**4. Other brain disorders**

Results concerning an association between high serum cholesterol levels and the risk for **Parkinson disease (PD)** have been conflicting. However, this possible association may not exist in older subjects (≥55 years). As for AD, low serum total and LDL-cholesterol levels may increase the risk of PD with advancing age [97-99]. In this context, it is intriguing that hyperlipidemia probably has also a protective role on the neurodegenerative process of **amyotrophic lateral sclerosis (ALS)** [100-101]. PD and ALS also involve inflammatory processes and it has been noted some convergence in the mechanisms underlying neurodegeneration in these disorders, in AD and MS. [102]. An abnormal brain cholesterol homeostasis may also contribute to the pathophysiology of **Huntington's disease** [103]. In what concerns PD, and in contrast to AD, an involvement of apoE genotypes is not clarified. Several studies reported no influence of apoE4 allele in the development of PD or in dementia associated with the disease, which is in contrast to its established role in AD pathogenesis [104]. However, apoE and LRP1 were found to be increased in brain from PD patients, suggesting an involvement in the deposition of α-sinuclein aggregates (Lewy bodies) typical of this disease [105].

pathogenesis of AD and MS.

**4. Other brain disorders** 

aggregates (Lewy bodies) typical of this disease [105].

integrity and white-matter connective functions.

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

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

In Figure 1 are presented some of the suggested implications of lipoproteins in the

Results concerning an association between high serum cholesterol levels and the risk for **Parkinson disease (PD)** have been conflicting. However, this possible association may not exist in older subjects (≥55 years). As for AD, low serum total and LDL-cholesterol levels may increase the risk of PD with advancing age [97-99]. In this context, it is intriguing that hyperlipidemia probably has also a protective role on the neurodegenerative process of **amyotrophic lateral sclerosis (ALS)** [100-101]. PD and ALS also involve inflammatory processes and it has been noted some convergence in the mechanisms underlying neurodegeneration in these disorders, in AD and MS. [102]. An abnormal brain cholesterol homeostasis may also contribute to the pathophysiology of **Huntington's disease** [103]. In what concerns PD, and in contrast to AD, an involvement of apoE genotypes is not clarified. Several studies reported no influence of apoE4 allele in the development of PD or in dementia associated with the disease, which is in contrast to its established role in AD pathogenesis [104]. However, apoE and LRP1 were found to be increased in brain from PD patients, suggesting an involvement in the deposition of α-sinuclein

animal studies demonstrating an effect in decreasing Aβ formation [96].

**Figure 1.** Some putative implications of lipoproteins for the pathogenesis of Multiple Sclerosis and Alzheimer disease (see text for interpretation).

As mentioned above, apolipoprotein D in the CNS is normally synthetized by glial cells (astrocytes and oligodendrocytes). Although present in the CSF in lower concentrations than apoE, A-I and J, some studies have suggested a possible neuroprotective role of apoD in neuropathological states [1,106]. ApoD is a member of the lipocalin family of proteins that are involved in the transport of small hydrophobic ligands. Among several proposed ligands (cholesterol, progesterone, pregnenolone, bilirubin), apoD can bind with high affinity arachidonic acid (AA). Inflammatory responses and oxidative stress associated with brain insults are known to mobilize AA from membranes. Therefore, apoD could have a neuroprotective role by controlling oxidative damage [106-107]. In fact, higher levels of apoD have been found in brain or CSF of AD and other neuropathologies [108]. Curiously, an increase of apoD has also been reported in plasma and certain brain regions of patients with **schizophrenia** and **bipolar disorder**. In these conditions, a disturbance of phospholipid metabolism has been proposed and apoD could represent a response addressed to stabilize membrane AA or bind free AA [106]. The fact that atypical antipsychotics such as clozapine up-regulate apoD expression supports neurotrophic effects of this protein [106]. It should be noted that other apolipoproteins have been implicated in these neuropsychiatric disorders, including apoE, and apoA-I [106, 109-110]. Interestingly, as observed for AD and MS, lower serum apoA-I levels were found in schizophrenia [110].

Overall, these data emphasizes the relevance of plasma lipoprotein metabolism in brain physiology and the convergence of similar dysfunctions of this metabolism associated with several neuropathologies.
