Although dementia of the Alzheimer's type (DAT) is the most common form of dementia, the severity of dementia is only weakly correlated with DAT pathology. In contrast, postmortem measurements of cholinergic function and membrane ethanolamine plasmalogen (PlsEtn) content in the cortex and hippocampus correlate with the severity of dementia in DAT. Currently, the largest risk factor for DAT is age. Because the synthesis of PlsEtn occurs via a single nonredundant peroxisomal pathway that has been shown to decrease with age and PlsEtn is decreased in the DAT brain, we investigated potential relationships between serum PlsEtn levels, dementia severity, and DAT pathology. In total, serum PlsEtn levels were measured in five independent population collections comprising .400 clinically demented and .350 nondemented subjects. Circulating PlsEtn levels were observed to be significantly decreased in serum from clinically and pathologically diagnosed DAT subjects at all stages of dementia, and the severity of this decrease correlated with the severity of dementia. Furthermore, a linear regression model predicted that serum PlsEtn levels decrease years before clinical symptoms. The putative roles that PlsEtn biochemistry play in the etiology of cholinergic degeneration, amyloid accumulation, and dementia are discussed. The most severe consequence of the aging brain is dementia. The number of elderly people is increasing rapidly within our society, and as a consequence, dementia is growing into a major health problem. It has been estimated that 25% of the population older than 65 years has some form of dementia (1) and that the cumulative incidence of dementia in individuals living to the age of 95 years is .80% (2, 3).The clinical manifestation of dementia can result from neurodegeneration [e.g., dementia of the Alzheimer's type (DAT), dementia with Lewy bodies, and frontotemporal lobe dementia], a vascular event (e.g., multi-infarct dementia) or anoxic event (e.g., cardiac arrest), brain trauma [e.g., dementia pugilistica (boxer's dementia)], or exposure to an infectious agent (e.g., Creutzfeldt-Jakob disease) or a toxic agent (e.g., alcohol-induced dementia) (4). Given that dementia can result from diverse neurological insults, the biochemical mechanism of dementia is likely to be separate and distinct from these precipitating events.The differential diagnosis of the types and causes of dementia is not straightforward. A prospective study of the prevalence of DAT in people older than 85 years indicated that more than half of the individuals with neuropathological criteria for DAT were either nondemented or incorrectly diagnosed with vascular dementia. As well, 35% of the clinically diagnosed DAT subjects did not exhibit neuropathological features sufficient to support the diagnosis (5). Clearly, dementia can arise from multiple pathological states that are often clinically indistinguishable. Because DAT is the most common type of dementia and
