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Objective-LR11 (aka sorLA) is a multifunctional neuronal receptor that binds apolipoprotein E and interacts with amyloid precursor protein to regulate amyloidogenesis. Reduced expression of LR11, as occurs in the brains of individuals with Alzheimer's disease (AD), increases amyloidogenesis, and variants in the gene that encodes LR11, SORL1, have recently been linked to risk for late-onset AD. In this study, we sought to determine whether reduced expression of LR11 occurs early in the disease process and whether protein levels in cortical neurons are associated with clinical and pathological changes in mild cognitive impairment (MCI), a condition that may represent prodromal AD.Methods-A novel quantitative immunohistochemical approach was used to measure LR11 levels in brain tissue collected from subjects diagnosed antemortem with either no cognitive impairment, MCI, or AD from the Rush University Religious Orders Study.Results-LR11 levels in MCI were intermediate between no cognitive impairment and AD. LR11 expression was heterogeneous in MCI, forming low-and high-level LR11 subgroups. MCI subjects with low LR11 were significantly more cognitively impaired than the high LR11 subjects. We also found a significant correlation between cognitive performance and LR11 levels across all clinical groups examined. There was no association between LR11 and plaque and tangle pathology.Interpretation-Neuronal LR11 levels are reduced in prodomal AD. The correlation between LR11 expression and cognitive performance indicates that reduced LR11 levels reflect disease severity and may predict progression to AD in a subgroup of individuals with MCI.Alzheimer's disease (AD) is the most common form of dementia in the elderly. Clinical manifestations include memory loss, deterioration of language skills, and impaired ability to perform daily activities. 1 Although the exact mechanisms remain unknown, it is widely accepted that amyloid-beta peptide (Aβ) plays a key role in AD pathogenesis. Subjects and Methods Case MaterialReligious Orders Study participants undergo an annual clinical evaluation as described previously. 15 Diagnosis of AD follows criteria implemented by the Consortium to Establish a Registry for Alzheimer's Disease, with MCI and NCI classifications following the logic of these criteria. 19 Neuropathological evaluation is based on the National Institute on Aging/ Reagan Consensus criteria, 19 and all cases received a Braak stage. 20 Our study consisted of 9 NCI, 15 MCI, and 10 AD cases chosen from the Religious Orders Study cohort and matched on sex, education, and postmortem interval (Table 1). Apolipoprotein E (ApoE) genotyping was performed as described previously, 21,22 although ApoE genotype was not considered in case selection. To ensure that the NCI group did not include cases at preclinical stages of AD, we included only control cases lacking significant amyloid pathology. Every attempt was made to match for age, though the exclusion of control cases with significant amyloid pathology resulted in a y...