**4. Genes associated with age-dependent dementia**

Several genes are involved in age-dependent dementia. Most of them, such as *ABCA7, APOE, APOC1, BIN1, CASS4, CELF1, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA*-*DRB5*/*DBR1, IL1RAP, INPP5D, MEF2C, MS4A6A/MS4A4E, NME8, PCDH11X, PICALM, PLD3, PTK2B, TOMM40, TREM2, TRIP4, TRPC4AP, SLC24H4*-*RIN3, SORL1*, and *ZCWPW1*, are associated with AD, which is the most prevalent cause of dementia in elders [48]. AD affects 24 million people worldwide and accounts for 60–80% of dementia cases [49]. *APOE* cluster (*APOE, TOMM40*) and *CLU* gene of the genes mentioned above, as well as Aβ cascade genes (*APP, PSEN1, PSEN2*), have also been mentioned as linked to memory decline in cognitively normal adults.

### **4.1.** *APP, PSEN1***, and** *PSEN2*

Aβ is formed in a process called an amyloid cascade which involves the amyloid precursor protein (APP), encoded by the *APP* gene located on chromosome 21. APP is a transmembrane protein with high expression in developing human neurons. In normal conditions, APP is truncated by proteolytic enzymes such as α- and β-secretases. However, in individuals developing AD, APP is processed by an alternative pathway involving γ-secretase. This leads to the production of the 40–42 amino-acid Aβ peptide. The active subunits of γ-secretase presenilin 1 and/or 2 are encoded by genes *PSEN1* and *PSEN2*, respectively. So far, 230 clinically significant mutations have been described in *APP, PSEN1*, and *PSEN2* genes; however, these mutations are very rare and account for around 0.5% of dementia cases. Moreover, most of these mutations are considered to be associated with a familial form of AD. On the other hand, asymptomatic carriers of the mutations in Aβ cascade genes demonstrate significant changes in cognitive functions, advancing with age [48].

#### **4.2.** *TOMM40***, translocase of the outer mitochondrial membrane 40 homolog (TOM40)**

*TOMM40* is a gene encoding for translocase of the outer mitochondrial membrane 40 homolog (TOM40). The gene is located on chromosome 19 in a cluster with *APOE*. Both genes remain in linkage disequilibrium and are associated with dementia [50]. Most reports concerning the role of *TOMM40* in developing dementia have focused on a variable length poly-T sequence polymorphism (rs10524523) located in intron 6 [51–53]. The number of deoxythymidine residues in the rs10524523 polymorphism comprise the so-called "alleles" of the poly-T repeat as "short" (abbreviated here as S), "long" (L), or "very long" (VL). These remain in strong linkage with the *APOE* variants, as the *TOMM40* L allele is almost exclusively observed in the *APOE* E4 carriers, while *TOMM40* S and/or the VL variants are associated with *APOE* E3 [51– 53]. The poly-T variation in *TOMM40* was shown to be significantly associated with the age of onset of dementia [52]. Moreover, as shown in [51], the *TOMM40* poly-T variant may facilitate the estimation of dementia progression in AD patients, independently from the status of other dementia loci. They also implied that the genome-wide association studies (GWAS) signals recorded in the *APOE* locus may indeed arise from *TOMM40*.

It has been suggested that Aβ may exert intracellular toxicity mediated by TOM40, for example, by affecting the function of cellular power plants—the mitochondria. According to [50], the mechanism underlying TOM40's role in dementia involves its ability to uptake Aβ to the mitochondrion, as Aβ has been found to be co-localized with cristae proteins in the mitochon‐ dria. Subsequently, after absorption the intracellular Aβ would cause increased production of ROS, thus leading to DNA damage and premature neuronal death.

**4. Genes associated with age-dependent dementia**

significant changes in cognitive functions, advancing with age [48].

signals recorded in the *APOE* locus may indeed arise from *TOMM40*.

normal adults.

256 Update on Dementia

**4.1.** *APP, PSEN1***, and** *PSEN2*

Several genes are involved in age-dependent dementia. Most of them, such as *ABCA7, APOE, APOC1, BIN1, CASS4, CELF1, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA*-*DRB5*/*DBR1, IL1RAP, INPP5D, MEF2C, MS4A6A/MS4A4E, NME8, PCDH11X, PICALM, PLD3, PTK2B, TOMM40, TREM2, TRIP4, TRPC4AP, SLC24H4*-*RIN3, SORL1*, and *ZCWPW1*, are associated with AD, which is the most prevalent cause of dementia in elders [48]. AD affects 24 million people worldwide and accounts for 60–80% of dementia cases [49]. *APOE* cluster (*APOE, TOMM40*) and *CLU* gene of the genes mentioned above, as well as Aβ cascade genes (*APP, PSEN1, PSEN2*), have also been mentioned as linked to memory decline in cognitively

Aβ is formed in a process called an amyloid cascade which involves the amyloid precursor protein (APP), encoded by the *APP* gene located on chromosome 21. APP is a transmembrane protein with high expression in developing human neurons. In normal conditions, APP is truncated by proteolytic enzymes such as α- and β-secretases. However, in individuals developing AD, APP is processed by an alternative pathway involving γ-secretase. This leads to the production of the 40–42 amino-acid Aβ peptide. The active subunits of γ-secretase presenilin 1 and/or 2 are encoded by genes *PSEN1* and *PSEN2*, respectively. So far, 230 clinically significant mutations have been described in *APP, PSEN1*, and *PSEN2* genes; however, these mutations are very rare and account for around 0.5% of dementia cases. Moreover, most of these mutations are considered to be associated with a familial form of AD. On the other hand, asymptomatic carriers of the mutations in Aβ cascade genes demonstrate

**4.2.** *TOMM40***, translocase of the outer mitochondrial membrane 40 homolog (TOM40)**

*TOMM40* is a gene encoding for translocase of the outer mitochondrial membrane 40 homolog (TOM40). The gene is located on chromosome 19 in a cluster with *APOE*. Both genes remain in linkage disequilibrium and are associated with dementia [50]. Most reports concerning the role of *TOMM40* in developing dementia have focused on a variable length poly-T sequence polymorphism (rs10524523) located in intron 6 [51–53]. The number of deoxythymidine residues in the rs10524523 polymorphism comprise the so-called "alleles" of the poly-T repeat as "short" (abbreviated here as S), "long" (L), or "very long" (VL). These remain in strong linkage with the *APOE* variants, as the *TOMM40* L allele is almost exclusively observed in the *APOE* E4 carriers, while *TOMM40* S and/or the VL variants are associated with *APOE* E3 [51– 53]. The poly-T variation in *TOMM40* was shown to be significantly associated with the age of onset of dementia [52]. Moreover, as shown in [51], the *TOMM40* poly-T variant may facilitate the estimation of dementia progression in AD patients, independently from the status of other dementia loci. They also implied that the genome-wide association studies (GWAS) Several studies have shown that poly-T *TOMM40* variation may influence cognitive perform‐ ance in healthy elderly people. The authors of study [54] investigated a cohort of 1613 elderly volunteers whose cognitive decline was followed for a period of 14 years (range = 12–18 years). This study showed that the *TOMM40* S variant repressed the activity of luciferase assay. Correspondingly, expression of the S variant was half of that in the VL variant. Moreover, they observed that the S variant significantly reduced vocabulary ability, diminished age-depend‐ ent vocabulary decline, in subjects as compared to the VL variant carriers. Other authors [55] conducted longitudinal modeling of a cognitive aging study on a cohort of 639 subjects with no signs of dementia, aged 21 to 97 years with a known *TOMM40* and *APOE* status. The volunteers underwent neuropsychological testing every 2 years. This study [55] showed that the influence of *TOMM40* variation on memory decline was particularly visible in subjects before 60 years of age (*p* = 0.009), however only in *TOMM40* VL/VL carriers whose improve‐ ment after the test-retest was significantly less pronounced than in the S/S and S/VL carriers. Moreover, the authors performed a neuropsychological examination and testing using the human analog of the Morris water maze and brain MRI on 59 cognitively normal volunteers, stratified as S/S, S/VL, and VL/VL carriers. They found that the S/S group performed better on world-centered navigation (*p* ≤ 0.004) and world-centered delayed recall (*p* ≤ 0.014) but not on self-centered navigation tests. They also found that the *TOMM40* variants significantly influenced the brain structure. The S/S group had a thicker right entorhinal cortex (*p* ≤ 0.043) than the S/VL and VL/VL groups, whereas significant thinning of the left entorhinal cortex and the left posterior cingulate cortex was present only in the VL/VL group (*p* = 0.043 and *p* = 0.024, respectively) as compared to the S/S group [55]. In another interesting study [56], the authors stratified 117 healthy adults (medium age: 55 years) with the *APOE* E3/E3 genotype according to the *TOMM40* status into three groups, S/S, S/VL, and VL/VL, and performed memory tests and structural brain imaging. They found that the asymptomatic carriers of the *TOMM40* VL/ VL genotype performed worse on testing of episodic learning and had a smaller volume in the posterior cingulate as compared to the S/S and S/VL groups [56].

These studies suggest that the *TOMM40* role is not limited to decreasing age at the onset of dementia but may also influence the brain structure and hasten memory decline in cognitively normal, healthy individuals.
