Accelerated decline in apolipoprotein E-ϵ4 homozygotes with Alzheimer's disease
Abstract
Background The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon4 homozygotes have an earlier age at onset, increased amyloid burden, and decreased acetylcholine levels--findings that suggest differences in disease severity or rate of progression. Studies of genotype differences in rate of decline, however, have produced negative results that may be due to methodologic biases. The current study examined rate of decline in the largest sample of APOE-genotyped AD patients for whom longitudinal cognitive data have been reported. Methods Newly diagnosed patients with probable AD (n = 201) comprised four genotype groups: epsilon2/3 (n = 14), epsilon3/3 (n = 75), epsilon3/4 (n = 82), and epsilon4/4 (n = 30). The Dementia Rating Scale (DRS) was administered at baseline and then annually for 1 to 6 years (mean, 2.5 years). For each subject, a DRS slope was calculated reflecting annual rate of decline. Rate of decline as measured by DRS slope differed according to genotype, with the effect modified by DRS score (p Conclusions APOE-epsilon4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon2 allele slows disease progression. These findings suggest that APOE plays a mechanistic role in the progression of AD, and is not simply related to disease onset.
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ApoE4 carriers exhibit accelerated rates of cognitive decline related to aging and Alzheimer's disease.
“Clinically, ApoE4 carriers exhibit accelerated rates of cognitive decline related to aging and AD (Craft et al., 1998;Martins et al., 2005;Caselli et al., 2009Caselli et al., , 2011)).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Craft et al., 1998
ApoE2 is rare, occurring in about 5% of the population, and shows protection against Alzheimer's disease.
“ApoE2 is rare, occurring in 5% of the population, and it shows protection against AD.”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Craft et al., 1998
ApoE2 slows Alzheimer's disease progression and is positively associated with cognitive functions during aging.
“ApoE2 has been found to slow AD progression and be positively associated with cognitive functions during aging (Nagy et al., 1995;Craft et al., 1998;Martins et al., 2005;Shinohara et al., 2016).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Craft et al., 1998
There have been numerous conflicting reports regarding whether different apoE alleles influence the rate of cognitive decline following dementia onset.
“While the effect of the ε4 allele on the risk and age of onset for AD is generally consistent in most studies, there have been numerous conflicting reports regarding whether different apoE alleles influence the rate of cognitive decline following dementia onset (Asada et al., 1996; Craft et al., 1998; Frisoni et al., 1995; Growdon et al., 1996; Hoyt et al., 2005; Kurz et al., 1996).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Craft et al., 1998
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- Authors
- Craft, S., Teri, L., Edland, S. D., Kukull, W. A., Schellenberg, G., McCormick, W. C., Bowen, J. D., & Larson, E. B.
- Affiliations
- University of Washington (US)
- Venue
- Neurology
- Published
- 1998-07
- Volume
- 51
- Issue
- 1
- Pages
- 149-153
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W1995006422
- Cited by
- 152
- References
- 2
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 6 · 2017: 4 · 2016: 2 · 2015: 2 · 2014: 7 · 2013: 8 · 2012: 3
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (U01AG006781, R01AG05136, R01AG010880)
- 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
- APOE ε4, APOE genotype, Alzheimer's disease, Mattis Dementia Rating Scale, disease progression, genetic risk factors, APOE ε2, APOE ε3, longitudinal cognitive assessment, amyloid burden, age of onset
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Homozygote, Humans, Male, Age of Onset, Disease Progression, Apolipoprotein E4
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