Not All Bad? APOE4 Sharpens Memory in Older People

APOE4, the strongest genetic risk factor for sporadic Alzheimer’s disease, has been tied to slightly better memory in the young. Now, researchers led by Sebastian Crutch and Jonathan Schott, University College London, find a similar benefit in older people. In the October 7 Nature Aging, they reported that cognitively intact 70-year-olds carrying the APOE4 allele edged out noncarriers on a short-term visual memory task. The advantage was slight, but showed up even in people who had brain amyloid. “It was surprising that the E4 memory advantage endured in people with Aβ,” Nahid Zokaei, University of Oxford, U.K., wrote to Alzforum.

  • APOE4 carriers remembered objects and their whereabouts better than noncarriers.
  • Carriers who had brain amyloid maintained this slight edge.
  • This advantage may explain why APOE4 persists in the genome despite increasing a person's risk of AD.

Renaud La Joie and Marianne Chapleau, University of California, San Francisco, went one further. “That they could see a cognitive benefit from APOE4 in older people is very surprising,” they said.

APOE4 increases the risk for amyloidosis and dementia (Apr 2009 news; June 2011 news; Morris et al., 2010). Against this uncontested backdrop, some controversial research over the years has been suggesting that throughout early to mid-adulthood APOE4 carriers have a slight cognitive advantage, which then begins to wane (Rusted et al., 2013; Zink et al., 2019; Jochemsen et al., 2011). 

To find out, first author Kirsty Lu and colleagues correlated APOE genotype, amyloid PET, structural MRI, and cognitive test data from a subset of the British 1946 Birth Cohort. These volunteers were all born during the same week after World War II and researchers have been following them ever since. Of the 398 cognitively normal participants selected for the present analysis, 30 percent carried an APOE4 allele. One-third of them also had brain amyloid, compared to just 10 percent of noncarriers.

The researchers gauged visual working memory by asking participants to recall an object they had seen on a computer a few seconds earlier, and to remember where it had been on the screen (see image below). Each volunteer repeated this task 24 times. Lu and colleagues adjusted raw data for confounding factors, including hippocampal and white-matter volume, and childhood cognitive abilities. Jennifer Rusted, University of Sussex, U.K., noted that most studies do not have this level of demographic detail, nor the statistical power to isolate multiple confounding factors that influence a specific measure of cognition.

What Was Where? In this test, participants had to recall which object they had seen and where it had been on the screen. The test measures the ability to identify things and place them in space. [Courtesy of Lu et al., Nature Aging, 2021.]

As expected, amyloid-positive volunteers did worse at object recognition, picking the one they had not seen 19 percent more often than did the amyloid-negative group, though both similarly misremembered where the objects had been. In contrast, APOE4 carriers did better than noncarriers. They were 14 percent less likely to recall the wrong object, and dragged the symbols 7 percent closer to their original location, even when the object they selected was the wrong one.

What about in people who harbored both APOE4 and plaques? When push came to shove, E4 prevailed. Among amyloid-positives, APOE carriers still recalled an object’s location more precisely than their non-E4 counterparts (see image below). I certainly thought the impact of the amyloid would swamp the more subtle E4 effect,” Crutch admitted, and Schott agreed. “This study suggests E4-associated compensation may extend into older adulthood and, in high-functioning individuals, could offset the negative impact of low-level Aβ deposits,” wrote Rusted.

The E4 Effect. When recalling which object they had seen before (left), and where it was (right), APOE4 carriers (red) made fewer mistakes than noncarriers (blue), even if they had amyloid in the brain. This effect was more pronounced in people who had plaques (right columns). [Courtesy of Lu et al., Nature Aging, 2021.]

Jacob Raber, Oregon Health & Science University, Portland, emphasized that the E4 enhancement is specific for short-term memory—the allele impairs long-term memory in healthy older people (Zokaei et al., 2019).

Ralph Martins, Edith Cowan University, Joondalup, Australia, cautiously interpreted the results. He noted that the shortened version of the “What was where?” test, which usually involves more than 100 iterations rather than the 24 used here, has not been clinically validated. However, La Joie and Chapleau pointed out that people carrying E4 also performed better on classical verbal memory tests. “Carriers did not just do better on one test by chance, there was a pattern in this cohort,” La Joie told Alzforum.

La Joie and Chapleau were curious how long the cognitive benefits last as E4 carriers age. Rusted said that a full model must include how tangles fit into the E4-Aβ-cognition puzzle. To this end, Schott said that they will continue following up with this cohort subset, collecting tau PET scans on amyloid-positive participants. About one-third of volunteers have given cerebrospinal fluid, in which Schott and colleagues plan to measure phospho-tau species and neurofilament light.

On a final note, the authors suggest that ApoE’s slight boost to working memory may explain why it has persisted in the human gene pool despite being a major risk factor for disease—an example of “antagonistic pleiotropy.” Other commentators agreed. Neill Graff-Radford, Mayo Clinic, Jacksonville, wrote, “This excellent paper convincingly illustrated antagonist pleiotropy for ApoE4 in aging.”—Chelsea Weidman Burke

Comments

  1. The authors provide modest statistical evidence of superior visual working memory in APOE ε4 carriers who are around 70 years of age. They state that their findings are consistent with the antagonistic pleiotropy hypothesis and claim that the beneficial effects of APOE ε4 on specific cognitive functions may persist into old age.

    The study has a number of limitations, particularly the shortened version of the cognitive visual memory test used, which has not been validated. There is a significant bias in cohort selection that may impact their reported findings. Education, overall health, ethnicity, and gender need to be adequately controlled to prevent bias.

    Nevertheless, these findings are intriguing and warrant further investigation in a larger, better-characterized cohort, where the APOE ε4 carrier-to-noncarrier ratio is balanced, to determine whether these initial findings have clinical significance.

    APOE ε4, the ancestral allele of APOE, clearly has been shown to have population survival benefits against a number of diseases of younger individuals. Whether there are selected cognitive benefits in the aging brain remains to be determined. It is highly likely that lifestyle factors may mask the superior visual working memory of APOE ε4 carriers and these factors should be carefully controlled for in future studies.

    View all comments by Ralph Martins

  2. In this important study, Lu et al. assessed differential effects of APOE4 and PET-quantified Aβ pathology on visual working memory. In 398 cognitive healthy elderly (69-71 years of age and part of the U.K. 1946 Birth Cohort), carrying E4 predicted better recall, while Aβ pathology predicted poorer recall. E4 carriers also recalled locations more precisely; this effect was more pronounced in those with more Aβ pathology.

    While antagonistic pleiotropy, with beneficial effects earlier in life and detrimental effects later in life, might play a role in the E4 effects seen, the consistent pattern of genotype differences seen in young, middle-aged, and aged human ApoE-targeted replacement mice suggests that factors other than APOE genotype might be important here. What is remarkable is that there was an interaction between E4 and amyloid burden for this enhanced cognitive performance; the enhanced cognitive performance of E4 carriers was greater when there was more Aβ plaque pathology.

    The enhanced recall of object locations of E4 carriers after a delay of a few seconds is consistent with earlier studies the authors cite. Important to note is that this effect is specific for short-term memory. As reported by Zokaei et al., in cognitively healthy elderly, long-term memory, involving a 20-min delay, is impaired in E4 carriers that show enhanced short-term memory for object locations (Zokaei et al., 2019). Consistent with impaired object-location memory in cognitively healthy elderly E4 carriers, we reported poorer performance in a humanized object-recognition test based on our rodent studies (Novel Image, Novel Location, or NINL test). In this test, the participants were presented with the first set of 12 panels (reference set), one at a time, for eight seconds each and asked to memorize the images and their position. Without delay, they were presented with the second set of 12 panels and were prompted to identify each panel as being either identical to the corresponding panel in the first set [No Change score], or containing a novel image [Novel Image score] or a novel location of a familiar image [Novel Location score]. Their answers provided the total Novel Image Novel Location immediate score with a maximum of 12 points [NINL I]. After five minutes (and without seeing the reference set again), participants were presented with the second set and asked the same questions.

    In 115 oldest-old cognitively healthy study participants (mean age ± S.E.M., 81.60 ± 0.57 years), at any given age, non-E4 carriers had a higher estimated NINL total score than E4 carriers. Consistent with the opposing effects seen in E4 carriers following shorter versus longer delays, there also was a trial by E4 interaction; comparing the immediate and delayed object-recognition test total scores, E4 carriers showed a larger decline in performance than non-E4 carriers. For the Novel Location scores, non-E4 carriers outperformed E4 carriers and women outperformed men. In the current study, there was also a sex difference in localization memory but there was no sex x E4 interaction as reported in the study by Zokaei et al., 2017. 

    Considering sex differences in longevity, cohort differences in the proportion of non-E4- and E4-carrying males might contribute to those divergent results. Salivary testosterone levels might be important here. For salivary testosterone levels, we found a sex x E4 interaction, with higher salivary testosterone levels in E4-carrying than non-E4-carrying men and lower salivary testosterone levels in E4-carrying than non-E4-carrying women. Salivary cortisol might play a role in performance on the object-recognition test as well. In men, salivary cortisol levels were negatively correlated with total NINL and Novel Image scores. In a follow-up study, NINL scores correlated with logical-memory and word-recall lists, cognitive tasks used to detect dementia in the clinic, as well as clinical dementia rating scales (Haley et al., 2012). 

    Consistent with enhanced cognitive performance of E4 carriers in tests involving shorter delays, in young, middle-aged, and old female mice expressing human ApoE under control of the mouse ApoE promoter, E4 mice showed better performance than E2 and E3 mice in locating a visible or hidden platform in the water maze, while no genotype differences were seen in spatial memory retention in the probe trial (no platform), administered one hour after the last hidden-platform training trails on each day of hidden-platform training (Siegel et al., 2012). Similarly, compared to E3 mice, E4 mice required fewer trials to reach criterion in a passive-avoidance test while no differences in memory retention between E3 and E4 mice were seen 24 hours after training. In the passive-avoidance test, mice will step quickly through the gate and enter the dark compartment because mice prefer to be in the dark. Upon entering the dark compartment, the mice received a brief foot shock (0.3 mA for 3 sec) and were immediately removed from the chamber. If the mouse remained in the light compartment for the duration of the trial (120 seconds), the gate closed and the mouse was removed from the light compartment. The next trial began after an inter-trial interval of 180 seconds. Mice were trained until they met a learning criterion of three consecutive trials without entering the dark compartment, or up to 10 trials, whichever came first. After a 24-hour retention period, the mice were placed back into the light compartment, and the time to re-enter the dark compartment (latency) was measured up to 300 seconds. These data indicate that the enhanced short-term memory of E4 carriers might not be limited to recalling the location of objects.

    The immune system might play an important role in these E4-dependent cognitive effects. Both Aβ (Kumar et al., 2016) and ApoE (Vitek et al., 2009) modulate the immune response. For example, amyloid precursor protein (APP) binds the HIV-1 gag protein, retains it in lipid rafts, and blocks HIV-1 virion production and spread (Chai et al., 2017). The HIV-1 gag protein induces the generation of Aβ40 and Aβ42 and amyloid is elevated in HIV-1 infected brains and binds HIV-1. Aβ42 inhibits influenza A viral replication (White et al., 2014). E4 is associated with enhanced entry of human immunodeficiency virus 1 (HIV-1) cell entry and HIV-1 disease progression (Burt et al., 2008). In a herpes simplex virus 1 (HSV-1) mouse model, the cerebral load of latent HSV-1 genomic copies, is 10-fold higher in E4 than E3 mice (Burgos et al., 2006). E4 has also been associated with COVID19 severity and mortality (Gkouskou et al., 2021) while there was a higher uptake of the SARS-CoV-2 S1 protein in liver, spleen, and kidney of E3 than E4 mice (Rhea et al., 2020). Increased efforts are warranted to assess whether the ApoE isoform-dependent cognitive effects are related to differential immune effects of ApoE isoforms, Aβ, and exposure to immune-related pathogens.

    References:

    Zokaei N, Čepukaitytė G, Board AG, Mackay CE, Husain M, Nobre AC. Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories. Neurobiol Aging. 2019 Jan;73:115-122. Epub 2018 Sep 25 PubMed.

    Zokaei N, Giehl K, Sillence A, Neville MJ, Karpe F, Nobre AC, Husain M. Sex and APOE: A memory advantage in male APOE ε4 carriers in midlife. Cortex. 2017 Mar;88:98-105. Epub 2016 Dec 24 PubMed.

    Haley GE, Berteau-Pavy F, Berteau-Pavy D, Raber J. Novel image-novel location object recognition task sensitive to age-related cognitive decline in nondemented elderly. Age (Dordr). 2012 Feb;34(1):1-10. PubMed.

    Siegel JA, Haley GE, Raber J. Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice. Neurobiol Aging. 2012 Feb;33(2):345-58. PubMed.

    Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 2016 May 25;8(340):340ra72. PubMed.

    Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009 Sep;30(9):1350-60. PubMed.

    Chai Q, Jovasevic V, Malikov V, Sabo Y, Morham S, Walsh D, Naghavi MH. HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration. Nat Commun. 2017 Nov 15;8(1):1522. PubMed.

    White MR, Kandel R, Tripathi S, Condon D, Qi L, Taubenberger J, Hartshorn KL. Alzheimer's associated β-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One. 2014;9(7):e101364. Epub 2014 Jul 2 PubMed.

    Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8718-23. PubMed.

    Burgos JS, Ramirez C, Sastre I, Valdivieso F. Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol. 2006 Jun;80(11):5383-7. PubMed.

    Gkouskou K, Vasilogiannakopoulou T, Andreakos E, Davanos N, Gazouli M, Sanoudou D, Eliopoulos AG. COVID-19 enters the expanding network of apolipoprotein E4-related pathologies. Redox Biol. 2021 May;41:101938. Epub 2021 Mar 10 PubMed.

    Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nat Neurosci. 2020 Dec 16; PubMed.

    View all comments by Jacob Raber

  3. Lu and colleagues present compelling evidence demonstrating superior visual working memory in a population-based cohort of cognitively normal APOEε4 carriers. This advantage persisted (albeit to a lesser extent) amidst cerebral amyloidosis (preclinical AD), measured by 18F-Florbetapir-PET. As Aβ was almost certainly driven by APOEε4 carrier status in these patients, this study presents a nice juxtaposition of the “bad” and the “good” aspects of APOEε4 in the same patients, suggesting that APOEε4 may impart resilience to the deleterious effects of early AD neuropathologic change on item localization.

    The authors discuss the possible contributors to this effect, suggesting that differences in attention and precision of encoding may explain the APOEε4 effect. In support of this hypothesis, ε4 carriers performed well on other tasks with strong attentional and working memory demands, implicating relative preservation of top-down frontal and parietal networks.

    Yet, other possible explanations bear consideration. In addition to frontoparietal networks, the “What was where?” task places demands upon the dorsal stream of the visual system, encompassing areas of posterior parietal and occipital cortex. These areas derive a substantial proportion of their blood supply from the posterior circulation—blood vessels that are more susceptible (versus anterior circulation) to autoregulatory failure (e.g., posterior reversible encephalopathy syndrome, PRES) (Roth et al., 2017) and age-related atherosclerotic changes (Gewirtz et al., 2021). Could APOEε4 exert a protective effect against these processes, leading to conveying regional-specific resiliency to Aβ deposition via effects on the neurovascular unit?

    Beyond mechanisms, the possibility that ε4 carriers may be resilient to AD-driven declines in visual memory may help explain the lower-than-expected prevalence of ε4 carriers reported in several series enrolling patients with visual variant Alzheimer disease (AKA, posterior cortical atrophy, PCA). (Schott et al., 2016; Crutch et al., 2012). This effect could be mediated through APOEε4 effects on the patterns of neurodegeneration—predisposing carriers to medial temporal lobe degeneration (Crutch et al., 2012; La Joie et al., 2021). 

    Alternatively, ε4 carriers could develop posterior predominant atrophy due to AD yet remain resilient to the cardinal clinical manifestations that define PCA due to superior visual memory, presenting later in the disease course, or not at all. Autopsy studies reporting regional burden of AD neuropathologic change in PCA ε4 carriers and noncarriers are needed to test this hypothesis, theorizing that ε4 carriers with PCA would demonstrate greater pathological burdens despite similar levels of symptoms.

    It would seem that the relationships among APOEε4, AD neuropathology, and brain function are more complex than first thought. Decoding this interaction may offer additional insights into the contributors to cognitive reserve, resilience, and broad phenotypic variability in patients with symptomatic AD.

    References:

    Roth W, Morgello S, Goldman J, Mohr JP, Elkind MS, Marshall RS, Gutierrez J. Histopathological Differences Between the Anterior and Posterior Brain Arteries as a Function of Aging. Stroke. 2017 Mar;48(3):638-644. Epub 2017 Feb 14 PubMed.

    Gewirtz AN, Gao V, Parauda SC, Robbins MS. Posterior Reversible Encephalopathy Syndrome. Curr Pain Headache Rep. 2021 Feb 25;25(3):19. PubMed.

    Schott JM, Crutch SJ, Carrasquillo MM, Uphill J, Shakespeare TJ, Ryan NS, Yong KX, Lehmann M, Ertekin-Taner N, Graff-Radford NR, Boeve BF, Murray ME, Khan QU, Petersen RC, Dickson DW, Knopman DS, Rabinovici GD, Miller BL, González AS, Gil-Néciga E, Snowden JS, Harris J, Pickering-Brown SM, Louwersheimer E, van der Flier WM, Scheltens P, Pijnenburg YA, Galasko D, Sarazin M, Dubois B, Magnin E, Galimberti D, Scarpini E, Cappa SF, Hodges JR, Halliday GM, Bartley L, Carrillo MC, Bras JT, Hardy J, Rossor MN, Collinge J, Fox NC, Mead S. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. Alzheimers Dement. 2016 Aug;12(8):862-71. Epub 2016 Mar 15 PubMed.

    Crutch SJ, Lehmann M, Schott JM, Rabinovici GD, Rossor MN, Fox NC. Posterior cortical atrophy. Lancet Neurol. 2012 Feb;11(2):170-8. PubMed.

    La Joie R, Visani AV, Lesman-Segev OH, Baker SL, Edwards L, Iaccarino L, Soleimani-Meigooni DN, Mellinger T, Janabi M, Miller ZA, Perry DC, Pham J, Strom A, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Association of APOE4 and Clinical Variability in Alzheimer Disease With the Pattern of Tau- and Amyloid-PET. Neurology. 2021 Feb 2;96(5):e650-e661. Epub 2020 Dec 1 PubMed.

    View all comments by Gregory Day

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References

News Citations

  1. More ApoE4 Means More Amyloid in Brains of Middle-Aged
  2. Paper Alert: ApoE Affects Alzheimer's Risk via Aβ Clearance

Paper Citations

  1. Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. PubMed.
  2. Rusted JM, Evans SL, King SL, Dowell N, Tabet N, Tofts PS. APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. Neuroimage. 2013 Jan 15;65:364-73. Epub 2012 Oct 11 PubMed.
  3. Zink N, Bensmann W, Arning L, Beste C, Stock AK. Apolipoprotein ε4 is associated with better cognitive control allocation in healthy young adults. Neuroimage. 2019 Jan 15;185:274-285. Epub 2018 Oct 18 PubMed.
  4. Jochemsen HM, Muller M, van der Graaf Y, Geerlings MI. APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiol Aging. 2011 Sep 9; PubMed.
  5. Zokaei N, Čepukaitytė G, Board AG, Mackay CE, Husain M, Nobre AC. Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories. Neurobiol Aging. 2019 Jan;73:115-122. Epub 2018 Sep 25 PubMed.

Further Reading

Papers

  1. Evans S, Dowell NG, Tabet N, Tofts PS, King SL, Rusted JM. Cognitive and neural signatures of the APOE E4 allele in mid-aged adults. Neurobiol Aging. 2014 Jul;35(7):1615-23. Epub 2014 Feb 5 PubMed.
  2. O'Donoghue MC, Murphy SE, Zamboni G, Nobre AC, Mackay CE. APOE genotype and cognition in healthy individuals at risk of Alzheimer's disease: A review. Cortex. 2018 Jul;104:103-123. Epub 2018 Mar 30 PubMed.
  3. Zokaei N, Giehl K, Sillence A, Neville MJ, Karpe F, Nobre AC, Husain M. Sex and APOE: A memory advantage in male APOE ε4 carriers in midlife. Cortex. 2017 Mar;88:98-105. Epub 2016 Dec 24 PubMed.

Primary Papers

  1. Lu K, Nicholas JM, Pertzov Y, Grogan J, Husain M, Pavisic IM, James SN, Parker TD, Lane CA, Keshavan A, Keuss SE, Buchanan SM, Murray-Smith H, Cash DM, Malone IB, Sudre CH, Coath W, Wong A, Henley SM, Fox NC, Richards M, Schott JM, Crutch SJ. Dissociable effects of APOE-ε4 and β-amyloid pathology on visual working memory. Nat Aging. 2021 Nov;1(11):1002-1009. Epub 2021 Oct 7 PubMed.

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