The often-mooted question of whether “aging itself” is or is not a “disease” has long been mooted in biogerontological circles, with a long-held rhetorical preference for asserting that it is not, but rather, that it is a risk factor for the specific diseases of aging.1 By contrast, the same fundamental semantic dispute was initially resolved in the opposite direction with regard to age-related cognitive decline and dementia, beginning in the early decades after Alois Alzheimer and Emil Kraepelin first identified the pathological basis of the Alzheimer’s disease (AD) until the early 1970s. For most of the twentieth century, it was held that dementia occurring in younger people should be classified as a disease, whereas dementia should be expected and accepted when it occurred in people at more advanced ages, despite the knowledge that the lesions linked to Alzheimer’s dementia accumulated throughout the course of “normal” aging in middle age and onward, and that the pathological basis of the disorder was the same in both cases.2
But beginning in the 1960s, a loose alliance led by social gerontologists but quickly coming to include biogerontologists, geriatricians, and patient advocacy groups successfully campaigned for a new understanding: that while some level of minor cognitive decline was indeed a “normal” and inevitable part of aging, the newly-rediscovered clinicopathological entity, “Alzheimer’s disease,” was exactly that: a disease, against which the full force of public and private biomedical research should be mobilized in the pursuit of a cure.2
The veneer of coherence to this division has been peeling away for some years now, with the identification of mild cognitive impairment (MCI) as a prodromal or “preclinical” stage of AD, with cerebrospinal, pathological, and neuroimaging evidence linking it clearly to the core pathology of the clinical disease itself. Indeed, it is now well-established that aggregated beta-amyloid protein (Aβ) and neurofibrillary tangles (NFT — cytoplasmic inclusions composed of phosphorylated and abnormally-cleaved species of tau protein) accumulate progressively in the “normally” aging brain and precede the onset of dementia by decades.5,6 Two recent publications 3,4 clearly refute the principle arguments in favor of this dichotomy, firmly rooting the basis of “normal” age-related cognitive decline in the same pathological lesions of the brain that drive the “dementia” of Alzheimer’s.
In one report,3 researchers at the Rush Alzheimer’s Disease Center used data from 354 older clergy from the prospective Religious Orders Study, who had undergone baseline and up to 13 annual followup rounds of medical and psychological testing which included sound composite measures of global cognition and of specific cognitive functions, and culminated in postmortem brain autopsy. In order to distinguish the long course of age-related cognitive decline from the widely-observed rapid phase of antemortem cognitive decline without falling into the petitio principii of using the clinical diagnostic criteria for dementia or Alzheimer’s disease, the investigators tested a series of statistical models that each fit the observed rates of cognitive decline with an hypothesized acceleration in the last n months of life, and selected the best fit model as the analysis with the highest log likelihood value. The inflection point was thereby determined to occur at ~52 mo antemortem.3
Into this model they fit in the interactions of a pathologic index for lesions related to age-related cognitive decline and dementia: density of NFT, the lesion most strongly associated with the level of cognition in AD; Lewy bodies, the characteristic marker of Lewy body dementia (DLB); and gross and microscopic cerebral infarcts occurring at least 6 mo anemortem. as indicators of stroke and transient ischemic attack. With this analysis, they evaluated relationships between each pathological lesion, as well as a final model including all, with “normal” vs. “disease” related (accelerated terminal) decline.
The results (all emphasis mine):
higher tangle density was associated with more rapid age-related and disease-related decline in global cognition. … [V]irtually no age-related change in global cognition occurred at low levels of tangles (25th percentile…) compared to substantial decline at high levels (75th percentile…). By contrast, much disease-related global cognitive decline occurred despite low levels of tangles, suggesting the involvement of other pathologic factors. …
[B]oth gross … and microscopic … infarction were associated with a more than 2-fold increase in rate of age-related global cognitive decline. By contrast, neither gross nor microscopic infarction was associated with disease-related [global] cognitive decline. … The presence of neocortical Lewy bodies … was associated with an approximate doubling of disease-related decline relative to those without Lewy bodies … and [with] a nearly significant effect on age-related decline. By contrast, nigral/limbic Lewy bodies [characteristic of the movement disorders of Parkinson’s disease] … were not associated with either age-related or disease-related decline in global cognition …
Higher tangle density was associated with more rapid age-related and disease-related decline in all cognitive systems … By contrast, cerebral infarction … and Lewy bodies … had selective effects across time and cognitive systems. … It is noteworthy that Lewy bodies were associated with decline in episodic memory, a defining characteristic of AD, and that all forms of pathology contributed to age-related decline in working memory, a change often attributed to normal aging. …With all pathologic measures in the same model, tangles continued to be associated with age-related and disease-related decline in multiple cognitive systems; gross infarction was associated with age-related working memory decline; and neocortical Lewy bodies were associated with age-related perceptual speed decline and disease-related decline in episodic and semantic memory …
Age-related cognitive decline was associated with neurofibrillary tangles, cerebral infarction, and Lewy bodies, and was not evident in the absence of these lesions. This indicates that the neurodegenerative lesions traditionally associated with dementia are principally responsible for the gradual age-related cognitive decline that precedes dementia and that AD and related disorders have a much greater impact on late-life cognitive functioning than previously recognized. …
Gradual cognitive decline in old age has mainly been thought to reflect normative age-related developmental processes. In this cohort, however, there was no age-related cognitive decline absent postmortem evidence of neurodegenerative disease, and multiple pathologic lesions were associated with rate of age-related cognitive decline. These data challenge the concept of normative cognitive aging and suggest instead that neurodegenerative disease plays a role in virtually all late-life cognitive decline …
The results also indicate that factors other than tangles and neocortical Lewy bodies are contributing to variability in disease-related [terminal] cognitive decline. This could include other pathologic features such as the TAR DNA-binding protein 43 [TDP-43]. In addition, neurodegeneration in the form of loss of neurons and synapses may be the most proximate cause of precipitous cognitive decline, leaving less variability to be accounted for by more distal contributors to neurodegeneration such as tangles and Lewy bodies.3
The second paper4 gave context to this latter allusion: the fact that neuron loss is minimal in the “normally” aging brain, but is prevalent in the late stages of dementia. This relatively recent observation was greeted with surprise, because it stood in curious contrast to the much longer-established fact of extensive volumetric shrinkage of the brain across the course of “normal” cognitive aging, which had previously been assumed to imply a lifelong process of neuronal loss. Once it became clear that little such loss occurred, this fact was often invoked as evidence of a clear distinction between the age-related changes occurring in “normal” cognitive aging and the pathological processes contributing to dementia. But it left the exact structural basis of age-related brain shrinkage largely unexplained.
The new study4 shows that this long process of brain shrinkage during “normal” aging is largely the result, not of neuronal loss, but of premorbid neuronal atrophy:
This paper reviews recent evidence from magnetic resonance imaging (MRI) studies about age-related changes in the brain. The main conclusions are that
(1) the brain shrinks in volume and the ventricular system expands in healthy aging. However, the pattern of changes is highly heterogeneous, with the largest changes seen in the frontal and temporal cortex, and in the putamen, thalamus, and accumbens. With modern approaches to analysis of MRI data, changes in cortical thickness and subcortical volume can be tracked over periods as short as one year, with annual reductions of between 0.5% and 1.0% in most brain areas.
(2) The volumetric brain reductions in healthy aging are likely only to a minor extent related to neuronal loss. Rather, shrinkage of neurons, reductions of synaptic spines, and lower numbers of synapses probably account for the reductions in grey matter. In addition, the length of myelinated axons is greatly reduced, up to almost 50%.
(3) Reductions in specific cognitive abilities–for instance processing speed, executive functions, and episodic memory–are seen in healthy aging. Such reductions are to a substantial degree mediated by neuroanatomical changes, meaning that between 25% and 100% of the differences between young and old participants in selected cognitive functions can be explained by group differences in structural brain characteristics.4
Ultimately, whether we speak of aging as a biological process that can be separated from specific age-related diseases, or as the premorbid structural basis of age-related disease and frailty, or as itself the ultimate age-related disease, should be regarded as a conceptual convenience bordering on a literary conceit, of no ultimate clinical significance. The aging of the body is a process of accumulating cellular and molecular lesions that degrade the fidelity of the structural basis of normal homeostasis; from an heuristic point of view, it can and should be understood to be a pathological process with a biomedical solution. The strategy of rejuvenation biotechnology is to remove, repair, replace, or render harmless such lesions, restoring the structural integrity of the body to the original order seen in youth. In the process, we will restore health and vigor that emerges from youthful biological structures, eliminating age-related disease and disability even as we eliminate the damage that underlies it.
1: de Grey AD. Resistance to debate on how to postpone ageing is delaying progress and costing lives. Open discussions in the biogerontology community would attract public interest and influence funding policy. EMBO Rep. 2005 Jul;6 Spec No:S49-53. PubMed PMID: 15995663; PubMed Central PMCID: PMC1369265.
2: Ballenger JF. Progress in the history of Alzheimer’s disease: the importance of context. J Alzheimers Dis. 2006;9(3 Suppl):5-13. PubMed PMID: 17004361.
3: Wilson RS, Leurgans SE, Boyle PA, Schneider JA, Bennett DA. Neurodegenerative basis of age-related cognitive decline. Neurology. 2010 Sep 21;75(12):1070-8. Epub 2010 Sep 15. PubMed PMID: 20844243; PubMed Central PMCID: PMC2942064.
4: Fjell AM, Walhovd KB. Structural brain changes in aging: courses, causes and cognitive consequences. Rev Neurosci. 2010;21(3):187-221. Review. PubMed PMID: 20879692.
5:Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol. 2010 Feb;6(2):108-19. PubMed PMID: 20140000; PubMed Central PMCID: PMC2864089.
6: Braskie MN, Klunder AD, Hayashi KM, Protas H, Kepe V, Miller KJ, Huang SC, Barrio JR, Ercoli LM, Siddarth P, Satyamurthy N, Liu J, Toga AW, Bookheimer SY, Small GW, Thompson PM. Plaque and tangle imaging and cognition in normal aging and Alzheimer’s disease. Neurobiol Aging. 2010 Oct;31(10):1669-78. Epub 2008 Nov 11. PubMed PMID: 19004525; PubMed Central PMCID: PMC2891885.