Human‐specific Derived Alleles of CD33 and Other Genes Protect Against Post‐Reproductive Cognitive Decline
Authors: Springer Stevan A , Schwarz Flavio , Altheide Tasha , Varki Nissi A , Gagneux Pascal , Varki Ajit 
Published: November 2023

The prolonged post‐reproductive human lifespan is unusual, the individuals of most vertebrate species die when they can no longer reproduce. We investigated the contribution of the immunoregulatory receptor CD33 to a uniquely human post‐reproductive disease, late onset Alzheimer's dementia (LOAD). CD33 has two splice variants. CD33M is a full‐length transcript produced primarily by the LOAD‐risk allele. CD33m is missing the terminal V‐set domain, which contains the sialic acid recognition function, and is produced primarily by the LOAD‐protective allele. Existing studies suggest that CD33M suppresses microglial uptake of amyloid beta peptide, and that the CD33m splice form does not inhibit microglial activity. Thus, individuals with the protective allele may accumulate less amyloid beta in their central nervous systems reducing their risk of LOAD.Since our closest evolutionary relatives do not seem to develop the complete pathology of LOAD, we investigated the allelic state of CD33 in human and non‐human primates. Analysis of the 1000 Genomes dataset shows the LOAD‐protective allele is polymorphic in the human population, ranging from 0.05 in Africans to 0.48 in Native Americans. Analysis of Neanderthal, Denisovan, Chimpanzee, Bonobo and Gorilla genomes finds only the allele that predisposes humans to LOAD. Thus, the LOAD‐protective CD33 allele is a derived state unique to humans.We studied expression of CD33 on human and chimpanzee peripheral blood mononuclear cells using antibodies specific for the two splice forms. Chimpanzee monocytes show lower cell surface expression of CD33M than human monocytes. Immunohistochemistry of brain micro‐sections detects both CD33 isoforms on human and chimpanzee microglia, but at different levels. Immunoblots comparing human and chimpanzee brains confirm a four‐fold increase in CD33M expression in humans homozygous for the LOAD‐risk allele. Expression of CD33m was found to be similar in both species. The increased splicing of the CD33m form in the protective allele causes a CD33M/CD33m ratio that resembles the molecular state of CD33 in chimpanzee. The protective CD33 allele may be compensatory, and restore interactions altered as a consequence of human‐specific brain evolution.Surprisingly, even though selection at advanced age is expected to be weak, a CD33 allele protective against Alzheimer's disease is derived and unique to humans. We found several other examples of derived alleles at other human loci that protect against age‐related cognitive deterioration arising from neurodegenerative disease or cerebrovascular insufficiency. Selection by inclusive fitness may be strong enough to favor alleles protecting specifically against cognitive decline in post‐reproductive humans. Such selection would operate by maximizing contributions of post‐reproductive individuals to the fitness of younger kin.Support or Funding InformationThis work was supported by grants from the National Institute of Health (P01 HL107150 to Ajit Varki and RO11065732 to Pascal Gagneux) and by the Harold and Leila Mathers Foundation.