The risk of Alzheimer’s disease in APOE4 homozygotes

Apolipoprotein E (APOE), the major genetic risk factor for Alzheimer’s disease (AD), has three common alleles (ε2, ε 3 and ε 4), giving rise to six genotypes (ε2/ε 2, ε2/ε3, ε3/ ε3, ε2/ ε4, ε3/ ε4, and ε4/ε4). Whereas each additional copy of APOE2 is associated with a lower risk of AD, each additional copy of APOE4 is associated with a higher risk and younger average ages at its biological and ensuing clinical onset.^1–4 Based on a recent study using cross-sectional biological measurements, Fortea et al suggest that APOE4 homozygotes who live to older ages are nearly certain to meet biological criteria for AD, have a categorically distinct genetic form of AD, similar in several respects to that in persons with autosomal dominant AD (ADAD) mutations and Down syndrome, and merit a distinctive approach to the development and evaluation of disease-modifying and prevention therapies.⁵ While biological measurements promise to inform the risk and time course of AD and its ensuing clinical features in people with each APOE genotype, more work is needed to draw firm conclusions.

For instance, it is too soon to conclude that APOE4 homozygotes who live to older ages are destined to develop the biological and ensuing clinical manifestations of AD. Population-based longitudinal studies that incorporate scalable biomarkers of AD in people with each APOE genotype, including those from understudied ethnic, racial, and geographic groups, are needed to provide more accurate risk estimates. Until then, there is reason for cognitively unimpaired APOE4 homozygotes to have a more optimistic view about their risk of developing mild cognitive impairment (MCI) or dementia due to AD.

While studies using cross-sectional neuropathological or biomarker data suggest that about 90% of APOE4 homozygotes who live to older ages meet biological criteria for AD and clinical criteria for dementia,^1–4 cross-sectional data should not be used to determine a person’s risk for several reasons. The estimates are derived from convenience cohorts, are not reflective of the general population, and have potential selection biases. Most of these studies do not account for possible differences in the impact of APOE4 in persons from understudied groups or the impact of mortality in estimating a person’s risk.

Ethnicity, race, age, sex, protective genetic variants, and other factors have the potential to modify the impact of APOE4 allelic dose on the biological and clinical onset of AD, and suggested differences need to be clarified further. For example, in large cross-sectional case-control studies, the impact of APOE4 allelic dose on the clinical diagnosis of AD dementia is highest in East Asian and lowest in Hispanic and Non-Hispanic Black groups.^4,6 Studies have found lower AD dementia odds ratios and lower Aβ PET measurements in those APOE4 homozygotes and heterozygotes who remain unimpaired in their 70s, such that those who remain unimpaired at older ages may have protective factors that account for their resistance to AD.^4,7 At an individual level, it is difficult to provide an exact risk estimate for developing MCI or AD dementia based on a person’s APOE genotype. Current genetic counseling best practice involves providing a lifetime risk estimate range based on data from longitudinal population-based studies, explaining there are factors that can increase or decrease a person’s likelihood of developing MCI or dementia, and reinforcing that not all APOE4 homozygotes will develop cognitive impairment.

For reasons that are not entirely clear, there is a discrepancy between the high prevalence of AD dementia calculated using data from cross-sectional studies and the lower incidence of all-cause MCI or dementia obtained from longitudinal studies of population-based cohorts.⁸ Using population-based longitudinal data from over 10,000 persons who were initially 60–75 years old and cognitively unimpaired at the time of study entry, lifetime risk of developing MCI or dementia by age 85 is approximately 10–15% for APOE4 non-carriers, 20–25% for heterozygotes, and 30–55% for homozygotes.⁸ Longitudinal studies have limitations as well. Like the cross-sectional studies, population-based longitudinal studies have only just begun to capitalize on blood biomarkers to estimate the biological and ensuing clinical risk of AD in cognitively unimpaired persons with different APOE genotypes or account for the differential impact of ethnic, racial, and geographic background on a person’s APOE-related risk. Population-based longitudinal studies in diverse populations are needed to characterize the impact of APOE4 allelic dose on the biological and ensuing clinical features of AD. Blood biomarkers of AD could be obtained using legacy blood samples to provide some of this information relatively quickly.

While the field continues to debate the terminology used to characterize its biological and clinical manifestations, AD is now conceptualized as a progressive sequence of pathophysiological changes, some of which can be used to inform a person’s diagnosis and biological stage, and which correspond roughly to cognitively unimpaired (preclinical), MCI, and disabling cognitive impairment (dementia) clinical stages.⁹ It may be possible to generate AD biomarker data from legacy blood samples in population-based longitudinal studies and use it along with relevant cognitive data relatively quickly to further inform a cognitively unimpaired person’s risk of developing AD, its preclinical, MCI and dementia stages, and MCI and dementia unrelated to AD based on their biomarker results, APOE genotype, age, sex, race, ethnicity, and factors.

When it comes to AD research, drug development and clinical care, there appears to be little reason to treat APOE4 homozygosity as a categorically distinct genetic form of AD. First, it is possible to recognize, capitalize on, account for, and elucidate differences among persons with each APOE genotype (e.g., in their AD risk, onset age, or differential beneficial or adverse response to treatment) without making this categorical distinction--and without excluding APOE4 homozygotes from trials. Second, while APOE4 homozygotes are likely to have a very high risk of Aβ plaque deposition, their incidence of Aβ plaque deposition and the ensuing biological and clinical features of AD remains to be clarified in diverse, population-based longitudinal studies. Third, it is unclear how this categorical distinction would further inform the discovery or evaluation of APOE-modifying drug or gene therapies, including those efforts that are already underway.

There is a more accurate and hopeful way for cognitively unimpaired APOE4 homozygotes (and heterozygotes) to understand their risk of AD, one that is derived from less alarming population-based longitudinal studies, incorporates appropriate genetic counseling principles, and includes information about recent scientific progress identifying new treatments. Indeed, there is a realistic opportunity for the field to develop, secure regulatory approval of, and support access to the first effective preventative drug therapies within the next few years.¹⁰ Ongoing “secondary prevention” trials in cognitively unimpaired APOE4 homozygotes, heterozygotes and non-carriers with biomarker evidence of amyloid plaques may be able to find and support access to an amyloid plaque-clearing antibody therapy that substantially averts the clinical onset of AD within two years; pending “primary prevention” trials in unimpaired persons who are at increased risk for AD based on their age and APOE genotype but do not yet have biomarker evidence of amyloid plaques may be able to find and support access to a plaque-clearing antibody therapy that substantially averts both the biological and ensuing clinical onset of AD soon after; and trials of other prevention therapies are likely to follow. Longitudinal studies that use highly scalable blood-based biomarkers to clarify the risk of developing AD and ensuing MCI and dementia stages in cognitively unimpaired APOE4 homozygotes, heterozygotes, and non-carriers will playing important roles in this endeavor.