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  • Review Article
  • Published:

Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses

Nature Reviews Neuroscience volume 9, pages 768–778 (2008)Cite this article

Key Points

  • Alzheimer's disease (AD) is a highly heritable disorder, the genetic underpinnings of which remain incompletely understood despite intense research over the past 30 years.

  • Over 1,000 individual genetic-association studies have been published in the field of AD; these studies are exhaustively annotated and systematically meta-analysed in a continuously updated online database called AlzGene.

  • Genome-wide association (GWA) studies, which have the potential to pinpoint new pathogenetic pathways by simultaneously testing thousands of genetic markers in a largely hypothesis-free fashion, are becoming increasingly available for AD.

  • Over 20 genetic loci currently show evidence for a significant role in modifying risk for AD in the AlzGene meta-analyses. One-third of these were originally described in GWA studies.

  • The potential functional and pathogenetic implications of some of the most interesting of these genes (angiotensin I converting enzyme (ACE); cholesterol 25-hydroxylase (CH25H); cholinergic receptor, nicotinic, β2 (CHRNB2); cystatin C (CST3); GRB2-associated binding protein 2 (GAB2); lamin A/C (LMNA); microtubule-associated protein tau (MAPT); prion protein (PRNP); sortilin-related receptor, L(DLR class) A repeats-containing (SORL1) and transferrin (TF)) can now be summarized.

Abstract

The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

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Figure 1: Summary of possible pathogenetic roles for candidate early-onset familial AD genes covered in this Review.

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Acknowledgements

This work was sponsored by grants from the National Institute on Aging (5R01AG23667 to L.B.) and the National Institute of Mental Health (5R37MH60009 to R.E.T.). The AlzGene database was developed in collaboration with the Alzheimer Research Forum and is funded by the Cure Alzheimer's Fund.

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  1. Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Massachusetts General Hospital, 114 16th Street, Charlestown, 02129, Massachusetts, USA

    Lars Bertram & Rudolph E. Tanzi

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Lars Bertram and Rudolph E. Tanzi

Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nature Reviews Neuroscience 9, 768–778 (2008); doi:10.1038/nrn2494

Rudolph Tanzi and Lars Bertram are both consultants to, and equity holders in, TorreyPines Therapeutics, Inc. Rudolph Tanzi is a consultant to, and an equity holder in, Prana Biotechnology, Limited. Rudolph Tanzi is a co-founder of both TorreyPines Therapeutics and Prana Biotechnology.

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Thirty years of AD genetics (PDF 287 kb)

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DATABASES

Alzgene

1q23

1q31–42

3q22

10q23

11q14

11q24

14q24.3

17q21

17q23

20p13

20q11

21q21.3

ACE

CH25H

CHRNB2

CST3

GAB2

LMNA

MAPT

PRNP

rs13500

rs505058

rs1049296

rs1064039

rs1799990

rs1800764

rs2070045

rs2373115

rs2471738

rs4845378

SORL1

TF

FURTHER INFORMATION

AD and FTD mutation database

Alzheimer Research Forum

PDGene

SzGene

Glossary

Autosomal-dominant inheritance

A type of inheritance in which the phenotype of a trait is determined completely by one of two alleles on the non-sex-chromosomes. There can be either one (heterozygous state) or two (homozygous state) copies of the dominant allele.

Senile plaque

An extracellular pathological lesion in the brains of patients with AD. Senile plaques have a core of aggregated amyloid-β protein and a periphery that consists primarily of dystrophic neurites.

Polymorphism

Genetic variation (for example, a single base change or the insertion or deletion of a piece of DNA) that occurs with at least 1% frequency in a population.

Linkage disequilibrium

(LD). The non-random association of alleles at two or more loci. In other words, when a combination of alleles at different loci occurs more (or less) frequently in a population than would be expected on the basis of the alleles' frequencies. The degree of LD can be quantified by different measures, for example r2 or D'. Both of these measures can take values ranging from 0 to 1, where 0 indicates no LD and 1 indicates strong LD.

Genetic-association study

A study that aims to determine whether a certain allele or set of alleles at polymorphic sites shows differences in distribution between samples of disease-affected and -unaffected individuals. In the simplest setting, single base changes (single-nucleotide polymorphisms (SNPs)) are assayed across unrelated cases and controls.

Odds ratio

(OR). A measure of effect size (for example, of risk effects). The OR measures the ratio of the odds of an event occurring in one group (for example, disease cases) to the odds of that same event occurring in another group (for example, healthy controls). An OR of 2 indicates that carriers of a certain risk factor are at twice the risk of developing the disease as non-carriers; an OR of 0.5 indicates that the risk in carriers is only half that in non-carriers.

Autosomal-recessive inheritance

A type of inheritance in which a certain phenotype of a trait arises only if two copies of a particular allele are present on the non sex-chromosomes (that is, the homozygous state).

Alu repeat

A dispersed, repetitive DNA sequence that is present in the human genome in ∼300,000 copies. It is named after the restriction endonuclease (AluI) that cleaves it.

Haplotype

Alleles located in close proximity on the same chromosome that, as a result, are inherited together. In a population, the genome is partitioned into haplotype blocks of varying length depending on the strength of the LD between the alleles, and the different combinations of alleles that are located in these blocks are called haplotype clades or haplotype alleles.

Alternative splicing

A process whereby different mRNAs can be produced from a single gene through the differential incorporation of exons into the mature transcript during splicing. Frequently, various mature proteins are generated from a single gene.

Adaptor protein

An accessory to the main signalling proteins in a signal-transduction pathway. Adaptor proteins tend to lack any intrinsic enzymatic activity themselves, but instead mediate specific protein–protein interactions that drive the formation of protein complexes.

Hardy–Weinberg equilibrium

(HWE). A principle that postulates that the genotype frequencies of a population remain constant over time. In the case of a bi-allelic polymorphism with frequencies p and q, genotype frequencies can be calculated as 1 = p^2 + 2pq + q^2. HWE can be disturbed by effects such as selection, mutations and non-random mating. In genetic-association studies, large deviations from HWE can be an indicator of genotyping error.

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Bertram, L., Tanzi, R. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9, 768–778 (2008). https://doi.org/10.1038/nrn2494

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