Neurochemical Mechanisms in Disease P72 doc

The Genetics of Alzheimer’s Disease and Parkinson’s Disease Lynn M. Bekris, Chang-En Yu, Thomas D. Bird, and Debby Tsuang Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder. It is characterized by progressive loss of memory and other cognitive domains along with functional decline that can occur in the third to eighth decades. The early onset (<60 years old) familial forms of AD have an autosomal dominant inheritance linked to three causative genes: APP, PSEN1, and PSEN2. The most common sporadic form of AD occurs after the age of 60 and is associated with the APOE gene. The mechanistic contribution of these genes in AD pathogenesis has been studied extensively but is still unclear, suggesting that other AD associated genes remain to be elucidated. Parkinson’s disease (PD) i s the second most common neurodegenerative disorder. Idiopathic PD is the most frequent form of Parkinsonism, although rare forms of PD in which genetic factors dominate exist. Family studies have identified 13 causative genetic loci linked to PD of which 8 genes have been described: four autosomal dominant (SNCA, LRRK2, UCHL1, and HTRA2) and four autosomal recessive (PRKN, DJ1, PINK1, and ATP13A2). In addition, another gene has recently been described as a possible risk factor for PD (GBA). The function of these genes and their contribution to PD pathogenesis remains to be fully elucidated. Like AD, other genes that contribute to PD risk likely exist. The prevalence, incidence, clinical manifestations, and genetic components of these two neurodegenerative disorders, AD and PD, are discussed in this chapter. Keywords Alzheimer’s disease · Parkinson’s disease · Presenilin · Amyloid precursor protein · Apolipoprotein E · Synuclein · Parkin · LRRK2 · PINK1 · neurodegeneration Contents 1 Alzheimer’s Disease 696 1.1 Introduction 696 D. Tsuang (B) Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Mental Illness Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA e-mail: dwt1@u.washington.edu 695 J.P. Blass (ed.), Neurochemical Mechanisms in Disease, Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_21, C  Springer Science+Business Media, LLC 2011 696 L.M. Bekris et al. 1.2 Genetics of Alzheimer’s Disease 699 1.3 Summary 711 2 Parkinson’s Disease 711 2.1 Introduction 711 2.2 Genetics of Parkinson’s Disease 712 2.3 Summary 731 References 732 1 Alzheimer’s Disease 1.1 Introduction 1.1.1 Prevalence and Incidence Alzheimer’s disease (AD) (OMIM #104300) is the most common irreversible, progressive brain disease. It is characterized by a gradual loss of memory and cognitive skills. AD accounts for over 50% of all dementia cases, and presently affects more than 24 million people worldwide, with over 5 million new cases each year, a figure that is likely to increase as a greater proportion of the population ages (Ferri et al., 2005). Age is the largest known risk factor, with AD prevalence increasing significantly with age. AD incidence increases from 2.8 per 1000 person-years when 65–69 years and to 56.1 per 1000 person-years when older than 90 years (Kukull et al., 2002). Approximately 10% of persons older than 70 years have significant memory loss and more than half of these individuals have probable AD. An estimated 25–45% of persons older than 85 years have dementia (Bird, 2008). The duration of disease is typically 8–10 years, with a range from 2 to 25 years after diagnosis. The disease is divided into two subtypes based on the age of onset: early-onset AD (EOAD) and late-onset AD (LOAD). EOAD accounts for approximately 1–6% of all cases and ranges roughly from 30 years to 60 or 65 years. On the other hand, the most common form of AD, LOAD, is defined as an age-at-onset later t han 60 or 65 years. Both EOAD and LOAD may have a positive family history of AD. With the exception of a few autosomal dominant families that are single-gene disorders (see below), most AD appears to be a complex disorder that is likely to involve multiple susceptibility genes and environmental factors (Bertram and Tanzi, 2004b;Bird,2008; Kamboh, 2004; Roses, 2006; Serretti et al., 2005). Approximately 60% of EOAD is familial, with multiple cases of AD within a family. Thirteen percent of these familial cases are inherited in an autosomal dominant manner with at least three generations affected (Brickell et al., 2006; Campion et al., 1999). Early-onset cases can also occur in families with late-onset disease (Bird, 2008). 1.1.2 Clinical Symptoms Both EOAD and LOAD present clinically as dementia that begins with a gradual decline of memory which slowly increases in severity until symptoms eventually Genetics of AD and PD 697 become incapacitating. Other common symptoms are confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Rare symptoms include seizures, Parkinsonism, increased muscle tone, myoclonus, incontinence, and mutism. Death commonly occurs from general inanition, malnutrition, and pneumonia (Bird, 2008). Treatment of AD with cholinesterase inhibitors and memantine may have some improvement in cognitive decline in mild to moder- ate dementia cases but overall there is clinically marginal improvement in measures of cognition and global assessment of dementia (Raina et al., 2008; Raschetti et al., 2007). 1.1.3 Clinical Diagnosis Currently, the diagnosis of AD is based on clinical history and neuropsycho- logical tests. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for diagnosing dementia requires loss of two or more of the following: memory, language, calculation, orientation, or judgment (Kawas, 2003). The Mini-Mental State Examination (MMSE) helps to evaluate changes in a patient’s cognitive abilities. In addition, a diagnosis of probable AD necessitates the exclusion of other degenerative disorders associated with dementia, such as frontotemporal dementia (including frontotemporal dementia with Parkinsonism-17 and Pick’s disease), Parkinson’s disease, diffuse Lewy body disease, Creutzfeldt–Jakob disease, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Rogan and Lippa, 2002). Discrimination f rom other forms of dementia is usually based on clinical history and neuroimaging (Bird, 2008). In addition, other possible causes of dementia also need to be excluded, especially the treatable forms of cognitive impairment, such as that due to depres- sion, chronic drug intoxication, chronic central nervous system infection, thyroid disease, vitamin deficiencies (i.e., B 12 and thiamine), central nervous system angi- tis, and normal-pressure hydrocephalus (Bird, 2008). Individuals who do not meet these criteria but have short-term memory loss and have only minimal impairment in other cognitive abilities and are not functionally impaired at work or at home are considered to have “mild cognitive impairment” (Petersen et al., 2001). 1.1.4 Neuropathological Diagnosis A definitive diagnosis of AD requires not only the presence of severe dementia in life but also postmortem confirmation, with the presence of two histopathologi- cal features: neurofibrillary tangles and amyloid plaques (Braak and Braak, 1997; Goedert and Spillantini, 2006; Nussbaum and Ellis, 2003). The clinical diagnosis of AD, before autopsy confirmation, is correct about 80–90% of the time by expert clinicians (Kaye, 1998). Even though plaques and tangles are often also found in cognitively normal age-matched controls, the density and distribution are more severe in patients with AD, according to standardized histological assessments (Braak and Braak, 1997). Amyloid plaques are extracellular with a cross-beta structure and characteristic dye-binding (neuritic amyloid plaques contain thioflavin S and Congo red-positive fibrillar deposits with both Aβ40 and Aβ42 present; Kidd, 698 L.M. Bekris et al. Fig. 1 APP cleavage. The APP protein can be cleaved by three different secretases: α, β,orγ (panel a). Subsequent to “normal” α-secretase cleavage, sAPP α is produced and released into the extracellular space and the C83 peptide remains in the cell membrane (panel b). Subsequent to β- secretase cleavage, sAPPβ is produced and released into the extracellular space and the C99 peptide remains in the cell membrane (panel c). Subsequent to β-secretase cleavage, the C99 peptide is “abnormally” cleaved by γ-secretase to yield an Aβ peptide and the AICD peptide (panel d). Scale is approximate 1963; Terry et al., 1964). The major component of amyloid plaques is amyloid-beta (Aβ), which can be stained and detected using Aβ antibodies (Glenner et al., 1984; Iwatsubo et al., 1994). The most common form of Aβ is 40 amino acids long and is called Aβ40. A 42 amino acid long fragment, Aβ42, is less abundant and differs only by having two additional amino acid residues at the C-terminus. Aβ42 is associated with AD (Bentahir et al., 2006). Aβ is derived from the amyloid precursor protein (APP) by the action of two aspartyl proteases. First α-secretase (nonneuro- toxic “normal” cleavage) or β-secretase (potential neurotoxic “abnormal” cleavage) cleaves APP (Fig. 1). Second γ-secretases cleave APP (Haass et al., 1992; Seubert et al., 1992; Shoji et al., 1992). Upon cleavage by α-secretase, a large ectodomain referred t o as soluble APP alpha (sAPPα) is released and a C-terminal 83 amino acid f ragment (C83) remains membrane bound. Upon cleavage by β-secretase, APP sheds a large ectodomain referred to as soluble APP beta (sAPPβ) and leaves a membrane-bound C-terminal fragment (Cai et al., 2001; Vassar et al., 1999). This 99 amino acid fragment (C99) is membrane bound and is subsequently cleaved by γ-secretase to release Aβ and the APP intracellular domain (AICD) (De Strooper, 2000; Schroeter et al., 2003) (Fig. 1). Thus two main forms of Aβ are produced Genetics of AD and PD 699 depending on the point of cleavage by γ-secretase; producing either 40 or 42 amino acid residues. The proportion of Aβ42 to Aβ40 formed is particularly important in AD because Aβ42 is far more prone to oligomerize and form fibrils than the more abundantly produced Aβ40 peptide. In a small number of individuals an increased proportion of Aβ42 appears sufficient to cause EOAD even though it appears that the production of Aβ isoforms is a normal process of unknown function (Goedert and Spillantini, 2006; Irvine et al., 2008). Neurons bearing neurofibrillary tangles containing hyperphosphorylated tau are frequently found in AD brain (Kosik et al., 1986; Wood et al., 1986), and their tem- poral and spatial appearance more closely reflects disease severity than does the presence of amyloid plaques (Braak and Braak, 1991; Thal et al., 2006). However, neurofibrillary tangles are not specific to AD, are found in other disorders (such as frontotemporal dementia and progressive supranuclear palsy), and are not neces- sarily associated with the cognitive dysfunction and memory impairment typical of AD, and mutations in the gene that encodes the tau protein (MAPT) have not been genetically linked to AD (Iwatsubo et al., 1994). 1.2 Genetics of Alzheimer’s Disease 1.2.1 Introduction To date autosomal dominant early-onset familial AD (EOFAD) is associated with three genes: the APP gene, the presenilin 1 gene (PSEN1), and the presenilin 2 gene (PSEN2) (Goedert and Spillantini, 2006). However, it is likely that other genes will be identified as a cause of EOFAD because there are still kindreds with autosomal- dominant EOFAD with no known mutations in these three genes (Bird, 2008;Cruts and Van Broeckhoven, 1998; Raux et al., 2005). Despite evidence from family studies that genetic mutations cause EOFAD, more than 90% of AD cases appear to be sporadic, without a family history, and have a later age-at-onset of 60–65 years (Bertram and Tanzi, 2004a). The only gene consistently found to be associated with sporadic LOAD, across multiple studies, is the apolipoprotein E gene (APOE) (Coon et al., 2007; Couzin, 2008; Roses et al., 1995; Schellenberg, 1995; Selkoe, 2001) (Table 1). Although twin studies support the existence of a genetic component in LOAD, no causative gene has been yet identified. The age-at-onset of LOAD is significantly more variable for dizygotic twins than for monozygotic twins, suggesting that both genetic and environmental factors play a role in the disease (Gatz et al., 2006). The APOE gene is the only well-validated gene strongly associated with LOAD risk (Coon et al., 2007; Couzin, 2008; Roses et al., 1995; Schellenberg, 1995; Selkoe, 2001). However, many carriers of the APOE risk allele (4) live into their 90s, suggesting the existence of other LOAD genetic and/or environmental risk factors yet to be identified. Several other genetic variants have been reported and suggest that there may be five to seven major LOAD susceptibility genes, but most are without replication among studies (Bird, 2008; Chai, 2007; Daw et al., 2000). For a catalogue of candidate gene association studies, please refer to the AlzGene online database (http://www.alzforum.org/res/com/gen/alzgene/default.asp). 700 L.M. Bekris et al. Table 1 Alzheimer’s disease and Parkinson’s disease genes. Alzheimer’s disease genes; AD1–4 (panel A) and Parkinson’s disease genes; PARK1–13 (panel B) 1.2.2 Genes Associated with Autosomal Dominant Alzheimer’s Disease AD1: App Inheritance and Clinical Features The purification of both plaque and vascular amyloid deposits and the isolation of their 40-residue constituent peptide (Aβ) led to the cloning of the APP type I integral membrane glycoprotein from which Aβ is proteolytically derived (Kang et al., 1987). The APP gene was mapped to chromosome 21q which accounts for the observation that Down syndrome patients (trisomy 21) develop amyloid deposits and the neuropathological features of AD in their 40 s (Giaccone et al., 1989; Iwatsubo et al., 1994; Lemere et al., 1996; Mann et al., 1989). Subsequent searches for autosomal dominant EOAD families with genetic linkage to chromosome 21 resulted in the identification of six different missense mutations in APP, five associated with familial AD (Chartier-Harlin et al., 1991a, b;Goateetal.,1991; Mullan, 1992; Murrell et al., 1991), and one with the neuropathologically related syndrome of hereditary cerebral hemorrhage with amyloidosis of the Dutch type (Levy et al., 1990). Subsequently, over 20 different APP missense mutations have been identified in 60 families. Interestingly, most of these mutations are located at exons 16 and 17 where the secretase cleavage sites or the APP transmembrane domain are located (Fig. 2). Information regarding APP mutations is available in the NCBI database and the Alzheimer Disease Mutation Database (www.molgen.ua.ac.be/ ADMutations) (Cruts and Van Broeckhoven, 1998). Mutations within APP account for 10–15% of EOFAD (Bird, 2008; Janssen et al., 2003; Raux et al., 2005; Sherrington et al., 1996), appear to be family specific, and do not occur within the Genetics of AD and PD 701 Fig. 2 AD1: APP structure and mutations. SP, signal peptide; KPI, Kunitz protease inhibitor domain; Aβ, amyloid beta; TM, transmembrane domain. Scale is approximate majority of sporadic AD cases. The majority of these EOFAD mutations are located in or adjacent to the Aβ peptide sequence (Fig. 2), the major component of the amyloid plaques (Esler and Wolfe, 2001; Suzuki et al., 1994). Most cases containing APP mutations have an age of onset in the mid-40 s and 50 s ( Hardy, 2001). Gene Location and Structure Sequences encoding APP were first cloned by screening cDNA libraries (Kang et al., 1987). The i nitial full-length cDNA clone encoded a 695 amino acid protein (APP695) (Schellenberg, 1995) and consisted of 18 exons. The APP gene, located at chromosome 21q21, is alternatively spliced into several products, named according to their length in amino acids (i.e., APP695, APP714, APP751, APP770, and APP563) and expressed differentially by tissue type whereby three isoforms, most relevant to AD, are restricted to the central nervous system (APP695) or expressed in both the peripheral and CNS tissues (APP751 and APP770) (de Sauvage and Octave, 1989; Golde et al., 1990; Goldgaber et al., 1987; Kang et al., 1987; Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988; Yoshikai et al., 1990). Gene Function and Expression APP is a type I integral membrane protein (Kang et al., 1987) that resembles a signal-transduction receptor. It is expressed in many tissues and concentrated in the 702 L.M. Bekris et al. synapses of neurons. Its primary function is not known, although it has been implicated in neural plasticity (Turner et al., 2003) and as a regulator of synapse formation (Priller et al., 2006). APP is synthesized in the ER, posttranscriptionally modified in the Golgi (N- and O-linked glycosylation, sulfation, and phosphorylation), and transported to the cell surface via the secretory pathway. APP is also endocytosed from the cell surface and processed in the endosomal–lysosomal pathway (Bossy- Wetzel et al., 2004; Koo and Squazzo, 1994). APP and Aβ have been found to be translocated inside mitochondria and implicated in mitochondrial dysfunction (Anandatheerthavarada et al., 2003; Devi et al., 2006; Lin and Beal, 2006). Proteolysis of APP by α-secretase or β-secretase leads to the secretion of sAPPα or sAPPβ. This proteolysis generates C-terminal fragments of 10 kDa and 12 kDa, respectively, which are inserted into the membrane. These fragments can be cut by γ-secretase to release the Aβ peptide extracellularly (Walter et al., 2001) and a cytoplasmic fragment identified as AICD intracellularly (Sastre et al., 2001) (Fig. 1). Intriguingly, AICD starts at position 49/50 and does not correspond to the end of Aβ variants Aβ40 and Aβ42. Therefore this cleavage site has been termed the - cleavage site, and interestingly, it is topologically highly similar to the S3 cleavage of Notch (Sastre et al., 2001; Weidemann et al., 2002). Recently, a new cleavage site was described for γ-secretase. The ξ-cleavage occurs between the - and γ-cleavage sites and generates longer Aβ isoforms within cells and in the brain, including Aβ43, Aβ45, Aβ46, and Aβ48 (Qi-Takahara et al., 2005; Zhao et al., 2004). The majority of EOAD mutations alter this processing of APP in such a way that Aβ 42 levels relative to other Aβ isoforms are changed (Scheuner et al., 1996; Walker et al., 2005). The function of these APP proteolytic fragments is still unclear. The missense APP “Swedish” mutations (APPSW, APPK670N, and M671L) and the “London” mutations (APPLON and APPV717I) are examples of APP mutations that lead to increased Aβ production and development of AD (Goate et al., 1991; Mullan, 1992). Transgenic mouse models of APP mutations have been devel- oped such as: PDAPP, Tg2576, APP23, TgCRND8, and J20 ( Higgins and Jacobsen, 2003). Each of these transgenic mouse models has different mutations and different promoters that lead to different expression levels and different levels of neuroanatomical abnormalities (Higgins and Jacobsen, 2003; Mineur et al., 2005). For example, the Tg2576 mouse model that carries the “Swedish” mutation has high APP levels, high Aβ levels, and cognitive disturbances (Irizarry et al., 1997) that are progressive and start as early as six months of age (Westerman et al., 2002). Genetic Variation APP transcripts have been identified in which exons 7, 8, and 15 are alternatively spliced. Exon 7 encodes 57 amino acids with homology to the Kunitz-type protease inhibitor (KPI) domain (Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988) and exon 8 (Kitaguchi et al., 1988; Lemaire et al., 1989). The Aβ peptide is encoded by parts of both exons 16 and 17 (exon and codon numbering based on the APP770 splice variant) (Lemaire et al., 1989) (Fig. 2). In neurons, t he predominant isoform is APP695 (Weidemann et al., 1989), which contains exon 15 but excludes exons Genetics of AD and PD 703 7 and 8. The major isoforms in peripheral tissue (APP751 and APP770), and also in neurons, encode KPI-containing forms of APP (Kitaguchi et al., 1988; Ponte et al., 1988; Sandbrink et al., 1994; Tanzi et al., 1988). Other splice variants have been observed that are missing exon 15 in various combinations with exons 7 and 8 and are referred to as L-APPs (Konig et al., 1991; Sandbrink et al., 1994). A number of studies have indicated that alternative splicing of exons 7 and 8 in APP mRNAs is changed in the brain during aging and possibly during AD (Johnson et al., 1989; Konig et al., 1991; Neve et al., 1988; Palmert et al., 1988; Sisodia et al., 1990; Tanaka et al., 1988). Even though the function of APP and its various splice variants is unknown, differential expression of these splice variants between tissues may imply functional differences. It is important to note that although most of the described splice variants contain Aβ-encoding sequences, two additional rare transcripts, APP365 and APP563, do not, implicating additional variability in APP function (de Sauvage and Octave, 1989; Jacobsen et al., 1991). The first described and best characterized APP mutation (V717I) was identified in a London family and is located within the transmembrane domain near the γ-secretase cleavage site (Goate et al., 1991) (Fig. 2). Subsequently, other substi- tutions at this site have been identified and many other groups have reported the V717I mutation in other families. Many other mutations have been identified, most of which are located near the gamma-secretase cleavage site and have been associated with modulation of Aβ levels. For example, a C-terminal L723P mutation was identified in an Australian family and is reported to generate an increase of Aβ42 peptide levels in CHO cells (Kwok et al., 2000). The majority of EOAD mutations alter processing of APP in such a way that the relative level of Aβ42 is increased, either by increasing Aβ42 or decreasing Aβ40 peptide l evels or both (Scheuner et al., 1996; Walker et al., 2005). AD3: Presenilin 1 Inheritance and Clinical Features Linkage studies established the presence of an AD3 locus on chromosome 14 (Schellenberg et al., 1992) and positional cloning led to the identification of mutations in the PSEN1 gene, which encodes a polytopic membrane protein (Sherrington et al., 1995). Presenilins are major components of the atypical aspartyl protease complexes responsible for the γ-secretase cleavage of APP (De Strooper et al., 1998; Wolfe et al., 1999b). Mutations in PSEN1 are the most common cause of EOFAD. PSEN1 missense mutations account for 18–50% of the autosomal dominant EOFAD (Theuns et al., 2000). PSEN1 mutations appear to increase the ratio of Aβ42 to Aβ40, and this appears to result in a change in function that leads to reduced γ-secretase activity (Citron et al., 1997). In preclinical cases with PSEN1 mutations, deposition of Aβ42 may be an early event (Lippa et al., 1998). Defects in PSEN1 cause the most severe forms of AD, with complete pen- etrance and an onset occurring as early as 30 years of age. A second form of PSEN1-associated AD has a mean age of onset greater than 58 years. Both are autosomal dominant neurodegenerative disorders characterized by progressive 704 L.M. Bekris et al. dementia, Parkinsonism, and notch signaling, as well as Aβ intracellular domain generation (Goedert and Spillantini, 2006;Wolfe,2007). There is considerable phe- notypic variability in EOFAD, including some patients with spastic paraparesis and other atypical AD symptoms. Some of these variable clinical phenotypes have been described by specific mutations. Neuropathological studies often confirm the clinical diagnosis of AD with measurement of amyloid plaque and Braak stage (as described above) but vary in other brain areas according to the presence of specific PSEN1 mutations (Moehlmann et al., 2002; Rudzinski et al., 2008). For example, clinical and neuropathologic features of a Greek family with a PSEN1 mutation (N135S) include memory loss in their 30 s, as well as variable limb spasticity and seizures. Upon neuropathological examination, the diagnosis of AD was confirmed but in addition, there was histological evidence of corticospinal tract degeneration (Rudzinski et al., 2008). A PSEN1 mutation (I143M) that lies in a cluster in the second transmembrane domain of the protein has been described in an African family with an age-at-onset in the early 50 s that lasts for 6–7 years. Neuropathologically, these cases were characterized by neuronal loss, abundant Aβ neuritic plaques, and neurofibrillary tangles as well as degeneration extending into the brainstem (Heckmann et al., 2004). Gene Location and Structure PSEN1 is located on chromosome 14q24.2 and consists of 12 exons that encode a 467 amino acid protein that is predicted to traverse the membrane 6–10 times; the amino and carboxyl termini are both oriented toward the cytoplasm (Hutton and Hardy, 1997). Gene Function and Expression PSEN1 is a polytopic membrane protein that forms the catalytic core of the gamma- secretase complex (De Strooper et al., 1998; Wolfe et al., 1999a). Gamma-secretase is an integral membrane protein found at the cell surface, but it may also be found in the Golgi, endoplasmic reticulum, and mitochondria (Baulac et al., 2003;De Strooper et al., 1998). PSEN1, nicastrin (Nct), anterior pharynx defective 1 (Aph- 1), and presenilin enhancer 2 (PSENEN) are required for the stability and activity of the γ-secretase complex (Edbauer et al., 2003; Francis et al., 2002; Goutte et al., 2002; Kimberly et al., 2003; Takasugi et al., 2003). This complex cleaves many type I transmembrane proteins including APP and Notch (De Strooper et al., 1999, 1998) in the hydrophobic environment of the phospholipid bilayer of the membrane (Kimberly et al., 2003). Gamma-secretase is biologically and biochemically hetero- geneous, consisting of four and potentially more different complexes that result from the mutually exclusive incorporation of PSEN1, PSEN2, and PSENEN or Aph-1-A and Aph-1-B protein subunits (Kimberly et al., 2003; Serneels et al., 2005). PSEN1 knock-out mice are not viable (Shen et al., 1997) but a conditional PSEN1 knock-out mouse model, where the loss of the gene is limited to the postnatal forebrain, shows mild cognitive impairments in long-term spatial reference memory and retention (Yu et al., 2001 ), suggesting that presenilins play a role in cognitive memory. Knock-in . PD, are discussed in this chapter. Keywords Alzheimer’s disease · Parkinson’s disease · Presenilin · Amyloid precursor protein · Apolipoprotein E · Synuclein · Parkin · LRRK2 · PINK1 · neurodegeneration Contents 1. with cholinesterase inhibitors and memantine may have some improvement in cognitive decline in mild to moder- ate dementia cases but overall there is clinically marginal improvement in measures of. dementia (including frontotemporal dementia with Parkinsonism-17 and Pick’s disease) , Parkinson’s disease, diffuse Lewy body disease, Creutzfeldt–Jakob disease, and cerebral autosomal dominant arteriopathy

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