title: Alzheimer's disease in late-life dementia: a minor toxic consequence of devastating cerebrovascular dysfunction.
abstract: Alzheimer's disease (AD) is thought to be the most common cause of late-life dementia. But pure AD is infrequent whereas AD pathology is often insufficient to explain dementia in the elderly. Conversely, cerebrovascular disease is omnipresent and the crucial role of microvascular alterations increasingly recognized in late dementia or "Alzheimer syndrome". Pathomechanisms of vascular cognitive impairment are still debated but recent data indicate that the initial concept of chronic low grade cerebral hypoxia should not have been abandoned. Thus, it is proposed that windkessel dysfunction is the missing link between vascular and craniospinal senescence on the one hand, and chronic low grade cerebral hypoxia, "senile brain degeneration" and "Alzheimer syndrome" on the other hand. An age-related decrease in the buffering capacity of both the vessels and the craniospinal cavity favours cerebral hypoxia; due to increased capillary pulsatility with disturbances in capillary exchanges or due to a marked reduction in craniospinal compliance with a mechanical reduction in cerebral arterial inflow. "Invisible" windkessel dysfunction, most often related to "hardening of the arteries" may be the most frequent pathomechanism of late-onset dementia whereas associated mild or moderate AD may be merely a toxic manifestation of a primarily hypoxic disease. Structural patterns of arteriosclerotic dementia fit well with an underlying arterial windkessel dysfunction: with secondary mechanical damage to the cerebral small vessels and the brain and predominantly deep hypoxia. The clinical significance of leukoaraïosis, small foci of necrosis, ventricular dilatation, hippocampal and cortical atrophy is in good agreement with their value as indirect markers of windkessel dysfunction. An age-related "invisible" reduction in craniospinal compliance may also contribute to the associations between heart failure, arterial hypotension and cognitive impairment in the elderly and to the high percentage of dementia of unknown origin in the very old. Both neuropathological and clinical overlap between AD and windkessel dysfunction can explain that cerebrovascular dysfunction remains misdiagnosed for AD in the elderly. Evidence of the key role of cerebrovascular dysfunction should markedly facilitate and widen therapeutic research in late-life dementia. Routine MRI including direct assessment of intracranial dynamics should be increasingly used to define etiological subtypes of the "Alzheimer syndrome" and develop a well-targeted therapeutic strategy.
authors.affiliation: Department of Radiology, Bichat-Claude Bernard University Hospital, AP-HP, Paris Cedex 18, France. marie-cecile.henry-feugeas@bch.aphp.fr
authors.forename: M C
authors.initials: MC
authors.lastname: Henry-Feugeas
mesh_terms: D000368:Aged; D000375:Aging; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000473:pathology*; D001161:Arteriosclerosis / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002561:Cerebrovascular Disorders / Q000175:diagnosis* / Q000473:pathology; D003704:Dementia / Q000175:diagnosis* / Q000473:pathology*; D015140:Dementia, Vascular / Q000175:diagnosis* / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D008962:Models, Theoretical; D009336:Necrosis / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D016896:Treatment Outcome