Forget sword and lance. It was a sharp mind that sliced through the genetics of neurodegenerative diseases. And it earned John Hardy, a lad from the town of Warrington in central England, a knighthood. Hardy and 1,277 others found themselves on the U.K.’s New Year Honours list for their contributions to politics, business, sports, entertainment—and science. Most received the Order of the British Empire, aka OBE. Hardy joins an elite group of 23 others who received knighthoods.

Hardy's award cites “Services to Human Health in Improving Understanding of Dementia and Neurodegenerative Diseases.” 

Sir John helped establish the molecular biology of Alzheimer’s disease when he and his colleagues discovered a point mutation in the amyloid precursor protein that caused AD in a U.K. family (Goate et al., 1991). He helped formulate the amyloid cascade hypothesis, positing that Aβ deposition kick-starts a pathological cascade that leads to neurofibrillary tangles and eventually neuron loss and dementia (Hardy and Allsop 1991; Hardy et al., 1998).  Though often embattled, the hypothesis still stands and draws support from new findings, including fluid and imaging biomarker data, and discovery of genetic variants that curb Aβ production and protect against AD (Sep 2021 newsJul 2012 news). 

Hardy’s quest to understand the genetics of neurodegeneration led to the identification of variants in the TREM2 gene that increase the risk for AD and frontotemporal dementia, to a triplication of the synuclein gene that causes Parkinson’s, and to numerous common variants that increase risk for AD discovered in large collaborations with other geneticists (Nov 2012 news; Oct 2012 news; Singleton et al., 2003; Mar 2019 news). 

Hardy shared the Potamkin Prize in 1993, won the Lifesciences Breakthrough Prize in 2016, and shared the Brain Prize with Bart de Strooper, Michel Goedert, and Christian Haass in 2018 (Nov 2015 news; Mar 2018 news). The knighthood is his own. In a congratulatory announcement, friends and colleagues at the UK Dementia Research Institute cheekily anticipated seeing their knight in a suit.—Tom Fagan


  1. John in a suit—now that would be worth the price of admission! Congratulations, John—cannot imagine a more fitting tribute to your many contributions that have furthered our understanding of the role of neurogenetics in AD and non-AD dementia.

  2. Congratulations, John, on the well-deserved knighthood. I hope you will post a photo of you at the ceremony!

  3. I am so pleased that John has received this richly deserved honor. In 1984, John and I spent a summer in Bengt Winblad's lab in Umea, Sweden. We both were neurochemists working with postmortem tissue and recognized the extreme challenges of this end-stage analysis. "It's nothing but methane," John opined. Out of our discussions, John chose instead to turn to genetics. I turned to animal models. We overlapped again in the early '90s at U. South Florida, where John and Karen Duff combined APP and PS1 mice, which our group characterized.

    John is a relentless worker and has tremendous strategic vision. He is a very generous person (he loaned me his TV while we were in Sweden), and always attributes the contributions of others. He has parented four wonderful children, largely on his own. He is indeed a "man for all seasons."

  4. We would like to congratulate John Hardy for receiving the accolade of Knight Bachelor (i.e., a knighthood) as part of the New Year Honors 2022 list awarded by Queen Elizabeth II. Knighthood is generally conferred for exceptional public service, caries the prefix of “Sir” to the recipient’s forenames, and, in this case, was awarded “for services to human health in improving understanding of dementia and neurodegenerative diseases”. This is well-deserved given that Sir John is a pioneer in our field.

    We take great pride in having collaborated in research with him. He always encouraged and encourages alternate ideas. When our research group worked on regulation of the amyloid-beta (Aβ) precursor protein (APP) gene promoter and was receiving heavy flak from peer reviewers, Sir John supported the idea of gene regulation work that resulted in the characterization of APP, APOE, and, later, BACE1 promoters. We studied genetic variability at the APP locus and identified functional SNPs in the APP promoter in collaboration with Sir John’s laboratory (Lahiri et al., 2005; Wavrant-De Vrièze et al., 1999). This led to further characterization of the APP mRNA 5’-UTR and ultimately identified it as a key target when developing the anti-Alzheimer drug Posiphen (Lahiri et al., 2007; Shaw et al., 2001), which now is being clinically developed as Buntanetap. In addition, with his collaboration, we elucidated the functions of three SNPs in the APOE promoter that were not present in mouse Apoe sequences (Maloney et al., 2010).

    At a time when the field focused almost exclusively on Aβ enzymatic production pathways, John supported our work on promoter regulation. Such reinforcement and research further prompted us to characterize translational regulation via microRNA species in AD-related genes (Long et al, 2012). Besides research work, when we founded a new journal "Current Alzheimer Research" (CAR, Bentham Sciences) in 2004, it proved challenging at the time to attract top-quality submissions from “hot labs”. Sir John encouraged us and contributed an early, strong, concept-driven paper elucidating the amyloid hypothesis (Hardy, 2006), which we were able to publish side-by-side with two papers from other leaders in the field. Indeed, our journey with CAR continues since 2004, without interruption. In synopsis, we wish to acknowledge Sir John’s profound contributions to the medical sciences, particularly to emerging journals and in collaboration with lesser known labs. His generosity and intellect have always been assets to the field. His tireless effort to understand and eradicate AD will be of lasting benefit to humanity.

    Authors: Debomoy K. Lahiri*, Bryan Maloney* and Nigel H. Greig#, Affiliation: *Departments of Psychiatry, and Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; #Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA Correspondence with:


    . Has the amyloid cascade hypothesis for Alzheimer's disease been proved?. Curr Alzheimer Res. 2006 Feb;3(1):71-3. PubMed.

    . Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease. Neurobiol Aging. 2005 Nov-Dec;26(10):1329-41. PubMed.

    . The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther. 2007 Jan;320(1):386-96. PubMed.

    . Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions. Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):185-201. PubMed.

    . Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7605-10. PubMed.

    . Genetic variability at the amyloid-beta precursor protein locus may contribute to the risk of late-onset Alzheimer's disease. Neurosci Lett. 1999 Jul 9;269(2):67-70. PubMed.

  5. And yet, I feel like in the end John may have led the field astray by sending everyone down the garden path of the amyloid hypothesis. It is now clear that amyloid pathology does not correlate well with cognitive decline in humans with sporadic AD—that tau pathology correlates better. And yet, we continue to see outpourings of preclinical studies on amyloid-genic mouse lines, and basic biology studies of interactions of microglia, TREM2, ApoE, etc., on amyloid genesis in amyloidogenic mouse lines.

    Clearly, LOAD is a multifactorial disease—no two LOAD patients have the same etiology, and the common denominator seems more likely to be tau pathology rather than amyloid pathology. I think the field in general has lost the plot.

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News Citations

  1. PET Firms Up Amyloid Cascade: Plaques, Inflammation, Tangles
  2. Protective APP Mutation Found—Supports Amyloid Hypothesis
  3. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  4. Mutations in TREM2 Cause Frontotemporal Dementia
  5. Paper Alerts: Massive GWAS Studies Published
  6. And the Oscar of Science Goes to …
  7. De Strooper, Goedert, Hardy, Haass Share 2018 Brain Prize

Paper Citations

  1. . Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PubMed.
  2. . Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991 Oct;12(10):383-8. PubMed.
  3. . Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau. Nat Neurosci. 1998 Sep;1(5):355-8. PubMed.
  4. . alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. PubMed.

External Citations

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Further Reading

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