Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-analysis

Cell counts in the cholinergic nucleus basalis (NB), noradrenergic locus coeruleus (LC), dopaminergic substantia nigra (SN), and the serotonergic dorsal raphe nucleus (DRN) were assessed from primary-level reports in patients with Alzheimer disease (AD) and in controls. Sixty-seven studies that covered about 20 years were included in the meta-analysis. Effect sizes were computed as a standardized mean difference (d) in cell counts between AD and controls. Effect sizes were largest in magnitude for the NB (mean d=2.48, 33 studies, N=585), and the LC (d=2.28, 24 studies, N=545), then the DRN (d=1.79, 11 studies, N=234), and were smallest for the SN (d=0.61, 14 studies, N=440). In general, the overall effect size estimates for the four cell areas were reliable. Using effect size magnitude in the SN as a referent, cell loss was about three times greater in the DRN and four times greater in the NB and LC. Symptomatic drug treatment for AD might be beneficially directed toward ameliorating multiple neurotransmitter deficiencies, particularly cholinergic and noradrenergic.