanek KD, Murphy SL, Xu J, Tejada-Vera B. Deaths: Final data for 2014. National Vital Statistics Reports 2016; 65 (4): 1–122. 
  4. Miniño AM, Arias E, Kochanek KD, et al. Deaths: Final data for 2000. National Vital Statistics Reports 2002; 50 (15): 1–120. 
  5. Weuve J, Hebert LE, Scherr PA, Evans DA. Deaths in the United States among persons with Alzheimer’s disease (2010–2050). Alzheimers Dement 2014; 10: e40–e46. 
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Alzheimer’s disease has a large impact on caregivers​
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The pressure of AD on caregivers is highlighted on this slide. 

Information from the dementia carer’s survey shows that the time spent caring for people with dementia increases as the disease severity progresses.1 However, it is quite striking that one-fifth of carers for people with early stage AD spent >10 hours per day providing care.1 Of all the caregivers that participated in the survey, 32% spent ≥14 hours per day caring for the person with dementia, and a further 12% dedicated 10–14 hours per day to caregiving.1

  1. Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551. ​
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Caregiver burden
References
  1. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12 (4): 459–509.​
  2. Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551.​
  3. Kamiya M, Sakurai T, Ogama N, et al. Factors associated with increased caregivers’ burden in several cognitive stages of Alzheimer’s disease. Geriatr Gerontol Int 2014; 14 (Suppl 2): 45–55.​
  4. Suehs BT, Shah SN, Davis CD, et al. Household members of persons with Alzheimer’s disease: health conditions, healthcare resource use, and healthcare costs. J Am Geriatr Soc 2014; 62 (3): 435–441.​
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Caregiver burden​
References
  1. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12 (4): 459–509.​
  2. Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551.​
  3. Kamiya M, Sakurai T, Ogama N, et al. Factors associated with increased caregivers’ burden in several cognitive stages of Alzheimer’s disease. Geriatr Gerontol Int 2014; 14 (Suppl 2): 45–55.​
  4. Suehs BT, Shah SN, Davis CD, et al. Household members of persons with Alzheimer’s disease: health conditions, healthcare resource use, and healthcare costs. J Am Geriatr Soc 2014; 62 (3): 435–441.​
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Caregiver burden
References
  1. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12 (4): 459–509.​
  2. Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551.​
  3. Kamiya M, Sakurai T, Ogama N, et al. Factors associated with increased caregivers’ burden in several cognitive stages of Alzheimer’s disease. Geriatr Gerontol Int 2014; 14 (Suppl 2): 45–55.​
  4. Suehs BT, Shah SN, Davis CD, et al. Household members of persons with Alzheimer’s disease: health conditions, healthcare resource use, and healthcare costs. J Am Geriatr Soc 2014; 62 (3): 435–441.​
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Caregiver burden
References
  1. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12 (4): 459–509.​
  2. Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551.​
  3. Kamiya M, Sakurai T, Ogama N, et al. Factors associated with increased caregivers’ burden in several cognitive stages of Alzheimer’s disease. Geriatr Gerontol Int 2014; 14 (Suppl 2): 45–55.​
  4. Suehs BT, Shah SN, Davis CD, et al. Household members of persons with Alzheimer’s disease: health conditions, healthcare resource use, and healthcare costs. J Am Geriatr Soc 2014; 62 (3): 435–441.​
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Caregiver burden
References
  1. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12 (4): 459–509.​
  2. Georges J, Jansen S, Jackson J, et al. Alzheimer’s disease in real life – the dementia carer’s survey. Int J Geriatr Psychiatry 2008; 23 (5): 546–551.​
  3. Kamiya M, Sakurai T, Ogama N, et al. Factors associated with increased caregivers’ burden in several cognitive stages of Alzheimer’s disease. Geriatr Gerontol Int 2014; 14 (Suppl 2): 45–55.​
  4. Suehs BT, Shah SN, Davis CD, et al. Household members of persons with Alzheimer’s disease: health conditions, healthcare resource use, and healthcare costs. J Am Geriatr Soc 2014; 62 (3): 435–441.​
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Conclusion​
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AD is a complex disease of multifactorial etiology that, despite a wealth of clinical research, is not yet completely understood. Among various genetic and environmental factors implicated in AD, age is the most important risk factor for the disease. As the aging population grows, the prevalence of AD is increasing (more so after the age of 65 years), as is the burden of the disease on patients, caregivers, healthcare systems, and on society as a whole. While clinical research continues to search for a cure, it is important to remember those individuals who are currently living with AD, for whom more effective symptomatic treatments would make a big difference to their lives.​

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