. Dissociable effects of APOE ε4 and β-amyloid pathology on visual working memory. Nat Aging (2021).


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  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.


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    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.


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    View all comments by Gregory Day

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  1. Not All Bad? APOE4 Sharpens Memory in Older People