|Year : 2016 | Volume
| Issue : 1 | Page : 36-43
Recent advances in the understanding of cognitive decline among the elderly
Vinod Kumar Gangolli
Department of Psychiatry and Neuro-behavioral Sciences, McMaster's University, Hamilton, Ontario, Canada
|Date of Web Publication||6-May-2016|
Vinod Kumar Gangolli
Department of Psychiatry and Neuro-behavioral Sciences, McMaster's University, Hamilton, Ontario
Source of Support: None, Conflict of Interest: None
Age-associated cognitive decline or normal (nonpathological, normative, usual) cognitive aging has been found to be an inevitable part of increased age in humans and differs in extent among individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences.  The phenotype of normal cognitive aging is well-described. Some mental capabilities are well-maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory, and executive functions, some of which are underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive aging from genetics, general health, and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet, and lifestyle. Many of the effect sizes are small; some are poorly replicated and in some cases, there is a possibility of reverse causation, with prior cognitive ability causing the supposed "cause" of cognitive ability in old age.  Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive aging is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation, and lifestyle factors such as exercise. There are marked advances in brain imaging, with better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily aging also influence cognitive functions in old age. 
Keywords: Aging, cognition, heritability, neurobiology, risk factors
|How to cite this article:|
Gangolli VK. Recent advances in the understanding of cognitive decline among the elderly. J Geriatr Ment Health 2016;3:36-43
|How to cite this URL:|
Gangolli VK. Recent advances in the understanding of cognitive decline among the elderly. J Geriatr Ment Health [serial online] 2016 [cited 2019 Aug 25];3:36-43. Available from: http://www.jgmh.org/text.asp?2016/3/1/36/181914
| Introduction|| |
India is a "graying nation" by the United Nations' standards (i.e., >7% of total population). Currently, the elderly population is greater than 90 million and is expected to double by the year 2031. Two-third of the elderly population lives in rural areas.  With an increasingly aged population in India, cognitive impairment is a major health and social issue. Cognitive decline is among the most feared aspects of growing old. It is also the most costly, in terms of the financial, personal, and societal burdens. It is important because cognitive decline heralds dementia, illness, and death.
In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association to evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association reported there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and that some modifiable risk factors may be associated with a reduced risk of dementia. Specifically, the Association mentions that there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also states that there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline. 
Cognitive decline represents a major factor involved in the pathogenesis of age-related frailty and functional decline. Intellectual disability is associated negatively with life expectancy. When a person has had a decline in cognitive dysfunction, he/she becomes more vulnerable to the development of delirium when he/she develops physical illnesses. Persons with delirium often present with new-onset falls. As the population ages, risks for cognitive decline threaten the independence and quality of life of older adults and present challenges to the health care system. 
| Aging and cognition|| |
There is little age-associated decline in some mental functions such as verbal ability, some numerical abilities, and general knowledge, but other mental capabilities decline from middle age onward or even earlier.  The latter include aspects of memory, executive functions, processing speed, and reasoning. All of these so-called "fluid" mental abilities are important for carrying out everyday activities, living independently, and leading a fulfilling life. When one fluid mental domain declines, others also tend to do so.  Slowed speed of information processing appears to account for a substantial proportion of age-associated decline in all affected cognitive domains; the slowing begins by the 30s (as has the age-associated decline in some other aspects of cognitive functions). , The definition of "normal cognitive aging" includes people who would not meet the criteria for dementia or any of the varieties of "mild cognitive impairment". People differ greatly in the degree to which their brains decline with age. Identifying the risk factors for cognitive decline and the mechanisms of individual differences in age-associated cognitive decline is among the greatest challenges to improve the well-being of older people.
| Genetic contributions to cognitive aging|| |
Heritability studies - using data from twins and families with adopted children - have estimated that the heritability of general cognitive ability is 50%, increasing from childhood to adulthood into old age. Some studies have shown that heritability decreases in very old age though the contribution of genes to cognitive ability remains above 50%. It is likely that there are genetic influences on both the lifelong trait of intelligence and specifically on age-associated cognitive decline. ,
There have been a number of published associations between candidate genes and cognitive aging but the gene coding for apolipoprotein E (APOE), a risk factor for Alzheimer's disease, is one of the few to have been replicated in multiple studies. , In people within the normal range of cognitive aging, possessors of the E4 allele of the APOE gene perform slightly worse on general cognitive ability and on the specific domains of perceptual speed, episodic memory, and executive functioning. The influence of specific variants in 10 genes, e.g., BDNF, COMT, DISC1, and PRNP that had been previously associated with cognitive aging, cognitive ability, Alzheimer's disease, and autism were recently examined in a cohort of 1,000 Scots with cognitive ability test scores available from ages 11 years and 70 years. There was no evidence that they were associated with cognitive aging. 
| Neurobiology and cognitive aging|| |
The brain undergoes pronounced age-associated structural changes in old age. The most obvious is a steady decrease in brain size, balanced by increase in ventricular spaces, and cerebrospinal fluid. Brain atrophy accelerates in old age and shows an anterior-posterior gradient, with the most severe effects occurring in the prefrontal regions.  Compared with the overall brain, age-associated shrinkage is much smaller in the cerebral parenchyma. In the latter, atrophy starts much earlier in life and is more steady in gray matter (the neuronal cell bodies) and cortical thickness than in white matter (the nerve fibers connecting different brain areas). The white matter volume in the brain tends to be relatively stable in healthy adults until about the age of 70 years, when a steep decline, with an even more pronounced anterior-posterior gradient, can set in.  Also, cerebral dopamine receptor density depletes with age, which plays a central role in regulating attention and in modulating response to contextual stimuli.  A variety of mechanisms are likely to be causal in the normative age-associated decline in brain structure including hypertension, age-associated vascular and microvascular changes, oxidative stress, recurrent inflammation, and stress-related corticosteroid levels. 
It has been proposed that the loss of white matter integrity is an especially critical factor in normal cognitive aging since it leads to impaired information transfer between different cortical areas, from a loss of transfer speed in the case of demyelination to complete disconnection when axonal disruptions occur. Interactions between distant cortical areas are considered as crucial for the emergence of higher cognitive functions.  Until recently, problems with white matter integrity could mainly be detected as lesions that appear as hyperintensive patches on structural magnetic resonance imaging (MRI) scans and were mostly quantified using visual rating scales. Even though this procedure is laden with various measurement issues, small but consistent relationships with higher cognitive functions have been detected this way.  The advent of various new neuroimaging techniques, most notably diffusion tensor MRI, now allow for a much more detailed look at microstructural changes in cerebral white matter including fiber tract-specific assessments of white matter integrity (quantitative tractography). However, despite these technological advances, the studies to date report associations between structural brain differences and cognitive ability measures in old age that tend to be modest in size and sometimes elusive. 
| Risk factors for cognitive decline|| |
"The Dementia India Report 2010" estimated that 4.3 million people in India are living with dementia in 2015, and this number is projected to increase to 14.32 million by 2050. It was estimated the total societal costs of dementia for India would range between US$9.4 billion and US$13.7 billion, depending on the quantum of informal care (1.6 h per day or 3.7 h per day, respectively).  Decline in mortality rate in the elderly population has created a high incidence of morbidity. A key finding from the Global Burden of Disease (GBD) report is that chronic noncommunicable diseases are rapidly becoming the dominant causes of ill-health.  Comorbidities such as hypertension, strokes, metabolic disorders, dyslipidemia, chronic obstructive pulmonary disease, and arthritis, along with usual age-related cataracts and hearing loss, are on the rise in India. The GBD report indicates that dementia is one of the main causes of disability in later life. The World Alzheimer's Report  highlights the importance of comorbidity in the causation of disability and dependence. Therefore, in the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes on added importance.
In December 2013, the G8 nations - Canada, France, Germany, Italy, Japan, Russia, the United Kingdom, and the United States - created the WDC to provide global advocacy and leadership on key dementia challenges. The WDC is composed of individuals from around the world with a wide range of expertise and from a wide range of disciplines. One of the WDC's priority areas is potential risk reduction, both in the absence of treatments and after the time at which a treatment or treatments become available. The WDC requested the Alzheimer's Association to evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia to support the WDC in future recommendations. 
The Alzheimer's Association - from both scientific and population-based perspectives - weighed the evidence for cognitive decline and all-cause dementia based on the consistency of previous reviews, meta-analyses, and scientific peer-reviewed publications, the number and strength of individual studies (including the number of participants, duration of the study, and diversity of the participants), and the types of those studies (prospective, longitudinal, observational, or randomized controlled trials). The summary of the Association's evaluation was presented at the October 2014 WDC meeting. 
The author has summarized below the evidence of individual risk factors involved in age-related cognitive decline. According to the Alzheimer's Association's report, there are some unmodifiable risk factors, which have a strongest link to dementia that cannot be altered with medical treatment and modifiable risk factors with varying degree of link to dementia, which can be modified or altered with preventive medicine, medical treatment, and public health programs.
The greatest risk factors for late-onset "sporadic" Alzheimer's disease and other dementias are age,  family history,  and genetic susceptibility genes such as the APOE å4 allele; , none of these risk factors can be modified by medical interventions or by individual behavior. A 2010 National Institutes of Health (NIH) State-of-the-Science Conference found insufficient evidence, on a clinical level, to support the association of any modifiable risk factors and Alzheimer's disease. The evidence in many cases (particularly with respect to dementia as opposed to cognitive decline) is inconclusive due in large part to the limited data collected to date and the limited number of clinical studies involving specific interventions.
The Alzheimer's Association believes there is sufficient evidence:
- To support the association between several modifiable risk factors and a reduced risk for cognitive decline; and
- To suggest that some modifiable risk factors may be associated with reduced risk of dementia.
This report discusses these risk factors. Conclusions are summarized in [Figure 1]. 
|Figure 1: Strength of evidence on risk factors for cognitive decline |
M. Baumgart et al./Alzheimer's and Dementia 11 (2015) 718-726
Click here to view
Cardiovascular risk factors
Based on several meta-analyses, systematic reviews, and recent studies, more than a dozen prospective, observational, and longitudinal studies have shown lower cognitive performance and an increase in the risk of dementia among individuals with diabetes; on balance, the association between diabetes and dementia appears strong, but not conclusive. ,,, Further, a recent meta-analysis demonstrated that individuals with mild cognitive impairment (MCI) and diabetes were more likely to progress to dementia than individuals with MCI and no diabetes.  Some evidence suggests that diabetes increases the risk of dementia not only through vascular pathways, but also through interactions of other biological mechanisms related to diabetes itself. ,,
Based on several meta-analyses, systematic reviews, and individual studies, evidence from at least a half dozen prospective studies found that midlife obesity is associated with an increased risk of dementia. Most postulate this is a strong link, especially with regard to cognitive decline. ,, The association may change with age and being overweight - and, even possibly being obese - in later life has been associated with a reduced risk of dementia. , A recent, large, retrospective cohort study found a lower risk of dementia among those who were overweight even in midlife while those who were underweight had an elevated risk 
Meta-analyses of clinical trials and prospective, observational, longitudinal, and cross-sectional studies, including a Cochrane review, have not indicated a consistent relationship between high blood pressure and dementia; there is stronger evidence for a link with cognitive decline. , A systematic review of meta-analyses, observational studies, and randomized controlled trials has found that treatments of hypertension may reduce the risk of cognitive decline,  while another meta-analysis of longitudinal studies concluded the opposite.  Similar to data on the link between obesity and cognitive decline/dementia, studies demonstrate that later-life hypertension may be protective against cognitive decline. 
Hyperlipidemia (elevated cholesterol)
Systematic reviews of prospective studies have found mixed results on the relationship between both midlife and late-life high cholesterol levels and dementia including no association between cholesterol levels and vascular dementia.  While some observational studies have suggested that statin medications used to control cholesterol levels may reduce the risk of dementia,  a Cochrane review and systematic reviews found none or inconsistent evidence that the use of statins reduces risk.  The effect has not been seen to date in trials and high-quality cohort studies.
Lifestyle risk factors
According to several systematic reviews and meta-analyses, prospective and longitudinal studies have found strong evidence that current smoking increases the risk of cognitive decline and possibly dementia. ,, Quitting smoking may reduce the associated risk to levels comparable to that in those who have not smoked. , One study of a large multiethnic cohort found heavy smoking in middle age as much as doubled the risk of later-life dementia. 
According to systematic reviews and meta-analyses, more than 20 prospective, longitudinal, and cross-sectional studies as well as randomized controlled trials have shown physical activity and in some cases, mild physical activity, such as walking, to be associated with a decreased risk of cognitive impairment and/or improved cognitive function. ,, Several randomized controlled trials and a Cochrane review of such trials have found that inactive but otherwise healthy seniors, who begin an exercise program, experience significantly improved cognitive function.  Studies most consistently demonstrate that the exercise must be regular and tend toward the more vigorous side;  However, to date, they have failed to pinpoint the optimal duration of the activity, the type and intensity of the exercise, and what period during a person's lifespan it should occur that would maximize potential protective effects.
Information on the effects of various aspects of diet (including various nutrients and vitamins, foods, or food groups) on reducing risk is limited and conflicting. Given that many elements of the diet are interrelated and interactive, the idea of a whole dietary pattern approach has gained some ground. However, interpretation is challenging as dietary pattern often varies with other lifestyle factors and with demographic variables that may also have an impact on risk. A few cohort studies on the Mediterranean diet (relatively little red meat with an emphasis on whole grains, fruits and vegetables, fish, nuts, and olive oil) or a combined Mediterranean Dietary Approaches to Stop Hypertension (DASH) diet suggest an association between these diets and reduced risk. 
Meta-analyses of prospective and case-control studies of older adults suggest that small or moderate alcohol consumption by older individuals may decrease the risk of cognitive decline and dementia.  The evidence is not strong enough, however, to suggest that those who do not drink should start drinking, especially when weighed against the potential negative effects of excessive alcohol consumption, such as an increased risk of falls among older adults. 
A Cochrane review found three dozen randomized controlled trials of mental engagement/cognitive training interventions showing improvements in immediate and delayed recalls among those in the treatment group compared with the control group.  Systematic reviews of observational studies and randomized controlled trials reached similar conclusions.  However, based on these analyses, it is unclear whether the improvement is attributed specifically to the cognitive intervention. Despite the large number of trials, most were fairly small, and the data overall were inconclusive. As with physical activity, the "recipe" for any successful engagement remains unknown.
There are very few systematic reviews of the evidence on social engagement - such as doing volunteer work, joining a club, or going to church - as a potential protective factor against cognitive decline or dementia.  Some individual studies have shown that social activities, larger social networks, and a history of social contact are associated with better cognitive function and reduced risk for cognitive decline.  However, an independent coordinated analysis of four longitudinal studies found no effect on cognitive functioning.  Looking at the totality of the evidence, most studies in this area are small, are combined with cognitive training and/or physical activities (making it difficult to disaggregate the potential benefits solely of social engagement), and/or are too dissimilar in types of social engagement to draw any conclusions.
Other risk factors
Years of formal education
Among potentially modifiable risk factors, the most consistent evidence surrounds years of formal education (years of schooling in a classroom-based setting taught by professionally trained teachers). People with more years of formal education (measured by grade level attained and/or college attendance) or greater literacy have a lower risk for dementia than those with fewer years of formal education. ,
Traumatic brain injury
Solid evidence exists that moderate and severe traumatic brain injuries (TBIs) increase the risk of developing certain forms of dementia , and those who experience repeated head injuries (such as boxers, football players, and combat veterans) may be at an even higher risk. , While it is not known what specific aspect of TBI (force, repetitiveness, etc.) leads to disrupted brain function, the multiple studies taken together strongly link TBI to increased risk of cognitive decline and dementia.
Meta-analyses of cohort and longitudinal studies, as well as additional cohort studies, have shown a history of depression increases the risk for dementia.  While a recent cohort study found that depressive symptoms are independently associated with cognitive decline,  questions remain regarding whether depression may increase an individual's risk or be an early marker of brain changes associated with dementia. In addition, the effect of treatment for depression on subsequent cognitive functioning is not well-understood.
Several cohort and observational studies link sleep disturbances (for example, insomnia and sleep apnea) to increased risk of cognitive decline. , A recent study further suggested that treatment for breathing disorders that occur during sleep, specifically with continuous positive airway pressure (CPAP), may reduce the risk of cognitive decline.  However, how the exact nature or duration of an individual's sleep problems are related to increased risk is neither well-understood and nor is it clear whether the sleep disturbances are a cause of or a related precursor to dementia.
| Conclusion|| |
Rapid demographic changes taking place in the country and the country becoming a "graying" nation means that our care services and economies would have to be better placed to cope with the increasing burden of cognitive aging. In the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes an added importance. Even when effective treatments become available, risk reduction would remain a fundamental strategy for reducing the number of affected individuals. For many noncommunicable diseases with available treatments (such as diabetes, cancer, and heart disease), risk reduction efforts remain a major component of the campaigns against them.
The Alzheimer's Association states there is sufficiently strong evidence, from a population-based perspective, to conclude:
- Regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia.
- A healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.
The evidence has now reached a point when it can no longer remain simply an exercise in academic discussion. The public should know what the science concludes: Certain healthy behaviors known to be effective for diabetes cardiovascular disease and cancer, and are also good for brain health and for reducing the risk of cognitive decline. For maximum impact, a broader effort must be undertaken - and governments must be involved - to increase public awareness and education about known and potentially modifiable risk factors of cognitive decline and dementia. 
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Deary IJ, Corley J, Gow AJ, Harris SE, Houlihan LM, Marioni RE, et al
. Age-associated cognitive decline. Br Med Bull 2009;92:135-52.
India Census Report 2011. Office of the Registrar General and Census Commissioner, Government of India. Chapter 2, Population composition.
Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement 2015;11:718-26.
Banks WA, Morley JE. Memories are made of this: Recent advances in understanding cognitive impairments and dementia. J Gerontol A Biol Sci Med Sci 2003;58:314-21.
Hedden T, Gabrieli JD. Insights into the ageing mind: A view from cognitive neuroscience. Nat Rev Neurosci 2004;5:87-96.
Wilson RS, Beckett LA, Barnes LL, Schneider JA, Bach J, Evans DA, et al
. Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging 2002;17:179-93.
Der G, Deary IJ. Reaction time age changes and sex differences in adulthood. Results from a large, population based study: The UK Health and Lifestyle Survey. Psychol Aging 2006;21:62-73.
Salthouse TA. When does age-related cognitive decline begin? Neurobiol Aging 2009;30:507-51.
Deary IJ, Wright AF, Harris SE, Whalley LJ, Starr JM. Searching for genetic influences on normal cognitive ageing. Trends Cogn Sci 2004;8:178-84.
Deary IJ, Johnson W, Houlihan LM. Genetic foundations of human intelligence. Hum Genet 2009;126:215-32.
Small BJ, Rosnick CB, Fratiglioni L, Bäckman L. Apolipoprotein E and cognitive performance: A meta-analysis. Psychol Aging 2004;19:592-600.
Wisdom NM, Callahan JL, Hawkins KA. The effects of apolipoprotien E on non-impaired cognitive functioning: A meta-analysis. Neurobiol Aging 2011;32:63-74.
Houlihan LM, Harris SE, Luciano M, Gow AJ, Starr JM, Visscher PM, et al
. Replication study of candidate genes for cognitive abilities: The Lothian birth cohort 1936. Genes Brain Behav 2009;8:238-47.
Raz N, Rodrigue KM. Differential aging of the brain: Patterns, cognitive correlates and modifiers. Neurosci Biobehav Rev 2006;30:730-48.
Sullivan EV, Pfefferbaum A. Diffusion tensor imaging and aging. Neurosci Biobehav Rev 2006;30:749-61.
Whalley LJ, Deary IJ, Appleton CL, Starr JM. Cognitive reserve and the neurobiology of cognitive aging. Ageing Res Rev 2004;3:369-82.
Frisoni GB, Galluzzi S, Pantoni L, Filippi M. The effect of white matter lesions on cognition in the elderly - Small but detectable. Nat Clin Pract Neurol 2007;3:620-7.
Alzheimer′s and Related Disorders Society of India. The Dementia India Report: Prevalence, impacts, costs and services for Dementia. New Delhi, India: ARDSI; 2010.
World Health Organization. The Global Burden of Disease: 2004 Update. Geneva: WHO; 2008.
Prince M, Jackson J. Alzheimer′s Disease International World Alzheimer′s Report 2009.
Lautenschlager NT, Cupples LA, Rao VS, Auerbach SA, Becker R, Burke J, et al
. Risk of dementia among relatives of Alzheimer′s disease patients in the MIRAGE study: What is in store for the oldest old? Neurology 1996;46:641-50.
Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ. Diabetes and other vascular risk factors for dementia: Which factor matters most? A systematic review. Eur J Pharmacol 2008;585:97-108.
Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies. Intern Med J 2012;42:484-91.
Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: A meta-analysis of prospective observational studies. J Diabetes Investig 2013;4:640-50.
Roberts RO, Knopman DS, Cha RH, Mielke MM, Pankratz VS, Boeve BF, et al
. Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med 2014;55:759-64.
Cooper C, Sommerlad A, Lyketsos CG, Livingston G. Modifiable predictors of dementia in mild cognitive impairment: A systematic review and meta-analysis. Am J Psychiatry 2015;172:323-34.
Mushtag G, Khan JA, Kamal MA. Biological mechanisms linking Alzheimer′s disease and type-2 diabetes mellitus. CNS Neurol Disord Drug Targets 2014;13:1192-201.
De Felice FG, Ferreira ST. Inflammation, defective insulin signalling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 2014;63:2262-72.
Yang Y, Song W. Molecular links between Alzheimer′s disease and diabetes mellitus. Neuroscience 2013;250:140-50.
Sellbom KS, Gunstad J. Cognitive function and decline in obesity. J Alzheimers Dis 2012;30(Suppl 2):S89-95.
Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: A systematic review and meta-analysis. Obes Rev 2008;9:204-18.
Loef M, Walach H. Midlife obesity and dementia: Meta-analysis and adjusted forecast of dementia prevalence in the United States and China. Obesity (Silver Spring) 2013;21:E51-5.
Barnes DE, Covinsky KE, Whitmar RA, Kuller LH, Lopez OL, Yaffe K. Predicting risk of dementia in older adults: The late-life dementia risk index. Neurology 2009;73:173-9.
Dahl AK, Löppönen M, Isoaho R, Berg S, Kivelä SL. Overweight and obesity in old age are not associated with greater dementia risk. J Am Geriatr Soc 2008;56:2261-6.
Qizilbash N, Gregson J, Johnson ME, Pearce N, Douglas I, Wing K, et al
. BMI and risk of dementia in two million people over two decades: A retrospective cohort study. Lancet Diabetes Endocrinol 2015;3:431-6.
Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker D. The association between blood pressure and incident Alzheimer disease: A systematic review and meta-analysis. Epidemiology 2011;22:646-59.
Sharp SI, Aarsland D, Day S, Sonnesyn H, Ballard C. Alzheimer′s Society Vascular Dementia Systematic Review Group. Hypertension is a potential risk factor for vascular dementia: Systematic review. Int J Geriatr Psychiatry 2011;26:661-9.
Rouch L, Cestac P, Hanon O, Cool C, Helmer C, Bouhanick B, et al
. Antihypertensive drugs, prevention of cognitive decline and dementia: A systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS Drugs 2015;29:113-30.
Chang-Quan H, Hui W, Chao-Min W, Zheng-Rong W, Jun-Wen G, Yong-Hong L, et al
. The association of antihypertensive medication use with risk of cognitive decline and dementia: A meta-analysis of longitudinal studies. Int J Clin Pract 2011;65:1295-305.
Corrada M, Hayden KM, Bullain SS, Paganini-Hill A, De Moss J, Aguirre C, et al
. Age of onset of hypertension and risk of dementia in the oldest-old: The 901 study. Alzheimers Dement 2014;10(Suppl):501.
Anstey KJ, Lipnicki DM, Low LF. Cholesterol as a risk factor for dementia and cognitive decline: A systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry 2008;16:343-54.
Muangpaisan W, Brayne C; Alzheimer′s Society Vascular Dementia Systematic Review Group. Systematic review of statins for the prevention of vascular dementia or dementia. Geriatr Gerontol Int 2010;10:199-208.
McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev 2009;CD003160.
Anstey KJ, von Sanden C, Salim A, O′Kearney R. Smoking as a risk factor for dementia and cognitive decline: A meta-analysis of prospective studies. Am J Epidemiol 2007;166:367-78.
Cataldo JK, Prochaska JJ, Glantz SA. Cigarette smoking is a risk factor for Alzheimer′s disease: An analysis controlling for tobacco industry affiliation. J Alzheimers Dis 2010;19:465-80.
McKenzie J, Bhatti L, Tursan d′Espaignet E. WHO Tobacco Knowledge Summaries: Tobacco and Dementia. Geneva: World Health Organization; 2014.
Zhong G, Wang Y, Zhang Y, Guo JJ, Zhao Y. Smoking is associated with an increased risk of dementia: A meta-analysis of prospective cohort studies with investigation of potential effect modifiers. PLoS One 2015;10:e0118333.
Sabia S, Elbaz A, Dugravot A, Head J, Shipley M, Hagger-Johnson G, et al
. Impact of smoking on cognitive decline in early old age: The Whitehall II cohort study. Arch Gen Psychiatry 2012;69:627-35.
Rusanen M, Kivipelto M, Quesenberry CP Jr, Zhou J, Whitmer RA. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Arch Intern Med 2011;171:333-9.
Rolland Y, Abellan van Kan G, Vellas B. Physical activity and Alzheimer′s disease: From prevention to therapeutic perspectives. J Am Med Dir Assoc 2008;9:390-405.
Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease: A systematic review of prospective evidence. Psychol Med 2009;39:3-11.
Blondell SJ, Hammersley-Mather R, Veerman JL. Does physical activity prevent cognitive decline and dementia? A systematic review and meta-analysis of longitudinal studies. BMC Public Health 2014;14:510.
Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev 2008;CD005381.
Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: A meta-analytic study. Psychol Sci 2003;14:125-30.
Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer′s disease. Alzheimers Dement 2015;11:1007-14.
Peters R, Peters J, Warner J, Beckett N, Bulpitt C. Alcohol, dementia and cognitive decline in the elderly: A systematic review. Age Ageing 2008;37:505-12.
Mukamal KJ, Mittleman MA, Longstreth WT Jr, Newman AB, Fried LP, Siscovick DS. Self-reported alcohol consumption and falls in older adults: Cross-sectional and longitudinal analyses of the cardiovascular health study. J Am Geriatr Soc 2004;52:1174-9.
Martin M, Clare L, Altgassen AM, Cameron MH, Zehnder F. Cognition-based interventions for healthy older people and people with mild cognitive impairment. Cochrane Database Syst Rev 2011;CD006220.
Stern C, Munn Z. Cognitive leisure activities and their role in preventing dementia: A systematic review. Int J Evid Based Healthc 2010;8:2-17.
Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol 2004;3:343-53.
Karp A, Paillard-Borg S, Wang HX, Silverstein M, Winblad B, Fratiglioni L. Mental, physical and social components in leisure activities equally contribute to decrease dementia risk. Dement Geriatr Cogn Disord 2006;21:65-73.
Brown CL, Gibbons LE, Kennison RF, Robitaille A, Lindwall M, Mitchell MB, et al
. Social activity and cognitive functioning over time: A coordinated analysis of four longitudinal studies. J Aging Res 2012;2012:287438.
Meng X, D′Arcy C. Education and dementia in the context of the cognitive reserve hypothesis: A systematic review with meta-analyses and qualitative analyses. PLoS One 2012;7:e38268.
Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Influence of education and occupation on the incidence of Alzheimer′s disease. JAMA 1994;271:1004-10.
Lye TC, Shores EA. Traumatic brain injury as a risk factor for Alzheimer′s disease: A review. Neuropsychol Rev 2000;10:115-29.
Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: Substrates of dementia? Nat Rev Neurol 2013;9:211-21.
Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990;53:373-8.
Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, et al
. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 2005;57:719-26.
Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: Systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006;63:530-8.
Wilson RS, Capuano AW, Boyle PA, Hoganson GM, Hizel LP, Shah RC, et al
. Clinical-pathologic study of depressive symptoms and cognitive decline in old age. Neurology 2014;83:702-9.
Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology - A bidirectional relationship. Nat Rev Neurol 2014;10:115-9.
Sterniczuk R, Theou O, Rusak B, Rockwood K. Sleep disturbance is associated with incident dementia and mortality. Curr Alzheimer Res 2013;10:767-75.
Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, Lim J, et al
. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology 2015;84:1964-71.