Dementia in the oldest old: a multi-factorial and growing public health issue

The population of oldest old, or people aged 85 and older, is growing rapidly. A better understanding of dementia in this population is thus of increasing national and global importance. In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropathological and imaging features, risk factors, and treatment of dementia in the oldest old. Prevalence estimates for dementia among those aged 85+ ranges from 18 to 38%. The most common clinical syndromes are Alzheimer's dementia, vascular dementia, and mixed dementia from multiple etiologies. The rate of progression appears to be slower than in the younger old. Single neuropathological entities such as Alzheimer's dementia and Lewy body pathology appear to have declining relevance to cognitive decline, while mixed pathology with Alzheimer's disease, vascular disease (especially cortical microinfarcts), and hippocampal sclerosis appear to have increasing relevance. Neuroimaging data are sparse. Risk factors for dementia in the oldest old include a low level of education, poor mid-life general health, low level of physical activity, depression, and delirium, whereas apolipoprotein E genotype, late-life hypertension, hyperlipidemia, and elevated peripheral inflammatory markers appear to have less relevance. Treatment approaches require further study, but the oldest old may be more prone to negative side effects compared with younger patients and targeted therapies may be less efficacious since single pathologies are less frequent. We also highlight the limitations and challenges of research in this area, including the difficulty of defining functional decline, a necessary component for a dementia diagnosis, the lack of normative neuropsychological data, and other shortcomings inherent in existing diagnostic criteria. In summary, our understanding of dementia in the oldest old has advanced dramatically in recent years, but more research is needed, particularly among varied racial, ethnic, and socioeconomic groups, and with respect to biomarkers such as neuroimaging, modifiable risk factors, and therapy.

in the mid-1980s in an eff ort to focus attention on this growing segment of the population [8,9]. It is important to note that the cutoff at age 85 is fairly arbitrary and largely serves to create consensus and uniformity between studies. As the population has continued to age since the term 'oldest old' was originally coined, there are those who may argue that the defi nition should be revised to include only those aged 90 and older.
In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropatho logical and imaging features, risk factors, and treatment of dementia in the oldest old after highlighting the limitations and challenges of current medical research in this important area. Th is subject does not lend itself well to a systematic review given the evolving nature of this fi eld. Th e information presented in this review was thus gathered via PubMed searches using a variety of search terms (including but not limited to 'oldest old' , 'dementia' , 'nonagenarian' , and 'centenarian') and review of references from these publications. Th roughout the text we will use the terms Alzheimer's dementia (AD) to refer to the clinical syndrome, while the phrase AD pathology will refer to the neuropathological entity. Lastly, while we ack nowledge that many important epidemiological studies have included large numbers of oldest old subjects [10], for the purposes of this review we have chosen to focus on studies that have included only the oldest old or who have reported results of subgroup analyses of the oldest old. Th is decision was made in an eff ort to focus on what is known about this specifi c population without diluting the results with those from the younger old.

Challenges of diagnosing dementia in the oldest old
Numerous challenges are identifi ed in diagnosing dementia among the oldest old (Table 1) and must be kept in mind whenever interpreting studies of dementia in this population. Many current research studies of the oldest old utilize the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) [11] or revised 3rd edition [12] criteria for a diagnosis of dementia. Criteria from both of these Diagnostic and Statistical Manual of Mental Disorders versions require manifestation of impair ment in memory and one or more other cognitive domains that is severe enough to produce signifi cant functional decline. In the oldest old population, the growing number of noncognitive physical (sensory, musculoskeletal) and medical co-morbidities contribute to functional decline and may lead to overdiagnosis of signifi cant functional decline. On the other hand, restricted cognitive demands on this population (who are generally no longer working and may have more limited household duties due to medical co-morbidities), societal perceptions about cognitive decline being a part of normal aging, or even the increased likelihood of cognitive impair ment in the collateral informants of oldest old compared with younger old patients, could lead to underdiagnosis of decline.
Accurate neuropsychological assessment is challenging given the limited age-specifi c normative data in this population. Consensus criteria for cognitive impairment often require >1 or >1.5 standard deviations below norms [13]. While a few recent studies describe normative neuropsychological data among the oldest old [14][15][16][17], more research is needed particularly among diff erent socioeconomic and ethnic/racial groups. Normative values for a neuropsychological battery among Puerto Rican nonagenarians were recently published [18], which will be helpful for testing Spanish-speaking older people but may have limited applicability to subjects outside Puerto Rico.
Lastly, while the current DSM-IV criteria may be appropriate for identifying typical cases of AD, in which memory is aff ected early, they would be less accurate for vascular dementia, dementia with Lewy bodies (DLB), or mixed dementia in which memory may be relatively spared in the earlier disease stages. Th e DSM-IV criteria are currently undergoing revision and the revised version is expected to at least partially address this concern. Furthermore, the recently updated National Institute on Aging-Alzheimer's Association guidelines for the diagnosis of AD incorporate a broadened understanding of the diff erent clinical presentations due to AD pathology.

Major epidemiological studies of the oldest old
Most study cohorts of the oldest old to date have either been small [19] or have been located in the United States or Europe, where predominantly white elders of high socioeconomic status were included. Most epidemiological data in this population were derived from four large cohort studies: the 90+ Study [6], the Leiden 85-Plus Study [20], the Vantaa 85+ Study [21], and the Women Cognitive Impairment Study of Exceptional Aging (WISE) [22], an ancillary study to the Study of Osteoporotic Fractures. Th e Kungsholmen Project [23,24], the Eurodem group [25], the Canadian Study of Health and Aging [26], and the Cache County Study on Memory, Health, and Aging [27] -while not dedicated exclusively to the study of the oldest old -all included very large cohorts of oldest old subjects, allow ing contributions to our understanding of dementia in this demographic (Table 2). Th e Cache County Study was conducted within a unique population of men in Utah noted to have among the longest life expectancies in the United States, potentially limiting applicability to the broader US or global population. Dementia is a growing global health concern with most of the projected increases in preva lence over the next 40 years expected to occur in low and middle-income countries [28]. Studies completed among diff erent racial, ethnic, and socioeconomic groups as well as across diff erent continents are thus greatly needed.

Prevalence and incidence of dementia in the oldest old
Based on these eight large epidemiological studies, dementia prevalence ranges from 18 to 38% among those aged 85 and older, and from 28 to 44% among those aged 90 and older ( Table 2). Th e Eurodem collaboration provided the fi rst large prevalence study as they pooled multiple studies across Europe, and reported that dementia preva lence and incidence continue to increase dramatically with age, even beyond age 90 [29]. More recently, the 90+ Study confi rmed that dementia prevalence and incidence continue to increase after age 90, but only for women [6,30]. Th e prevalence of dementia was found to double roughly every 5 years such that 27% of women aged 90 to 91 were diagnosed with dementia compared with 71% of women aged 98 to 99. Interestingly, the prevalence for men remained fairly stable, increasing only from 21% in the low-90s age group to 33% in men aged over 100. Th e overall prevalence of dementia for the entire cohort, which was mostly women, was 41%; the overall incidence of dementia was 18% and appeared to nearly double every 5 years after age 90. Th is disparity between demen tia prevalence among oldest old women versus oldest old men is consistent with most prior prevalence studies [20,23,24,26,[31][32][33]. Th is diff erence in prevalence is possibly due in part to women's diff erent reproductive hormonal exposure, increased capacity for survival with any degree of cognitive or medical illness as compared with men [34], as well as lower levels of education among current oldest old women, a factor that is associated with higher rates of dementia [22,30]. WISE focused on oldest old women and assessed dementia and mild cognitive impairment (MCI). Th ey reported that the prevalence of signifi cant cognitive impairment is 41% among women aged 85 and over. Of these, 18% were diagnosed with dementia (28% of women aged 90 and over), while 23% were diagnosed with MCI [22]. Th e dementia prevalence was somewhat lower than most prior studies, including the 90+ Study. Since MCI was not specifi cally assessed in prior studies, it is possible that some MCI cases were inaccurately categorized as dementia.
Th e 90+ Study and WISE were both comprised predominantly of white subjects with high socioeconomic status. Th ere is a small body of literature examining dementia prevalence in diff erent ethnic/racial groups within the United States. Th e North Manhattan Aging Project, for example, included a small cohort of 85+ year olds and found that dementia prevalence was higher in Latinos (63%) and African-Americans (59%) compared with non-Latino whites (30%) [35]. Rural populations are diffi cult to access, are understudied, and may be at increased risk for cognitive decline as demonstrated by a small study of elders living in rural Oregon aged 97+ that found near-universal cognitive impairment (61% with dementia; 29% with MCI) [36]. Th ese dramatic disparities require further study in larger populations and, if confi rmed, should stimulate research to better understand underlying risk factors or biological diff erences.
Th e variability in prevalence rates reported by diff erent studies may thus be indicative of diff erences between populations, diff erences in study design and diagnostic criteria, or even shifting prevalence rates over time. A recent Swedish study assessed dementia prevalence among the oldest old in two separate population-based assessments 5 years apart, each including >400 subjects with equivalent age and gender distributions. Th e prevalence of dementia in the earlier study was 27% versus 37% in the later study, in which subjects were taking significantly more β-blockers and anti-lipid agents [37]. Th ese fi ndings suggest that prevalence of dementia among oldest old may gradually increase over time either because patients with dementia are living longer or because increased medical interventions are inadvertently contributing to cognitive dysfunction in this vulnerable population.

Clinical presentation of dementia in the oldest old
Th ere is some debate in the literature regarding clinical subtypes of dementia in the oldest old, which may be, in part, due to methodological diff erences among studies. Th e most common subtypes of dementia identifi ed in the 90+ Study, the Canadian Study of Health and Aging, and a large European meta-analysis were AD and vascular dementia [26,30,38]. Th e most common subtypes in WISE, however, were AD and mixed dementia (defi ned as evidence of multiple etiologies), the latter of which was not assessed in most prior studies. Th ere is little known about behavioral changes that may accompany cognitive decline in the oldest old, aside from the development of depression as discussed below in the risk factor section. Th ere is some evidence that dementia, particularly AD, has a slower rate of progression (according to neuropsychiatric measures and cerebrospinal fl uid and imaging biomarkers) in the oldest old compared with the younger old [39]. Progression of functional decline and dependency, however, may be more rapid [40]. Th ese fi ndings could have major implications for treatment trials because any therapeutic drug eff ect, as measured by cognitive testing or other disease-specifi c biomarkers, could be much smaller than in a younger old population.

Alzheimer's dementia pathology and Lewy body pathology become less clinically relevant with age
Th ere is mounting evidence that the underlying neuropathological basis of dementia among the oldest old is quite diff erent from that of younger old patients. Two large autopsy series have reported decreasing density of AD pathology and decreasing association between AD pathology and dementia with advancing age [41,42]. Interestingly, cortical cerebral atrophy remained strongly associated with dementia despite advancing age [41]. Subsequently, an analysis of a large autopsy dataset from the National Alzheimer's Coordinating Center database noted that, while there was a continued association between AD pathology and clinical dementia even in the oldest old, this relationship declined with age, specifi cally for neurofi brillary tangle pathology [43]. Others have reported a continued association between AD pathology and dementia in the oldest old [44,45], but the strength of the association is generally less than that reported in the younger old [46]. Th ese fi ndings suggest that there is something other than or in addition to AD pathology that is driving cerebral atrophy, and resultant dementia, in the oldest old.
Similar fi ndings have been reported for Lewy body pathology. A large autopsy series reported an age-related decline in the prevalence of pathological diagnoses of DLB, less severe Lewy body pathology among cases that met pathological criteria for DLB, a shift in Lewy body distribution from diff use neocortical localization in the younger old to brainstem restricted localization, and no association between either AD or Lewy body pathology and cognitive impairment in the oldest old. In this study, none of the oldest old patients with dementia and brainstem restricted Lewy body pathology met the pathological criteria for AD, suggesting that an additional pathological process may have been responsible for their dementia [47]. Th e National Alzheimer's Coordinating Center dataset study also reported a decreasing association between Lewy body pathology and dementia with age [43]. Th ese fi ndings hint at the possibility that the pathological phenotype of DLB in the oldest old is diff erent from that in the younger old, and suggest that dementia in the oldest old is probably a result of mixed pathology rather than a single neuropathological entity.
Other recent work has investigated additional neuropathological contributors to dementia in the oldest old. Cerebrovascular pathology appears to correlate well with cognition across all ages, even among the oldest old [48]. With age, mixed pathology with AD and vascular disease has been reported to increase while pure AD or pure Lewy body pathology decreases [49]. A careful study assessing diff erent types of vascular pathology in the oldest old found that cortical microinfarcts correlate best with cognitive impairment rather than diff use white matter disease, periventricular disease, or even thalamic and basal ganglia lacunes [45]. Others report that as the prevalence of AD pathology begins to decline in extreme old age (95+), the prevalence of TAR DNA protein 43 (TDP-43)-associated hippocampal sclerosis begins to dramati cally increase, an association that is not seen in younger patients with hippocampal sclerosis [50]. Th e etiology of this TDP-43-associated hippo campal sclerosis of aging is currently poorly understood and requires further research.
Overall, there is mounting evidence that with advancing age there are increasing burdens of often co-morbid AD, vascular, and Lewy body pathology [51]. A recent large autopsy series demonstrated that AD plus vascular disease appears to be the most common type of mixed pathology in the oldest old. Furthermore, co-existing pathologies appear to increase risk for dementia, with proportionally greater numbers of oldest old patients with mixed pathology demonstrating dementia compared with the oldest old with single pathologies [52].

Imaging
Th ere is limited literature on imaging fi ndings in the oldest old. A postmortem radiological-pathological study from the Vantaa 85+ Study demonstrated that frontal lobe white matter lesions on magnetic resonance imaging were more common in brains that had concomitant AD pathology, and demonstrated that medial temporal lobe atrophy was not specifi c for AD pathology in the oldest old [53,54]. A computed tomography study of 236 subjects aged 85 and older found higher rates of white matter hypo densities in demented compared with nondemented subjects [55]. Furthermore, the severity of white matter lesion burden correlated with increasing risk for dementia. A small fl orbetapir F18 positron emission tomo graphy study of 13 nondemented older people from the 90+ Study reported that greater amyloid load was associated with worse cognitive performance and faster cognitive decline [56]. Th e authors argue that the discre pancy with neuropathological fi ndings arises from the high number of nondemented oldest old with substantial burden of amyloid pathology and suggest that these older people may be in the early preclinical stages of dementia. Th ese imaging fi ndings further support the idea that dementia in the oldest old has important contributions from multiple pathologies occurring simultaneously, but more imaging research is needed in this understudied population.

Risk factors for dementia in the oldest old
Studying dementia risk factors in the oldest old is limited by major confounders of survival eff ect and cohort eff ect. Survival eff ect may lead the same factors that increase risk of dementia and mortality in the younger old to no longer appear as risk factors for dementia in the oldest old, since those who survive despite these risk factors may somehow be resilient to them. Cohort eff ects may cause certain risk factors to become more or less relevant across time and place, due to, for example, increasing rates of mid-life obesity in the United States or declining rates of gender disparity in level of education. With these confounders in mind, we summarize fi ndings from the growing, but still incomplete, body of literature regarding dementia risk factors in this population (Table 3).

Cognitive reserve and level of education
Similar to studies of the younger old, both the 90+ Study and WISE have confi rmed an association between lower level of education and increased risk of dementia in the oldest old [6,22]. Th is fi nding highlights the importance of cognitive reserve, even in the most advanced ages. A lingering unanswered question remains of whether continued learning into advanced age is similarly protective.

Mid-life medical illness
A compelling analysis from the Honolulu Asia Aging Study of Japanese-American men found an association between mid-life general health and the likelihood of disability-free and cognitive-impairment-free survival until age 85. Healthy survival was signifi cantly associated with higher grip strength, leaner body habitus, absence of hyperglycemia, hypertriglyceridemia, or hypertension, avoidance of excessive alcohol intake or smoking, and higher level of education in mid-life [57]. Th is study was methodologically strong since it examined these men in mid-life and then re-examined them again in late life.

Late-life cardiovascular risk factors Diabetes
In the Vantaa 85+ Study, a history of diabetes was associated with more extensive vascular pathology at autopsy and a doubled dementia incidence during life [58]. In WISE, however, diabetes was not a risk factor for dementia -an unexpected fi nding that was attributed to increased mortality among patients with diabetes and cognitive impairment [59]. Overall, these data indicate that diabetes may increase the risk of dementia among the oldest old, specifi cally by increasing the burden of vascular, rather than AD, pathology, and they highlight the importance of controlling diabetes earlier in life before vascular injury has been sustained.

Hypertension
Th e Kungsholmen Project reported that systolic blood pressure <130 mmHg or >180 mmHg may increase risk of cognitive decline in people aged 75 and older [60]. More recently, both the Leiden 85-Plus and Vantaa 85+ study groups have examined this question among the oldest old. Th e Leiden 85-Plus group reported that higher blood pressure at age 85 was associated with less functional and cognitive decline over time, particularly among subjects with more physical disability, defi ned as disability in activities of daily living. Th is fi nding was independent of cardio vascular risk factors or even heart failure [61]. Th e authors speculate that the oldest old with physical disa bility may require higher blood pressure to maintain adequate cerebral perfusion to prevent cognitive decline. Th e Vantaa 85+ group reported increased mortality among the oldest old with lower blood pressure [21] but no signifi cant relationship between baseline blood pressure and incident dementia [62]. Th ese studies raise the question of whether relative hypotension in the oldest old is a direct consequence of the pathophysiology of dementia and other medical comorbidities or actually a risk factor for dementia. Th us, while midlife hypertension appears to be a risk factor for development of later-life dementia, more research is needed to pinpoint the ideal blood pressure range for the oldest old population.

Dyslipidemia
A higher total cholesterol level has been associated with improved memory function [63] and increased longevity [64] in the oldest old. Lower high-density lipoprotein cholesterol, however, has been associated with increased risk of dementia in the oldest old, independent of prior history of cardiovascular disease or stroke [65]. Th us, while it seems that controlling dyslipidemia in middle-life is quite important for the prevention of stroke and probably also dementia in later life, it is unclear whether there is a role for continued lipid control in very advanced age or whether aggressive lipid control could actually be detrimental. Further research in this area is needed.

Late-life medical illness
Th e above discussion of late-life cardiovascular risk factors raises the question of whether optimizing general health at or after the age of 85 has any measurable eff ect on dementia risk. A small observational study from the Oregon Brain Aging Study prospectively followed 100 optimally healthy subjects aged 85+ for an average of 5.6 years [66]. Over the study period, 23 subjects developed AD. Overall, the lifetime risk of AD was similar to the general population, but the age of onset was dramatically later (mean age of onset for AD was 100). Th is study suggests that while being in optimal general medical health at age 85+ does not guarantee against development of AD, it may delay the onset, which could have signifi cant public health implications.

Physical activity
Studies of younger older people have demonstrated that physical activity throughout the lifespan as well as physical activity in late-life is associated with reduced risk of dementia [67,68]. Th ere is mounting evidence that physical activity may remain important for modifying dementia risk even for the oldest old. An analysis from the Oregon Brain Aging Study prospectively followed 66 initially healthy men and women aged 85+, demonstrating that women who self-reported at least 4 hours of exercise per week had an 88% reduced risk of cognitive decline compared with women who reported exercising less than 4 hours per week. In men, a similar but insignifi cant association was found, probably due to the smaller sample size (27 men versus 39 women) [69]. Th ese fi ndings warrant further study and intervention trials in the oldest old population.

Depression
Depression is common among older adults and has been associated with increased risk of cognitive decline [70,71]. Until recently, little was known about the relation ship of depression to dementia among the oldest old. WISE found that 65% of women with depressive symptoms at baseline developed dementia over a 5-year follow-up compared with only 37% of those without signifi cant depressive symptoms [72]. Th ese fi ndings raise the question of whether depression is the earliest sign of cognitive decline or an actual risk factor for dementia. Research on subjects of various ages has demonstrated that a history of repeated episodes of major depression correlates with smaller hippocampal volumes [73], suggesting a possible causal relationship but not ruling out the possibility of a shared underlying disease process.

Delirium
Neurologists have long suspected that delirium may be a marker of preclinical dementia. Th is association was rigorously evaluated by the Vantaa 85+ investigators, where a history of delirium increased the incident dementia odds ratio more than eightfold, was associated with more severe dementia, increased mortality among those already demented, and was associated with faster decline in cognitive scores across the entire cohort. Th ese fi ndings support the idea that dementia is a risk factor for delirium and vice versa. Among the 288 members of their cohort that underwent autopsy, staging of classical neuro pathological entities such as AD, vascular, and αsynuclein pathology was associated with dementia in subjects without a history of delirium, but was not associated with dementia in subjects with a history of delirium [74]. Th is neuropathological fi nding, while under powered, raises the question of whether patients with delirium have been exposed to certain environmental or iatrogenic factors that play a signifi cant role in development and progression of dementia and whether delirium may not only be a marker of but a contributor to cognitive decline. Th ese are questions that require further research.

Apolipoprotein E genotype
Th e prevalence of apolipoprotein E (APOE) ε4 alleles drops signifi cantly with age (50% lower in octogenarians compared with middle-aged adults) while the prevalence of APOE ε2 alleles may remain static or increase slightly with age [75]. Th ese age-related shifts in APOE genotype prevalence are interesting in light of recent literature regarding APOE genotype and dementia risk in the oldest old. Th e Vantaa 85+ Study reported no increased incidence of dementia among oldest old APOE ε4 allele carriers compared with noncarriers. Among the oldest old already found to have dementia at the baseline assessment, however, the rate of progression was faster among APOE ε4 carriers [76]. Interestingly, WISE reported no evidence of a protective eff ect from the APOE ε2 allele with respect to lowering the risk of dementia in the oldest old, an association that has been reported previously for younger old. Th ese results are similar to those reported in the 90+ Study [77]. Th ese fi ndings may refl ect a survival eff ect or may suggest that once an older person reaches a very advanced age in a dementia-free state, then both the protective and deleterious eff ects of the APOE genotype may be outweighed by other more powerful genetic or environ mental factors. In conclusion, the role of APOE ε4 and APOE ε2 alleles may have declining relevance among dementia-free oldest old, thus arguing against the concept that the high-risk APOE ε4 allele may be fully penetrant if one lives long enough.

Peripheral infl ammation
Many large epidemiological studies have reported an association between higher levels of serum infl ammatory markers and increased risk of cognitive decline among older adults. Th e role of infl ammation among the oldest old remains unclear. For example, while the 90+ Study reported increased all-cause dementia prevalence and mortality among the oldest old with higher levels of Creactive protein, particularly among women, elevated Creactive protein levels did not increase the incidence of all-cause dementia [78,79]. Similarly, the Vantaa 85+ Study reported only a weak association between cognitive decline and infl ammatory markers among nondemented oldest old enrollees [80]. Others have reported a lower risk of dementia in relatives of oldest old cognitively intact subjects with elevated C-reactive protein, suggesting a possible genetic predisposition for successful aging in these subjects [81]. A rigorous autopsy analysis of brain gene and protein expression in demented and nondemented older adults reported that immune response genes are downregulated in nondemented younger old subjects, but are actually upregulated in nondemented oldest old subjects. Th us, increased immune activation in the brain may actually be protective against cognitive impairment in the oldest old [82]. An important question raised by this line of research is whether the fi nding is due to survival eff ect.

Treatment of dementia in the oldest old
To date, no drug trials have been targeted specifi cally at dementia in the oldest old. As mentioned above, the slower rate of pro gression among the oldest old with dementia may present a challenge to the design of clinical trials, as more subjects may be needed to observe an eff ect. Further more, the increasing prevalence of mixed pathologies among the oldest old renders targeted disease-modifying agents less appealing in this population.
Another important consideration in this population is the possibility that side eff ects may diff er from those observed in the younger old. For example, one study recently reported on the safety and tolerability of donepezil at 10 mg versus 23 mg dose in a large cohort of older patients with dementia, including 116 patients aged 85 to 90 years [83]. Th ey reported higher rates of diarrhea and urinary tract infections with increasing age regardless of dose. Th ey also found higher rates of fatigue, somnolence, and urinary incontinence with increasing age only in the 23 mg dose group. Th ese fi ndings raise concern that the 23 mg dose of donepezil may be relatively contraindicated in the oldest old.
Th ere are thus few data on which to base recommendations for alterations in the pharmacologic management of dementia in the oldest old. Th e geriatrician's mantra of 'start low and go slow' may be wisely employed in this population, which may be more prone to adverse side eff ects that their younger old counterparts.

Future directions and recommendations
As the global population of the oldest old continues to increase, the number of oldest old living with dementia in the United States could increase from 1 to 2 million in 2010 to more than 8 million by 2050 or 2060. Research into the prevalence, clinical presentation, neuropathology, and risk factors of dementia in the oldest old has advanced considerably in recent years, but further research is greatly needed. Improved diagnostic criteria and neuropsychological norms are needed to ensure accurate diagnosis in this population. Our understanding of the prevalence of dementia among the oldest old of diff erent socioeconomic, ethnic, and racial backgrounds is lacking. Small studies hint at dramatic disparities between dementia prevalence among Caucasians, Hispanics, African Americans, and rural populations in the United States; a fi nding that may ultimately render estimates from the major epidemiological studies profoundly inaccurate. Th e growing evidence for the importance of mixed pathology with Alzheimer's, vascular, and Lewy body pathology as well as TDP-43mediated hippocampal sclerosis and the possibility of additional undiscovered neuropathologies accounting for cognitive decline among the oldest old requires further study and makes targeted disease-modifying therapies less appealing in this population. Th e possibility of slower rates of progression of dementia among the oldest old may make it more diffi cult to adequately power therapeutic trials. Th e role of many traditional risk factors for dementia, such as cardio vascular risk factors and infl ammation, remain unclear in extreme old age, but may have important relevance for the delivery of primary care to these patients.
In conclusion, based on the current evidence, a focus on establishing and maintaining a healthy active lifestyle from mid-life onwards appears to be of utmost importance with respect to staving off dementia in old age. Once a patient reaches old age, aggressive treatment of cardiovascular risk factors should perhaps be approached with caution. In the event that dementia develops at the age of 85+, the utility of targeted therapy should be carefully weighed against potential side eff ects and the likelihood of mixed underlying pathology.