Many studies have reported on the relationship between the apolipoprotein E (APOE) gene and Alzheimer’s disease, but its role in other dementia-related outcomes isn’t clear.
At the 2024 American Geriatrics Society meeting, a study led by Santiago Clocchiatti-Tuozzo, MD, a postdoctoral research fellow at Yale University in New Haven, Connecticut, tested the hypotheses that APOE4 would increase and APOE2 would decrease the risk of a composite endpoint.
“Our study adds significant evidence of an association between the APOE4 and APOE2 genotypes with a patient-centered, functionally relevant, composite outcome of dementia, disability, and death, which is of increasing importance in geriatric clinical trials,” Clocchiatti-Tuozzo said.
“Our results support the collection of DNA in ongoing and future clinical trials, and the use of genetics to evaluate for effect modification in interventions,” he added.
Dementia, Disability, and Death
Clocchiatti-Tuozzo and co-authors evaluated data from an overall population of 14,527 older adults in the Health and Retirement Study (HRS). The HRS is a federally supported longitudinal panel study that surveys a representative sample of older adults in the U.S.
No participant had a history of dementia or disability at baseline. Exposures of interest were APOE4 and APOE2 variants, which were ascertained using the single-nucleotide polymorphisms rs429358 and rs7412.
The primary outcome was a composite of dementia, disability, and death. Secondary outcomes analyzed each of the three components independently. This composite outcome is relevant to older adults and has been used in other geriatric research like the ASPREE study of aspirin and the PREVENTABLE trial of lipid-lowering drugs, Clocchiatti-Tuozzo pointed out.
The primary analysis looked at all participants without a previous history of dementia or disability. A secondary analysis was limited to individuals 75 or older without previous dementia, disability, heart disease, or stroke.
The sample included 9,399 APOE noncarriers, 3,655 APOE4 carriers, and 1,927 APOE2 carriers. About 58% of all participants were women.
In results adjusted for age, sex, ethnicity, and cardiovascular risk factors, APOE4 carriers had an increased risk for achieving the composite outcome compared with participants who did not have an APOE4 allele (HR 1.13, P<0.001). For the components, HRs were 1.45 for dementia and 1.19 for death (P<0.001 for both). The HR was not significant for disability (HR 0.98, P=0.6).
An analysis comparing APOE2 carriers with participants who carried neither APOE4 nor APOE2 trended toward showing a protective benefit (HR 0.91, P=0.055) on the composite outcome, but was not significant after accounting for age, sex, ethnicity, and cardiovascular risk factors.
Analysis restricted to adults 75 or older without previous dementia, disability, heart disease, or stroke showed APOE4 carriers had a higher adjusted risk for the composite outcome than non-carriers (HR 1.16, P<0.001). The APOE4 results were significant for the dementia and death components of the primary outcome, but not for disability. Outcomes for APOE2 carriers in this subgroup were not significant.
A Closer Look at Genotypes
The results for APOE4 in the HRS were consistent with earlier findings, Clocchiatti-Tuozzo observed.
“The APOE4 allele remains the strongest genetic risk factor for sporadic Alzheimer’s disease and the APOE2 allele the strongest genetic protective factor after multiple large-scale genome-wide association studies and genome-wide association meta-analyses,” noted Bradley Hyman, MD, PhD, of the Massachusetts Alzheimer’s Disease Research Center in Charlestown, and co-authors in a Lancet Neurology review. “However, no therapies directed at APOE are currently available.”
A 2020 study reported APOE2 homozygotes had a significantly lower risk of Alzheimer’s dementia than APOE3 homozygotes and APOE4 homozygotes. The effect of APOE4 and APOE2 gene dose was significantly greater in neuropathologically confirmed Alzheimer’s cases than in others.
Differences in APOE genotype may point to an important higher-level distinction, as suggested by a recent investigation that concluded APOE4 homozygosity was a distinct genetic form of Alzheimer’s disease. The study, led by Juan Fortea, MD, PhD, of the Sant Pau Research Institute in Barcelona, Spain, examined 3,297 pathological samples and analyzed biomarkers and other data from 10,039 clinical trial participants.
Compared with APOE3 homozygotes, nearly all APOE4 homozygotes had Alzheimer’s pathology and higher levels of Alzheimer’s biomarkers from age 55. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid and 75% had positive amyloid scans. Both measures increased with age, indicating near-full penetrance of Alzheimer’s disease biology. The predictability of symptom onset and biomarker changes mirrored those seen in autosomal dominant Alzheimer’s disease and Down syndrome.
“These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene,” Fortea said. This was “similar to what we proposed from Sant Pau with Down syndrome, which a few years ago was also not considered a genetically determined form of Alzheimer’s,” he added.
The findings emphasize a need for preventive strategies for APOE4 homozygotes, the researchers noted. “This gene has been known for over 30 years and it was known to be associated with a higher risk of developing Alzheimer’s disease,” Fortea said. “But now we know that virtually all individuals with this duplicated gene develop Alzheimer’s biology. This is important because they represent between 2% and 3% of the population.”
Disclosures
Clocchiatti-Tuozzo reported no disclosures.
Fortea reported relationships with AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Eli Lilly, Lundbeck, Perha, and Roche.
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