Laminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer's disease. Correlations with the amyloid load and the density of tau‐positive neurofibrillary tangles

Presenilin 1 has been shown to be mutated in a high proportion of cases of familial Alzheimer's disease. Immunoreactive epitopes of the protein have been found mainly in neurones devoid of neurofibrillary tangles – an observation that has led to the conclusion that presenilin 1 could have a protective role. In this study, the relationship between deposits of Aβ peptide (both the 40 and 42 isoforms), tau positive neurofibrillary tangles and presenilin 1‐positive neuronal profiles were analysed in three cases of presenilin 1 mutation, four cases of sporadic Alzheimer's disease and five controls. Immunohistochemistry was performed in a sample from the supramarginal gyrus. The proportion of volume occupied by the Aβ1–40 and Aβ1–42 deposits (amyloid load) was evaluated by a point‐counting technique. Tau‐positive neurofibrillary tangles, and presenilin 1‐positive neuronal profiles were directly counted. The location of the lesions in the thickness of the cortex was recorded. The density of PS1‐positive neuronal profiles in Alzheimer's disease cases was lower than in the controls. The deficit was significant only in the upper layers of the cortex. The density of presenilin 1 neuronal profiles was negatively correlated with Aβ1–40 and Aβ1–42 loads, and with the density of tau‐positive neurofibrillary tangles. Multivariate analysis showed that the Aβ1–42 load was the best determinant of the decrease in presenilin 1‐positive neuronal profiles. Presenilin 1‐positive neurones appear to be lost rather than protected in the course of Alzheimer disease.