There are multiple pathways that can mediate the effects of early life experiences on cognition and AD neuropathology. First of all, there are pathways that are affected by early life experiences, and that are known to directly affect either the production or clearance of Aβ. The steady-state levels of Aβ depend on a balance between APP processing, the rate of Aβ production, and clearance of the peptide from the brain [
55]. Likewise, tau hyper-phosphorylation can also be potentiated by factors induced early in life.
Hypothalamus–pituitary–adrenal axis
The hypothalamus–pituitary–adrenal (HPA) axis controls circulating glucocorticoid hormones (cortisol in humans, corticosterone in rodents). In response to corticotrophin releasing hormone (CRH), the pituitary releases adrenocorticotropin hormone (ACTH), which in turn stimulates the release of glucocorticoid hormones from the adrenal cortex [
56]. At the early stages of AD, basal levels of circulating cortisol are often elevated [
26,
57‐
59]. AD and dementia patients also show a failure to suppress their endogenous cortisol after administration of the synthetic glucocorticoid dexamethasone [
25,
60,
61], indicating a dysfunction in the feedback of the HPA axis. Elevated basal cerebrospinal fluid (CSF) cortisol levels were specifically found in MCI patients who later developed AD, but not in MCI patients with other underlying neuropathologies. Moreover, higher baseline CSF cortisol levels were associated with a faster clinical worsening and cognitive decline in the MCI patients who were developing AD [
62]. However, HPA dysfunction does not seem to worsen any further as the disease progresses [
63,
64], suggesting that early life-induced alterations in HPA axis function, possibly acting via glucocorticoids, may in particular contribute to the onset and acceleration of AD pathogenesis, after which a new balance in HPA axis activity is reached. Rodent studies further indicate that pharmacological treatment with (synthetic) glucocorticoids or repeated stress exposure can induce pathological processing of both Aβ and tau. Both stress-level glucocorticoid administration in 3xTg-AD mice [
65] and stress induction in wild-type rats [
66] increase the levels of APP and the β-APP cleaving enzyme 1 (BACE1), which in turn increases amyloidogenic processing of APP and results in elevated levels of APP-derived fragments (C99 and C83) and Aβ peptides.
The early life postnatal environment is a strong determinant of HPA axis activity and later-life sensitivity to stressors [
67]. In rodents, positive early life experiences generally dampen HPA axis reactivity, resulting in lower CRH and glucocorticoid levels in response to a stressor, whereas early life adversity generally increases HPA axis reactivity [
67,
68]. As a consequence, the subsequent, cumulative exposure to glucocorticoids and/or CRH in adult animals is often persistently enhanced by early life stress. The notion that elevated glucocorticoid levels can promote Aβ levels (see earlier) may point to a critical role for these hormones in moderating AD neuropathology after early life adversity [
65,
69,
70].
This points to the possible involvement of glucocorticoids in the initial development, or later promotion, of AD neuropathology, rather than that the alterations in glucocorticoids observed in AD may result from disease progression. However, prolonged glucocorticoid exposure, or exposure after early life stress, most likely cannot fully account for the neuropathological effects observed. Following chronic early life stress, wild-type animals show decreased corticosterone levels in response to an acute stressor, whereas APPswe/PS1dE9 mice exposed to the same paradigm, but not control-reared AD mice, display elevated corticosterone levels [
44]. Thus, AD neuropathology by itself can also affect HPA axis functioning, which may depend on disease severity.
Notably, early life stress also increases the expression of BACE1 in adult wild-type mice [
47,
71,
72] and APPswe/PS1dE9 mice [
44]. The enhanced BACE1 expression following early life or adult stress exposure can be a direct effect of altered glucocorticoid signalling, as BACE1 contains glucocorticoid binding sites [
73]. Indeed, short-lasting treatment with the glucocorticoid receptor antagonist mifepristone rescued the early life stress-induced cognitive impairments in APPswe/PS1dE9 mice and reduced the Aβ load and BACE1 expression [
44]. In addition, a reduction in APP-derived C99 and C83 fragments was reported in 3xTg-AD mice after a similar treatment [
74]. This suggests that the same pathway was affected by both manipulations and hence that APP processing is specifically targeted by (anti)-glucocorticoid actions. Alternatively, it has also been suggested that epigenetic modifications are responsible for the enhanced BACE1 expression [
75].
Besides glucocorticoids, other stress mediators (such as CRH) have also been implicated in AD-related neuropathology. AD patients display reduced levels of CRH in the cortex and CSF [
76,
77]. Rodent studies have further identified a role for CRH in protecting neurons against Aβ-associated cell death [
78], possibly by promoting non-amyloidogenic APP cleavage [
79,
80]. In contrast to these findings is the observation that stress exposure elevated CRH levels as well as Aβ expression [
81,
82]. The role of CRH in Aβ pathology therefore needs further investigation.
Although less extensively described in recent literature, chronic stress or glucocorticoid exposure also induces abnormal hyper-phosphorylation of tau in wild-type mice [
50] and 3xTg-AD mice [
65]. Glucocorticoids potentiate the ability of centrally infused Aβ to induce hyper-phosphorylation of tau epitopes associated with AD [
50], suggesting that tau pathology is also affected by HPA axis-related mechanisms [
83,
84]. Although speculative, this could be a mechanism by which early life experiences, via alterations in HPA axis activity, could modulate tau pathology. Together, these studies highlight the potential of alterations in glucocorticoids and CRH, both factors affected by early life experiences, to be involved in promoting AD pathology, and that modulating these systems may directly affect pathological markers such as Aβ production and tau hyper-phosphorylation. However, further research is warranted to understand the exact mechanisms how this occurs, and the causative nature of the effects, in particular regarding tau pathology.
Blood–brain barrier integrity
Aβ in the brain is controlled via a steady-state homeostatic balance of production and removal. In humans, approximately 25% of Aβ is cleared from the brain via the blood–brain barrier (BBB) [
85]. Post-mortem studies have shown that BBB integrity declines with age [
86,
87], and might be involved in the onset of dementia [
88]. Both acute and chronic activations of the stress system may compromise the permeability of the blood–brain barrier [
89,
90]. Restraint stress in rodents induces damage in the capillary brain endothelial cells and alters expression of the tight-junction proteins occludin, claudin-5, and glucose transporter-1 in these brain capillaries, pointing to impaired BBB functioning [
90]. Interestingly, mice that are resistant to the induction of a depression-like phenotype after exposure to chronic social defeat stress (CSDS) showed an upregulation of claudin-5 levels and more intact brain endothelial cell morphology compared to mice sensitive to CSDS [
89]. Although further experimental validation is required, particularly with regard to how early life experiences regulate BBB stability and permeability for life, (early) stress could possibly influence Aβ clearance from the brain through altering the permeability of the BBB.
Neuroinflammation
Another mechanism possibly involved in the clearance of Aβ from the brain is via the brain’s neuroinflammatory response. For example, microglia bind Aβ oligomers and fibrils and clear Aβ from the brain through the secretion of Aβ-degrading enzymes like neprilysin [
91] and insulin-degrading enzyme (IDE) [
92], and through the phagocytic uptake and active degradation of Aβ. Both IDE and neprilysin activities are reduced in AD, and, interestingly, are further inhibited by glucocorticoids [
93]. In response to Aβ oligomers, microglia induce an acute inflammatory response to aid clearance and restore homeostasis [
94‐
96]. In the prolonged presence of Aβ accumulation, however, the physiological functions of microglia, such as synaptic remodelling, are thought to be compromised and may lead to a chronic neuroinflammatory response [
97]. This progressive microglial activation, elevated pro-inflammatory cytokine levels, and morphological changes of microglia may result in functional and structural alterations that ultimately can promote neuronal degeneration [
97]. Adverse early life experiences have been reported to alter the number of microglial cells, their morphology, phagocytic activity, and gene expression in the developing hippocampus that extend into the juvenile period (reviewed in [
98‐
100]). These changes in microglial function are associated with abnormalities in developmental processes known to be mediated by microglia, including synaptogenesis, synaptic pruning, axonal growth, and myelination (reviewed in [
100,
101]), and make them more responsive to subsequent inflammatory challenges like Aβ (microglial ‘priming’) [
99,
102‐
104]. Conversely, neonatal handling programmes the expression of the anti-inflammatory cytokine IL-10 early in development by decreasing its methylation within microglia, attenuating glial activation [
105]. Recently, exposure to early life stress in APPswe/PS1dE9 mice was shown to increase the plaque load while attenuating microglial responses in a lasting manner [
45]. Whether enhanced Aβ pathology reduces microglial response, or whether early life programming is truly causing alterations in microglial activation, which in turn may modulate Aβ neuropathology, requires further investigation.
Thus, impairments in glial functioning and/or in the inflammatory response to Aβ, possibly modulated or ‘primed’ by early life experiences, could lead to an altered Aβ phagocytic capacity or clearance, and hence an altered Aβ burden with increasing age. Further studies are required, both with regard to whether positive early life experiences increase AD resilience via the modulation of such neuroinflammatory responses, and regarding the extent to which, and how, early life events can indeed programme microglia directly and indirectly.