**3. Alzheimer disease**

568 Lipoproteins – Role in Health and Diseases

neurodegenerative pathologies.

Ludewig and Laman (2004) remarked the similarities that may exist between the atherosclerotic plaque development and MS lesions and suggested: "*Systematic comparison of these two diseases involving foam cells in chronic lesions may prove fruitful*" [57]. As we have reviewed, recent research clearly supports this prediction. Moreover, patients with MS have several vascular abnormalities and a higher risk for ischemic stroke [58]. In 2003, our group first reported a pilot trial suggesting a benefit of statin monotherapy in the pathogenesis process (assessed by MRI) and clinical activity of RR-MS patients [59]. These beneficial effects were confirmed by Vollmer *et al* trial in 2004 [60] and in a long-term follow-up of our patients [61]. Very recently, beneficial effects of statin monotherapy were reported in patients with a first clinical episode (CIS) suggestive of MS [62-63]. A synthesis of some shared pathophysiological factors involved in MS and atherosclerosis is presented on Table 1. As we will discuss below, the presence of similar mechanisms involving plasma lipoprotein metabolism in the pathogenesis of atherosclerosis/ischemic and demyelinating lesions may be extensive to other chronic inflammatory and

**Pathophysiology Comment References**  *Lesions*

*Lipoprotein Related*

early lesion formation [36-37]

and/or progression [13-16]

protective [26-27]

protective [8-10, 12]

reactivity and lesion formation [49-50]

formation [51-53]

cells in lesions [37]

and/or progression [13, 16-17, 47]

Foam Cells Plaques Macrophage lipid uptake in

Total and LDL cholesterol Promotion of lesion formation

HDL-Cholesterol Protective of lesion formation

ApoA-I Immunosuppressive and

ApoE Immunosuppressive and

Sphingosine-1-phosphate Modulation of immune

Oxidative stress and oxLDL Lipid peroxidation in lesion

M2-Macrophages Anti-inflammatory, phagocytic

Secretory phospholipase A2 Increased expression [115]

T-Cells Promoting lesion formation [33] Inflammatory cytokines Promoting lesion formation [33] Interleukin-10 Protective of lesion formation [116]

*Immunopathogenesis*

Possession of the apoE4 allele is the major genetic risk factor for sporadic late-onset AD [64- 65]. This observation led to a large body of research on cholesterol and lipid metabolism in patients and animal models of AD during the last two decades. However, the investigation of this metabolism in patients with clinical AD is not sufficient to clarify its role in the pathogenesis of the dementia. It is generally accepted that the pathogenic processes in AD begin many decades before the appearance of evident symptoms. More recently, a major focus of interest has been on longitudinal studies addressing the association between lipoprotein profiles and clinical evolution of cognitive normal subjects or patients with mild cognitive impairment (MCI). A large percentage of patients with the diagnosis of MCI by the 6th decade are known to develop AD later in life. Therefore prospective studies are crucial for development of efficient preventive or therapeutic measures.

Amyloid-β (Aβ) deposition in plaques (AP) (also known senile or neuritic plaques (NP)) and neurofibrillary tangles (NFT), characterized by hyperphosphorylated tau protein aggregates, are pathologic hallmarks of AD [66-67]. The association between plasma lipoprotein profiles and risk of development of clinical manifestations of dementia has been controversial. An association between high cholesterol levels in midlife and an increased

risk for dementia in old age has been suggested by several publications [68], but it was not confirmed by a recent large population study [69]. Instead, this study found that low cholesterol levels in late life were predictive of subsequent dementia. Supporting this conclusion, another study in elderly individuals found that low HDL-cholesterol and low total and Non-HDL cholesterol were associated with higher AD risk [70]. These authors suggested a protective effect of late life total cholesterol level on the risk for mild cognitive impairment and AD. Low HDL-cholesterol levels were also associated with decline of memory in middle-aged adults [71]. Within this framework, decreased plasma apoA-I levels have also been found in AD as well as in vascular dementia, and higher apoA-I levels associated with decreased risk of dementia [72-73]. Few studies have investigated the association of lipid profiles with AD-related pathology. A recent work has found that high total cholesterol, LDL-cholesterol and non-HDL-cholesterol levels were associated with risk of development of AP, but not NFT [74]. However, as we will discuss below, the genesis of pathological hallmarks of AD is not invariably associated with clinical manifestations of cognitive impairment and dementia.

The apoE4 allele is an established risk factor for the development of sporadic AD; it is associated with an early age at onset of dementia in an allele dose-dependent manner; and with increased Aβ burden. Moreover, in MCI it predicts conversion to AD. In contrast, apoE2 allele is associated with delayed age of onset of AD [66]. Recent data have provided evidence for an important role of apoE protein levels, independently of the genotype. In one study, middle-aged offspring with familial history of AD were found to have lower plasma apoE levels when compared with offspring without familial history of AD, independent of APOE genotype [75]. In other study, plasma apoE levels were found to be lower in patients with AD and decreased with Aβ load [76].

Overall the reviewed data strongly support a role of plasma lipoprotein metabolism in the pathogenesis of AD, as discussed in more detail below.

#### **3.1. Pathophysiological mechanisms**

As already mentioned, NP and NFT are the hallmarks of AD pathology. However, these aggregates are present in a variable extend in about 30% of cognitively normal elderly subjects. In AD, synaptic structural and functional alterations also occur early and are more pronounced than in normal ageing individuals. ApoE-containing lipoproteins, mainly derived from astrocytes, may influence these pathogenic processes in several ways. Cholesterol associated with these lipoproteins is necessary for neurons and to stimulate axonal growth and synaptogenesis. Lipidate-apoE contributes for clearing out Aβ from the brain, a process mediated by apoE receptors (especially LRP1) present in glial cells, neurons and in endothelium of the BBB. Pathways for Aβ clearance also include proteolytic degradation and oligomerization in the aggregates of amyloid plaques, mechanisms also modulated by apoE. For all these processes the isoform apoE4 (which is in general associated with less secreted production of the protein) is less efficient and promotes synaptic dysfunction, toxicity of soluble Aβ and NP deposits. Moreover, it is suggested that apoE4 fragments induce mitochondrial dysfunction and neurotoxicity and that cholesterol levels may regulate Aβ production [65, 66]. Supporting this important role of apoE for AD and the harmful effects of Aβ on cognitive functions, cognitive performance in normal older adults was associated with Aβ load (PET), mainly in ε4 carriers [77].

570 Lipoproteins – Role in Health and Diseases

cognitive impairment and dementia.

with AD and decreased with Aβ load [76].

**3.1. Pathophysiological mechanisms** 

pathogenesis of AD, as discussed in more detail below.

risk for dementia in old age has been suggested by several publications [68], but it was not confirmed by a recent large population study [69]. Instead, this study found that low cholesterol levels in late life were predictive of subsequent dementia. Supporting this conclusion, another study in elderly individuals found that low HDL-cholesterol and low total and Non-HDL cholesterol were associated with higher AD risk [70]. These authors suggested a protective effect of late life total cholesterol level on the risk for mild cognitive impairment and AD. Low HDL-cholesterol levels were also associated with decline of memory in middle-aged adults [71]. Within this framework, decreased plasma apoA-I levels have also been found in AD as well as in vascular dementia, and higher apoA-I levels associated with decreased risk of dementia [72-73]. Few studies have investigated the association of lipid profiles with AD-related pathology. A recent work has found that high total cholesterol, LDL-cholesterol and non-HDL-cholesterol levels were associated with risk of development of AP, but not NFT [74]. However, as we will discuss below, the genesis of pathological hallmarks of AD is not invariably associated with clinical manifestations of

The apoE4 allele is an established risk factor for the development of sporadic AD; it is associated with an early age at onset of dementia in an allele dose-dependent manner; and with increased Aβ burden. Moreover, in MCI it predicts conversion to AD. In contrast, apoE2 allele is associated with delayed age of onset of AD [66]. Recent data have provided evidence for an important role of apoE protein levels, independently of the genotype. In one study, middle-aged offspring with familial history of AD were found to have lower plasma apoE levels when compared with offspring without familial history of AD, independent of APOE genotype [75]. In other study, plasma apoE levels were found to be lower in patients

Overall the reviewed data strongly support a role of plasma lipoprotein metabolism in the

As already mentioned, NP and NFT are the hallmarks of AD pathology. However, these aggregates are present in a variable extend in about 30% of cognitively normal elderly subjects. In AD, synaptic structural and functional alterations also occur early and are more pronounced than in normal ageing individuals. ApoE-containing lipoproteins, mainly derived from astrocytes, may influence these pathogenic processes in several ways. Cholesterol associated with these lipoproteins is necessary for neurons and to stimulate axonal growth and synaptogenesis. Lipidate-apoE contributes for clearing out Aβ from the brain, a process mediated by apoE receptors (especially LRP1) present in glial cells, neurons and in endothelium of the BBB. Pathways for Aβ clearance also include proteolytic degradation and oligomerization in the aggregates of amyloid plaques, mechanisms also modulated by apoE. For all these processes the isoform apoE4 (which is in general associated with less secreted production of the protein) is less efficient and promotes synaptic dysfunction, toxicity of soluble Aβ and NP deposits. Moreover, it is suggested that The above findings do not exclude the contribution of other apolipoproteins for Aβ pathology. For example, apoJ and apoD (see below) also modulate Aβ deposition, a deficiency of apoA-I promotes cognitive impairment and polymorphisms of all these apolipoproteins were associated with risk for AD [1]. Interestingly, increased plasma levels of apoJ (clusterin) are not present before the development of AD but are indeed associated with the severity and progression of the disease, supporting a neuroprotective role [78].

The link between a lipoprotein dysregulation and tau pathology (NFT deposition), in contrast, is not well understood. Beyond the involvement of cholesterol and apolipoproteins, AD is associated with disturbances of sphingolipids and phospholipid metabolism that may contribute for its pathogenesis [67]. Moreover, cognitive impairment and dementia, including AD, are frequently associated with markers of systemic and brain inflammatory activity [79], vascular atherogenic [80] and white-matter (myelin) pathology [81]. An underlying dysregulation of lipoprotein metabolism could be linked to all these pathogenic pathways.

The scenario briefly described above is clearly consistent with the observations that low plasma apoE may be associated with increased risk of AD and correlates with Aβ load, as assessed by PET [75-76]. As remarked, the last studies emphasized the importance of total apoE levels, independently of the genotype. Supporting this concept, it was recently reported in AD mouse models a stimulation of Aβ clearance and cognitive function by inducing apoE expression [82]. After apoE-mediated transport through the BBB, plasma Aβ transport is accomplished by triglyceride-rich lipoproteins (TRL) rich in apoE, for uptake in liver [83]. These findings are also consistent with the risk conferred by low plasma apoE levels. Low plasma apoE levels could also promote systemic immune reactivity and atherogenic pathology in these patients.

Although no relation exists between plasma and brain apoE levels, a strong correlation was found between HDL-cholesterol and apoA-I in serum and in CSF lipoproteins (which are HDL-like particles) [2]. This scenario could contribute to the risk of cognitive impairment and AD conferred by low plasma HDL-cholesterol and apoA-I levels [70-73]. On one hand, these deficiencies could be linked to an increased systemic inflammatory and oxidative status and promotion of atherogenesis. On the other hand, low HDL and apoA-I levels would provide less neurotrophic and immunosuppressive abilities to the brain [84]. If high total and LDL or non-HDL cholesterol in plasma cannot influence its levels in the brain, how could they be associated in some studies with an increased AD risk and Aβ load (NPs)? Experimental studies suggest that plasma cholesterol levels do not normally regulate production of brain Aβ [85]. One possibility resides in the fact that high non-HDL cholesterol in these patients may be associated with low HDL, apoE and apoA-I levels, a pro-inflammatory systemic status and increased atherogenic/ischemic pathology. Supporting this hypothesis, in animal models, cognitive impairment following high fat diet consumption was associated with brain inflammation [86]. Among other markers of inflammation [79], serum levels of adipocytokines have been associated with cognitive impairment and progression of AD, as well as atherogenic/ischemic disease [87-88]. Metabolic syndrome [89] and insulin resistance and type 2 diabetes [90] are associated not only with higher risk of vascular disease but also with risk of dementia, including AD. All these conditions may promote the development of dementia also by affecting myelin integrity and white-matter connective functions.

It should be noted that clinical overt cognitive impairment and dementia do not depend solely on the severity of neurodegenerative and vascular pathologies. Human brain is provided with potential compensatory or plastic mechanism, which may mitigate the clinical impact of ageing-associated pathologies [91-92]. This means that in old age, risk factors for dementia may not have the same significance they have in previous decades. Those factors may include high total and non-HDL cholesterol plasma levels, which may have a major impact in promoting atherogenesis/ischemic/inflammatory processes and ADrelated pathology in middle-life, but not in neuroplastic mechanisms increasingly required with advancing age. Lower total and LDL cholesterol have indeed been associated with a poor prognosis in the ischemic stroke [93] and in elderly individuals, as observed above, this profile may increase the risk for overt dementia. Increased body mass index (BMI) in middle life appears to be a risk factor for latter development of cognitive decline and AD, but in late life the burden of cerebral amyloid and tau is associated with lower BMI in cognitively normal and MCI subjects [94-95]. These facts could contribute to the inconsistent results regarding the benefits of statins on prevention and treatment of AD, despite in vitro and animal studies demonstrating an effect in decreasing Aβ formation [96].

In Figure 1 are presented some of the suggested implications of lipoproteins in the pathogenesis of AD and MS.
