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The failure rate of clinical trials is very high, in part due to the premature translation of successful results in transgenic mouse models to patients. Extensive evidence suggests that dysregulation of innate immunity and microglia\/macrophages plays a key role in Alzheimer\u2019s disease pathogenesis. Activated resident microglia and peripheral macrophages can display protective or detrimental phenotypes depending on the stimulus and environment. Toll-like receptors (TLRs) are a family of innate immune regulators known to play an important role in governing the phenotypic status of microglia. We have shown in multiple transgenic Alzheimer\u2019s disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-\u03b2, tau pathology, and cerebral amyloid angiopathy (CAA) while promoting cognitive benefits. In the current study we have used a non-human primate model of sporadic Alzheimer\u2019s disease pathology that develops extensive CAA\u2014elderly squirrel monkeys. The major complications in current immunotherapeutic trials for Alzheimer\u2019s disease are amyloid-related imaging abnormalities, which are linked to the presence and extent of CAA; hence, the prominence of CAA in elderly squirrel monkeys makes them a valuable model for studying the safety of the CpG ODN-based concept of immunomodulation. We demonstrate that long-term use of Class B CpG ODN 2006 induces a favourable degree of innate immunity stimulation without producing excessive or sustained inflammation, resulting in efficient amelioration of both CAA and tau Alzheimer\u2019s disease-related pathologies in association with behavioural improvements and in the absence of microhaemorrhages in aged elderly squirrel monkeys. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. The present evidence together with our earlier, extensive preclinical research, validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach, increasing the likelihood of CpG ODN therapeutic efficacy in future clinical trials.<\/jats:p>","DOI":"10.1093\/brain\/awab129","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T16:11:05Z","timestamp":1615997465000},"page":"2146-2165","source":"Crossref","is-referenced-by-count":45,"title":["Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer\u2019s disease pathology in aged squirrel monkeys"],"prefix":"10.1093","volume":"144","author":[{"given":"Akash G","family":"Patel","sequence":"first","affiliation":[{"name":"Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod N","family":"Nehete","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, the University of Texas MD Anderson Cancer Center, Bastrop, TX 78602, USA"},{"name":"The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1398-071X","authenticated-orcid":false,"given":"Sara R","family":"Krivoshik","sequence":"additional","affiliation":[{"name":"Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewei","family":"Pei","sequence":"additional","affiliation":[{"name":"Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L","family":"Cho","sequence":"additional","affiliation":[{"name":"Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharti P","family":"Nehete","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, the University of Texas MD Anderson Cancer Center, Bastrop, TX 78602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1152-4793","authenticated-orcid":false,"given":"Margish D","family":"Ramani","sequence":"additional","affiliation":[{"name":"Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhao","family":"Shao","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence E","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, the University of Texas MD Anderson Cancer Center, Bastrop, TX 78602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3379-8966","authenticated-orcid":false,"given":"Thomas","family":"Wisniewski","sequence":"additional","affiliation":[{"name":"Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, New York, NY 10016, USA"},{"name":"Department of Pathology, New York University School of Medicine, New York, NY 10016, USA"},{"name":"Department of Psychiatry, New York University School of Medicine, New York, NY 10016, 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