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EDITORIAL
Year : 2013  |  Volume : 3  |  Issue : 3  |  Page : 162-163

Toward a better comprehension of genetics of Alzheimer's disease and frontotemporal lobar degeneration


Co-Investigator, Ageing and Dementia Research group, Sultan Qaboos University, Oman, Department of Medicine, Division of Neurology, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Postal Code 123, Muscat, Oman

Date of Web Publication10-Jul-2013

Correspondence Address:
Ammar Abd Alrahman Alobaidy
Co-Investigator, Ageing and Dementia Research group, Sultan Qaboos University, Oman, Department of Medicine, Division of Neurology, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Postal Code 123, Muscat
Oman
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.114831

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How to cite this article:
Alobaidy AA. Toward a better comprehension of genetics of Alzheimer's disease and frontotemporal lobar degeneration. Int J Nutr Pharmacol Neurol Dis 2013;3:162-3

How to cite this URL:
Alobaidy AA. Toward a better comprehension of genetics of Alzheimer's disease and frontotemporal lobar degeneration. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2020 Aug 9];3:162-3. Available from: http://www.ijnpnd.com/text.asp?2013/3/3/162/114831

Within the rapidly growing knowledge in the field of neurodegenerative disorders, both Alzheimer's disease (AD) followed by frontotemporal lobar degeneration (FTLD) stand out in importance as the most common causes of early onset dementia. The discovery of novel mutations in both disorders had significantly promoted our understanding of the pathomechanism behind neuronal degeneration. This review will cover briefly the fundamental concepts and new advances in the genetics of AD and FTLD.


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The subdivision into late onset Alzheimer disease (LOAD) and early onset Alzheimer's disease (EOAD) is substantially used to elucidate the interaction between heritable and non-heritable factors in AD. LOAD constitutes the vast majority of cases and it is usually encountered in subjects aged 65 years and above. If AD is diagnosed before 65 years of age, it will be considered EOAD. [1] In less than 1% of all AD cases, autosomal dominant familial AD is recognized as important cause of EOAD, including three distinctive genetic mutations : a0 myloid precursor protein (APP), presenilin 1 and presenilin 2 on chromosome 21q, 14q, and 1q respectively. The direct causation between these mutant genes and the neuronal degeneration is not well-understood, but it was postulated that they eventually affect production, metabolism and clearance of amyloid-beta of the amyloid cascade hypothesis. [2] This may explain the high prevalence of AD in patients with Down syndrome (trisomy 21) due to the extra copy of APP gene.

Apolipoprotein E type 4 allele (APOE epsilon4) is considered a risk factor, not a direct genetic correlation for LOAD and non-familial EOAD. Everyone inherits one form of the APOE gene from each parent; those who inherit one APOE-e4 gene, i.e., heterozygotes, have increased risk of developing AD and of developing it at an earlier age than those who inherit the APOE-e2 or APOE-e3 forms. Those who inherit two APOE-e4 genes, i.e., homozygotes, have an even higher risk. [3]

Recently, A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), was found to confer a risk of LOAD and non-familial EOAD in Icelandic and Spanish cohorts. [4],[5] Although, the frequency of rs75932628-T was low compared to APOE-e4 (0.63% vs. 17.3% respectively in the Icelandic population), it conferred a risk of AD that was similar to, and independent from the risk the APOE-e4 allele. [4] TREM2 gene mutation was proposed to predispose for AD via impairment of its anti-inflammatory role in the brain. [4]

Several genomic loci have been identified as low-risk factors for LOAD, implicating clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1), bridging integrator 1 (BIN1), membrane-spanning 4-domains, subfamily A (MS4A), CD2-associated protein (CD2AP), and ATP-binding cassette sub-family A member 7(ABCA7). [6]


   Frontotemporal Lober Degeneration (FTLD) Top


The most recent and widely used classification divides the neuropathological designation of FTLD into two clinical subtypes : 0 behavioral variant frontotemporal dementia (bvFTD) and language variant called primary progressive aphasia (PPA) including non-fluent/agrammatic, semantic, and logopenic PPA. [7]

Up to 40% of FTLD patients have a history that is suggestive of familial transmission, with roughly 10% of patients showing an autosomal dominant inheritance pattern. Familial FTLD is most common in patients with bvFTD and FTLD-amyotrophic lateral sclerosis (ALS) and least common in patients with the language variant FTLD. [8] Mutations in the microtubule associated protein tau (MAPT) and progranulin (GRN) genes account for 10-20% of familial cases and are both located on chromosome 17q21. The most common clinical phenotype associated with both MAPT and GRN mutations is bvFTD, although a more varied clinical spectrum has been associated with GRN mutations, including diagnoses such as PPA and corticobasal syndrome. [8]

A major recent discovery has identified a novel gene mutation that appears to be the most common genetic abnormality both in familial FTLD and ALS, accounting for 11.7% of familial FTLD and 23.5% of familial ALS. This new mutation is an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene and is genetically linked to chromosome 9p. [9] More recently, the pathogenic C9ORF72 expansion was implicated as an indirect risk factor in the pathogenesis of AD as well. [10]

Other rare mutations explain less than 1% of familial FTLD. Mutations in the gene encoding valosin-containing protein on chromosome 9p13 can cause a syndrome associated with Paget's disease and inclusion body myositis. Mutations in the charged multivesicular body protein 2B on chromosome 3p11 are linked to ALS. [8]

Finally, there is increasing evidence that APOE polymorphism is considered as a risk factor for both LOAD and FTLD, especially if associated with polymorphisms in the translocase of the outer mitochondrial membrane 40 gene. [11],[12]


   Summary Top


Genetic knowledge of AD and FTLD is rapidly growing and several novel mutations had been discovered that influence the development of these disorders either directly or being risk factors. APOE polymorphism and C9ORF72 mutation were implicated in both AD and FTLD; this may shed more light on understanding the pathogenesis of both disorders, aiming to reach a satisfactory treatment and prevention strategies.


   Acknowledgement Top


This work supported partially by The Research Council Oman (RC/AGR/FOOD/11/01) in the form of research grant was gratefully acknowledged.

 
   References Top

1.Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer's disease: More than age alone. J Alzheimers Dis 2010;19:1401-8.  Back to cited text no. 1
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2.Dong S, Duan Y, Hu Y, Zhao Z. Advances in the pathogenesis of Alzheimer's disease: A re-evaluation of amyloid cascade hypothesis. Transl Neurodegener 2012;1:18.  Back to cited text no. 2
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3.Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: Normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2012;2:a006312.  Back to cited text no. 3
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4.Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 2013;368:107-16.  Back to cited text no. 4
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5.Benitez BA, Cooper B, Pastor P, Jin SC, Lorenzo E, Cervantes S, et al. TREM2 is associated with the risk of Alzheimer's disease in Spanish population. Neurobiol Aging 2013;34:1711.e15-7.  Back to cited text no. 5
    
6.Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer's disease. N Engl J Med 2013;368:117-27.  Back to cited text no. 6
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7.Chow TW, Alobaidy AA. Incorporating new diagnostic schemas, genetics, and proteinopathy into the evaluation of frontotemporal degeneration. Continuum (Minneap Minn) 2013;19:438-56.  Back to cited text no. 7
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8.Rabinovici GD, Miller BL. Frontotemporal lobar degeneration: Epidemiology, pathophysiology, diagnosis and management. CNS Drugs 2010;24:375-98.  Back to cited text no. 8
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9.Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012;135:794-806.  Back to cited text no. 9
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10.Cacace R, Van Cauwenberghe C, Bettens K, Gijselinck I, van der Zee J, Engelborghs S, et al. C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2013;34:1712.e1-7.  Back to cited text no. 10
    
11.Seripa D, Bizzarro A, Pilotto A, Palmieri O, Panza F, D'Onofrio G, et al. TOMM40, APOE, and APOC1 in primary progressive aphasia and frontotemporal dementia. J Alzheimers Dis 2012;31:731-40.  Back to cited text no. 11
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12.Bagnoli S, Piaceri I, Tedde A, Bessi V, Bracco L, Sorbi S, et al. Tomm40 polymorphisms in Italian Alzheimer's disease and frontotemporal dementia patients. Neurol Sci 2013. [Epub ahead of print]  Back to cited text no. 12
    




 

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