APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review
Alzheimer's Research & Therapy volume 12, Article number: 141 (2020)
Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer’s disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4−) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4− AD patients. On the other hand, APOE4− AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4− AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.
APOE4 carriers have an increased risk of developing AD
In 1993, Roses and colleagues first reported that an individual’s risk of developing Alzheimer’s disease (AD) is increased if they carry the ε4 allele of apolipoprotein E (APOE) [1,2,3], an important apolipoprotein that had primarily been studied for its role in transporting cholesterol and other lipids through the periphery and within the brain [4,5,6]. Since that time, the link between APOE4 and AD susceptibility has been extensively validated and characterized. A 1997 meta-analysis by Farrer et al. nicely summarizes the general associations between APOE genotype and AD susceptibility , which has remained relatively consistent in future studies [8,9,10]. For example, while the APOE2, APOE3, and APOE4 alleles are present in cognitively normal Caucasians at a relative frequency of about 8%, 78%, and 14%, respectively, APOE4 has an allele frequency of about 37% in Caucasian AD patients . When broken down by the specific genotype frequencies, APOE3/4 individuals represent about 21% of the cognitively normal Caucasian population, vs. about 41% of Caucasian AD patients (odds ratio [OR] 3.2), whereas APOE4/4 individuals have a genotype frequency of about 2% in the cognitively normal Caucasian population, vs. about 15% in the AD-affected Caucasian population (OR 14.9) . Furthermore, while possession of the APOE2 allele is protective against AD [2, 10, 11], with Caucasian individuals who possess either the APOE2/2 or the APOE2/3 genotype having an OR of 0.6, this protective effect is overtaken by the risk effect of the APOE4 allele in APOE2/4 individuals (OR 2.6) .
These numbers shift, however, when the APOE4-associated risk of AD is stratified by traits such as age, gender, and ancestry. For example, the effects of the APOE4 allele on AD risk are greatest in younger individuals, with the risk of AD among Caucasian APOE3/4 individuals peaking at age 65 (OR ~ 4) and the risk of AD among Caucasian APOE4/4 individuals peaking at age 60 (OR ~ 15.5) . In terms of gender, numerous studies have found that the effects of APOE4 on AD susceptibility are greater in women than in men [7, 12, 13], although these gender differences appear to decrease after age 75 [7, 8, 14]. For example, in the Farrer et al. meta-analysis, the authors reported that a 65-year-old Caucasian woman with an APOE3/4 genotype has an OR of developing AD of over 4, whereas a 65-year-old Caucasian man with the same genotype has an OR of less than 2 . Perhaps the most intriguing differences in APOE4’s effect size, however, are seen in individuals with different ancestral backgrounds. For example, individuals from African-ancestry populations, such as African Americans, have a higher general frequency of APOE4 (APOE4 allele frequency ~ 19%) than Caucasian populations, but these individuals are at a relatively lower risk of developing AD (APOE3/4 OR 1.1; APOE4/4 OR 5.7) . However, the opposite appears to be true for East-Asian populations; for example, individuals of Japanese ancestry have a relatively low APOE4 allele frequency (~ 9%), but a relatively high APOE4-related risk (APOE3/4 OR 5.6; APOE4/4 OR 33.1) .
It is clear from these studies that the APOE4 allele is a strong genetic risk factor for developing AD, even though the disease penetrance varies greatly with regard to age, gender, and ancestry. However, while extensive studies have characterized the role of APOE4 in conferring AD risk, far fewer studies have investigated the effects of APOE4 on the cognitive and pathological manifestation of the disease in individuals who have already converted to AD. In order to understand how a patient’s APOE genotype affects their disease presentation, we have performed a qualitative systematic literature review of the human studies that have been published to date examining the cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4−) AD patients. Interestingly, these studies suggest that possession of APOE4 does in fact result in phenotypic differences between APOE4+ vs. APOE4− AD patients, with APOE4+ AD patients appearing to possess relatively more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, than APOE4− AD patients, while APOE4− AD patients appear to possess relatively more fronto-parietal lobe tau accumulation and brain atrophy, resulting in greater impairment in executive function, visuospatial abilities, and language, than APOE4+ AD patients (Fig. 1).
The data and information utilized in this qualitative systematic review were obtained from literature published between January 1, 1993, and June 1, 2020. A literature search using both electronic and manual search components was performed, with the goal of identifying all studies published during this time period that specifically compared AD presentation in APOE4 carriers vs. APOE4 non-carriers who were diagnosed with AD using standard methods. In order to accomplish this, PubMed was exhaustively searched to help identify articles containing a combination of keywords: Apoliprotein E, APOE, APOE4, APOE4-positive, APOE4-negative, Alzheimer’s disease, AD, and patients, which was followed by a first level screening of the articles’ titles and abstracts to identify studies that directly investigated our review topic. These searches were limited to studies with human subjects that were published in the English language. A manual reference check of the bibliographies of the relevant studies was also performed in order to identify additional articles that were not identified by the electronic search.
The full article of each identified study on this topic was downloaded and stored in a single folder, at which time a second level of screening of the full text was performed to confirm that each article directly compared the cognitive and/or pathological characteristics of APOE4+ vs. APOE4− AD patients. Lastly, each study was sorted into one or more of the following diagnostic categories: rate of cognitive decline (17 studies), neuropsychological profile (12 studies), brain atrophy (13 studies), Aß pathology (7 studies), or tau pathology (6 studies). Those studies that did not fit into one of these five categories were not included in the primary review.
We did not exclude studies based on any patient demographic characteristics or any specific methodologies employed. This broad inclusion criterion was utilized in order to provide the scientific community with a comprehensive record of the studies that have investigated the cognitive and pathological differences between APOE4+ vs. APOE4− AD patients to date. However, the demographic and methodological differences between studies were carefully considered in our overall conclusions, as is discussed throughout the review.
APOE4+ AD patients do not appear to differ in their overall rates of cognitive decline compared to APOE4− AD patients
Although the heterogeneity between APOE4+ vs. APOE4− AD patients is an understudied phenomenon, one question that has been repeatedly investigated over the years is whether or not APOE4+ AD patients undergo an accelerated rate of cognitive decline as compared to APOE4− AD patients. However, the results of these studies have been decidedly mixed. While numerous groups have reported that APOE4+ AD patients do in fact experience a more accelerated cognitive decline compared to APOE4− AD patients [15,16,17,18,19,20], other studies have shown either no APOE genotype-associated differences in the rate of cognitive decline in AD patients [21,22,23,24,25,26,27] or slower cognitive decline in APOE4+ vs. APOE4− AD patients [28,29,30] (Table 1).
In general, these discrepancies between the reported rates of cognitive decline in APOE4+ vs. APOE4− AD patients highlight the difficulty of trying to determine a consensus about the contributions of one single trait, such as APOE genotype, on the overall presentation of AD. Adding to this difficulty, each of the studies that we have cited in this review utilizes different methods for their analysis, and the patient populations that they assessed often vary widely in their demographic characteristics. As discussed in the “Introduction” section, differences in age, gender, and ancestral background are known to affect AD susceptibility among APOE4 carriers; therefore, it is likely that these differences also affect AD presentation among APOE4 carriers. Furthermore, in some of the studies we have cited, the authors have utilized a relatively small number of AD patients for their analysis; because of this, it is possible that type II statistical errors may affect the conclusions that these authors reported (i.e., a study's small sample size may have resulted in no differences being observed between APOE genotype groups, even if actual differences exist).
It should also be noted that a large number of the studies investigating the effects APOE genotype on AD presentation have focused on “probable” AD patients. Probable AD is classified using standardized cognitive screening tools and robust neuropsychological tests, and must follow a strict criteria, such as those described by the NINCDS-ADRDA workgroup in 1984 , or an updated criteria described by the NIA-AA workgroup in 2011 . However, the utilization of cognitive profiles alone (or, likewise, the utilization of pathological markers alone) cannot give a 100% confident diagnosis of AD. Given this information, it is possible that some probable AD patients included in the studies cited in this review were misdiagnosed. Notably, it has been reported that APOE4− individuals make up the majority of AD-diagnosed patients who are later found to be Aß-negative by PET or at autopsy [34, 35]. For this reason, it is possible that the sole reliance on probable AD diagnosis in some of these studies could result in type I statistical errors that may affect their findings (i.e., a study's potential inclusion of non-AD patients, especially if this was weighted towards the APOE4− individuals, may have resulted in significant differences being observed between APOE genotype groups, even if none exist). Rather than excluding such studies, however, we chose to include them, but to take their limitations into account in our overall, qualitative assessment of the data.
In regard to APOE4’s effects on the rate of cognitive decline in AD, assessing the demographic and methodological differences between the studies listed above does provide some clarity. For example, in many of these studies, the authors had access to a relatively small number of AD patients. One potential approach to assess the findings, therefore, is to focus only on the studies with a relatively large number of participants. Interestingly, when we only include the studies that meet a conservative threshold of n > 100 AD patients, there are three studies that reported accelerated cognitive decline in APOE4+ vs. APOE4− AD patients [15,16,17], four that reported no difference [21, 23, 26, 27], and only one that reported slower cognitive decline in APOE4+ vs. APOE4− AD patients . Importantly, in the three largest studies from this group, a study by Kleiman et al. that analyzed 366 patients with probable AD , a study by Farlow et al. that analyzed 374 placebo-treated AD clinical-trial participants , and a study by Aerssens et al. that analyzed 504 placebo-treated AD clinical-trial participants , the authors did not find any APOE4-associated differences in the rate of cognitive decline in AD. These studies suggest that, when analyzed in a broad fashion, AD patients who carry the APOE4 allele do not appear to possess a more aggressive form of the disease.
However, more work is needed to determine if APOE genotype may have a significant effect on the rate of cognitive decline in specific subsets of AD patients, such as within a given age group or gender or ancestry. For example, two of the highly powered studies referenced above, by Cosentino et al. and Craft et al., reported significant APOE4-associated increases in the rates of cognitive decline when looking specifically at incident (i.e., newly diagnosed) AD cases [15, 17]. This suggests that APOE4 may accelerate cognitive decline at the earliest stages of AD diagnosis, but that these effects may dissipate with increasing disease severity. This possibility would be in line with what occurs prior to AD diagnosis, where APOE4 carriers show increased conversion from mild cognitive impairment (MCI) to AD compared to non-carriers [36,37,38]. Similarly, non-demented elderly APOE4 carriers have also been reported to undergo increased cognitive decline compared to non-demented elderly non-carriers [39, 40], especially when these APOE4 carriers are positive for Aß [41,42,43].
APOE4+ AD patients have a more amnestic cognitive profile than APOE4− AD patients
Another factor that deserves critical attention is the multi-faceted nature of the cognitive presentation of AD. For example, AD patients are not only prone to the characteristic amnestic symptoms commonly associated with the disease; they are also prone to deficits in other cognitive domains, such as executive function, visuospatial abilities, and language . Indeed, some atypical AD patients present with distinct non-amnestic cognitive phenotypes, including corticobasal syndrome (CBS), where patients present with movement impairment; frontal variant Alzheimer’s disease (fvAD), where patients present with behavioral/executive function impairment; logopenic variant primary progressive aphasia (lvPPA), where patients present with language impairment; and posterior cortical atrophy (PCA), where patients present with visual impairment. Furthermore, even within the overarching concept of memory, there is significant complexity that must be considered during the neuropsychological assessment of AD patients. For example, poor performance on immediate recall, delayed recall, and delayed recognition is typically suggestive of amnesia [45, 46]. However, difficulties on immediate and delayed recall, in the absence of reduced performance on delayed recognition, are suggestive of problems with lexical access, a task that is associated with significant frontal lobe involvement .
In order to assess whether APOE genotype may alter the cognitive profile of AD patients, a number of studies have utilized neuropsychological assessment tools—including cognitive screening tools, such as the Mini-Mental State Examination (MMSE); brief neuropsychological tests, such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); or more in-depth neuropsychological tests, such as the California Verbal Learning Test (CVLT)—in an attempt to parse out the potential divergence in cognitive deficits between APOE4+ vs. APOE4− AD patients [48,49,50,51,52,53,54,55,56,57,58]. Interestingly, the majority of these studies have reported that APOE4+ AD patients possess relatively more pronounced memory deficits than APOE4− AD patients [49,50,51,52,53, 58, 59], although a few studies did not find an association between APOE genotype and memory function [54, 55, 57]. In addition, a number of these studies have also reported that APOE4− AD patients possess relatively more pronounced deficits in non-memory cognitive domains, such as executive function, visuospatial abilities, and language, than APOE4+ AD patients [48, 51,52,53,54,55,56,57,58], with a greater effect observed in younger APOE4− vs. APOE4+ AD patients [54, 58] (Table 2).
Although these studies utilized different methodological approaches, the results were generally consistent. For example, Scheltens et al. combined four large probable AD cohorts using a neuropsychologically derived cluster analysis and found two distinct groups—a memory-impaired group and a non-memory-impaired group, with the non-memory-impaired group comprised primarily of younger, APOE4− AD patients, as compared to the memory-impaired group . Kim et al. recruited 846 South Korean patients diagnosed with probable AD and categorized them into three groups with respect to their age (< 65, 65–74, and ≥ 75 years old). The authors discovered that younger (< 65 years old) APOE4− AD patients performed worse on executive function tasks compared to younger APOE4+ AD patients, while intermediate (65–74 year-old) APOE3/4 AD patients performed worse on visuospatial tasks compared to intermediate APOE4/4 AD patients, and older (≥ 75 years old) APOE4/4 AD patients performed worse on verbal memory compared to older APOE4− AD patients . Finally, Wolk et al. compared cognitive differences in 67 APOE4+ vs. 24 APOE4− patients diagnosed with mild AD and possessing CSF biomarker profiles consistent with AD . APOE4+ AD patients performed worse on memory retention, while APOE4− AD patients were more impaired on tests of working memory, executive function, and lexical access, but not on confrontational naming.
These results suggest that AD patients likely diverge in their cognitive presentations based on their APOE genotype, with APOE4+ AD patients presenting with relatively more pronounced amnestic deficits than APOE4− AD patients, and APOE4− AD patients presenting with relatively more non-memory deficits than APOE4+ AD patients. This conclusion is also consistent with the reported observation that AD patients presenting with atypical phenotypes, such as CBS, fvAD, lvPPA, and PCA, are less likely to be APOE4 carriers [60, 61].
Interestingly, possession of the APOE4 allele has also been associated with decreased memory performance in non-demented elderly individuals [62,63,64,65], as well as with increased incidence of amnestic MCI vs. non-amnestic MCI [66, 67]. This suggests that possession of the APOE4 allele may confer increased memory deficits throughout the aging to AD continuum, although it should be noted that APOE4 carriers have also been found to be at an increased risk of developing several non-AD dementias, including vascular dementia (VaD) [68,69,70,71], Lewy body dementia (LBD) [72,73,74], and frontotemporal dementia (FTD) [75, 76], which often do not present with a predominantly amnestic phenotype.
APOE4+ AD patients have more atrophy in the medial temporal lobe than APOE4− AD patients
The cognitive deficits observed in AD patients are a direct result of the pathological abnormalities that occur in a patient’s brain during the course of the disease. AD pathology is characterized by the hallmark accumulation of Aß-containing amyloid plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs). Amyloid plaques are extracellular and accumulate in the brain in a rather diffuse manner, typically starting in the neocortex (Thal phase 1), followed by the entorhinal cortex, hippocampus, and insular cortex (Thal phase 2), and eventually accumulating in subcortical regions such as the basal forebrain and brainstem (Thal phases 3–5) . On the other hand, NFTs are intracellular and accumulate in the brain in a more localized and regionally conserved manner, typically occurring first in the transentorhinal and entorhinal cortex regions (Braak stages I–II), followed by the hippocampus and neighboring neocortical regions (Braak stages III–IV), and eventually accumulating throughout the remainder of the neocortex (Braak stages V–IV) . The third major pathological feature of AD is “brain atrophy,” as measured by volumetric reduction or cortical thinning observed during magnetic resonance imaging (MRI). In general, the atrophy observed in the brains of AD patients has been found to follow along the same regional path as NFTs, with the first signs of volumetric loss observed in the medial temporal lobe during the MCI phase, followed by the neocortical portions of the temporal lobe, then the parietal lobe, and finally the frontal lobe during the course of MCI and AD progression . In addition to these three distinctive features of AD pathology, other important pathological events that also occur during the course of the disease include neuroinflammation, deficits in cellular metabolism, cholinergic dysfunction, aberrant network activity, and cerebrovascular pathology .
With respect to APOE genotype effects on AD pathology, the most compelling results published to date describe the differing regional patterns of brain atrophy observed in APOE4+ vs. APOE4− AD patients. While a couple of studies have not observed any differences in brain volume or cortical thickness between APOE4+ vs. APOE4− AD patients [81, 82], the vast majority of the studies that have investigated this topic to date have found that APOE4+ AD patients possess greater volumetric loss or cortical thinning in the medial temporal lobe than APOE4− AD patients [51, 57, 58, 83,84,85,86,87,88,89], with many reporting that APOE4+ vs. APOE4− AD patients display volumetric decreases in specific medial temporal lobe structures, such as the hippocampus [57, 83, 86, 87, 89], the amygdala [57, 83, 86, 87], and the entorhinal cortex [84, 89]. Furthermore, many of these studies also reported that APOE4− AD patients possess greater volumetric loss or cortical thinning in their frontal and parietal lobes than APOE4+ AD patients [51, 58, 85, 89, 90] (Table 3).
Importantly, a number of these studies noted a direct correlation between the regional brain atrophy patterns that they observed between APOE4+ vs. APOE4− AD patients and the differences in cognitive profile that they observed in these same patients [51, 57, 58, 84, 87, 90]. For example, in the Scheltens et al. study, the authors also analyzed MRI data from their four large probable AD cohorts and observed that in their non-memory-impaired group, which was enriched for APOE4− AD patients, there was less hippocampal volume loss and more posterior cortex volume loss than in the memory-impaired group . And in the Kim et al. study, the authors measured cortical thinning using MRI in their 846 South Korean probable AD patients and found that in the younger (< 65 years old) APOE4− AD patients, who performed worse on executive function tasks, there was increased bilateral cortical thinning in their lateral frontal, medial frontal, and perisylvian areas compared to the younger APOE4− AD patients, whereas in the older (≥ 75 years old) APOE4+ AD patients, who performed worse on verbal memory tasks, there was increased bilateral cortical thinning in their medial temporal areas compared to the older APOE4− AD patients . Finally, in the Wolk et al. study, the authors used MRI to measure brain volume and cortical thickness in their mild AD patients and found that APOE4+ AD patients, who performed worse on memory retention, displayed greater hippocampal volume loss than APOE4− AD patients, whereas APOE4− AD patients, who performed worse on working memory, executive function, and lexical access, displayed decreased cortical thickness in their superior parietal lobule, precuneus, and angular gyrus than APOE4+ AD patients.
APOE4+ AD patients do not appear to have higher Aß levels than APOE4− AD patients
As noted above, the regional brain atrophy that is observed in AD patients is thought to be a direct result of the tau accumulation that progressively occurs in neurons within these brain regions. And it is believed that this tau accumulation and the regional progression of NFTs likely occur downstream of the Aß accumulation/amyloid plaque deposition that begins early in AD pathogenesis. Given this information, it is important to determine whether the presentation of these two hallmark pathologies also displays heterogeneity in APOE4+ vs. APOE4− AD patients, and how this presentation may relate to the differences in brain atrophy and cognitive deficits that are observed in these patients. In terms of Aß, it has been well documented that individuals who carry the APOE4 allele accumulate Aß in their brains at an earlier age than non-carriers, and that this occurs long before the onset of AD. For example, a 2015 meta-analysis by Jansen et al. revealed that by the time APOE4/4 carriers turn 40 years old, about 15% of them will already be positive for cerebral Aß (as detected by PET or CSF), whereas this threshold is not reached until 55 years of age for APOE3/4 carriers and 65 years of age for APOE3/3 carriers . However, Aß levels have been shown to plateau before the clinical diagnosis of AD , so any differences in Aß levels associated with APOE genotype are not expected to be as dramatic once a patient converts to AD as it is during the linear phase of Aß accumulation. For this reason, it is perhaps not surprising that the handful of studies that have compared the levels of Aß in APOE4+ vs. APOE4− AD patients have shown conflicting results, with some studies reporting increased Aß levels in the brains of APOE4+ AD patients compared to APOE4− AD patients [81, 93, 94], some reporting no changes in Aß levels between these two groups [95, 96], and some reporting decreased Aß levels in the brains of APOE4+ AD patients compared to APOE4− AD patients [97, 98] (Table 4).
Looking closely at these studies, it is difficult to make a conclusive statement about how exactly APOE genotype affects Aß levels or amyloid plaque distribution in the brains of AD patients. For example, the studies by Drzezga et al. (32 patients with moderate AD) , Rowe et al. (53 patients with mild AD) , and Lehmann et al. (52 patients with probable AD)  each utilized Pittsburgh Compound B (PIB) PET analysis on age- and cognition-matched AD patients who were confirmed to be Aß-positive, but with each study arriving at a different conclusion about the relative levels of Aß in APOE4+ vs. APOE4− AD patients. Perhaps future work on this topic will reveal more regionally specific differences in how Aß is distributed in the brains of APOE4+ vs. APOE4− AD patients. This is hinted at by the Lehmann et al. study, where the observed decrease in Aß in APOE4+ AD patients was primarily localized to the right lateral frontotemporal regions of the brain .
Of course, it is also important to note that amyloid plaques are only one manifestation of Aß pathology that can occur in the brain. Aß can also build up in the walls of arteries (cerebral amyloid angiopathy; CAA) or inside of neurons (intraneuronal Aß). Interestingly, several studies have reported that APOE4+ AD patients have a more frequent CAA comorbidity than APOE4− AD patients [94, 99,100,101]. As for intraneuronal Aß, while one study did report that post-mortem brains from APOE4+ AD patients possess higher levels of intraneuronal Aß than those from APOE4− AD patients , much more investigation is required before any conclusive statements can be made on this topic.
APOE4+ AD patients appear to develop more tau pathology in their medial temporal lobe than APOE4− AD patients
As with Aß, there have been numerous reports that APOE4 carriers possess higher levels of tau pathology than non-carriers prior to AD onset, although this effect on preclinical tau pathology does not seem to be nearly as robust as it is with APOE4’s effects on preclinical Aß levels. For example, in a study where Braak and colleagues analyzed autopsied brain tissues specifically from individuals who reached Braak stage I (transentorhinal cortex only) at a relatively young age (less than 47 years old), the authors reported a significant increase in the percentage of APOE4 carriers in this group (36%) vs. the percentage of APOE4 carriers in the control group (16%) . A later, more generalized autopsy study from Braak and colleagues also observed that women who were APOE4 carriers met the criteria for Braak stages II (entorhinal cortex) and III (hippocampus) 3 years earlier than non-carriers . Several more recent studies have also reported a female-dominant effect of APOE genotype on tau levels prior to AD diagnosis [12, 105, 106]. In each of these studies, the authors reported that APOE4 possession increases CSF tau levels specifically in female APOE4 carriers, with two of the studies reporting that this APOE4-associated effect on CSF tau levels was only present when the women were positive for Aß pathology [105, 106].
In regard to APOE4+ vs. APOE4− AD patients, tau pathology also appears to differ according to APOE genotype, although the primary differences here appear to revolve around the regional pattern of NFT distribution, as opposed to the overall levels (Table 5). For example, Murray et al. have reported that, when AD autopsy cases were divided into three distinct groups based on the regional pattern of the NFT pathology observed (“hippocampal-sparing,” “typical,” and “limbic predominant”), there was a trend towards fewer APOE4 carriers in the “hippocampal-sparing” AD group, and there were significantly more late-onset (greater than 65 years old at diagnosis) APOE4 carriers vs. non-carriers in the “limbic predominant” AD group . Although a more recent study failed to replicate this finding in a set of AD autopsy cases enriched for atypical presentation (in which APOE4 carriers were underrepresented), there did appear to be a trend (p = 0.0992) towards more APOE4 carriers among “limbic predominant” AD cases and fewer APOE4 carriers among “hippocampal-sparing” AD cases . Interestingly, a recent follow-up paper by Murray and colleagues also reported that APOE4+ “typical” AD patients, as compared to APOE4− “typical” AD patients, possess more NFT pathology in their nucleus basalis of Meynert (nbM), the major source of cholinergic innervation in the brain .
To interrogate this correlation between APOE genotype and tau pathology in living individuals, researchers have begun utilizing recently developed tau PET imaging ligands to compare tau levels in APOE4+ vs. APOE4− AD patients. For example, a small study by Ossenkoppele et al. utilizing the 18F-AV-1451 tau PET ligand in 20 individuals diagnosed with MCI or AD found increased uptake of the PET ligand in bilateral medial temporal and right temporoparietal cortex of APOE4+ patients, as compared to APOE4− patients . And in a study by Whitwell et al. employing 18F-AV-1451 to investigate tau deposition in 62 amyloid-positive AD patients with a mix of typical and atypical AD presentations, the authors separated their subjects into three groups (ECLo/CLo, ECLo/CHi, and ECHi/CHi) based on the amount of tau deposition they observed in the entorhinal cortex (EC), as compared to the whole cortex (C) . The authors found that the APOE4 frequency was significantly lower in the ECLo/CHi group, suggesting that APOE4− AD patients have less relative tau accumulation in the entorhinal cortex region than APOE4+ AD patients in the context of high cortical tau load. Finally, in a study by Mattsson et al. that also utilized the 18F-AV-1451 tau PET ligand, again on a mixed group of MCI and AD patients (65 patients total), the authors reported an increased tau load in the entorhinal cortex (relative to the whole cortex) of APOE4+ patients compared to APOE4− patients, whereas the tau load in the parietal and occipital lobes was higher in APOE4− patients compared to APOE4+ patients .
To be clear, these studies on tau pathology in APOE4+ vs. APOE4− AD patients are still somewhat preliminary, with additional work required to confidently answer this question. Specifically, additional tau PET imaging ligand studies are required in pure AD populations, and with larger sample sizes. Also, as with the other studies on this topic, analysis of specific subgroupings needs to be performed with respect to age, gender, and ancestral background. However, based on these early results, it does appear that APOE4+ AD patients may possess relatively more NFTs in the medial temporal lobe, most notably in the entorhinal cortex, while APOE4− AD patients may possess more NFTs in other cortical regions, such as the frontal and parietal lobes.
Primary findings and key limitations
The majority of the previous research investigating the relationship between APOE4 and AD has focused on elucidating the patterns and mechanisms associated with the increased risk of developing AD among APOE4 carriers. And for good reason, after all, APOE4 is the primary genetic risk factor for sporadic AD. However, the possibility that APOE4 may also affect the cognitive and pathological presentation of AD deserves significant attention, as this possibility may elucidate differing pathogenic mechanisms between APOE4+ vs. APOE4− AD patients, both before and after disease onset, and may have important implications for how we should therapeutically treat APOE4+ vs. APOE4− AD patients.
Overall, the studies that have been performed on this topic to date suggest that APOE4+ vs. APOE4− AD patients do appear to possess both cognitive and pathological heterogeneity in their presentation of the disease, as depicted in Fig. 1. Specifically, the neuropsychological studies outlined above show that APOE4+ AD patients appear to possess relatively more pronounced memory deficits than APOE4− AD patients, while APOE4− AD patients appear to possess relatively more pronounced non-memory deficits (particularly deficits in executive function, visuospatial abilities, and language) than APOE4+ AD patients. The literature also points to divergent pathological underpinnings that likely explain the differences in cognitive profiles related to an AD patient’s APOE genotype. Most notably, APOE4+ AD patients appear to possess relatively more brain atrophy in their medial temporal lobe than APOE4− AD patients, while APOE4− AD patients appear to possess relatively more brain atrophy in their frontal and parietal lobes than APOE4+ AD patients. The literature also suggests that the upstream trigger of these regional brain atrophy differences is likely to be the observed differences in the regional distribution of NFTs in APOE4+ vs. APOE4− AD patients, with APOE4+ AD patients possessing a greater relative accumulation of NFTs in their medial temporal lobe (particularly in the entorhinal cortex) than APOE4− AD patients, and APOE4− AD patients possessing relatively more NFTs in their frontal and parietal lobes than APOE4+ AD patients. However, due to the limited number of studies performed using recently developed tau PET imaging ligands, this last conclusion is particularly unresolved.
It should also be noted that an AD patient’s APOE genotype may affect the presentation of several additional brain pathologies not covered in the “Results” section of this review. For example, in the previously discussed Lehmann et al. study, where the authors observed regional decreases in Aß deposition in APOE4+ vs. APOE4− AD patients, the authors also reported regional differences in glucose metabolism (as measured by FDG-PET), with APOE4+ AD patients displaying more hypometabolism in bilateral medial temporal and right lateral temporal regions than APOE4− AD patients, while APOE4− AD patients displayed more hypometabolism in other cortical areas, including supplementary motor cortex and superior frontal gyrus . Furthermore, autopsied brains from APOE4+ vs. APOE4−AD patients have also been reported to possess increased levels of two pathological comorbidities commonly associated with AD: TDP-43 [111,112,113] and Lewy bodies [114, 115].
As noted throughout this review, there are a number of limitations in the studies we cited, which decreases the overall confidence with which we can assert that there is a definitive difference in disease presentation between APOE4+ vs. APOE4− AD patients. For example, some of the studies performed on this topic utilized relatively small sample sizes, which may result in type II ("false-negative") statistical errors. In addition, many of the studies we cited utilized “probable AD” for their AD diagnosis, which may result in type I ("false-positive") statistical errors. Lastly, inherent differences among APOE4 carriers, like age, gender, and ancestral background, are likely to modulate the effects of APOE genotype on AD presentation, a possibility that requires much more investigation.
In order to address these issues, we propose that additional studies comparing the cognitive and pathological presentation of AD in APOE4+ vs. APOE4− AD patients should include the following criteria: (1) Comprehensive neuropsychological testing, or numerous cognitive tests measuring multiple cognitive domains, should be utilized to diagnose AD patients. Cognitive screeners, such as the MMSE, are helpful in identifying individuals who require more comprehensive assessment, but robust neuropsychological tests are far more capable of making accurate diagnoses and clear determinations of the severity of a patient’s cognitive impairment. (2) Pathological diagnosis should be confirmed using established biomarkers such PET tracers or CSF measurements, or histology on post-mortem tissues if the subjects are deceased. (3) Large, diverse cohorts of AD patients should be utilized. These cohorts should include hundreds of participants with different ages, genders, and ancestral backgrounds. Power analysis should be performed not only for the cohort as a whole, but also for the individual demographic subgroupings, in order to allow for statistically significant results from each independent subgroup. (4) All three of the first three criteria should be utilized in tandem in order to carefully match the APOE4+ AD patients to the APOE4− AD patients with which they are being compared. Matched APOE genotype groups should possess similar neuropsychological profiles, similar pathology levels, and similar demographics, although variations may be necessary depending on the specific question being tested. We anticipate that these robust future studies will definitively determine whether APOE4+ vs. APOE4− AD patients possess the cognitive and pathological heterogeneity that the initial studies on this topic suggest.
Why disease heterogeneity is important
In recent years, disease heterogeneity has gained increased attention in AD research, with numerous publications reporting on divergent aspects of AD such as atypical neuropsychological profiles and mixed pathologies in AD patients [116,117,118,119,120,121]. One reason why the topic of disease heterogeneity is so important in AD research is that it suggests a previously unappreciated complexity that may make therapeutic treatment of AD more difficult (and could also help to explain past clinical trial failures). If AD is not the single, uniform disease that researchers once believed it to be, then a single therapeutic strategy may not be able to help all AD patients equally. In respect to APOE genotype, disease heterogeneity may even point to divergent pathological mechanisms that will be particularly important to understand when attempting to treat APOE4 carriers vs. non-carriers.
On that topic, there have been numerous examples of therapies showing efficacy in APOE4 carriers, but not in non-carriers, or vice-versa. For example, currently approved acetylcholinesterase inhibitors have often been reported as having differential effects on APOE4+ vs. APOE4− AD patients, although these results have been mixed [122,123,124,125]. Investigations of intranasal insulin as an AD treatment have also shown mixed results, with an acute insulin treatment showing memory improvement in APOE4− MCI and AD patients, but not APOE4+ MCI and AD patients , while a chronic insulin treatment has shown memory improvement in APOE4+ MCI and AD patients, but not APOE4− MCI and AD patients . Differential APOE genotype effects have also been reported for the treatment of mild-to-moderate AD patients using the diabetes drug rosiglitazone, with APOE4− AD patients, but not APOE4+ AD patients, showing cognitive improvement . Furthermore, the retinoid x receptor (RXR) agonist bexarotene has been shown to reduce Aß levels in APOE4− AD patients, but not in APOE4+ AD patients . And in a phase 3 clinical trial of the anti-Aß antibody bapaineuzumab for mild-to-moderate AD, reductions of both Aß and tau levels were observed in APOE4+ AD patients, but not in APOE4− AD patients .
Given these potential differences in treatment efficacy for APOE4+ vs. APOE4− AD patients, it is important not only to elucidate any overall cognitive and pathological heterogeneity between these two groups, but also to understand the underlying mechanisms that may drive this heterogeneity. Indeed, the discovery of divergent pathological mechanisms between APOE4+ vs. APOE4− AD patients would not only point to important treatment differences for these two patient groups, but it could also help clarify the mechanism of AD pathogenesis in general. The majority of AD research has focused on Aß and tau accumulation, the pathological hallmarks of the disease. However, understanding the ways in which differential isoform expression of APOE, which primarily plays a role in cholesterol and lipid trafficking, mediates AD presentation would add important context to how AD develops and progresses.
For the most part, the studies referenced in this review do not attempt to pinpoint the underlying mechanism(s) responsible for the heterogeneity that they report between APOE4+ vs. APOE4− AD patients. However, it is worth discussing the potential mechanisms that may be responsible for this heterogeneity. First off, although the pathological differences that occur in APOE4+ vs. APOE4− AD patients appear to center around tau pathology and the resulting brain atrophy, it is still quite possible that the earlier onset of Aß pathology that occurs in APOE4 carriers vs. non-carriers may play a direct role in the pathological differences that appear to occur in APOE4+ vs. APOE4− AD patients. If tau aggregation is in fact a direct result of Aß pathology, as is proposed by the amyloid cascade hypothesis, it is probable that the earlier increases in Aß accumulation that are observed in the brains of APOE4 carriers would lead to an early and prolonged accumulation of tau pathology within the entorhinal cortex and hippocampus, the brain regions where NFTs are first observed. This possibility is hinted at by the recent studies showing that women who are positive for both APOE4 and Aß have higher levels of CSF tau compared to other groups [105, 106], even in the absence of any cognitive decline . That said, it would be anticipated that this increased early accumulation of tau pathology in the medial temporal lobe of APOE4 carriers would also translate to increased tau pathology in the fronto-parietal lobes as the disease progresses. However, these initial studies have observed the exact opposite, with decreased tau pathology and neurodegeneration occurring in the fronto-parietal lobes of APOE4+ vs. APOE4− AD patients.
Alternatively, it is possible that the mechanisms responsible for this observed cognitive and pathological heterogeneity in APOE4+ vs. APOE4− AD patients are independent of APOE4’s effects on Aß. To that end, it is important to note that APOE4 expression has been found to have a deleterious effect on numerous Aß-independent pathways within the brain, including cholesterol/lipid metabolism [131,132,133], endosomal-lysosomal processing [134,135,136,137,138,139,140,141,142], energy metabolism [143,144,145,146,147,148], neuroinflammation [149,150,151], and cerebrovascular integrity [152,153,154,155]. Furthermore, APOE appears to be highly expressed in the medial temporal lobe compared to other brain regions, as shown in this spatial modeling of APOE mRNA levels derived from Allen Brain Atlas mRNA expression data (http://www.meduniwien.ac.at/neuroimaging/lib/dlpage.php?value=348&name=apolipoprotein%20E) . Therefore, cells in the medial temporal lobe of APOE4 carriers may be particularly susceptible to deficits in the biological pathways listed above.
Clearly, there are still many questions left to be answered with regard to this apparent heterogeneity in APOE4+ vs. APOE4− AD patients, which we anticipate future studies will help to elucidate. We believe that validating and interrogating this APOE4-associated heterogeneity will yield important information for how best to treat AD patients based on their specific APOE genotype. In addition, uncovering the biological mechanism(s) responsible for this apparent heterogeneity may pave the way for the discovery of novel therapeutic strategies for treating or preventing AD in general.
Availability of data and materials
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We acknowledge Drs. Karen Duff and Mark Millan for their editing and advice on this review.
This work was supported by a career development award from the NIA to T.N. (AG061264).
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Emrani, S., Arain, H.A., DeMarshall, C. et al. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review. Alz Res Therapy 12, 141 (2020). https://doi.org/10.1186/s13195-020-00712-4