How Accurate is Alzheimer's Diagnosis Among Patients over 80?

The age-old question of why some elderly in their 80s and 90s remain cognitively sharp while other elderly develop dementia remains a puzzle. A new study offers a fresh challenge to the notion that Alzheimer pathology is the key culprit. Increasing forgetfulness and confusion among those older than 80 was documented as early as 7th century BC by Greek philosopher Pythogoras, who considered it a “return to imbecility of infancy”. 1 During each subsequent era, various hypotheses were heralded as the main etiology for late-life cognitive decline, ranging from “normal aging” to demonic possession, to syphilis, to strokes, to hardening of the blood vessels, and—since the late 20th century—to Alzheimer disease. “Senile dementia,” the term commonly used in the last two centuries, has become almost synonymous with Alzheimer disease.

The discovery that β-amyloid aggregation in the brain may be at the heart of a series of steps in a biochemical cascade that leads to dementia raised the hope for therapeutic interventions that one day could ease, or even end, late-life cognitive impairment.2 However, in the past two to three years, an Alzheimer-centric view of the brain with aging has been questioned. For example, pathological findings in large prospective studies have revealed similar degrees of plaques and tangles in the brains of elderly with dementia as in those without dementia.3 In fact, a substantial number of elderly beyond the age of 80 may have severe neuropathologic hallmarks of Alzheimer disease without any clinical evidence of dementia.4 Some vaccines have been successful in clearing amyloid plaques in the brain, but they have failed to slow or reverse any symptoms of dementia.5 Thus, the simple theory that late-life dementia is merely an Alzheimer issue is vanishing.

To complicate matters further, it appears that those prescribed antihypertensive medications may have less Alzheimer neuropathology in their brains than those who do not experience hypertension. 6 Moreover, ischemia and hypoxia can contribute to atrophy in the hippocampus, independent of plaques and tangles.7 Such findings have begun to blur the distinctions between vascular dementia, Alzheimer dementia, Normal Pressure Hydrocephalus, Lewy Body dementia, and the other potential causes for late-life dementia.8 It appears that most elderly beyond the age of 80 have a mixture of multiple pathologies that contributes to their dementia.3

The Evidence
A new study by Savva, Wharton, et al. from the Medical Research Council in England offers a fresh blow to the concept that Alzheimer pathology is the primary cause of cognitive impairment in elderly beyond the age of 80.9 The researchers performed detailed clinical-pathological evaluation of 456 elderly who had donated their brains for a longitudinal Cognitive Function in Ageing Study. Many of their findings are exactly opposite of what would have been expected based on the current views of late-life dementia. They show that the significance and relevance of plaques and tangles are age dependent. The association between Alzheimer pathology and dementia progressively weakens as people approach their late 90s. In elderly with dementia, the amount of plaques and tangles actually appears to decrease or remain constant in the hippocampus and neocortical areas. In elderly without dementia, the levels of Alzheimer pathology increase with each decade of life. In agreement with a number of other recent studies,4 this new study reports that the degree of atrophy in cortex and hippocampus remains the variable that best correlates with dementia—at any age.

As noted by Alois Alzheimer, the pathophysiology of dementia in a 55-year-old patient is quite different than that in an 85-year-old patient. He wrote: “Plaques are not the cause of senile dementia, but only an accompanying feature of senile involution of the central nervous system.”10 In those with early-onset dementia, plaques and tangles are the main culprits. In those with late-onset dementia, especially those beyond the age of 80 or 90, plaques and tangles are most likely co-players in causing brain atrophy, which is the real culprit.

The focus for finding etiologies for late-life dementia is now turning from what causes the accumulation of plaques and tangles to what causes cortical and hippocampal atrophy. One possibility is that a dynamic interaction of multiple pathological processes (including plaques, tangles, Lewy bodies, inflammation, exposure to various medications, and vascular injury from minor to large strokes) reduces the size of both cortex and hippocampus.

A recent clinicopathological study involving the analysis of 443 autopsies in individuals with detailed known clinical course shows that only 18.6 percent of elderly had Alzheimer pathology as the sole or dominant lesion to account for their dementia.11 Microvascular infarcts were the sole or dominant lesion in 14.2 percent of the participants with dementia while 87.9 percent had mixed pathologies.11 Thus, brain resilience may tolerate a certain degree of injuries caused by genetic and environmental hits, until a certain threshold is reached. At that point, cognitive abilities fall apart and the patient develops dementia

(Fig 1).
Another possibility is that the real culprit (factor X) may have not yet been discovered. In the early 1980s, Helicobacter pylori bacterium was identified as the real cause of peptic ulcer disease and thus completely changed our understanding of, and therapeutic approaches toward, this common condition. With regard to late-life dementia, we must keep an open mind and consider other factors (e.g., activation of new late-life genes, failure of protective repair mechanisms, accumulation of toxic metabolites, mitochondrial disease, and/or impairment of control over protein aggregation) that can bring about brain atrophy with aging. Pursuing therapeutic interventions that affect amyloid may be useful for a small portion of the population that has early-onset dementia but most likely would have minimal effect for tens of millions of patients with late-life dementia.

Rethinking Diagnoses
Recent studies challenge the accuracy of a diagnosis of Alzheimer disease for those in their 80s and 90s. If mixed pathologies (not plaques and tangles) account for their dementia, it would be more honest and accurate to label them as having dementia (or alternatively mild, intermediate, or severe cognitive impairment) until a specific and dominant pathological feature is identified. Clearly, the oldest old do not simply have Alzheimer disease. The high likelihood of heterogeneity of causes for latelife dementia must also serve as a sobering warning for researchers who are trying to identify a single “early” biochemical marker for elderly at risk for developing dementia in the future.

In summary, “the emperor has no clothes.” The burgeoning literature, coalescing in the Savva paper, leads one to conclude that Alzheimer disease is, as Dr. Alzheimer dubbed it, a “presenile dementia” and that there is no definitive evidence that Alzheimer's pathology is truly causal in dementia of the “elderly.” Thus, we need to be cautious in making a diagnosis of Alzheimer disease in our 80+ patients. Dementia, or ideally Cognitive Impairment, may be the preferred diagnostic terminology.

Majid Fotuhi, MD, PhD, is Director of the Center for Memory and Brain Health at The Sandra and Malcolm Berman Brain & Spine Institute at LifeBridge Health, Sinai Hospital of Baltimore, and is an Assistant Professor of Neurology at Johns Hopkins University School of Medicine.

1. Berchtold, N.C. & Cotman, C.W. Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s. Neurobiol Aging 19, 173-89 (1998).
2. Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-6 (2002).
3. Schneider, J.A., Arvanitakis, Z., Bang, W. & Bennett, D.A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197-204 (2007).
4. Erten-Lyons, D. et al. Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology 72, 354-60 (2009).
5. Williams, M. Progress in Alzheimer's disease drug discovery: an update. Curr Opin Investig Drugs 10, 23-34 (2009).
6. Hoffman, L.B. et al. Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology 72, 1720-1726 (2009).
7. Kril, J.J., Patel, S., Harding, A.J. & Halliday, G.M. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J Neurol Neurosurg Psychiatry 72, 747-51 (2002).
8. Viswanathan, A., Rocca, W.A. & Tzourio, C. Vascular risk factors and dementia: how to move forward? Neurology 72, 368-74 (2009).
9. Savva, G.M. et al. Age, neuropathology, and dementia. N Engl J Med 360, 2302- 9 (2009).
10. Alzheimer, A. Ueber eigenartige Krankheitsfaelle des spaeteren Alters, Zeitschrift fuer die gesamte. Neurologie und Psychiatrie 4, 256-286 (1911).
11. White, L. Brain Lesions at Autopsy in Older Japanese-American men as Related to Cognitive Impairment and Dementia in Final Years of Life: A Summary Report from the Honolulu-Asia Aging Study. J Alzheimer's Dis in press (2009).