The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD), "probable AD," "possible AD," and "normal brain" to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were approximately 650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by approximately 90%, and the number of neurons in layer IV decreased by approximately 70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.

Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (4 > 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-␤ (A␤) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A␤ deposition and AD pathology, we compared APP V717F transgenic (TG) mice expressing mouse, human, or no apoE (apoE ؊͞؊ ). A severe, plaque-associated neuritic dystrophy developed in APP V717F TG mice expressing mouse or human apoE. Though significant levels of A␤ deposition also occurred in APP V717F TG, apoE ؊͞؊ mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP V717F TG, apoE ؊͞؊ mice resulted in fibrillar A␤ deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP V717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD. M ultiple lines of evidence suggest that the deposition of amyloid-␤ (A␤) peptides is an early pathogenic event inAlzheimer's disease (AD) that initiates a cascade of changes ultimately resulting in neuronal dysfunction, neurodegeneration, and eventual death (1). Conversion of A␤ from a soluble to an aggregated, insoluble form(s) with a ␤-sheet conformation may be central to its accumulation and possibly for its detrimental effects (2). The formation of a prominent neuritic dystrophy (e.g., neuritic plaques) is likely to account for a significant amount of neuronal and accompanying cognitive dysfunction in AD (3). Whether, how, and what form of A␤ causes this prominent neuritic dystrophy is unclear. Understanding the pathogenesis of neuritic degeneration and its relationship to A␤ deposition and aggregation may allow for development of preventive treatments.Transgenic (TG) mice that develop age-and regiondependent A␤ deposition have provided a major advance in AD research (4, 5). These mice allow for the study of both disease pathogenesis and potential treatment strategies targeted at A␤ deposition and fibrillogenesis as well as their consequences such as neuritic degeneration (4-7). One protein that may play a role in A␤ deposition and neuritic degeneration is apolipoprotein E (apoE). We observed a severe, plaque-associated neuritic dystrophy in APP V717F TG mice with most fibrillar A␤ deposits surrounded by both large and fine dystrophic neurites. Importantly, we found that apoE is required for the extensive, plaqueassociated neuritic degeneration. In APP V717F TG, apoE Ϫ͞Ϫ mice, extensive, nonfibrillar A␤ deposits developed; however, A␤-associated neuritic degeneration almost never was observed. Astrocyte-specific expression of human apoE3 and E4 in APP V717F TG, apoE Ϫ͞Ϫ mice ultimately restored fibrillar A␤ deposition by 15 months of age, with expression of apoE4 having a markedly greater effect on neuritic plaque formation than apoE3. Our data strongly suggest a critical and isoform-specific role of apoE in influenci...

In addition to pathology in the gray matter, there are also abnormalities in the white matter in Alzheimer's disease (AD). Sulfatide species are a class of myelin-specific sphingolipids and are involved in certain diseases of the central nervous system. To assess whether sulfatide content in gray and white matter in human subjects is associated with both the presence of Alzheimer's disease (AD) pathology as well as the stage of dementia, we analyzed the sulfatide content of brain tissue lipid extracts by electrospray ionization mass spectrometry from 22 subjects whose cognitive status at time of death varied from no dementia to very severe dementia. All subjects with dementia had AD pathology. The results demonstrate that: (i) sulfatides were depleted up to 93% in gray matter and up to 58% in white matter from all examined brain regions from AD subjects with very mild dementia, whereas all other major classes of lipid (except plasmalogen) in these subjects were not altered in comparison to those from age-matched subjects with no dementia; (ii) there was no apparent deficiency in the biosynthesis of sulfatides in very mild AD subjects as characterized by the examination of galactocerebroside sulfotransferase activities in post-mortem brain tissues; (iii) the content of ceramides (a class of potential degradation products of sulfatides) was elevated more than three-fold in white matter and peaked at the stage of very mild dementia. The findings demonstrate that a marked decrease in sulfatides is associated with AD pathology even in subjects with very mild dementia and that these changes may be linked with early events in the pathological process of AD.