Skip to main content

Volume 10 Supplement 1

de Senectute: Age and Health Forum

Multidimensional evaluation in clinical diagnosis of Alzheimer’s disease: genetic risk in Alzheimer’s disease and neurodegenerative dementias


Late onset degenerative dementia is a growing, common and complex disorder in which the aetiological role played by environment and genes has not yet been established. A familial component is frequently ascertained in Alzheimer’s disease (AD) (30% of first degree relatives affected) and also in Frontotemporal Dementia (FTD) (40-60%).

Early onset degenerative dementia has sometimes been recognized as caused by autosomal dominant genes, Presenilines (PS1 and PS2) and the Amyloid Precursor Protein (APP) in AD, whereas in Frontotemporal dementia, two major genes (Microtubule Associated Protein tau, MAPT and Progranulin, PGRN) have also been identified.

PS1 and MAPT mutations have been identified also in in very early onset patients (PS1 24 years [1], MAPT 22 years [2]), but also in late onset patients (PS1 78 years [3], MAPT 75 years [4] 87 years [5].

To evaluate whether FAD and PGRN gene mutations account for late onset dementia.

Materials and methods

Late onset familial dementia patients (onset >65 years) were regularly diagnosed in our centre.

Diagnosis of dementia was performed through a detailed clinical assessment. The NINCDS-ADRDA and Lund-Manchester group criteria were used for diagnosis of AD and FTD respectively.

Molecular screening of PS1, PS2, APP and PGRN genes was performed.


A PS2 Ser130Leu [6] and a novel PS2 Val139Met [7] mutations have been found in two late onset AD cases with onset at 83 and 76.

Three more unrelated cases with an APP A713T mutation showed an onset age between 73 and 82 years [8]. A novel PGRN c1145insA has been identified in a FTD patient of 87 years belonging to a pedigree whose age at onset spans from 35 to 87 [5].


Several autosomal dominant genes, either in AD or in FTD show an impact on late onset dementia. Heritability in late onset forms is now more evident, probably due to longer life survival. It is possible that mutation frequency has been underestimated due to the lack of wide genetic epidemiology. Genetic screening of FAD and PGRN genes might be recommended in familial late onset dementia as a part of Multidimensional evaluation.


  1. Wisniewski T, Dowjat WK, Buxbaum JD, Khorkova O, Efthimiopoulos S, Kulczycki J, et al: A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport. 1998, 9 (2): 217-221. 10.1097/00001756-199801260-00008.

    Article  PubMed  CAS  Google Scholar 

  2. Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, et al: Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998, 7 (1): 43-51. 10.1093/hmg/7.1.43.

    Article  PubMed  CAS  Google Scholar 

  3. Neumann M, Diekmann S, Bertsch U, Vanmassenhove B, Bogerts B, Kretzschmar HA: Novel G335V mutation in the tau gene associated with early onset familial frontotemporal dementia. Neurogenetics. 2005, 6: 91-95. 10.1007/s10048-005-0210-y.

    Article  PubMed  Google Scholar 

  4. Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S, et al: Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Annals of Neurology. 2002, 51: 525-530. 10.1002/ana.10163.

    Article  PubMed  CAS  Google Scholar 

  5. Bruni AC, Momeni P, Bernardi L, Tomaino C, Frangipane F, Elder J, et al: Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation. Neurology. 2007, 69 (2): 140-147. 10.1212/01.wnl.0000265220.64396.b4.

    Article  PubMed  CAS  Google Scholar 

  6. Tomaino C, Bernardi L, Anfossi M, Costanzo A, Ferrise F, Gallo M, et al: Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007, 254 (3): 391-393. 10.1007/s00415-006-0373-y.

    Article  PubMed  CAS  Google Scholar 

  7. Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Puccio G, et al: Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008, 255 (4): 604-606. 10.1007/s00415-008-0764-3.

    Article  PubMed  CAS  Google Scholar 

  8. Bernardi L, Geracitano S, Colao R, Puccio G, Gallo M, Anfossi M, et al: AbetaPP A713T Mutation in Late Onset Alzheimer's Disease with Cerebrovascular Lesions. J Alzheimers Dis. 2009, [Epub ahead of print]

    Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Bruni, A.C. Multidimensional evaluation in clinical diagnosis of Alzheimer’s disease: genetic risk in Alzheimer’s disease and neurodegenerative dementias. BMC Geriatr 10 (Suppl 1), A90 (2010).

Download citation

  • Published:

  • DOI: