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Multiple substrates of late-onset dementia: Implications for brain protection

Lookup NU author(s): Professor Raj KalariaORCiD, Professor Rose Anne Kenny, Professor Ian McKeith, Dr Christopher Morris, Professor John O'Brien, Emeritus Professor Elaine Perry, Emeritus Professor Robert Perry, Professor Jim Edwardson


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Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid β deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E ε4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Publication metadata

Author(s): McKeith IG; Kalaria RN; Edwardson JA; Perry RH; Kenny RA; Perry EK; Morris CM; Ballard CG; Ince PG; O'Brien JT

Publication type: Article

Publication status: Published

Journal: Ageing Vulnerability: Causes and Interventions: Novartis Foundation Symposium 235

Year: 2001

Volume: 235

Pages: 49-65

Print publication date: 01/01/2001

ISSN (print): 1528-2511

ISSN (electronic): 1935-4657

Publisher: John Wiley & Sons


DOI: 10.1002/0470868694.ch6

PubMed id: 11280033


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