SignificanceRecessive Stargardt macular degeneration (STGD1) and a subset of cone–rod dystrophies are caused by mutations in the Abca4 gene. The ABCA4 protein is a flippase in photoreceptor cells that helps eliminate retinaldehyde, a toxic photoproduct of vision. Here we found that ABCA4 is additionally present in the retinal pigment epithelium (RPE) of mice at approximately 1% of its abundance in the neural retina. Genetically modified mice that express ABCA4 in RPE but not in photoreceptor cells showed partial rescue of both the lipofuscin accumulation and photoreceptor degeneration observed in Abca4−/− mice and in STGD1 patients. These observations suggest that ABCA4 in the RPE prevents photoreceptor degeneration in Abca4−/− mice and possibly in STGD1 patients.

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Dementia with brainstem and neocortical Lewy bodies (LB) is a source of ongoing nosologic controversy and confusion. Differing opinions about concomitant Alzheimer's disease (AD) have produced competing nomenclatures. We applied neocortical plaque-based criteria for the diagnosis of AD from the National Institute on Aging and from the Consortium to Establish a Registry for AD for definite, probable, and possible AD to 58 dementia brains with LB, 10 elderly nondemented controls, and 58 brains with neuropathologically pure AD. We also employed diagnostic criteria requiring both neocortical plaques and tangles, and assessed the extent of neurofibrillary pathology in all 126 specimens using a modified version of the Braak and Braak staging protocol for changes related to AD. The percentages of mixed LB disease and AD versus pure LB disease varied from 91% mixed and 9% pure to 34% mixed and 66% pure, depending upon which diagnostic criteria for AD were employed. Most dementia brains with LB occupied higher modified Braak stages than controls, but lower ones than pure AD specimens. A minority of the dementia brains with LB had no more AD-type pathology than controls.

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Our prior research on patients with Alzheimer's disease (AD) found a high correspondence between premortem dementia and accumulation of neurofibrillary tangles (NFTs) with concurrent loss of synapse density in several brain regions. In the present study, we examined these same clinicopathologic relationships in the context of seven subregions of the hippocampal formation using a sample of 16 AD patients who had been administered three well-known mental status tests antemortem. We found NFT counts to be most strongly correlated with degree of dementia when they were seen in CA1, the subiculum, and CA4; NFTs in these subregions appeared significantly clustered on factor analysis. Synapse loss was most strongly correlated with dementia when it occurred in the molecular layers of the dentate fasciculus and stratum lacunosum, CA2/3, and CA4; synapse loss in these subregions appeared significantly clustered on factor analysis. In general, these results were compatible with a two-component model of hippocampal connectivity and function in the context of AD. The first component consists of subregions preceding CA1 in a hypothesized input-processing sequence intrinsic to the hippocampus that summates neuronal excitation and that influences cognition primarily through synapse density. The second component consists of an "output module," mainly CA1 and the subiculum, that receives the processed signal, passes it on to extrahippocampal cortical and subcortical targets, and affects cognition primarily by NFT accumulation in output neurons. A "net pathology" score combining standardized z-scores for synapse density and NFTs was significantly correlated with all three mental status measures in all hippocampal subregions except the entorhinal cortex, and stepwise regressions on these data found net pathology in CA4 to be the most independent significant predictor of premortem dementia.