Figure 25.1

Overlap in neuropathology among dementia and non-dementia cases in the 90+ Study.

Corrada et al., Curr Alzheimer Res. 2012 July 1; 9(6): 709–17. (Reproduced with permission [47].)

This study further noted that Braak tangle stage was superior to Braak plaque stage or NIA-Reagan criteria in distinguishing clinical dementia, leading authors to speculate that accumulation of neurofibrillary tangles plays a more critical role in the oldest old [47]. Another autopsy study of individuals ranging from 62 to 103 years of age noted that the correlation between burden of both plaque and tangle pathology and dementia severity decreased two- to three-fold with increasing age [48]. However, this study found that choline acetyltransferase and acetyl-cholinesterase activity as a function of dementia severity remained despite differences in neuropathology [48].

In the elderly population, there often exists an accumulation of more than one disease process which impacts cognition. Multiple pathologies account for about 50% of cases in one study (mean age 85 years), and are most frequent among those older than age 90, and the probability of clinical dementia increases with dual compared to single pathologies [3, 52, 53]. Cerebrovascular disease is the most common comorbid pathology, with greater frequency in Alzheimer’s disease than in healthy age-matched controls or in combination with other neurodegenerative disorders [54].

Although cerebrovascular pathology is often present in dementia, pure vascular dementia occurring with low neuritic plaque burden is not common in the oldest old, accounting for only 6% of dementia cases over age 85 in one autopsy series, and demonstrates a lesser association with cardiovascular risk factors than seen in the younger old [55]. The Rush Memory and Aging Project and Religious Orders Study identified a 42% rate of cerebral infarcts, with or without other pathologies [52]. One study identified grossly apparent circle of Willis atherosclerosis increasing with age and occurring in more than 77% of Alzheimer’s disease cases compared to 47% of controls and another noted an association between autopsy cerebrovascular disease and the severity of Alzheimer’s disease [54, 57]. The authors theorize interrelated mechanistic pathways between vascular disease and Alzheimer’s disease.

Hippocampal sclerosis is more common in older age. Among over 1,000 consecutive dementia autopsy cases in Vienna, Austria, only cases over age 80 with mixed AD/vascular pathology had hippocampal sclerosis (accounting for 3.6% of AD cases in this age group) [55]. In the 90+ Study, investigators noted that specific neuronal loss and the gliosis of hippocampal sclerosis occurred in 19% of dementia cases and none of their non-dementia cases, providing evidence of specificity [51]. Here, hippocampal sclerosis was tightly linked to TDP-43 burden (79% of dementia cases with hippocampal sclerosis). Among 443 autopsies of Japanese-Americans in the Honolulu Asia Aging Study, about one-half of cases with hippocampal sclerosis (n = 41) appeared to be linked to AD [58].

Lewy body pathology appears to increase with age but is present in subjects with and without dementia. A Japanese study of 102 subjects including 29 with dementia (mean age 80 years) identified Lewy body pathology in 41% of dementia subjects and that concurrent severe AD pathology was associated with worse prognosis [59]. The Religious Orders Study (ROS) and the Memory and Aging Project (MAP) combined (n = 134, mean age in the early 80s) identified Lewy bodies in 13.4%, and, in the 90+ Study, 20% of dementia cases compared to 10% of non-dementia cases had limbic Lewy bodies or neuritis [20, 51].

Diagnostic challenges and clinical considerations: There are a number of technical and clinical challenges that impede precise diagnosis in the oldest old, where changes in cognitive performance may be due to a number of factors. To begin, the basis for assessing cognitive impairment requires comparison to what is “normal” for any age group, and normative data for the oldest old are limited [60–62]. Since cognitive impairment insufficient to meet dementia criteria is frequent in elders, accounting for about one-quarter to one-third of subjects over the age of 90, what constitutes “normal” in these normative samples is subject to scrutiny [63, 64]. This is exacerbated by the view that changes in some neuropsychological measures, such as slowed processing speed, are part of typical aging, despite the fact that they have been correlated to changes in white matter integrity [65].

Other factors such as age-associated physiological changes and non-central nervous system comorbidities can influence performance on cognitive tests or limit functional performance. Sensory changes, including vision and hearing changes, can have a profound impact on cognitive test performance and are sometimes difficult to distinguish from cognitive decline [66]. Ceiling effects hinder accurate assessment of functional decline, since the typical maximal level of physical and everyday activity decreases in older age in the absence of cognitive changes [2, 67]. The incidence of disability in the 90+ Study was over 15% per year and was only partially associated with cognitive decline [1, 4, 5].

The likelihood of multiple pathologies adds to the complexity of identifying a precise diagnosis through clinical data alone in the oldest old. About one-half of those over age 90 with dementia can be expected to have more than one pathology at autopsy [3, 7, 9]. This factor challenges clinical trials targeting one disease, and represents a significant burden for the interpretation of biological markers in the oldest old [6, 8, 11].

Depression can serve as a barrier to early diagnosis of dementia. Depressive symptoms commonly occur in both MCI and dementia and have been independently associated with perturbations in amyloid processing in elders [10, 12, 13, 15]. A recent prospective longitudinal investigation of women over age 85 noted the 5-year odds ratio for developing MCI associated with depression to be 3.71 (95% CI: 1.30–10.59) after adjustment for important confounders [14, 16]. This study further noted that only 19% of women over age 85 (n = 302) who endorsed more than six items on a 15-item geriatric depression scale were cognitively normal 5 years later [14, 18]. The Baltimore Longitudinal Study of Aging identified an increased risk for incident dementia associated with depressive symptoms in men but not in women, with hazard ratios that were approximately doubled [17, 20]. Symptoms of depression in elders can differ to encompass more executive dysfunction impacting insight, anhedonia, and psychomotor retardation, presenting a challenge to accurate diagnosis [19, 22]. These symptoms can resemble medial frontal lobe dysfunction seen with neurodegenerative syndromes, particularly when present with vascular risk factors [5, 21].

The likelihood of polypharmacy and multiple medical comorbidities increases with age and can contribute to cognitive impairment, often presenting as delirium (Table 25.1) [20, 23]. The cumulative burden of anticholinergic side effects, operationalized in an Anticholinergic Risk Scale, is associated with changes in functional performance and medication side effects [24–26, 28]. Sedatives and sleeping pills, including over-the-counter supplements with anticholinergic properties, contribute to poorer cognitive performance and confusion [11, 27].

Table 25.1 Classes of medications commonly used in elders and linked to cognitive symptoms

Antihistamines (e.g., over-the-counter cold remedies and sleeping pills)
Antidepressants with anticholinergic properties (e.g., fluoxetine, paroxetine, amitriptyline)
Opioids
Benzodiazepines
Anti-parkinsonian medications
Bladder stabilizers (e.g., oxybutin)
H2 receptor antagonists
Steroids
Antiemetics

Delirium is not only a confounding factor but is also carries a substantial risk for cognitive decline and dementia [29, 30]. Patients with a history of delirium who develop dementia are less likely to have neuropathological evidence typical of neurodegenerative disorders at autopsy, when compared to those without a history of delirium, suggesting unique contributions that may result in modifiable approaches [2, 29, 32]. Common theories of cognitive decline with delirium have immunologic underpinnings. It is not surprising that having a critical illness, particularly one involving major infections, increases risk for dementia [4, 5, 11, 34, 35, 37]. It has been hypothesized that the prolonged effects of delirium are due to inflammation-initiated neuronal loss and microglial activation in brain tissues primed by early neurodegenerative disorders or aging [15, 31, 36].

Treatments: There are few published data to inform whether treatment approaches should be altered in the oldest old compared to younger dementia populations. The increased frequency of polypharmacy and medical comorbidities mandates closer scrutiny of their contributions. In the oldest old, since care is more frequently provided in a nursing home, use of environmental and behavioral approaches to the neuropsychiatric aspects of dementia have unique complexities. The rate of decline in dementia decreases in older age; thus, as a group, older patients can anticipate a slower rate of progression [7, 9, 33, 40]. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) provides complementary imaging data demonstrating slower atrophy rates in both MCI and AD with advanced age. Among healthy controls, these rates were accelerated, likely representative of a higher incidence of MCI and AD in this age group [18, 33, 42]. This poses challenges in developing treatment trials that include the oldest old, as a longer course of observation would be needed to detect treatment-associated differences.

Side effects associated with medications used to treat cholinergic deficits are more frequent with older age and should lead to caution in using higher doses [5, 32, 38, 39, 41]. In older age groups, a 23 mg dose of donepezil was associated with an increased frequency of fatigue, somnolence, and urinary incontinence [38].

Metabolic factors appear to have less bearing as a risk factor in advanced age. Incident dementia cases in the 90+ Study were less likely to have hypertension, and there was no relationship to prior stroke or transient ischemic attack [32]. Unlike findings in younger groups, in the oldest old from the Leiden 85+ Cohort, metabolic syndrome was not associated with cognitive decline [68]. Although midlife elevated blood pressure is associated with incident dementia in late life, low blood pressure appears more detrimental in the very old, based on cross-sectional studies [69–73]. Whether changes in late life blood pressure are part of the pathophysiology of dementia or a risk factor cannot be determined from these cross-sectional studies, but these data should raise concerns about overly aggressive management of blood pressure in the oldest old and have led some to consider preventative strategies beginning in midlife [74].

Normal gait and better overall physical health measured during early old age are associated with a reduced risk of developing dementia within 6 years [75, 76]. In old age, better physical functioning is similarly associated with reduced dementia [77]. Higher degree of physical activity is associated with decreased incidence of cognitive decline and, in the very old, is associated with improved brain MRI integrity measures [78–80]. These data are supportive that maintaining physical activity and independence are reasonable considerations into old age and provide opportunities for new investigations in dementia prevention for the oldest old.

Conclusions: There is ample evidence that cognitive disorders in the very old do not follow precise trajectories, and do not maintain the established associations to neuropathology more common in younger age. The heterogeneity of dementia in the very old has underpinnings in many factors including resilience, medical comorbidities and a host of accumulated lifetime behavioral and biological factors, but may also be due to factors, potentially modifiable, yet to be discovered. Approaches to care must consider individual variability, including that due to comorbidity and environment. Existing data point to challenges in applying therapeutic interventions that have proven efficacy in younger age, such as aggressive management of blood pressure or high doses of medications, where changes in physiology in the oldest old may impact usefulness and safety of these approaches.

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