Multiple substrates of late-onset dementia: implications for brain protection.
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 beta 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 epsilon 4 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.
MRC-Newcastle University Centre Development in Clinical Brian Ageing, Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK.
R N
RN
Kalaria
C G
CG
Ballard
P G
PG
Ince
R A
RA
Kenny
I G
IG
McKeith
C M
CM
Morris
J T
JT
O'Brien
E K
EK
Perry
R H
RH
Perry
J A
JA
Edwardson
D017668:Age of Onset; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D018376:Cardiovascular Abnormalities / Q000378:metabolism / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000378:metabolism / Q000503:physiopathology; D003704:Dementia / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D015140:Dementia, Vascular / Q000378:metabolism / Q000503:physiopathology; D005838:Genotype; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism / Q000503:physiopathology; D012307:Risk Factors
D001057:Apolipoproteins E