Exercise as Potential Therapeutic Target to Modulate Alzheimer’s Disease Pathology in APOE ε4 Carriers: A Systematic Review

Cognitive decline in AD dementia affects most daily life activities. Thus, a growing need arises to ameliorate progressive cognitive symptoms. There is some evidence supporting the effectiveness of exercise as therapy (Table 1). Jensen et al. found that AD patients carrying the APOE ε4 gene and who were engaged in an exercise intervention showed an improvement of neuropsychiatric symptoms and stabilized cognition as assessed by the symbol digit modalities test (SDMT) in comparison to non-carriers and controls [23]. The exercise intervention consisted of supervised aerobic exercise three times a week for 16 weeks. Results showed that these carriers improved the physical, cognitive and neuropsychiatric outcomes compared to non-carriers. Similarly, APOE ε4 mice engaged in aerobic exercise demonstrated improved cognition and hippocampal function [24]. Cognition in these transgenic mice was tested by object and place recognition tests. A study by Etnier et al. supported the protective effect of aerobic exercise on cognition in cognitively normal older women carrying the APOE4 ε4 allele [25], based on different cognitive tests including an auditory verbal learning test, the complex figure test and the Wisconsin Card Sorting Test. Lautenschlager et al. studied the effect of a 24-week home-based physical activity intervention on cognitive function in adults with subjective memory impairment [26]. Physical activity was assessed with a survey in combination with data obtained from a pedometer to avoid bias. This study demonstrated that exercise improved cognitive function in adults aged 50 years or older, of whom 30% were carriers of the APOE ε4 allele. Additional analysis revealed that APOE ε4 non-carriers in the intervention group scored better on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) test compared to carriers and controls, as expected. On the contrary, a recent study by Sanders et al. showed that a 24-week aerobic exercise program did not modify cognitive function in APOE ε4 carriers with dementia [27]. Methods used to quantify the physical activity in this study were highly variable among patients with dementia. Therefore, the association between physical activity and cognitive function in APOE ε4 carriers could be absent.

The majority of studies assessed the physical activity by self-reported questionnaires (Table 1). Smith et al. found that high physical activity promoted cortical semantic processing activity on the name discrimination task among APOE ε4 carriers who were older cognitively intact adults [28]. Greater cortical semantic activation may protect older adults against future cognitive decline [29]. A follow-up study revealed that reduced predicted probability of cognitive decline in APOE ε4 carriers was associated with high physical activity [30]. Furthermore, APOE ε4 carriers with low physical activity in daily life had decreased hippocampal volume after 18 months, whereas the high physical activity group remained stable over time [31]. Physical activity could have a protective effect against hippocampal atrophy in APOE ε4 carriers, which in turn may reduce cognitive decline. A magnetoencephalography (MEG) study of participants aged between 50 and 70 found that highly active APOE ε4 carriers had a faster processing speed in working memory executive function [32]. In addition, carriers with low levels of physically activity showed decreased right temporal lobe activation. Another study on working memory revealed higher glucose uptake in core regions involved in working memory such as frontal, parietal, temporal and cerebellar regions in highly active ε4 carriers with a mean age of 63.67 ± 6.37 years [33]. However, a recent multi-cohort study by Stringa et al., consisting of older adults with a mean age of 67.8 years at baseline, indicated that physical activity did not moderate cognitive decline in APOE ε4 carriers [34]. For each cohort, a different self-reported questionnaire was used to assess the physical activity, which was classified into three categories including inactive, light and moderate–high activity based on walking, cycling, diverse sports and hobbies. Cognitive function was assessed with the Mini-Mental State Examination (MMSE).

Midlife or late-life exercise influences dementia risk. Some studies examined the effect of mid-life exercise on dementia risk in adults aged younger than 65. APOE ε4 carriers showed a significant inverse association between midlife physical activity and dementia risk compared to non-carriers [35], while in the AGES-Reykjavik study, the association between midlife physical activity and late-life cognition was strongest in non-carriers [36]. The combination of physical activity and the presence of an APOE ε4 allele may modify the risk of developing AD dementia later in life, but more replication is required. On the contrary, late-life physical activity seems to be effective in reducing dementia risk. The beneficial effect of late-life physical activity on the risk of cognitive decline was more pronounced in APOE ε4 carriers [37]. In addition, physical activity in late life may be beneficial in APOE ε4 carriers by reducing the risk of AD dementia and delaying its onset [38].

One of the studies that did not find any significant interaction between physical activity and the APOE4 genotype is the Cardiovascular Health Cognition Study, wherein a significant association between physical activity and dementia was observed in non-carriers, but not in APOE ε4 carriers, after a follow-up period of approximately 5 years [39]. However, only 28 APOE ε4 carriers showed cognitive decline in this period, making the interaction with physical activity subject to variability. In addition, the Framingham study showed increased risk of dementia in sedentary non-carriers aged 60 years and older, suggesting an inverse association between physical activity and dementia risk [40]. A study of 1646 older adults followed over a 5-year period reported that physical exercise was effective in preventing dementia in non-carriers [41]. No significant differences were observed between active and non-active APOE ε4 carriers. Several findings have been reported about the association between midlife or late-life exercise and AD dementia risk in APOE ε4 carriers. Exercise seems to modify AD dementia risk, but more replication is required to infer whether this is characteristic of APOE ε4 carriers.

Aggregation of Aβ peptides in the brain is one of the pathological hallmarks of AD. The most abundant forms are Aβ40 and Aβ42, with the latter known to be deposited more easily because of its hydrophobic and fibrillogenic composition [42]. In the healthy central nervous system, Aβ is rapidly produced and cleared, with a production rate of 7.6% per hour and a clearance rate of 8.3% per hour [43]. Due to molecular, cellular and genetic imbalances, the clearance of Aβ via the blood circulation system is deficient in late-onset AD. Mawuenyega et al. found impaired clearance of both Aβ40 and Aβ42 in the central nervous system of late-onset AD patients compared with cognitively healthy controls, whereas the production rates did not differ [44]. The effectiveness of Aβ clearance depends on APOE isoforms, decreasing from APOE2 to APOE3 to APOE4 [45]. This defect in clearance could lead to Aβ plaques that aggregate in the cortex. Transgenic AD mice showed reduced Aβ plaques and amyloid angiopathy if they performed aerobic exercise in their enriched housing [46]. This raises the question of whether exercise is associated with cerebral Aβ deposition in APOE ε4 carriers. Head et al. suggested that APOE ε4 carriers with low exercise levels might have increased risk for cerebral Aβ deposition [47]. A recent study by Jeon et al. investigated whether APOE ε4 status combined with high midlife physical activity could modify Aβ retention [48]. APOE ε4 carriers with a mean age of 72 years in a low physical activity state had higher Aβ accumulation, and this was absent in highly active carriers. Furthermore, a study of 546 cognitively healthy elderly individuals with an average age of 69.6 ± 6.8 years revealed decreased cerebral amyloid load in physically active APOE ε4 carriers, whereas high physical activity was associated with a reduced plasma Aβ42/40 ratio only in non-carriers [49].

A difference between Aβ in the brain and the periphery related to the ApoE4 protein seems plausible. The APOE ε4 allele alters the permeability of the blood–brain barrier, which may result in increased levels of Aβ in the peripheral system of carriers compared to non-carriers [50]. This could be one explanation why reduced plasma Aβ levels were observed only in highly physically active non-carriers. Aβ fibrils in the periphery have an increased affinity for binding erythrocytes that can take up these fibrils, resulting in oxidative stress [51]. Piccarducci et al. confirmed that APOE ε4 carriers have higher levels of Aβ in erythrocytes than non-carriers [52]. The Aβ levels in erythrocytes decreased with physical activity in both carriers and non-carriers, but the decrease in APOE ε4 in non-carriers was significantly greater than that in carriers. Although the reduction in Aβ accumulation in erythrocytes related to physical activity seems to be independent of the APOE4 genotype, physical activity may have a beneficial role in relieving oxidative stress in APOE ε4 carriers.

Neprilysin (NEP) and insulin-degrading enzyme (IDE) are important enzymes in maintaining the Aβ levels in the brain. NEP, a zinc metalloendopeptidase, is involved in the degradation of Aβ in monomeric and oligomeric forms in the brain [53]. IDE, also a zinc metalloendopeptidase, has the ability to degrade extracellular Aβ in the brain and to clear cytoplasmic products of APP [54]. Studies have shown that these enzymes are downregulated due to age-dependent genetic mutations which could lead to AD by disrupting cerebral Aβ clearance (Fig. 1) [54‐56]. Moore et al. used AD transgenic mice with elevated Aβ levels to show the effect of exercise on Aβ metabolism [57]. They investigated reduced levels of both soluble Aβ40 and Aβ42 in the cortex and hippocampus by exercise in a dose-dependent manner. Exercise may be beneficial for APOE ε4 carriers, since the ApoE4 protein can enhance Aβ40 and Aβ42 aggregation compared to the other two isoforms [58]. NEP and IDE expression were also increased in the exercise groups in a dose-dependent fashion, providing further evidence that exercise may upregulate these Aβ degradation enzymes, leading to Aβ clearance (Fig. 1).

Lipids are crucial molecules in the human body. The central nervous system has the second highest lipid content after the adipose tissue [59]. Signal transduction in the brain depends on lipids as well, since axons are surrounded by a myelin sheath consisting of lipids. In addition, the ApoE protein is involved in lipid transport by regulating lipoprotein concentrations. ApoE proteins are attached to the surface of lipoproteins filled with lipids, enabling the binding to receptors on tissue or cells. In the central nervous system, ApoE released by astrocytes is needed to transport cholesterol inside lipoproteins to neuronal cells [6, 52]. This process starts with the binding of ApoE to high-density lipoprotein (HDL) filled with cholesterol. ApoE has high affinity for binding to the low-density lipoprotein (LDL) receptor family at cell surfaces mediating endocytosis, where HDL is degraded and cholesterol is released [60]. Cholesterol is crucial for axonal growth and formation and remodelling of synapses, which are important for learning, memory formation and neuronal repair [6]. Previous studies found lower ApoE levels in the serum, brain and cerebrospinal fluid in both APOE ε4-carrying AD patients and cognitively normal persons [61]. A reduction in ApoE can affect cholesterol transport in the brain. In AD, brain cholesterol levels are commonly reduced in hippocampal neurons and cortical areas. Furthermore, cholesterol transport to hippocampal neurons occurs in an isoform-dependent manner, where the ApoE3 protein is more efficient than ApoE4 [62]. Animal studies have shown consistent results of decreased brain cholesterol in homozygous ε4 mice [63].

Cholesterol can be transported by either HDL or LDL in serum; the latter enhances the risk of atherosclerosis, leading to cardiovascular disease, stroke and dementia [64]. It has been widely demonstrated that APOE ε4 carriers show lower HDL and higher LDL cholesterol serum levels [52, 65]. ApoE4-knock-in mice also showed increased serum LDL cholesterol [63]. Evidence was found that physical activity may modify the altered lipid profile; for instance, physical activity in older adults was positively associated with HDL cholesterol [49]. Bernstein et al. (2002) found that high levels of physical activity may reduce the atherosclerosis risk of the APOE4 genotype on the lipid profile [66]. Furthermore, highly active APOE ε4 carriers consisting of men and women between the ages of 35 and 74 years showed enhanced HDL cholesterol. Due to the large age range, the groups were divided into < 55 and 50+ years, where the association between high physical activity and the APOE4 genotype was more pronounced among the 50+ group. Lee et al. (2018) suggested that exercise training may decrease LDL cholesterol levels and total cholesterol in APOE ε4-carrying ischemic stroke patients [64]. In particular, in relatively young participants, no change in HDL or LDL cholesterol level was observed after physical training in APOE ε4 carriers [67]. These results indicate that age is an important factor in modifying cholesterol levels in APOE ε4 carriers by exercise. High physical activity reduces the high-risk LDL cholesterol in older APOE ε4 carriers compared to their younger counterparts. Taken together, these observations build a strong case supporting the association between exercise and lipid profiles of APOE ε4 carriers.

Neuroinflammation is involved in the neurodegenerative process in AD. Microglia and astrocytes are the central innate immune cells of the central nervous system. Microglia can be activated by the presence of Aβ to induce phagocytosis of Aβ plaques. However, activated microglia are not able to clear Aβ aggregation, leading to inflammation and thereby recruitment of more microglia, which can lead to cytotoxicity [68]. Upon activation, microglia release cytokines to regulate neuroinflammation, but these pro-inflammatory cytokines can induce damage to surrounding neurons and even cause neurodegeneration as occurs in later stages of AD. ApoE is involved in microglia suppression, which has a protective effect on neuroinflammation by inducing anti-inflammatory cytokines. ApoE-deficient mice showed enhanced levels of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-1β (IL-1β) and interleukin 6 (IL-6) mRNA by stimulation with lipopolysaccharide [69]. These pro-inflammatory cytokines were significantly increased, especially in APOE4 mice [70]. Administration of an ApoE-mimetic peptide derived from the receptor-binding region of the ApoE holoprotein counteracts this effect, showing its protective role in neuroinflammation. The innate immune response seems to be influenced by specific APOE isoforms. Soto et al. demonstrated evidence to support ApoE as a key player in neuroinflammation [71]. Aged mice engaged in exercise showed a reduction in microglia activation and improved neurovascular functioning and behaviour, whereas ApoE-deficient mice did not benefit from the intervention, suggesting the important role of ApoE in neurovascular functioning. Another animal study revealed that exercise in an enriched housing environment was effective in downregulating pro-inflammatory genes and upregulating anti-inflammatory genes in transgenic AD mice, which may reduce Aβ deposition in the brain [46]. Braskie et al. studied the relation between physical activity, inflammation and risk of AD in cognitively healthy older adults and AD patients [72]. They did not find an association between physical activity and TNFα, but lower TNFα and high physical activity levels were both independently associated with reduced regional brain atrophy. On the contrary, the animal study by Nichol et al. showed that exercise in aged AD mice reduced pro-inflammatory cytokines such as TNFα and IL-1β, thereby activating an adaptive response around Aβ plaques leading to decreased Aβ [73].

During inflammation, C-reactive protein (CRP) is mainly upregulated in serum. At the same time, pro-inflammatory cytokines are released. The study by Corlier et al. (2018) followed cognitively healthy older adults for 9 years [74]. Over time, CRP levels were enhanced, which was associated with greater cortical thinning. Physical activity was not related to CRP levels, which could be due to bias in the self-reports. The APOE4 genotype showed lower CRP levels and thinner cortex, which is contradictory in terms of inflammation. Therefore, Corlier et al. suggested that other mechanisms could be responsible for the enhanced AD risk in APOE4 carriers. The low CRP in APOE ε4 carriers was also supported by a previous study [75]. It was suggested that the low CRP levels in ε4 carriers are not associated with neuroinflammation, due to contradictory findings of increased inflammation in these carriers and low CRP levels. It remains unclear, but a possible explanation may be the production of cholesterol by the mevalonate pathway of the liver, because this pathway is known to be downregulated in APOE ε4 carriers, leading to low levels of CRP [75].

We previously mentioned that exercise can reduce pro-inflammatory cytokines. Exercise is also indirectly involved in growth factor stimulation. Insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor (BDNF) are growth factors involved in hippocampal function, synaptic functioning and learning. Exercise may upregulate both growth factors in the brain and periphery directly by increasing the concentrations or indirectly by reducing pro-inflammatory cytokines, which could alter IGF-1 and BDNF signalling in neurons [76]. IGF-1 has a protective role in AD because of its ability to decrease Aβ deposition. This growth factor is involved in upregulating the transport of Aβ carrier proteins to the brain to increase the clearance of Aβ plaques [77]. In this way, cognitive functioning is improved. A recent study by Galle et al. found low IGF-1 levels in homozygous APOE ε4 carriers showing increased risk of dementia [77]. Besides the role of IGF-1 in AD, BDNF is important in maintaining the memory function. The APOE ε4 allele reduces BDNF expression, which may induce synaptic loss in the hippocampus, leading to cognitive deficits [78]. Aerobic exercise was found to compensate the hippocampal volume loss in late adulthood that was associated with increased plasma levels of BDNF [79]. In addition, plasma BDNF levels were increased in AD patients due to aerobic exercise [80]. Conversely, BDNF levels were upregulated due to aerobic exercise only in APOE ε4 non-carriers and not in carriers [81]. However, this study was restricted to one ethnic group with a higher risk of AD. An animal model showed increased hippocampal BDNF levels upon exercise in both APOE ε4 and APOE ε3 transgenic mice [24]. Studies assessing the effects of exercise on neurotrophic factors in APOE e4 carriers are sparse, but the available evidence may support a relation between the two, suggesting more replication is needed.

Vascular risk factors including hypertension, hypercholesterolemia, atrial fibrillation and smoking can affect the incidence and progression of AD [82]. For example, high systolic blood pressure in APOE ε4 carriers may lead to cognitive decline [83, 84]. Caselli et al. noted that any of the cerebrovascular risk factors including hypercholesterolemia, hypertension, smoking and diabetes mellitus may potentiate age-dependent memory deficits in APOE ε4 homozygotes [85]. These vascular risk factors induce vascular oxidative stress by downregulation of vascular nitric oxide (NO) and endothelial NO synthase (eNOS) pathways, which can impair vascular reactivity in the form of hypercontractility. Cerebral blood flow (CBF) will decrease due to impaired vasodilation, which mediates oxidative stress and promotes neuronal degeneration. In addition, Aβ plays a role in this process by inhibiting eNOS activity. This is supported by the finding that hypertensive mice showed increased permeability of the blood–brain barrier in the cortex and hippocampus and Aβ deposition [86]. A human study demonstrated that hypertensive APOE ε4 carriers aged 49–89 years had greater cortical amyloid burden as quantified by PET imaging compared to hypertensive non-carriers, normotensive carriers and non-carriers [87]. Zhang et al. found decreased eNOS activity, increased Aβ in the hippocampus and cortex, and decreased cognition in hypertensive mice [88]. Engagement in exercise led to improved eNOS levels, cognition and AD pathology. In addition, long-term exercise increased IGF-1 levels in these hypertensive mice, which is important in attenuating Aβ clearance.

Reduced CBF is another hallmark of AD. Older adults carrying the APOE ε4 allele showed lower CBF than non-carriers, along with reduced memory [89]. Adult APOE4-mice had reduced CBF in regions susceptible to AD pathology compared to wild-type mice and younger mice with the APOE ε4 allele, suggesting an age-dependent interaction [90]. Since APOE ε4 carriers have lower levels of the ApoE protein, a complete knock-out of the ApoE protein resulted in lower CBF compared to wild-type mice already at a young age, demonstrating the importance of the ApoE protein. It has been shown that exercise is effective in increasing CBF. Aged mice showed increased CBF in the hippocampus with walking [91]. Burdette et al. reported increased hippocampal CBF with a 16-week exercise program in older adults at risk for cognitive decline and with subjective cognitive impairment [92]. Furthermore, greater hippocampal connectivity was observed in the exercise group. Conversely, a 16-week aerobic program was not sufficient to increase CBF in AD patients [93].

Vascular endothelial-derived growth factor (VEGF) is another important factor involved in vascularization. VEGF is lower in AD [94], and especially in APOE ε4 carriers, compared to the other isoforms, which may lead to vascular impairment. By increasing the VEGF levels using a viral vector, the AD-related pathology in APOE ε4-carrying mice was reversed [95]. Exercise may increase the VEGF plasma levels to improve vascularization [76]. Increased VEGF expression was found to induce angiogenesis in aged mice through exercise engagement [96]. Studies about the association between VEGF levels in APOE ε4 carriers and exercise are sparse.