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A 64-year-old man presented with concern about an abnormal genetic test result for apolipoprotein E (APOE) obtained through his primary care physician. He reported forgetfulness and word-finding difficulties for 3 years but performed all activities of daily living independently and was generally healthy. His father and maternal great aunt developed dementia in their 70s. Physical (including neurologic) examination, basic laboratory studies, and brain magnetic resonance imaging results were normal. The Short Test of Mental Status (STMS) score was 33 (maximal attainable score of 38 indicates best performance). Neuropsychological assessment showed average to above-average performance in all cognitive domains, accounting for age and education. Results of his genetic testing for APOE were reported as follows: “This individual possesses an apolipoprotein E genotype (3 and 4) that indicates, with high specificity, that Alzheimer’s disease is the cause of or a contributor to the observed dementia.”
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C. Reassure and address patient’s concerns and follow up in 1 year.
Most cases of Alzheimer disease are sporadic and are thought to be influenced by multiple heritable and nonheritable factors. The APOE gene (19q32.13) codes for apolipoprotein E and has 3 common isoforms (ɛ2, ɛ3, and ɛ4) defined by specific base-pair variations (ie, single-nucleotide variations [SNVs]). APOE ɛ3 is the most common allele (worldwide prevalence, 78%) and has no association with Alzheimer disease risk.1 While APOE ɛ2 (worldwide prevalence, 8%) is associated with a lower rate of Alzheimer disease (odds ratio [OR], 0.6 vs ɛ3/ɛ3), APOE ɛ4 (14%) is the strongest known genetic susceptibility factor for sporadic Alzheimer disease (OR, 8-12 for ɛ4/ɛ4 vs ɛ3/ɛ3; Table)2,3 and is associated with reduced age of Alzheimer disease onset by approximately 2.5 years per allele copy.4 The main function of apolipoprotein E is mediating extracellular lipid transport and cellular lipid uptake, the latter through a process known as endocytosis. Although its precise role in Alzheimer disease pathophysiology is unclear, proposed mechanisms for APOE ɛ4 include promoting amyloid deposition, impairing amyloid clearance via modulating the activity of macrophages known as microglia, and influencing synaptic plasticity, defined as the ability to change the strength of connections between neurons.1
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Corresponding Author: Bradley F. Boeve, MD, Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (firstname.lastname@example.org).
Published Online: January 14, 2021. doi:10.1001/jama.2020.15085
Author Contributions: Dr Choudhury and Dr Ramanan contributed equally to this article.
Conflict of Interest Disclosures: Dr Boeve reported grants from Biogen, Alector, EIP Pharma, and personal fees from Rainwater Charitable Foundation outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank the patient for granting permission to publish this information.
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