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Cited by 151Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease

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Sirkis, Daniel W., Bonham, Luke W., Johnson, Taylor P., La Joie, Renaud, Yokoyama, Jennifer S.·2022·Molecular Psychiatry
DOI 10.1038/s41380-022-01531-9PMC PMC9156414
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Abstract

Early-onset Alzheimer’s disease (EOAD) is a rare but particularly devastating form of AD. Though notable for its high degree of clinical heterogeneity, EOAD is defined by the same neuropathological hallmarks underlying the more common, late-onset form of AD. In this review, we describe the various clinical syndromes associated with EOAD, including the typical amnestic phenotype as well as atypical variants affecting visuospatial, language, executive, behavioral, and motor functions. We go on to highlight advances in fluid biomarker research and describe how molecular, structural, and functional neuroimaging can be used not only to improve EOAD diagnostic acumen but also enhance our understanding of fundamental pathobiological changes occurring years (and even decades) before the onset of symptoms. In addition, we discuss genetic variation underlying EOAD, including pathogenic variants responsible for the well-known mendelian forms of EOAD as well as variants that may increase risk for the much more common forms of EOAD that are either considered to be sporadic or lack a clear autosomal-dominant inheritance pattern. Intriguingly, specific pathogenic variants in PRNP and MAPT —genes which are more commonly associated with other neurodegenerative diseases—may provide unexpectedly important insights into the formation of AD tau pathology. Genetic analysis of the atypical clinical syndromes associated with EOAD will continue to be challenging given their rarity, but integration of fluid biomarker data, multimodal imaging, and various ‘omics techniques and their application to the study of large, multicenter cohorts will enable future discoveries of fundamental mechanisms underlying the development of EOAD and its varied clinical presentations.

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  • In all degenerative dementias, onset of symptoms is associated with already established brain pathology, which develops many years before symptom onset.

    “In all the degenerative dementias the onset of symptoms is associated with already established brain pathology, which develops many years before symptom onset [3, 4].”

    From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [4]

    The “Amyloid-positivity in asymptomatic individuals” section reports amyloid-PET signal emerging 15–25 years before expected symptom onset and describes a long preclinical phase in Alzheimer’s disease. The paper does not extend that finding to all degenerative dementias. Page numbers were not provided in our copy. (LLM, conf=0.88)

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Authors
Sirkis, D. W., Bonham, L. W., Johnson, T. P., La Joie, R., & Yokoyama, J. S.
Affiliations
University of California, San Francisco (US)
Corresponding author
Yokoyama, Jennifer S.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-04-07
Volume
27
Issue
6
Pages
2674-2688
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-022-01531-9
PMC
PMC9156414
OpenAlex
W4225634431
Cited by
151
References
244
Citations by year
2026: 34 · 2025: 32 · 2024: 45 · 2023: 35 · 2022: 5
FWCI
5.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG062588, AG057234, AG062422, AG065501)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS123985)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
early-onset Alzheimer's disease, clinical heterogeneity, fluid biomarkers, neuroimaging, genetic risk variants, prion protein gene, MAPT, tau pathology, diagnostic biomarkers
MeSH terms
Alzheimer Disease, Humans, Language, Phenotype, Syndrome, Multicenter Studies as Topic, Age of Onset

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