Do Two APOE4 Alleles Always Mean Alzheimer's?

For 30 years, APOE4 has ranked as the strongest genetic risk factor for Alzheimer’s disease, with two copies boosting the odds up to 15-fold. Now, scientists make the case that people with two APOE4 alleles are not merely at risk, but are destined to develop AD. As reported in Nature Medicine on May 6, researchers led by Juan Fortea and Victor Montal at the Biomedical Research Institute Sant Pau, Barcelona, Spain, compiled neuropathological, biomarker, and clinical evidence from more than 13,000 participants in research studies and clinical trials to assess how APOE4 genotype relates to AD. By age 65, 95 percent of ApoE4 homozygotes had brain amyloid and, on average, memory problems surfaced then, too, a decade sooner than in noncarriers.

  • By age 65, 95 percent of APOE4 homozygotes have amyloid plaques.
  • This is on par with autosomal-dominant forms of AD.
  • On average, symptoms emerge at age 65, a decade earlier than in noncarriers.
  • Scientists call APOE4 homozygosity a genetic form of AD.

The penetrance of this age at onset resembles that of autosomal-dominant forms of AD. The genotype is not an absolute dementia predictor because a proportion of APOE4/4 carriers do live into old age without symptoms. Even so, given this data, the authors call for APOE4 homozygosity to be reconceptualized from risk factor to cause. This would elevate APOE4/4 to be the most common genetic cause of AD, affecting up to 3 percent of the world’s population. The study was covered at news outlets across the world.

“Redefining APOE4 homozygosity as a genetic form of Alzheimer’s disease will have a substantial effect on Alzheimer’s disease diagnosis, research, and therapeutic development,” wrote Qin Xu, Zherui Liang, and Yadong Huang of the Gladstone Institute of Neurological Disease in San Francisco, in an editorial in Nature.

Essentially, genetic risk and genetic determination exist on a continuum of sorts. Not everyone is convinced that moving ApoE4/4 from the former to the latter is warranted. For one, while two copies of ApoE4 provoke Alzheimer's pathology with near full penetrance, the extent to which that leads to clinical disease during life is less absolute. For another, most data in the new study came from white participants, but the effect of ApoE4 on AD risk differs by racial and ethnic ancestry. To some scientists, this suggests that ApoE4 homozygosity might not constitute genetically determinant AD. Studies in more diverse populations will tell, they said.

Thirty years from being outed as an AD risk factor, why hasn't this been settled? For one, homozygotes are rare, around 3 percent in the general population and 15 percent among people with Alzheimer’s. Therefore, most AD studies have simply lumped them into one group with heterozygotes. Complicating matters, ApoE4 was categorized a risk factor for late-onset AD. Its effects tend to emerge along with an array of other age-related comorbidities and brain pathologies that contribute to AD risk and cognitive decline. Older onset means many people die of other causes before AD symptoms become obvious, masking the true prevalence in this population. A previous study calculated a 60 percent chance of being diagnosed with AD during life for APOE4 homozygotes (Genin et al., 2011).

Revisiting this question, Fortea and colleagues investigated the penetrance of biological, as opposed to clinical, AD. They collected pathology data from 3,297 brain donors to the National Alzheimer’s Coordinating Center (NACC), 64 percent of whom had had AD dementia. They surveyed cross-sectional fluid and imaging biomarker data from 10,039 people from five clinical cohorts: 2,214 participants in the AD Neuroimaging Initiative (ADNI); 5,477 from the A4 clinical prevention trial; 418 from the ALFA natural history cohort in Barcelona; 612 from the Wisconsin Registry for Alzheimer’s Prevention; and 1,317 from Washington University’s Open Access Series of Imaging Studies (OASIS) 3 Project. Apart from the NACC cohort, 83 percent of participants in the other studies were cognitively unimpaired. For A4, participants were unimpaired at baseline, when these biomarkers were measured. All told, the combined study included 792 ApoE4 homozygotes, more than any other to date.

What did it show? In the NACC sample, 95 percent of APOE4 homozygote but only half the APOE3 homozygote cases had a high or intermediate burden of AD neuropathology (image below). In the clinical cohorts, the researchers looked at fluid and imaging biomarkers, including amyloid-PET, CSF Aβ42, CSF p-tau181. Starting at age 55, APOE4 homozygotes had consistently more abnormal readings than noncarriers; by 65, nearly all APOE4 homozygotes had abnormal CSF Aβ42 and 75 percent had positive amyloid scans. By age 80, 88 percent were positive for all biomarkers. Gene dosage mattered, too, with heterozygotes falling in between noncarriers and homozygotes for both neuropathological and biomarker measures.

A Penetrating Pathology. In NACC, most APOE4/E4 carriers who died in their mid-50s and beyond had intermediate or high AD neuropathological change (ADNC) scores (left). Half of APOE3/E3 carriers did (right). [Courtesy of Fortea et al., Nature, 2024.]

Next, the scientists asked how ApoE4 influenced the age at which NACC participants and their caregivers reported first noticing symptoms, such as memory problems. On average, first symptoms emerged when homozygotes were 65, followed by MCI at 71, dementia at 73, and death at 77. This pattern started seven to 10 years later in APOE4 noncarriers. Once it did, it proceeded at a similar pace. The finding jibes with numerous studies over the past decades that showed ApoE4 hastens the onset of the AD cascade (for example, Corder et al., 1993; Gomez-Isla et al., 1996; Blacker et al., 1997; Mishra et al., 2018).

How predictable was age at onset? For APOE4 homozygotes, 95 percent developed symptoms within a 32-year span, from age 49 to 81. This seems wide, but is similar to the time span of ADAD mutations, or Down’s syndrome when measured across affected families. Symptoms cropped up over a 47-year span in APOE3 homozygotes.

To monitor the trajectory of biomarker change over the course of disease, the researchers deployed a technique developed for studies of ADAD mutation carriers. They plotted values against estimated years to symptom onset, which they set at 65, the average. The earliest biomarker to shift—CSF Aβ42—was already low in APOE4 homozygotes in their late 40s. These were the youngest people included in the studies, so the researchers were unable to determine when CSF Aβ42 first became abnormal. Next came CSF p-tau181 and amyloid-PET, which turned abnormal in the early 50s.

On MRI, the youngest APOE4 homozygotes in the study had smaller hippocampi than their fellow noncarriers. The scientists ascribe this to neurodevelopmental effects of ApoE4. Later, their hippocampi shrank again, suggesting this atrophy was due to the AD cascade, Fortea told Alzforum. Previous studies have reported smaller regional brain volumes even among infants and young children who carry APOE4 (e.g., Dec 2013 news). Fortea does not know how this developmental influence relates to the atrophy that emerges in adulthood.

Pantheon of Bad. APOE4 homozygosity meets three criteria for genetically determinant forms of Alzheimer's disease, a group that currently includes ADAD and Down’s syndrome. [Courtesy of Xu et al., News and Views, Nature, 2024.]

The data suggests that APOE4 homozygosity meets three criteria for genetic forms of AD: nearly full penetrance, predictability of symptom onset, and predictable sequence of biomarker changes (image above). The authors therefore propose reframing the genetic landscape of AD, counting ApoE4 homozygosity alongside ADAD and Down’s syndrome as determinant forms of the disease. Because one copy of APOE4 causes intermediate disease phenotypes, APOE4 should be considered a semi-dominant gene, they say, as proposed more than a decade ago based on clinical symptoms. This is distinct from autosomal recessive conditions, in which two copies of the disease allele are needed to cause any harm.

Gaël Nicolas and Camille Charbonnier of Normandie University in Rouen, France, believe the findings convincingly demonstrate that APOE4 homozygosity leads to AD biology with near-full penetrance. However, they emphasized that about half of these will not develop dementia by age 85. “That is very important to keep in mind when dealing with such a concept in the clinic, especially with asymptomatic individuals,” they wrote. “In other words, penetrance of AD biology is not penetrance of AD dementia” (comment below).

Fortea and colleagues acknowledge that their study did not assess clinical penetrance. This was not possible in the cohorts at hand, which were biased either toward symptomatic volunteers in the case of NACC, or toward cognitively healthy people in the clinical cohorts. Even so, the near-absolute biological penetrance of APOE4 homozygosity across all studies strengthens the argument that this is a genetically determinant form. AD is increasingly being defined based on biomarkers, not clinical symptoms (Apr 2018 news; Aug 2023 conference news). This biological definition remains controversial, with some taking the view that people who have biomarkers but no symptoms are at risk and not destined to develop dementia (Dubois et al., 2021; Villain and Michalon, 2021; Nov 2023 conference news).

Jessica Langbaum and Eric Reiman of the Banner Alzheimer’s Institute in Phoenix wrote that while Fortea’s findings are consistent with other retrospective case-control studies, prospective cohort studies to date suggest a lower likelihood that APOE4 homozygotes will go on to get MCI or dementia. “For instance, we estimate the lifetime risk (through age 85) of an APOE4 homozygote developing MCI or dementia due to AD at 30 to 55 percent,” they wrote (Qian et al., 2017). They used these numbers to counsel participants in the Alzheimer’s Prevention Initiative’s Generation trial, which specifically enrolled APOE4 carriers (Sep 2016 news). They also noted that at the time of enrollment, a third of APOE4 homozygotes, between the ages of 60 to 75, did not meet the criteria for amyloid positivity. “While more work is needed to understand the differences between cross-sectional and longitudinal study findings, we think it would be inaccurate, and premature, to inform an unimpaired APOE4 homozygote about a nearly certain risk without more longitudinal data in unimpaired persons enrolled prior to age 60 to support this claim,” they wrote.

Langbaum and Reiman acknowledge that APOE4 homozygotes have earlier onset of AD biomarker changes and clinical decline than heterozygotes or noncarriers. They view this as a quantitative, not a categorical, difference from other APOE genotypes. “We don’t find the criteria used to distinguish between the categorical rather than quantitative distinction compelling,” they wrote.

David Holtzman, Washington University in St. Louis, thinks the findings merely further buttress APOE4 as the most powerful genetic risk factor for late-onset AD. Holtzman noted one major difference between APOE4 and autosomal-dominant variants. The risk provoked by the former varies substantially by race and ethnicity, ranging from strongest to weakest in East Asians, non-Hispanic whites, non-Hispanic blacks, and Hispanics (Belloy et al., 2023). In contrast, ADAD mutations, and the trisomy 21 triplication that causes Down’s syndrome, inflict AD equally across ethnoracial groups. “This differential risk … suggests that there must be factors, genetic and other, that can strongly affect risk for different aspects of AD due to APOE4. Given that, I’m not sure, at this point, that it is appropriate to think of APOE4 homozygosity in the same way as autosomal-dominant AD mutations or Down’s syndrome,” he wrote.

Michael Greicius of Stanford University had similar thoughts. “[These ancestral differences] speak to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk,” he wrote. “It is unlikely that the authors’ reconceptualization would hold up in an African-ancestry population.” Greicius added that this is important for counseling patients. Fortea and Montal believe more studies are needed to assess how a double dose of APOE4 affects AD risk in diverse groups.

Others question how broadly these findings apply. Ruth Frikke-Schmidt of the University of Copenhagen noted that because the analyses came from AD research cohorts, they may suffer from referral bias, a phenomenon in which people at greatest risk for the disease are more likely to enroll. She called for prospective studies in the general population, which would minimize the risk of overestimating the power of ApoE4.

Colin Masters of the University of Melbourne in Australia said the new study supports the concept—proposed three decades ago—that “sporadic” AD is largely genetic, driven by the APOE4 allele in a dose-dependent fashion (Strittmatter et al., 1993). “In today’s world of Aβ-PET and biofluid biomarkers, we have a clearer understanding that the APOE4 allele drives the onset of Aβ accumulation,” he wrote (comment below).

Fortea and Montal’s proposed reconceptualization would have consequences. The authors contend that because APOE4 homozygotes, regardless of their cognitive status, develop AD pathology in midlife, they should receive disease modifying treatments early and, like ADAD mutation carriers, should be offered enrollment in prevention trials. One fly in the ointment: Lecanemab, the only disease-modifying AD therapy with traditional FDA approval, carries a black-box warning for APOE4 homozygotes due to higher odds of amyloid-related imaging abnormalities (ARIA). Co-author Reisa Sperling of Brigham and Women’s Hospital in Boston, who heads the lecanemab AD prevention trial, AHEAD, said this needs to be addressed. “Even at age 55, APOE4 homozygotes are likely to have AD pathology,” she said. Perhaps treating them early with different dosing regimens, might be able to stave off symptoms while minimizing ARIA, she suggested.

Should APOE4 homozygotes be analyzed in their own right in trials and research studies? “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated,” wrote Huang and colleagues in their editorial. “Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively toward genetically defined patient populations.”

The ongoing, Phase 3 APOLLOE4 trial of ALZ-801, a follow-on drug of Alzhemed, is being conducted in APOE4 homozygotes, based on hints that the drug may benefit this group specifically. APOE-targeted gene therapy approaches include strategies that aim to reduce ApoE expression, transform APOE4 into the protective APOE2 allele, or overexpress ApoE2 in the hopes of counteracting ApoE4 (Aug 2023 conference news; Dec 2022 conference news; Jackson et al., 2024).

Fortea and Montal do not view ApoE4 homozygosity as a fundamentally different form of AD. Once it starts, the biomarkers and clinical symptoms progress much like in sporadic and familial forms of the disease. That said, Philippe Amouyel of the University of Lille in France thinks it’s possible ApoE4 homozygosity could cause a unique flavor of AD (comment below). “Hence, increased investment in basic research is imperative to fully comprehend how the APOE4 allele, identified over 30 years ago, precisely influences AD pathophysiology,” he wrote. “Once elucidated, powerful new drugs and a straightforward genetic screening test could mitigate the lifetime risk of AD development for APOE4 homozygotes.”—Jessica Shugart

Comments

  1. This is a very appealing study on neuropathological changes and in vivo biomarkers in APOE4 homozygotes. A better knowledge on the history of biomarkers in different genetic contexts is indeed required for the future of AD prevention, beyond autosomal dominant forms, and APOE is clearly the main gene to focus on first, along with rare variants in more recent genes (SORL1, TREM2, ABCA7, etc.).

    One of the messages in this paper, and which is always a useful reminder, is that AD is the same disease in autosomal dominant and non-autosomal dominant forms, with or without APOE4: Whatever the cause (monogenic versus complex, with or without APOE4), the course of biological alterations and CSF biomarkers is similar, only the rhythm of progression along the disease path differs. This adds more data to further demonstrate it.

    The main message is about the biological penetrance of AD. The data show quite convincingly that AD biological processes are identifiable at high levels from age 60 in 75 percent of E4 homozygotes and at high or intermediate levels in all E4 homozygotes by age 90. In that respect, the exact claim that APOE4 homozygotes present near-full penetrance of AD biology is justified and very interesting.

    Of note, it is important to remember that APOE4 homozygotes do not present near-full penetrance of AD dementia. Combining cross-sectional, age-category-specific odds ratios with data from cohorts allowed a first estimation of AD clinical penetrance per APOE genotype back in 2011 (Génin et al., 2011) and the penetrance was high in the E4-homozygote group (50-60 percent) but still far from full (and APOE genotypes were already split and not gathered as a whole group of E4+). This result was then confirmed in a nice way in the Rotterdam study, directly based on cohort data (Van der Lee et al., 2018), which is a gold-standard study design for assessing penetrance.

    The interpretation of the results is thus to be related to the actual definition of AD. It has been a hot topic (for more than a century!), but defining it exclusively with high/medium neuropathological changes, or using the ATN classification, makes a focus on biological/mechanistic changes only. Although this is meaningful from one point of view, it is not sufficient to predict dementia, which remains the main clinical question. Indeed, the discussion of this article suggests the use of APOE genotyping for genetic counseling with predicted age at onset, and it is reminded that roughly 2 percent of the population is homozygous. To us, this message is a bit dangerous. We know from previous large prospective cohorts that 50 percent of E4 homozygotes will not develop AD-dementia in their lifetimes. Admittedly, 50 percent will, and this number is indeed huge. In the Génin et al. paper on the “semidominant” inheritance of AD with APOE4 (meaning increased risk in heterozygotes and even more in homozygotes, in ranges not so far away from what we see in some Mendelian disorders), adding “with incomplete penetrance” in the title would have been more accurate. Not all E4-E4 individuals develop AD dementia, and that is very important to keep in mind when dealing with such a concept in the clinic, especially with asymptomatic individuals. In other words, penetrance of AD biology is not penetrance of AD dementia.

    Another important point is the prediction of the age of onset. In families, the age of onset of the transmitting parent can be used as a reference or an add-on to account for familial background risk. In the case of APOE4 homozygotes, it is obviously not possible. We already know that additional factors, including common variants in other genes and more importantly rare coding variants in recently identified genes (e.g., Schramm et al., 2022), drastically change the picture at the individual level, and that is without accounting for non-genetic factors. This is much less the case in dominantly inherited AD, where APOE genotype has only a modest effect on age at onset, and other modifier variants are only found in extremely rare outlier cases. We would thus disagree with the authors’ claim that ages of onset are predictable in APOE4-homozygous individuals. In addition, it appears questionable to predict ages of onset when we know that 50 percent of the E4 homozygotes do not develop AD dementia. How can the age at symptom onset be projected to be roughly between 50 and 80 years old for 95 percent of individuals (Fig 1d) of when 50 percent will not develop dementia by the age of 85? This appears paradoxical with the clinical cohort data.

    Overall, these data are extremely interesting, especially those suggesting that APOE4 homozygotes all develop AD-related changes, even though it cannot be used to predict ages of onset, to our point of view, and it is important to remind that this work does not report clinical penetrance. APOE is already considered a major AD gene, and it is uncertain that adding a category that is already in the mind of people would be required.

    —Camille Le Clézio Charbonnier is the co-author of this comment.

    References:

    Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011 Sep;16(9):903-7. Epub 2011 May 10 PubMed.

    van der Lee SJ, Wolters FJ, Ikram MK, Hofman A, Ikram MA, Amin N, van Duijn CM. The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study. Lancet Neurol. 2018 May;17(5):434-444. Epub 2018 Mar 16 PubMed.

    Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, Boland A, Deleuze JF, Olaso R, ADES consortium, Alarcon F, Campion D, Nuel G, Nicolas G. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022 Jun 28;14(1):69. PubMed. Correction.

    View all comments by Gael Nicolas

  2. We commend Fortea and colleagues for their analyses examining biomarker and clinical changes in a large number of cognitively impaired and unimpaired persons from NACC, Alfa plus, A4 trial, OASIS, ADNI, and WRAP. In general, the results from their retrospective case control study are consistent with those from other retrospective case control studies, showing much higher odds of Alzheimer’s pathophysiological changes and clinical decline, and younger ages at onset in those with two APOE4 alleles than those with other APOE genotypes. 

    Despite the value and consistency of results, we have concerns about the conclusions that 1) APOE4 homozygotes have a nearly certain likelihood of AD biology and symptom onset, 2) APOE4 homozygosity is categorically rather than quantitatively different from the other APOE genotypes, and 3) homozygotes should be evaluated separately from other groups in treatment and prevention trials.

    We’d like to note the following:

    1. In contrast to the extremely high likelihood that older adult APOE4 homozygotes are nearly certain to develop AD in retrospective case control studies (e.g., Corder et al., 1993; Reiman et al., 2020), prospective cohort studies to date suggest a lower likelihood of progressing to MCI or dementia. For instance, we estimate the lifetime risk (through age 85) of an APOE4 homozygote developing MCI or dementia due to AD is 30-55 percent (Qian et al., 2017), and we used that information to inform participants about their risk in prevention trials, such as the API Generation Program. While more work is needed to understand the differences between cross-sectional and longitudinal study findings, we think it would be inaccurate and premature to inform an unimpaired APOE4 homozygote about a nearly certain risk without more longitudinal data in unimpaired persons enrolled prior to age 60 to support this claim. Furthermore, we found that 35 percent of the 650 unimpaired APOE4 homozygotes ages 60-75 did not meet criteria for an elevated amyloid PET scan at the time of enrollment in the API Generation Program. This is consistent with the LP substudy in the Generation Program trials, with about 30 percent of the APOE4 homozygotes not meeting CSF criteria for amyloid positivity (mean age of participants in the substudy was 66 years). In our longitudinal cohort study of unimpaired APOE4 homozygotes, heterozygotes, and noncarriers, we observed that homozygotes who remained unimpaired after age 75 had a lower risk of amyloid positivity and the other pathophysiological and cognitive features of AD, perhaps due to other protective factors (Ghisays, 2020).
    2. While we appreciate that APOE4 homozygotes have an earlier onset of AD biomarker changes and of clinical decline than do the other genetic groups, and that they have greater ARIA risk, we do not see sufficient evidence to say that this difference is categorically rather than quantitatively different from the other APOE genotypes, and we don't find the criteria used to distinguish between the categorical rather than quantitative distinction compelling. Even when one finds differences among cognitively impaired persons with two, one, or no APOE4 alleles, including those related to treatment benefits and risks, it is hard to know whether those differences are attributable to differences in age at onset and duration of disease (e.g., amount of time amyloid has been accumulating) or to some other aspect of APOE.
    3. In particular, we do not think it prudent to routinely exclude APOE4 homozygotes from treatment and prevention trials. They comprise about 15 of those with MCI or dementia due to AD, there should still be some equipoise about the chance of a benefit in this group, and there are ways to mitigate risks of amyloid-modifying treatments and conduct exploratory, post-hoc analyses to compare benefits and risks based on APOE4 allelic dose (not just lumping together all carriers). That said, we agree that there are compelling reasons to consider dedicating a smaller number of treatment and prevention trials to APOE4 homozygotes based on considerations of benefits, risks, and statistical power. Examples include our discontinued API Generation Study 1 of cognitively unimpaired APOE4 homozygotes (included those with and without an elevated amyloid PET scan), Alzheon's ongoing trial of ALZ-801 in APOE4 homozygotes with early AD, and some of the future APOE-modifying gene therapy studies, which offer potential benefits and risks.

    Despite the high risk of developing AD in APOE4 homozygotes, we hope that this population shares our optimism about the chance to find effective disease-modifying and prevention therapies in the next few years, as well as the chance to develop and test investigational APOE-modifying treatments.

    References:

    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PubMed.

    Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J, Paul Vonsattel J, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Keene CD, Kamboh MI, Kofler JK, Duque L, Gilbert JR, Gwirtsman HE, Buxbaum JD, Dickson DW, Frosch MP, Ghetti BF, Lunetta KL, Wang LS, Hyman BT, Kukull WA, Foroud T, Haines JL, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Farrer LA, Schellenberg GD, Beecham GW, Montine TJ, Jun GR, Alzheimer’s Disease Genetics Consortium. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.

    Qian J, Wolters FJ, Beiser A, Haan M, Ikram MA, Karlawish J, Langbaum JB, Neuhaus JM, Reiman EM, Roberts JS, Seshadri S, Tariot PN, Woods BM, Betensky RA, Blacker D. APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med. 2017 Mar;14(3):e1002254. Epub 2017 Mar 21 PubMed.

    Ghisays V, Goradia DD, Protas H, Bauer RJ 3rd, Devadas V, Tariot PN, Lowe VJ, Knopman DS, Petersen RC, Jack CR Jr, Caselli RJ, Su Y, Chen K, Reiman EM. Brain imaging measurements of fibrillar amyloid-β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele. Alzheimers Dement. 2020 Apr;16(4):598-609. Epub 2020 Jan 16 PubMed.

    View all comments by Jessica Langbaum View all comments by Eric M. Reiman

  3. The authors of this manuscript analyzed, together, data from a number of previously published studies and comment that: “Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes.”

    Based on this re-analysis of published data, the authors concluded that APOE4 homozygosity is a distinct genetic form of AD. Their analysis is certainly correct from these previously published cohorts, and I agree that there is no question that APOE genotype is the strongest and most powerful genetic risk factor for late-onset AD. Further, there are some distinct features of AD pathology in the presence of APOE4 that is allele dose dependent, such as increase in CAA in addition to parenchymal amyloid deposition. 

    However, there is one major difference between the APOE4 heterozygous and homozygous state that differs from AD deterministic mutations in APP, PSEN1, PSEN2, and trisomy 21/trisomy for APP. The risk for AD biomarkers and dementia appears to be significantly different across race and ethnicity for APOE4 homozygotes, being in order of highest to lowest in East Asians, non-Hispanic whites, non-Hispanic blacks, and Hispanics (Belloy et al., 2023). Other work suggests similar findings. For example, see the figure below from the National Institute on Aging/Alzheimer’s Disease Sequencing Project Working Group on APOE (Vance et al., 2024). 

    As Belloy et al. pointed out, and certainly more work needs to be done on how different race and ethnic factors affect risk of AD conferred by APOE4 and other APOE genotypes, similar large changes in risk due to other differences across race and ethnicity have not been described for APP, PSEN1, PSEN2, or Down’s syndrome. Certainly, there are recent examples where a very rare variant in APOE itself (APOE3ch homozygosity) appears to delay age of onset of dementia in the setting of a specific PSEN1 mutation. However, the differential risk across race and ethnicity suggests that there must be factors, genetic and other, that can strongly affect risk for different aspects of AD due to APOE4. Given that, I’m not sure at this point it is appropriate to think of APOE homozygosity in the same way as autosomal-dominant AD mutations or Down’s syndrome. There are many reasons why both the genetics and biology of APOE and APOE4 homozygosity need to be studied even more than they are now, and to think about assessing APOE4 homozygotes in an individualized way for all clinical trials and treatments, and, at a minimum, to account for this group in relation to other groups in analyses.

    References:

    Belloy ME, Andrews SJ, Le Guen Y, Cuccaro M, Farrer LA, Napolioni V, Greicius MD. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023 Dec 1;80(12):1284-1294. PubMed.

    Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.

    View all comments by David Holtzman

  4. I think this paper is helpful in putting some biomarker and neuropathology heft behind the growing consensus in the field that E4 homozygosity, in European ancestry individuals at least, is all but deterministic for the development of Alzheimer’s disease by age 90.

    One important argument against their reconceptualization, which they mention briefly in their discussion, is that the risk of Alzheimer’s disease in E4 homozygotes varies substantially across different genetic ancestries. In our recent publication, we replicated and expanded upon an earlier, seminal meta-analysis from Lindsay Farrer and colleagues (Belloy et al., 2023). European-ancestry individuals with two copies of APOE4 have a 13-fold increased risk for Alzheimer’s, whereas in African-ancestry individuals with two copies of APOE4, their risk is 6.5-fold, or half of that seen in Europeans. This has critical implications when counseling patients, in that we really need to provide ancestry-informed genetic risk assessments for Alzheimer’s disease. It also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk. It is unlikely that their reconceptualization would hold up in an African-ancestry population.

    References:

    Belloy ME, Andrews SJ, Le Guen Y, Cuccaro M, Farrer LA, Napolioni V, Greicius MD. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023 Dec 1;80(12):1284-1294. PubMed.

    View all comments by Michael Greicius

  5. Perspective on the findings and their implications.

    Age-related Alzheimer’s disease (AD) is a neurodegenerative disorder with a complex pattern of genetic and environmental factors contributing to its pathogenesis. One gene stands, however, central for risk of AD, namely the apolipoprotein E gene (APOE) where two common genetic variants combine into six common APOE genotypes, APOE2/2, 3/2, 4/2, 3/3, 4/3, and 4/4. The APOE4 allele is a major risk factor for AD, with risk estimates for 4/4 homozygotes around 8-10 in prospective studies of the general population and up to approximately 15-fold in case control studies.  Insights into the APOE4 risk were already reported in the ’90s and have subsequently been shown in many populations around the world. In European populations, around 25 percent are APOE3/4 carriers and 2-3 percent are 4/4 carriers with a decreasing north to south APOE4 allele frequency gradient. Differences in frequency and effect size according to ethnicity are also observed.

    In this paper, scientists led by Juan Fortea and Victor Montal suggest that homozygosity for APOE ε4 constitutes a genetically determinant form of AD similar to autosomal dominant forms of AD, and that their results will have compelling consequences for public health and genetic counseling.

    Limitations to this claim are, however, important to emphasize. The current article builds on a case/control design, with cases identified through neuropathological evaluation or preclinical or established AD, recruited through AD-families, and with controls being cognitively intact. An inherent and well-established bias in case control studies is so-called referral bias, where  APOE 4/4 carriers who display altered AD biomarkers and/or cognitive symptoms, are referred to studies more often than APOE4/4 carriers who do not have such changes. This naturally leads to a circular argument, with inflation of risk estimates and penetrance, which may at least partly explain the high penetrance of APOE 4 homozygosity on AD biomarkers observed in the present case control study. To determine the penetrance in an unbiased way for a common genotype as the APOE4, prospective studies of the general population, with long follow-up, are needed. Such a design minimizes the risk of referral bias, because individuals are picked at random from the background population. It is also well-established that APOE genotypes are involved in many complex biological interactions, both in the brain and in peripheral lipid metabolism, and that the effect of APOE4 can be substantially modulated by other genetic risk markers spread across the genome, as well as by traditional cardiovascular risk factors.

    The risk associated with APOE4 homozygosity is important and should be taken seriously in clinical trial designs and in public health initiatives aiming at preserving brain health with early preventable measures. To categorize APOE4 homozygosity together with autosomal dominant forms of AD, as suggested by Fortea and Montal, is however an overly strong claim considering the current case control findings of a common genetic risk variant.

    View all comments by Ruth Frikke-Schmidt

  6. Is late-onset, “sporadic” Alzheimer’s disease genetic?

    Is this a trick question? Ever since Strittmatter and Roses published the first evidence of the association between ApoE and Aβ-amyloid in 1993 (Strittmatter et al., 1993), and as long as he lived, Alan Roses (1943-2016) promoted the idea that “sporadic” AD was largely genetic, driven by the ε4 allele in a dose-dependent fashion: one copy about 50 percent penetrance, two copies nearly 99 percent penetrance. In today’s world of amyloid PET and biofluid biomarkers, we have a clearer understanding that the ApoE4 allele drives the onset of Aβ accumulation. Our most recent data shows that carriage of one or two alleles of APOE4 reduces the age of onset (judged by Aβ-PET) by 7.5 years (Burnham et al., 2024), but the rates of accumulation in APOE4-positive and APOE4-negative subjects are the same. The current formulation of how the APOE4 allele works points to ApoE-Aβ interactions in the microglial clearance pathways, mediated by a gain of function through the Cys-Arg changes at codons 112 and 158.

    This paper by Fortea et al. serves to emphasize the ApoE4 gene-dosage effect: two copies are almost completely dominant in determining age at onset, but there are escapees. They compare E4 homozygotes with autosomal-dominant Alzheimer’s (ADAD) and Down’s syndrome AD (DSAD). But there are some subtle differences that we should remember. ADAD has a more aggressive presentation and regional accumulation of Aβ is more marked in the striatum, cerebellum (and in some cases in the cortico-spinal tracts, resulting in spastic paraparesis), which are not features of late-onset AD. DSAD is much more like late-onset AD, but with an earlier mean clinical onset at 55 years.

    Nevertheless, APOE4 homozygotes should be categorized as a defined subset of late-onset “sporadic” AD, simply because they can be easily identified well before onset of Aβ accumulation, and should be dealt with as a separate group in primary and secondary prevention trials with Ab-targeting immunotherapies.

    References:

    Burnham SC, Cox T, Benzinger T, et al. When Does Alzheimer's Disease Start? Robust Estimates Based on Longitudinal Aβ-Amyloid-PET in Three Large International Cohorts. The Lancet Preprint, March 18, 2024 The Lancet Preprint

    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PubMed.

    View all comments by Colin Masters

  7. The APOE4 allele constitutes a unique case among common genetic variants of chronic diseases, exerting a major influence on Alzheimer’s disease (AD) risk. AD also associates with three other distinct genetic forms, featuring rare variants of high effect, such as APP, PS1, PS2, and SORL1, as well as low-frequency variants with intermediate effects such as in TREM2, but the majority of cases involve common variants with minor effects, such as CLU or BIN1. Génin et al. in 2011 characterized APOE as a "major gene with semi-dominant inheritance," with lifetime risks akin to BRCA1 in breast cancer. This research by Fortea et al. further solidifies this assertion by revealing full pathological and biological penetrance in APOE4 homozygotes, and showcasing earlier clinical and biomarker changes. These findings advocate for reclassifying the APOE gene from a mere "risk factor" to a "major codominant gene," particularly among populations of European ancestry where 2 percent are homozygous for the APOE4 allele.

    Should we regard APOE4 homozygosity as a distinct genetic form of AD? Quite possibly. Recent analyses of anti-amyloid drugs, such as lecanemab, suggest contraindications in APOE4 homozygotes due to a 39 percent incidence of amyloid-related imaging abnormality microhemorrhages (ARIA-H), compared to 13 percent in other patients (Van Dyck et al., 2022). Conversely, some studies have identified genetic resilience to AD among APOE4 homozygotes, with some individuals not developing AD beyond the age of 75. Notably, CASP7 rs10553596 and SERPINA3 rs4934 A/A have emerged as two genetic variants offering significant protection against AD in APOE4 homozygotes (Huq et al., 2019). Therefore, this high-risk population warrants special attention, both due to the unclear pathophysiological processes underlying the effect of this major AD gene, and to the accessibility of APOE genotype testing through direct-to-consumer genomic tests. This may have adverse impacts on individuals' lives, as in the case of Chris Hemsworth, the famous interpreter of Thor in the Marvel films, who learned a few years ago that he carries two copies of the E4 allele.

    This extensively documented paper by Fortea and colleagues underscores the heterogeneous nature of the etiology, akin to other chronic diseases, such as hypertension, necessitating various treatment approaches combining prevention measures and diverse treatments, many of which are yet undiscovered in AD. Hence, increased investment in basic research is imperative to fully comprehend how the APOE4 allele, identified over 30 years ago, precisely influences AD pathophysiology. Once elucidated, powerful new drugs, and a straightforward genetic screening test, could mitigate the lifetime risk of AD for APOE homozygotes. However, until such treatments materialize, ignorance of one's APOE genotype may be preferable.

    References:

    Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011 Sep;16(9):903-7. Epub 2011 May 10 PubMed.

    Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, Montal V. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nat Med. 2024 May;30(5):1284-1291. Epub 2024 May 6 PubMed. Correction.

    van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. Epub 2022 Nov 29 PubMed.

    Huq AJ, Fransquet P, Laws SM, Ryan J, Sebra R, Masters CL, Winship IM, James PA, Lacaze P. Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review. Alzheimers Dement. 2019 Dec;15(12):1612-1623. Epub 2019 Sep 7 PubMed.

    View all comments by Philippe Amouyel

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References

Mutations Citations

  1. APOE C130R (ApoE4)
  2. Trisomy 21

News Citations

  1. Brain Volume, Myelination Different in Infants Carrying ApoE4
  2. New Definition of Alzheimer’s Hinges on Biology, Not Symptoms
  3. Revised Again: Alzheimer's Diagnostic Criteria Get Another Makeover
  4. New Alzheimer’s Diagnostic Criteria Remain ‘Research Only’
  5. To Know or Not to Know: Trial Participants Confront the Question
  6. Meet the Switching Mice: They Flip Their Glia APOE4 to APOE2
  7. In Small Trial, Gene Therapy Spurs ApoE2 Production

Therapeutics Citations

  1. ALZ-801

Paper Citations

  1. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011 Sep;16(9):903-7. Epub 2011 May 10 PubMed.
  2. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PubMed.
  3. Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, Perls TT, Lipsitz LA, Hyman BT. Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol. 1996 Jan;39(1):62-70. PubMed.
  4. Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS, Tanzi R. ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology. 1997 Jan;48(1):139-47. PubMed.
  5. Mishra S, Blazey TM, Holtzman DM, Cruchaga C, Su Y, Morris JC, Benzinger TL, Gordon BA. Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype. Brain. 2018 Jun 1;141(6):1828-1839. PubMed.
  6. Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert MO, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484-496. Epub 2021 Apr 29 PubMed.
  7. Villain N, Michalon R. What is Alzheimer's disease? An analysis of nosological perspectives from the 20th and 21st centuries. Eur J Neurol. 2024 Nov;31(11):e16302. Epub 2024 Apr 15 PubMed.
  8. Qian J, Wolters FJ, Beiser A, Haan M, Ikram MA, Karlawish J, Langbaum JB, Neuhaus JM, Reiman EM, Roberts JS, Seshadri S, Tariot PN, Woods BM, Betensky RA, Blacker D. APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med. 2017 Mar;14(3):e1002254. Epub 2017 Mar 21 PubMed.
  9. Belloy ME, Andrews SJ, Le Guen Y, Cuccaro M, Farrer LA, Napolioni V, Greicius MD. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023 Dec 1;80(12):1284-1294. PubMed.
  10. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PubMed.
  11. Jackson RJ, Keiser MS, Meltzer JC, Fykstra DP, Dierksmeier SE, Hajizadeh S, Kreuzer J, Morris R, Melloni A, Nakajima T, Tecedor L, Ranum PT, Carrell E, Chen Y, Nishtar MA, Holtzman DM, Haas W, Davidson BL, Hyman BT. APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. Mol Ther. 2024 May 1;32(5):1373-1386. Epub 2024 Mar 19 PubMed.

Further Reading

Papers

  1. Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.

Primary Papers

  1. Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, Montal V. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nat Med. 2024 May;30(5):1284-1291. Epub 2024 May 6 PubMed. Correction.

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