EDITORIAL OPEN ACCESS Race and Alzheimer Disease Biomarkers A Neglected Race Alberto Lleó, MD, PhD, and Marc Suárez-Calvet, MD, PhD Correspondence Dr. Lleó Neurol Genet 2021;7:e574. doi:10.1212/NXG.0000000000000574 alleo@santpau.cat Race is a social construct with profound consequences on health. Although race does not always RELATED ARTICLE segregate with genetic ancestry, some genetic variants are more frequently found in certain self- African Americans Have identified racial and ethnic groups. Differences in the epidemiology and the pathophysiology of Differences in CSF Soluble Alzheimer disease (AD) and other neurodegenerative conditions have been described in certain TREM2 and Associated racial groups. Unfortunately, most studies in the field of AD have mainly included non-Hispanic Genetic Variants White (NHW) participants, with an underrepresentation of other populations. In the past few Page e571 years, however, research on race and ethnic differences in AD has grown rapidly. Some studies indicate that African Americans (AA) have a greater risk for AD than NHW.1 The reasons hypothesized to account for this higher risk are certain genetic risk factors associated with AA, the higher prevalence of vascular risk factors in AA, and socioeconomic factors.2 In addition, some studies have reported a different pathophysiology and pattern of AD biomarkers. There is evidence that AA have lower concentrations of total-Tau, phosphorylated Tau, and neuro- filament light in the CSF compared with NHW.3 The differences in AD pathophysiology in racial groups can be due to various factors, such as genetic variants associated with that race, but also with other environmental factors such as socioeconomic status, diet, or medical comor- bidities. Another factor that could play a role in this association is a different innate immune response to AD pathology. In this issue of Neurology® Genetics, Schindler et al.4 take advantage of the racial and ethnical diversity of the Knight ADRC cohort to describe differences in soluble TREM2 (sTREM2) concentrations in the CSF in AA and NHW. AA participants had lower CSF sTREM2 con- centrations, a difference that was mainly driven by the higher frequency of certain TREM2 coding variants associated with lower CSF sTREM2. These results remained significant after adjusting by age, sex, education, history of dementia, and APOEe4 status. The authors also confirmed their findings in participants of the ADNI cohort. TREM2 is an innate immune receptor of the immunoglobulin family that is expressed on the plasma membrane of microglia and other myeloid lineage cells. TREM2 is involved in microglia migration, proliferation, phagocytosis, and lipid sensing.5 Low frequency coding variants in TREM2 increase the risk of AD.5 In mouse models of AD, impaired TREM2 function limits the microglia response around Amyloid-β (Aβ) plaques and leads to greater neuritic dystrophy.5 These observations are consistent with a model in which defective TREM2 function affects microglial response to Aβ plaques and increases neuronal and synaptic damage. CSF sTREM2 reflects the amount of TREM2 competent signaling on the surface of microglia and can thus be used as a biomarker of the TREM2-mediated microglia response. CSF sTREM2 dynamically changes throughout the Alzheimer continuum, with higher levels in the later asymptomatic stages and early symptomatic stages of both sporadic and autosomal-dominant AD.6,7 It is important that lower CSF sTREM2 concentrations have been associated with faster cognitive decline in patients with AD,8 which supports the notion that sTREM2 can be used as a From the Memory Unit (A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau-Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) (A.L.), Madrid; Barcelonaβeta Brain Research Center (BBRC) (M.S.-C.), Pasqual Maragall Foundation, Barcelona; Servei de Neurologia (M.S.-C.), Hospital del Mar, Barcelona; IMIM (Hospital del Mar Medical Research Institute) (M.S.-C.), Barcelona; and Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) (M.S.-C.), Madrid, Spain. Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 surrogate marker of microglial activity in AD. This observation Study Funding also suggests that TREM2-mediated microglial response may The authors report no targeted funding. have a beneficial effect in AD, at least at some disease stages. Disclosure The work of Schindler et al. has important clinical implications. A. Lleó has served as a consultant or at advisory boards for First, if AA have lower CSF TREM2 concentrations, the ques- Fujirebio-Europe, Roche Diagnostics, Biogen, and Nutricia. tion arises of whether AA may be less protected by TREM2- In addition, A. Lleó has a patent WO2019175379 A1 Markers related microglial function. Second, if AA show different AD of synaptopathy in neurodegenerative disease issued. M. biomarkers, it is important to account for race when designing Suárez-Calvet has served as a consultant and at advisory cutoffs in a diverse population. Third, because TREM2 is boards for Roche Diagnostics International Ltd and has given expressed in other tissue macrophages, TREM2 coding variants lectures in symposia sponsored by Roche Diagnostics. Go to associated with AA may also induce a different peripheral in- Neurology.org/NG for full disclosures. flammatory response. The peripheral inflammatory response is known to influence cognitive disorders and progression of AD,9 References which could also have an impact on AD pathophysiology. 1. Mayeda ER, Glymour MM, Quesenberry CP, Whitmer RA. Inequalities in dementia incidence between six racial and ethnic groups over 14 years. Alzheimers Dement 2016;12:216–224. Finally, the findings reported by Schindler et al. may have 2. Howard G, Safford MM, Moy CS, et al. Racial differences in the incidence of car- diovascular risk factors in older black and white adults. J Am Geriatr Soc 2017;65: therapeutic implications. Therapies that target TREM2 have 83–90. already reached clinical phase 2 (NCT04592874). There is an 3. Howell JC, Watts KD, Parker MW, et al. Race modifies the relationship between cognition and Alzheimer’s disease cerebrospinal fluid biomarkers. Alzheimers Res ongoing clinical trial with a TREM2 activating antibody that Ther 2017;9:88. enhances the protective functions of microglia in a mouse 4. Schindler SE, Cruchaga C, Joseph A, et al. African Americans have differences in CSF model of AD.10 It will be important to investigate whether soluble TREM2 and associated genetic variants. Neurol Genet 2021;7:e571. doi: 10. 1212/NXG.0000000000000571. TREM2 therapies have a different effect in participants with 5. Ulland TK, Colonna M. TREM2: a key player in microglial biology and Alzheimer lower TREM2 function, irrespective of self-identified race. If disease. Nat Rev Neurol 2018;14:667–675. 6. Suarez-Calvet M, Kleinberger G, Araque Caballero MA, et al. sTREM2 cerebrospinal true, then it would be key to monitor TREM2 function and fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s adjust the dose accordingly. This would require the de- disease and associate with neuronal injury markers. EMBO Mol Med 2016;8: 466–476. velopment of accurate assays to monitor microglial function 7. Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, et al. Early changes in CSF through the course of the disease. sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury. Sci Transl Med 2016;8:369ra178. 8. Ewers M, Franzmeier N, Suarez-Calvet M, et al. Increased soluble TREM2 in cere- In summary, the study by Schindler et al., adds on an im- brospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Sci Transl Med 2019;11:eaav6221. portant and under-investigated aspect of AD. Because clinical 9. Holmes C, Cunningham C, Zotpleaseova E, et al. Systemic inflammation and disease trials grow and enroll patients with different races and eth- progression in Alzheimer disease. Neurology 2009;73:768–774. 10. Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia pro- nicities, it will be important to take both into account when liferation and reduces pathology in an Alzheimer’s disease model. J Exp Med 2020; interpreting outcomes. 217:e20200785. 2 Neurology: Genetics | Volume 7, Number 2 | April 2021 Neurology.org/NG