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Cited by 307Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Early-onset Alzheimer Disease and Its Variants

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Mendez, Mario F.·2019·Continuum
DOI 10.1212/con.0000000000000687PMC PMC6538053
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Abstract

PURPOSE OF REVIEW: Early-onset Alzheimer disease (AD) is defined as having an age of onset younger than 65 years. While early-onset AD is often overshadowed by the more common late-onset AD, recognition of the differences between early- and late-onset AD is important for clinicians. RECENT FINDINGS: Early-onset AD comprises about 5% to 6% of cases of AD and includes a substantial percentage of phenotypic variants that differ from the usual amnestic presentation of typical AD. Characteristics of early-onset AD in comparison to late-onset AD include a larger genetic predisposition (familial mutations and summed polygenic risk), more aggressive course, more frequent delay in diagnosis, higher prevalence of traumatic brain injury, less memory impairment and greater involvement of other cognitive domains on presentation, and greater psychosocial difficulties. Neuroimaging features of early-onset AD in comparison to late-onset AD include greater frequency of hippocampal sparing and posterior neocortical atrophy, increased tau burden, and greater connectomic changes affecting frontoparietal networks rather than the default mode network. SUMMARY: Early-onset AD differs substantially from late-onset AD, with different phenotypic presentations, greater genetic predisposition, and differences in neuropathologic burden and topography. Early-onset AD more often presents with nonamnestic phenotypic variants that spare the hippocampi and with greater tau burden in posterior neocortices. The early-onset AD phenotypic variants involve different neural networks than typical AD. The management of early-onset AD is similar to that of late-onset AD but with special emphasis on targeting specific cognitive areas and more age-appropriate psychosocial support and education.

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  • The E280A mutation generally produces a more aggressive course of pathology than SAD.

    “which generally produces a more aggressive course of pathology than SAD [55, 56].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [55]

    The Clinical Features section says early-onset AD can have a more aggressive clinical course than late-onset AD, and the Neuropathology section describes differences in pathological burden. Neither passage establishes that the E280A mutation specifically produces a more aggressive course of pathology than sporadic AD (SAD). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Approximately 0.6% of AD cases present a hereditary form (FAD) caused by mutations in APP, PSEN1, or PSEN2 that lead to aberrant Aβ overproduction and aggregation.

    “However, approximately 0.6% of cases present a hereditary form (familial AD or FAD) caused by mutations in APP, PSEN1, or PSEN2 that lead to aberrant Aβ overproduction and aggregation [55, 56].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [55]

    The Genetics section states that about 0.6% of all patients with AD have familial AD associated with mutations in APP, PSEN1, or PSEN2. It says these mutations lead to aberrant cleavage or aggregation of amyloid precursor protein, but does not state that they cause Aβ overproduction and aggregation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Previous studies of our group have identified molecular differences between SAD and FAD in addition to divergences in clinical manifestations.

    “Previous studies of our group have identified molecular differences between SAD and FAD [55, 56, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] in addition to divergences in the clinical manifestations [55, 56].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [55]

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Cited by

Sorted by citations

Authors
Mendez, M. F.
Affiliations
VA Greater Los Angeles Healthcare System (US)
Corresponding author
Mendez, Mario F.
ORCID
Mendez, Mario F.
Venue
Continuum
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-02
Volume
25
Issue
1
Pages
34-51
ISSN
  • 1080-2371 (ISSN-L)
  • 1538-6899
DOI
10.1212/con.0000000000000687
PMC
PMC6538053
OpenAlex
W2912263089
Cited by
307
References
4
Citations by year
2026: 52 · 2025: 52 · 2024: 60 · 2023: 34 · 2022: 49 · 2021: 30 · 2020: 23 · 2019: 7
FWCI
4.56
Type
journal article
Language
en
Open access
Locations
  • CONTINUUM Lifelong Learning in Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Biogen
  • University of Cambridge
  • National Institutes of Health
  • National Institute on Aging (RF1AG050967)
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, late-onset Alzheimer's disease, polygenic risk, traumatic brain injury, hippocampal sparing, tau burden, connectomics, frontoparietal network, default mode network, neuroimaging, delayed diagnosis, psychosocial support
MeSH terms
Alzheimer Disease, Brain, Humans, Memory Disorders, Neuropsychological Tests, Age of Onset, Neuroimaging

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