**5. Cholesterol, lipoproteins, and dementia**

Of the many lipids, cholesterol is believed to play a major role in brain function and develop‐ ment, as the brain contains as much as 23% of the total cholesterol deposits [57]. One of the most pronounced groups of genes described as dementia risk factors are involved in the transport of cholesterol and may be accounted for as apolipoproteins [58]. A misbalanced lipid metabolism may be associated with memory loss [59]. According to another paper [60], patients with higher levels of high-density lipoproteins (HDLs) had a decreased risk of developing dementia at the time of the study and in the future. For patients from the upper quartile (with a plasma HDL concentration higher than 55 mg/dL), the dementia hazard was decreased by 60%. Studies on the subjects were continued by several other teams; however, the obtained results seem to be rather inconsistent [61–67].

Generally, the HDL level is believed to negatively correlate with the prevalence of dementia in elderly people; however, many studies have implied that HDL influence may be character‐ istic of the VD development [58, 68].

#### **5.1.** *CLU***, apolipoprotein J (apoJ)**

Apolipoprotein J (apoJ, also known as clusterin), encoded by the *CLU* gene, has been shown to probably be associated with dementia. Genome-wide association studies (GWAS) per‐ formed by authors [69] identified a genetic variation (rs11136000) which was a significant risk factor of dementia. The role of apoJ in the pathomechanism of AD is not fully understood. It has recently been shown that apoJ plasma levels positively correlate with the risk of dementia, as elevated apoJ levels have been reported in the plasma of AD patients as well as in their brain and cerebrospinal fluid (CSF). The study [70] showed that apoJ plasma, but not CSF, levels are elevated in AD patients and were a risk factor of dementia (HR 18.6). This biomarker was also shown to be significantly correlated with cognitive decline in AD patients and reversely correlated in individuals with mild cognitive impairment (MCI). Moreover, increased plasma apoJ levels in MCI indicated an amplified risk of further cognitive decline. Furthermore, it was shown that genetic variation in the *CLU* region may amplify the influence of personality type on the performance of declarative memory in older, non-demented adults [71].

#### **5.2.** *APOE***, apolipoprotein E (apoE)**

ApoE is encoded by the *APOE* gene, which is located on the long arm of chromosome 19. It comprises four exons. Two frequent polymorphisms were described on the last exon: rs7412 and rs429358. These variants encode for three common alleles of *APOE*: E2, E3, and E4, encoding for apoE ε2, ε3, and ε4, respectively.

ApoE in physiological conditions is a major cholesterol carrier and one of the most vital proteins responsible for maintaining cholesterol homeostasis in the brain. ApoE is mostly synthesized by astrocytes and probably does not cross the blood-brain barrier [72].

A recent study [73] on transgenic rabbit *Apoe* knockouts (*Apoe* -/-) showed that apoE is essential for cholesterol homeostasis under stress conditions. Under normal conditions, the transgenic animals were able to maintain a stable, physiological level of plasma cholesterol. However, when the animals were transitioned to a diet with high cholesterol content, its level increased dramatically (1070 ± 61 mg/dL in apoE KO vs 169 ± 79 mg/dL in the wild type, *p* < 0.001). Another study [74] showed that increased content of fat and cholesterol in the diet increased apoE production, probably due to transcriptional and posttranscriptional mechanisms. This suggests that functional apoE is essential for cholesterol regulation in mammals and protects against diet-induced atherosclerosis. The various variants of *APOE* have a distinct influence on apoE function and effect. Studies on humans and in apoE transgenic mice suggest that lipidation of apoE depends strongly on the *APOE* genotype, and that apoE ε2 and ε3 are significantly more lipidated than apoE ε4. Interestingly, cholesterol and proper apoE lipidation are essential for apoE function in sustaining synapses [75].

most pronounced groups of genes described as dementia risk factors are involved in the transport of cholesterol and may be accounted for as apolipoproteins [58]. A misbalanced lipid metabolism may be associated with memory loss [59]. According to another paper [60], patients with higher levels of high-density lipoproteins (HDLs) had a decreased risk of developing dementia at the time of the study and in the future. For patients from the upper quartile (with a plasma HDL concentration higher than 55 mg/dL), the dementia hazard was decreased by 60%. Studies on the subjects were continued by several other teams; however,

Generally, the HDL level is believed to negatively correlate with the prevalence of dementia in elderly people; however, many studies have implied that HDL influence may be character‐

Apolipoprotein J (apoJ, also known as clusterin), encoded by the *CLU* gene, has been shown to probably be associated with dementia. Genome-wide association studies (GWAS) per‐ formed by authors [69] identified a genetic variation (rs11136000) which was a significant risk factor of dementia. The role of apoJ in the pathomechanism of AD is not fully understood. It has recently been shown that apoJ plasma levels positively correlate with the risk of dementia, as elevated apoJ levels have been reported in the plasma of AD patients as well as in their brain and cerebrospinal fluid (CSF). The study [70] showed that apoJ plasma, but not CSF, levels are elevated in AD patients and were a risk factor of dementia (HR 18.6). This biomarker was also shown to be significantly correlated with cognitive decline in AD patients and reversely correlated in individuals with mild cognitive impairment (MCI). Moreover, increased plasma apoJ levels in MCI indicated an amplified risk of further cognitive decline. Furthermore, it was shown that genetic variation in the *CLU* region may amplify the influence of personality type

on the performance of declarative memory in older, non-demented adults [71].

ApoE is encoded by the *APOE* gene, which is located on the long arm of chromosome 19. It comprises four exons. Two frequent polymorphisms were described on the last exon: rs7412 and rs429358. These variants encode for three common alleles of *APOE*: E2, E3, and E4,

ApoE in physiological conditions is a major cholesterol carrier and one of the most vital proteins responsible for maintaining cholesterol homeostasis in the brain. ApoE is mostly

A recent study [73] on transgenic rabbit *Apoe* knockouts (*Apoe* -/-) showed that apoE is essential for cholesterol homeostasis under stress conditions. Under normal conditions, the transgenic animals were able to maintain a stable, physiological level of plasma cholesterol. However, when the animals were transitioned to a diet with high cholesterol content, its level increased dramatically (1070 ± 61 mg/dL in apoE KO vs 169 ± 79 mg/dL in the wild type, *p* < 0.001). Another study [74] showed that increased content of fat and cholesterol in the diet increased

synthesized by astrocytes and probably does not cross the blood-brain barrier [72].

the obtained results seem to be rather inconsistent [61–67].

istic of the VD development [58, 68].

**5.2.** *APOE***, apolipoprotein E (apoE)**

encoding for apoE ε2, ε3, and ε4, respectively.

**5.1.** *CLU***, apolipoprotein J (apoJ)**

258 Update on Dementia

A study [76] analyzing the association of plasma and CSF apoE concentrations showed that the CSF/serum ratios of apoE levels were associated with progression of dementia. Schmidt et al. observed that "the lower the ratio, the faster the deterioration," as measured by the MMSE, instrumental activities of daily living (iADL), or Geriatric Depression Scale (GDS). Subse‐ quently, another study [77] showed that plasma apoE may be a biomarker of dementia, as patients suffering from memory decline had lowered concentrations of plasma apoE.

The first reports indicating that *APOE* may be associated with dementia were published more than 20 years ago. Detailed studies of this gene were carried out mainly in AD; however, the literature data support *APOE* influence on memory in people with no symptoms of dementia. It is believed that *APOE* E3 is the most common allele in the population and does not modify the risk of memory decline. The *APOE* E4 variant was shown to be overrepresented in dementia patients, especially those with AD [78]. So far, *APOE* E4 remains the most significant risk factor of sporadic AD and accounts for 30% of cases [79]. *APOE* E2 was shown to be associated with reduced age-dependent cognitive decline. This observation occurred independently of agerelated neuroinflammation and synaptic changes or the Aβ burden [80]. The described effect may be explained by a higher apoE level in *APOE* E2 carriers as well as by more efficient Aβ clearance [81]. Moreover, according to study [75], the effects of *APOE* E2 and E4 counteract, and in transgenic mice the introduction of the E2 allele decreased Aβ deposition, while the E4 allele increased the Aβ burden.

According to [82], the most significant *APOE* effect on the onset of dementia may be observed in patients over the age of 60 (*p* = 0.006). This was visible as an accelerated memory decline in *APOE* E4 carriers. However, other authors [83] reported that characteristic changes in MRI may be observed even in healthy infants carrying the *APOE* E4 allele. According to authors of [84], the *APOE* E4 allele is not only responsible for a decline in episodic memory with age in cognitively normal adults but may also induce impaired olfaction due to deterioration of medial temporal lobe. This is consistent with the neuroimaging data, suggesting that in nondemented *APOE* E4 carriers, mediotemporal atrophy occurs prior to clinical dementia onset.

It is also interesting that multiple studies have confirmed that the *TOMM40/APOE* locus is associated not only with the risk of dementia but also with longevity. The GWAS confirmed that the rs4420638 polymorphism on chromosome 19q13.32 was significantly related to living longer than >85 years (OR = 0.72, *p* = 3.40 × 10-36) [85]. Similarly, according to a recent study [86], with the use of more sophisticated integrative GWAS (iGWAS) method to couple data from 14 meta-analyses, the locus housing *APOE* and *TOMM40* remained significantly associated with longevity, even when the false discovery rate (FDR) was set at 10%, which indicates that the *APOE/TOMM40* locus holds the key for healthy senescence without a pathological memory decline.
