In‐vivo and post‐mortem retinal and brain pathological findings in a homozygote for the A431E PSEN1 mutation

Abstract

AbstractBackgroundThe neuropathology associated with PSEN1 mutations shares many features with late‐onset Alzheimer’s disease although atypical features are also seen. An important question is whether the manifestations of PSEN1 mutations are dose‐dependent. We present the neuropathological findings of a homozygote for the pathogenic A431E mutation in PSEN1 relative to heterozygotes and the finding of retinal Aβ lesions consistent with those that were topographically detected in vivo by retinal fluorescence imaging.MethodsA homozygote for the A431E PSEN1 mutation began having symptoms at age 33 and underwent a comprehensive ophthalmic and neurologic evaluation at age 37 before passing away at age 39. Brain and eyes were collected and brain sections and retinal flatmounts and cross‐sections were processed and immunostained with 4G8 or 12F4 (anti‐Aβ), AT8 or pS396 (anti‐phosphoTau) antibodies. Retinal vascular and astrocytic markers were also assessed.ResultsBrain weight of the homozygote was 1180 grams relative to 840 and 860 grams in two heterozygotes with only mild to moderate gross atrophy appreciable relative to moderate to severe atrophy in the heterozygotes. More abundant 4G8 (Aβ) staining was appreciable in widespread brain areas in the homozygote relative to the heterozygotes with some having a “cotton wool” morphology. Conversely, neurofibrillary tangle density was markedly lower in the homozygote relative to heterozygotes in all areas assessed. Retinal in vivo imaging revealed very small, yellow deposits in the macula in both eyes that were atypical for a 37‐year‐old. These lesions correlated topographically with areas of Aβ deposits stained in post‐mortem flatmounts. In retinal cross‐section, Aβ accumulation, including vascular Aβ40 and Aβ42 deposits, pS396‐positive staining and NFTs are clearly detected, along with enhanced GFAP‐positive gliosis.ConclusionThe neuropathological changes seen in a person homozygous for the A431E PSEN1 mutation showed an increased degree of Aβ pathology and evidence of a lesser degree of downstream pathology, possibly representing a more rapidly evolving disease with progressive disability despite a relative lack of neurodegeneration. We also demonstrated that Aβ and tau pathology occurs in the retina in this form of AD and that it can be visualized on clinical examination during life.Funded by: P30AG066530, U01AG051218, R01AG062007