Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles.

Alzheimer's disease is the commonest cause of dementia in the elderly,
but its pathological determinants are still debated. Amyloid-β plaques
and neurofibrillary tangles have been implicated either directly as
disruptors of neural function, or indirectly by precipitating neuronal
death and thus causing a reduction in neuronal number. Alternatively,
the initial cognitive decline has been attributed to subtle
intracellular events caused by amyloid-β oligomers, resulting in
dementia after massive synaptic dysfunction followed by neuronal
degeneration and death. To investigate whether Alzheimer's disease is
associated with changes in the absolute cell numbers of ageing brains,
we used the isotropic fractionator, a novel technique designed to
determine the absolute cellular composition of brain regions. We
investigated whether plaques and tangles are associated with neuronal
loss, or whether it is dementia that relates to changes of absolute cell
composition, by comparing cell numbers in brains of patients severely
demented with those of asymptomatic individuals-both groups
histopathologically diagnosed as Alzheimer's-and normal subjects with no
pathological signs of the disease. We found a great reduction of
neuronal numbers in the hippocampus and cerebral cortex of demented
patients with Alzheimer's disease, but not in asymptomatic subjects with
Alzheimer's disease. We concluded that neuronal loss is associated with
dementia and not the presence of plaques and tangles, which may explain
why subjects with histopathological features of Alzheimer's disease can
be asymptomatic; and exclude amyloid-β deposits as causes for the
reduction of neuronal numbers in the brain. We found an increase of
non-neuronal cell numbers in the cerebral cortex and subcortical white
matter of demented patients with Alzheimer's disease when compared with
asymptomatic subjects with Alzheimer's disease and control subjects,
suggesting a reactive glial cell response in the former that may be
related to the symptoms they present.

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