ALZHEIMER DISEASE, PROTECTION AGAINST, INCLUDED
PRESENILE AND SENILE DEMENTIA ALZHEIMER DISEASE, FAMILIAL, 1, INCLUDED
ALZHEIMER DISEASE, EARLY-ONSET, WITH CEREBRAL AMYLOID ANGIOPATHY, INCLUDED
AD1, INCLUDED
AD
Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions ... Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT). Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the transcriptional regulation of the genes involved in Alzheimer disease. - Genetic Heterogeneity of Alzheimer Disease Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (104310), associated with the APOE*4 allele (107741) on chromosome 19; AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1; 104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene (600759) on 1q31. There is evidence for additional AD loci on other chromosomes; see AD5 (602096) on 12p11, AD6 (605526) on 10q24, AD7 (606187) on 10p13, AD8 (607116) on 20p, AD9 (608907) on 19p13, AD10 (609636) on 7q36, AD11 (609790) on 9q22, AD12 (611073) on 8p12-q22, AD13 (611152) on 1q21, AD14 (611154) on 1q25, AD15 (611155) on 3q22-q24, AD16 (300756) on Xq21.3, AD17 (615080) on 6p21.2, and AD18 (615590), associated with variation in the ADAM10 gene (602192) on 15q21. Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (502500). Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; 103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770), the transferrin gene (TF; 190000), the hemochromatosis gene (HFE; 613609), the NOS3 gene (163729), the vascular endothelial growth factor gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160) (see MOLECULAR GENETICS).
Alzheimer (1907) provided the first report of the disease (see HISTORY).
Schottky (1932) described a familial form of presenile dementia in 4 generations. The diagnosis was confirmed at autopsy in a patient in the fourth generation. ... Alzheimer (1907) provided the first report of the disease (see HISTORY). Schottky (1932) described a familial form of presenile dementia in 4 generations. The diagnosis was confirmed at autopsy in a patient in the fourth generation. Lowenberg and Waggoner (1934) reported a family with unusually early onset of dementia in the father and 4 of 5 children. Postmortem findings in 1 case were consistent with dementia of the Alzheimer type. McMenemey et al. (1939) described 4 affected males in 2 generations with pathologic confirmation in one. Heston et al. (1966) described a family with 19 affected in 4 generations. Dementia was coupled with conspicuous parkinsonism and long tract signs. Rice et al. (1980) and Ball (1980) reported a kindred in which members had clinical features of familial AD. Two patients had neuropathologic changes of spongiform encephalopathy of the Creutzfeldt-Jakob type (CJD; 123400) at autopsy, but the long clinical course was unusual for CJD. Corkin et al. (1983) found no difference in parental age of patients with AD compared to controls. Nee et al. (1983) reported an extensively affected kindred, with 51 affected persons in 8 generations. There was no increased incidence of Down syndrome (190685) or hematologic malignancy. Heyman et al. (1983) found dementia in first-degree relatives of 17 (25%) of 68 probands with AD. These families also demonstrated an increase in the frequency of Down syndrome (3.6 per 1,000 as compared with an expected rate of 1.3 per 1,000). No excess of hematologic malignancy was found in relatives. In a study of the families of 188 Down syndrome children and 185 controls, Berr et al. (1989) found no evidence of an excess of dementia cases suggestive of AD in the families of patients with Down syndrome. In a large multicenter study of first-degree relatives of 118 AD probands and nondemented spouse controls, Silverman et al. (1994) found no association between familial AD and Down syndrome. Stokin et al. (2005) identified axonal defects in mouse models of Alzheimer disease that preceded known disease-related pathology by more than a year; the authors observed similar axonal defects in the early stages of Alzheimer disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Stokin et al. (2005) suggested that reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein (104760), resulting in the development of senile plaques and Alzheimer disease. Bateman et al. (2012) performed a prospective, longitudinal study analyzing data from 128 subjects at risk for carrying a mutation for autosomal dominant AD. Subjects underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid and blood tests. Bateman et al. (2012) used the participant's age at baseline assessment and the parent's age at the onset of symptoms of AD to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). They then conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiologic changes. Concentrations of amyloid-beta-42 in the CSF appeared to decline 25 years before expected symptom onset. Amyloid-beta deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. Bateman et al. (2012) cautioned that their results required confirmation with use of longitudinal data and may not apply to patients with sporadic Alzheimer disease. - Familial Alzheimer Disease 1 Karlinsky et al. (1992) reported a family from Toronto with autosomal dominant inheritance of Alzheimer disease. The disorder was characterized by early onset of memory deficits, decreased speed of cognitive processing, and impaired attention to complex cognitive sets. The family immigrated to Canada from the British Isles in the 18th century. Genetic analysis identified a mutation in the APP gene (V717I; 104760.0002). Farlow et al. (1994) reviewed the clinical characteristics of the disorder in the AD family reported by Murrell et al. (1991) in which affected members had a mutation in the APP gene (V717F; 104760.0003). The mean age of onset of dementia was 43 years. The earliest cognitive functions affected were recent memory, information-processing speed, sequential tracking, and conceptual reasoning. Language and visuoperceptual skills were largely spared early in the course of the disease. Later, there were progressive cognitive deficits and inability to perform the activities of daily living. Death occurred, on average, 6 years after onset. The family was Romanian, many of its members having migrated to Indiana. Rossi et al. (2004) reported a family in which at least 6 members spanning 3 generations had Alzheimer disease and strokes associated with a heterozygous mutation in the APP gene (A713T; 104760.0009). At age 52 years, the proband developed progressive cognitive decline with memory loss and visuospatial troubles, as well as stroke-like episodes characterized by monoparesis and language disturbances detectable for a few days. MRI showed T2-weighted signal hyperintensities in subcortical and periventricular white matter without bleeding. Neuropathologic examination showed neurofibrillary tangles and A-beta-40- and A-beta-42-immunoreactive deposits in the neuropil. The vessel walls showed only A-beta-40 deposits, consistent with amyloid angiopathy. There were also multiple white matter infarcts along the long penetrating arteries. Other affected family members had a similar clinical picture. Several unaffected family members carried the mutation, and all but 1 were under 65 years of age. Edwards-Lee et al. (2005) reported an African American family in which multiple members spanning 3 generations had early-onset AD. The distinctive clinical features in this family were a rapidly progressive dementia starting in the fourth decade, seizures, myoclonus, parkinsonism, and spasticity. Variable features included aggressiveness, visual disturbances, and pathologic laughter. Two sibs who were tested were heterozygous for a mutation in the APP gene (T714I; 104760.0015). - Early-Onset Alzheimer Disease with Cerebral Amyloid Angiopathy Because Alzheimer disease associated with cerebral amyloid angiopathy (CAA) is also found in Down syndrome, Rovelet-Lecrux et al. (2006) reasoned that the APP locus located on chromosome 21q21 might be affected by gene dosage alterations in a subset of demented individuals. To test this hypothesis, they analyzed APP using quantitative multiplex PCR of short fluorescent fragments, a sensitive method for detecting duplications that is based on the simultaneous amplification of multiple short genomic sequences using dye-labeled primers under quantitative conditions. This analysis was performed in 12 unrelated individuals with autosomal dominant early-onset Alzheimer disease (ADEOAD) in whom a previous mutation screen of PSEN1 (104311), PSEN2 (600759), and APP had been negative; 5 of these individuals belonged to Alzheimer disease-affected families in which the cooccurrence of CAA had been diagnosed according to neuropathologic (Vonsattel et al., 1991) or clinical criteria (intracerebral hemorrhages (ICH) in at least 1 affected individual). In the 5 index cases with the combination of early-onset Alzheimer disease and CAA, they found evidence for a duplication of the APP locus (104760.0020). In the corresponding families, the APP locus duplication was present in affected subjects but not in healthy subjects over the age of 60 years. The phenotypes of the affected subjects in the 5 families were similar. None had mental retardation before the onset of dementia. None had clinical features suggestive of Down syndrome. The most common clinical manifestation was progressive dementia of Alzheimer disease type (mean age of onset 52 +/- 4.4 years) associated, in some cases, with lobar ICH. Neuropathologic examination of the brains of 5 individuals from 3 kindreds showed abundant amyloid deposits, present both as dense-cored plaques and as diffuse deposits, in all regions analyzed. Neurofibrillary tangles were noted in a distribution consistent with the diagnosis of definite Alzheimer disease. However, the most prominent feature was severe CAA. Rovelet-Lecrux et al. (2006) estimated that in their whole cohort of 65 ADEOAD families, the frequency of the APP locus duplication was roughly 8% (5 of 65), which corresponds to half of the contribution of APP missense mutations to ADEOAD.
In affected members of 2 families with AD1, Goate et al. (1991) identified a mutation in the APP gene (V717I; 104760.0002). The average age of onset in 1 family was 57 ... - Familial Alzheimer Disease 1 In affected members of 2 families with AD1, Goate et al. (1991) identified a mutation in the APP gene (V717I; 104760.0002). The average age of onset in 1 family was 57 +/- 5 years. The same mutation was found by Naruse et al. (1991) in 2 unrelated Japanese cases of familial early-onset AD, and Yoshioka et al. (1991) found it in a third Japanese family with AD. In affected members of 2 large Swedish families with early-onset familial Alzheimer disease, Mullan et al. (1992) identified a double mutation in exon 16 of the APP gene (104760.0008). The 2 families were found to be linked by genealogy. - Protection Against Alzheimer Disease Jonsson et al. (2012) searched for low-frequency variants in the amyloid-beta precursor protein gene with a significant effect on the risk of Alzheimer disease by studying coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. Jonsson et al. (2012) found a coding mutation (A673T; 104760.0023) in the APP gene that protects against Alzheimer disease and cognitive decline in the elderly without Alzheimer disease. This substitution is adjacent to the aspartyl protease beta-site in APP, and resulted in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer disease provided proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer disease, Jonsson et al. (2012) hypothesized that the 2 may be mediated through the same or similar mechanisms. - Modifier Genes It is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (see AD2; 104310); however, estimates of the total contribution of apoE to the variance in onset of AD vary widely. In an oligogenic segregation analysis of 75 families ascertained through members with late-onset AD, Daw et al. (2000) estimated the number of additional quantitative trait loci (QTLs) and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex. They found evidence that 4 additional loci make a contribution to the variance in age at onset of late-onset AD similar to or greater in magnitude than that made by apoE, with 1 locus making a contribution several times greater than that of apoE. They confirmed the previous findings of a dosage effect for the apoE epsilon-4 allele, a protective effect for the epsilon-2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Although Daw et al. (2000) estimated that the apoE genotype can make a difference of as many as 17 years in age at onset of AD, their estimate of the contribution of apoE (7 to 9%) to total variance in onset of AD was somewhat smaller than that previously reported. Their results suggested that several genes not yet localized to that time may play a larger role than does apoE in late-onset AD. Li et al. (2002) performed a genome screen to identify genes influencing age at onset in 449 families with Alzheimer disease and 174 families with Parkinson disease. Heritabilities between 40% and 60% for age at onset were found in both the AD and the PD data sets. For PD, significant evidence for linkage to age at onset was found on 1p (lod = 3.41); see 606852. For AD, the age at onset effect of APOE (lod = 3.28) was confirmed. In addition, evidence for age at onset linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on 10q between D10S1239 and D10S1237, with a maximum lod score of 2.62. These data suggested that a common gene affects age at onset in these 2 common complex neurodegenerative diseases. Li et al. (2003) combined gene expression studies on hippocampus obtained from AD patients and controls with their previously reported linkage data to identify 4 candidate genes on chromosome 10q. Allelic association studies for age-at-onset effects in 1,773 AD patients and 1,041 relatives and 635 PD patients and 727 relatives further limited association to GSTO1 (605482) (p = 0.007) and a second transcribed member of the GST omega class, GSTO2 (612314) (p = 0.005), located next to GSTO1. The authors suggested that GSTO1 may be involved in the posttranslational modification of IL1B (147720). Zareparsi et al. (2002) noted that several studies had found an increased frequency of the HLA-A2 (142800) allele in patients with early-onset AD and that others had found an association between the A2 allele and an earlier age of onset of AD. Among 458 unrelated patients with AD, Zareparsi et al. (2002) found that HLA-A2 homozygotes had onset of AD 5 years earlier, on average, than either A2 heterozygotes or those without A2, reflecting a gene dosage effect. The risk associated with the A2 homozygous genotype was 2.6 times greater in patients with early-onset AD (less than age 60 years) than in those with late-onset AD. These effects were present regardless of gender, familial or sporadic nature of the disease, or presence or absence of the APOE4 allele. The authors suggested that the A2 allele may have a role in regulating an immune response in the pathogenesis of AD or that there may be a responsible gene in close linkage to A2. The APBB2 gene (602710) encodes a protein that is capable of binding to APP. In a genetic association study of 3 independently collected case-control series totaling approximately 2,000 samples, Li et al. (2005) found that a SNP in the APBB2 gene, located in a region conserved between the human and mouse genomes, showed a significant interaction with age of disease onset. For this marker, Li et al. (2005) reported that the association of late-onset Alzheimer disease was most pronounced in subjects with disease onset before 75 years of age; odds ratio for homozygotes = 2.43 and for heterozygotes = 2.15. Go et al. (2005) performed linkage analysis on an NIMH Alzheimer disease sample and demonstrated a specific linkage peak for AD with psychosis on chromosome 8p12, which encompasses the NRG1 gene (142445). The authors also demonstrated a significant association between an NRG1 SNP (dbSNP rs3924999) and AD with psychosis (chi-square = 7.0; P = 0.008). This SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with the phenotype. Go et al. (2005) suggested that NRG1 plays a role in increasing the genetic risk for positive symptoms of psychosis in a proportion of late-onset AD families. Sweet et al. (2005) conducted a study to determine if genetic variation in the COMT gene (116790) was associated with a risk of psychosis in Alzheimer disease. The study included a case-control sample of 373 individuals diagnosed with AD with or without psychosis. Subjects were characterized for alleles at 3 COMT loci previously associated with schizophrenia (dbSNP rs737865, dbSNP rs4680, and dbSNP rs165599), and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Single-locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci and all analyses were stratified by sex. In female subjects, dbSNP rs4680 demonstrated a modest association with AD plus psychosis; dbSNP rs737865 demonstrated a trend towards an association. There was a highly significant association of AD plus psychosis with a 4-locus haplotype, which resulted from additive effects of alleles at and ERE6/dbSNP rs737865 (the latter were in linkage disequilibrium). In male subjects, no single-locus test was significant, although a strong association between AD with psychosis and the 4-locus haplotype was observed. That association appeared to result from interaction of the ERE6/dbSNP rs737865, dbSNP rs4680, dbSNP rs165599 loci. Genetic variation in COMT was associated with AD plus psychosis and thus appears to contribute to psychosis risk across disorders. - Associations with Susceptibility for Alzheimer Disease McIlroy et al. (2000) reported a case-control study of 175 individuals with late-onset Alzheimer disease and 187 age- and sex-matched controls from Northern Ireland. The presence of the butyrylcholinesterase K variant (BCHE; 177400.0005) was found to be associated with an increased risk of Alzheimer disease (odds ratio = 3.50, 95% CI 2.20-6.07). This risk increased in subjects 75 years or older (odds ratio = 5.50, 95% CI 2.56-11.87). No evidence of synergy between BCHE K and APOE epsilon-4 was found in this population. In a series of 239 necropsy-confirmed late-onset AD cases and 342 elderly nondemented controls older than 73 years, Narain et al. (2000) found an association between homozygosity for both the ACE I and D allele polymorphisms (106180.0001) and AD. Whereas the APOE epsilon-4 allele was strongly associated with AD risk in their series, Narain et al. (2000) found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A metaanalysis of all published reports (12 case-control series in total) suggested that both the I/I and I/D ACE genotypes are associated with increased AD risk (odds ratio for I/I vs D/D, 1.36, 95% CI = 1.13-1.63; OR for D/I vs D/D, 1.33, 95% CI = 1.14-1.53, p = 0.0002). In a metaanalysis of 23 independent published studies, Elkins et al. (2004) found that the OR for AD in individuals with the I allele (I/I or I/D genotype) was 1.27 compared to those with the D/D genotype. The risk of AD was higher among Asians (OR, 2.44) and in patients younger than 75 years of age (OR, 1.54). Elkins et al. (2004) concluded that the ACE I allele is associated with an increased risk of late-onset AD, but noted that the risk is very small compared to the effects of other alleles, especially APOE4. Prince et al. (2001) genotyped 204 Swedish patients with sporadic late-onset Alzheimer disease and 186 Swedish control subjects for polymorphisms within 15 candidate genes previously reported to show significant association in Alzheimer disease. The genes chosen for analysis were LRP1, ACE, A2M, BLMH (602403), DLST (126063), TNFRSF6 (134637), NOS3 (163729), PSEN1, PSEN2, BCHE, APBB1 (602709), ESR1 (133430), CTSD (116840), MTHFR (607093), and IL1A (147760). No strong evidence was found for genetic association among the 15 tested variants, and the authors concluded that with the exception of possession of the APOE4 allele, none of the other investigated single-nucleotide polymorphisms contributed substantially to the development of AD in the studied sample. In 2 groups of patients with AD, comprising a total of 201 patients, Papassotiropoulos et al. (2003) found that the frequency of a 24-cholesterol hydroxylase (CYP46; 604087) T-C polymorphism, CYP46*TT, was associated with increased risk of AD (OR = 2.16). The OR for the APOE4 allele carriers was 4.38. The OR for the presence of both CYP46*TT and APOE4 was 9.63, suggesting a synergistic effect of the 2 genotypes. Neuropathologic examination of AD patients and controls showed that brain beta-amyloid load, CSF levels of soluble beta-amyloid-42, and CSF levels of phosphorylated tau were significantly higher in subjects with the CYP46*TT genotype. Papassotiropoulos et al. (2003) suggested that functional alterations of cholesterol 24-hydroxylase may modulate cholesterol concentrations in vulnerable neurons, thereby affecting changes in amyloid precursor protein processing and beta-amyloid production leading to the development of AD. See also Wolozin (2003). Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for AD. De Quervain et al. (2004) analyzed SNPs in 10 glucocorticoid-related genes in 351 AD patients and 463 unrelated control subjects. A rare haplotype in the 5-prime regulatory region of the HSD11B1 gene (600713) was associated with a 6-fold increased risk for sporadic AD. The HSD11B1 enzyme controls tissue levels of biologically active glucocorticoids and thereby may influence neuronal vulnerability. In human embryonic kidney cells, the risk-associated haplotype reduced HSD11B1 transcription by 20% compared to the common haplotype. Robson et al. (2004) examined the interaction between the C2 variant of the TF gene (190000.0004) and the cys282-to-tyr allele of the HFE gene (C282Y; 613609.0001), the most common basis of hemochromatosis, as risk factors for developing AD. The results showed that each of the 2 variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. Furthermore, carriers of these 2 alleles plus APOE4 were at still higher risk of AD: of the 14 carriers of the 3 variants identified in this study, 12 had AD and 2 had mild cognitive impairment. Robson et al. (2004) concluded that the combination of TF*C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurons, which is exacerbated in carriers of APOE4. They noted that 4% of northern Europeans carry the 2 iron-related variants and that iron overload is a treatable condition. In a study of 148 patients from southern Italy with sporadic AD, Zappia et al. (2004) found that having a myeloperoxidase (MPO) polymorphism genotype, -463G/G (606989.0008), conferred an odds ratio of 1.65 for development of the disease. When combined with an alpha-2-macroglobulin polymorphism genotype, 1000val/val (103950.0001), the odds ratio increased to 23.19. The authors suggested that the synergistic effect of the 2 genotypes may represent a facilitation of beta-amyloid deposition or a decrease in amyloid clearance, and noted that MPO produces oxidizing conditions. The findings were independent of APOE4 status. Bian et al. (2005) found no association of 6 A2M gene (103950) polymorphisms with Alzheimer disease in a study of 216 late-onset AD patients and 200 control subjects from the Han Chinese population. Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects. Mace et al. (2005) found a significant association between a C-T SNP (dbSNP rs908832) in exon 14 of the ABCA2 gene (600047) and Alzheimer disease in a large case-control study involving 440 AD patients. Additional analysis showed the strongest association between the SNP and early-onset AD (odds ratio of 3.82 for disease development in carriers of the T allele compared to controls). In a survey of 138 published studies on genetic association for AD, Blomqvist et al. (2006) found evidence for publication bias for positive associations. The authors analyzed 62 genetic markers for AD risk in 940 Scottish and Swedish individuals with AD and 405 Scottish and Swedish controls and found no significant associations except for APOE. In particular, no association was found with variants in the PLAU gene (191840). Kamboh et al. (2006) studied the association of polymorphisms in the UBQLN1 gene (605046) on chromosome 9q21 with AD. They examined the association of 3 SNPs in the gene (intron 6 A/C, intron 8 T/C, and intron 9 A/G), all of which are in significant linkage disequilibrium (p less than 0.0001), in up to 978 late-onset Alzheimer disease patients and 808 controls. Modestly significant associations were observed in the single-site regression analysis, but 3-site haplotype analysis revealed significant associations (p less than 0.0001). One common haplotype, called H4, was associated with AD risk, whereas a less common haplotype, called H5, was associated with protection, Kamboh et al. (2006) suggested that genetic variation in the UBQLN1 gene has a modest effect on risk, age at onset, and disease duration of Alzheimer disease and that the presence of additional putative functional variants either in UBQLN1 or nearby genes exist. In a study of 265 AD patients and 347 controls, Ramos et al. (2006) reported a possible protective effect against AD development associated with a polymorphism in the TNF gene (-863C-A; 191160.0006). The -863A allele was present in 16.9% of controls and 12.6% of patients. Comparison of the 3 genotypes (C/C, C/A, and A/A) suggested a dose-response effect with the A/A genotype conferring an odds ratio of 0.58. The findings supported a role for inflammation in AD. Reiman et al. (2007) used a genomewide SNP survey to examine 1,411 individuals with late-onset AD and controls, including 644 carriers of the APOE4 allele and 767 noncarriers. The authors found a significant association between AD and 6 SNPs in the GAB2 gene (606203) that are part of a common haplotype block. Maximal significance of the association was at dbSNP rs2373115 with an odds ratio of 4.06 (uncorrected p value of 9 x 10(-11)). Carriers of the APOE4 alleles had an even higher disease risk when the SNP risk allele was present (odds ratio of 24.64) compared to noncarriers. Neuropathologic studies found that GAB2 was overexpressed in neurons from AD patients and the protein was detected in neurons, tangle-bearing neurons, and dystrophic neurites. In contrast, both Chapuis et al. (2008) and Miyashita et al. (2009) failed to detect an association between the GAB2 SNP dbSNP rs2373115 and risk of developing AD in Caucasian and Japanese individuals, respectively. Chapuis et al. (2008) studied 3 European Caucasian populations totaling 1,749 AD cases and 1,406 controls, and Miyashita et al. (2009) studied 1,656 Japanese cases and 1,656 Japanese controls; they suggested that GAB2 is, at best, a minor disease susceptibility gene for AD. See GSK3B (605004) for a discussion of a possible association between risk of AD and epistatic interaction between variants in the GSK3B and MAPT genes (157140).
In a population-based study in the city of Rouen, France (426,710 residents), Campion et al. (1999) estimated the prevalence of early-onset AD and autosomal dominant early-onset AD to be 41.2 and 5.3 per 100,000 persons, respectively. Early-onset AD ... In a population-based study in the city of Rouen, France (426,710 residents), Campion et al. (1999) estimated the prevalence of early-onset AD and autosomal dominant early-onset AD to be 41.2 and 5.3 per 100,000 persons, respectively. Early-onset AD was defined as onset of disease at age less than 61 years, and autosomal dominant early-onset AD was defined as the occurrence of at least 3 cases in 3 generations. They identified PSEN1 gene mutations in 19 (56%) of 34 families, and APP gene mutations in 5 (15%) families. In the 10 remaining families and in 9 additional autosomal dominant AD families, no PSEN1, PSEN2, or APP mutations were found. These results showed that PSEN1 and APP mutations account for 71% of autosomal dominant early-onset AD, and that nonpenetrance at age less than 61 years is probably infrequent for PSEN1 or APP mutations. Finckh et al. (2000) investigated the proportion of early-onset dementia attributable to known genes. They screened for mutations in 4 genes, PSEN1, PSEN2, APP, and the prion protein gene PRNP (176640), in patients with early-onset dementia before age 60 years. In 16 patients the family history was positive for dementia, in 17 patients it was negative, and in 3 patients it was unknown. In 12 patients, they found 5 novel mutations and 5 previously reported mutations that were all considered to be disease-causing. Nine of these 12 patients had a positive family history, indicating a detection rate of 56% (9/16) in patients with a positive family history.