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Changing perspectives regarding late-life dementia

Nature Reviews Neurology volume 5, pages 649–658 (2009)Cite this article

Abstract

Individuals over 80 years of age represent the most rapidly growing segment of the population, and late-life dementia has become a major public health concern worldwide. Development of effective preventive and treatment strategies for late-life dementia relies on a deep understanding of all the processes involved. In the centuries since the Greek philosopher Pythagoras described the inevitable loss of higher cognitive functions with advanced age, various theories regarding the potential culprits have dominated the field, ranging from demonic possession, through 'hardening of blood vessels', to Alzheimer disease (AD). Recent studies suggest that atrophy in the cortex and hippocampus—now considered to be the best determinant of cognitive decline with aging—results from a combination of AD pathology, inflammation, Lewy bodies, and vascular lesions. A specific constellation of genetic and environmental factors (including apolipoprotein E genotype, obesity, diabetes, hypertension, head trauma, systemic illnesses, and obstructive sleep apnea) contributes to late-life brain atrophy and dementia in each individual. Only a small percentage of people beyond the age of 80 years have 'pure AD' or 'pure vascular dementia'. These concepts, formulated as the dynamic polygon hypothesis, have major implications for clinical trials, as any given drug might not be ideal for all elderly people with dementia.

Key Points

  • Over the past 27 centuries, the perception of cognitive impairment with aging has changed from a normal inevitable part of aging to being mostly attributable to Alzheimer disease (AD)

  • Alois Alzheimer was one of the first clinician–scientists to describe the importance of vascular pathology and to de-emphasize the role of amyloid plaques in brain atrophy and late-life dementia

  • Clinicopathological studies have consistently shown that individuals over 80 years of age generally have 'mixed' pathologies (infarcts, plaques, tangles, Lewy bodies and inflammation) rather than 'pure AD'

  • The size of the cortex and hippocampus—more than AD or any other single pathological finding—correlates with the degrees of cognitive decline and dementia in elderly individuals

  • Appreciating the link between midlife risk factors and late-life size of the cortex and hippocampus has serious implications for disease diagnosis, patient management, and interpretation of research findings

  • The dynamic polygon hypothesis provides a new framework for thinking about aging and dementia that departs from the linear model proposed by the amyloid cascade hypothesis

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Figure 1: High density of blood vessels in the brain.
Figure 2: Factors that could cause brain atrophy and cognitive impairment.
Figure 3: Models to account for late-life cognitive impairment.

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Acknowledgements

V. Hachinski is funded by the Alzheimer Association, Award Number IIRG-08-91792. P. J. Whitehouse received support from the National Institute on Aging, Shigeo and Megumi Takayama, and the Greenwall Foundation. Barbara Crain, Miia Kivipelto and Michael Williams made significant suggestions, and we very much appreciate their critical and thoughtful comments. We thank Tzipora Sofare, Medical Editor at the Sandra and Malcolm Berman Brain & Spine Institute, for her help with the preparation of the tables and figures.

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Authors and Affiliations

  1. Center for Memory and Brain Health, The Sandra and Malcolm Berman Brain & Spine Institute, Baltimore, MD, USA

    Majid Fotuhi

  2. Department of Clinical Neurological Sciences, University Hospital, University of Western Ontario, London, ON, Canada

    Vladimir Hachinski

  3. Department of Neurology, Case Western Reserve University, Cleveland, OH, USA

    Peter J. Whitehouse

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Correspondence to Majid Fotuhi.

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Supplementary Table 1

Studies reflecting the heterogeneity of neuropathological findings in elderly people over the age of 80 years, with or without dementia. (DOC 66 kb)

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Fotuhi, M., Hachinski, V. & Whitehouse, P. Changing perspectives regarding late-life dementia. Nat Rev Neurol 5, 649–658 (2009). https://doi.org/10.1038/nrneurol.2009.175

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