Acta Neuropathologica

, Volume 124, Issue 3, pp 305–323 | Cite as

The genetics and neuropathology of Alzheimer’s disease

  • Gerard D. Schellenberg
  • Thomas J. MontineEmail author


Here we review the genetic causes and risks for Alzheimer’s disease (AD). Early work identified mutations in three genes that cause AD: APP, PSEN1 and PSEN2. Although mutations in these genes are rare causes of AD, their discovery had a major impact on our understanding of molecular mechanisms of AD. Early work also revealed the ε4 allele of the APOE as a strong risk factor for AD. Subsequently, SORL1 also was identified as an AD risk gene. More recently, advances in our knowledge of the human genome, made possible by technological advances and methods to analyze genomic data, permit systematic identification of genes that contribute to AD risk. This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM). We review the relationship between these mutations and genetic variants and the neuropathologic features of AD and related disorders. Together, these discoveries point toward a new era in neurodegenerative disease research that impacts not only AD but also related illnesses that produce cognitive and behavioral deficits.


Alzheimer’s disease Genetics Genome-wide association studies Neuropathology 



This work was supported by Grants from the NIH (U01AG032984, RC2AG036528, and AG05136) and the Nancy and Buster Alvord Endowment. We thank Dr. Kathleen Montine and Dr. Diane Durnam for their editorial assistance.


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PathologyUniversity of WashingtonSeattleUSA

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