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Review
. 2012 Sep;124(3):305-23.
doi: 10.1007/s00401-012-0996-2. Epub 2012 May 23.

The genetics and neuropathology of Alzheimer's disease

Gerard D Schellenberg  1 , Thomas J Montine
Affiliations
Review

The genetics and neuropathology of Alzheimer's disease

Gerard D Schellenberg et al. Acta Neuropathol. 2012 Sep.

Abstract

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.

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Figures

Figure 1
Figure 1. Photomicrograph of neuritic plaque and neurofibrillary tangle
Histologic section of neocortex from a patient who died of dementia that has been stained with a modified Bielschowsky method to reveal the hallmark lesions of AD: a large extracellular plaque with amyloid core and abnormal neuritic processes (neuritic plaque) and a skein of darkly staining threads that encircle a neuron’s nucleus and extend down a process (neurofibrillary tangle).
Figure 2
Figure 2. APP protein structure and processing
The APP protein is a single-pass transmembrane protein with an extracellular globular domain (top of the figure). The extracellular segment is illustrated here in blue. The transmembrane segment is composed in part of sequence that makes up the Aβ peptide (red). The amino acid sequence of Aβ peptides and flanking regions are shown at the bottom along with the position and amino acid changes of different APP mutations. Locations of the a-, β-, and y-secretase sites are shown. The γ -secretase site is shown with a red triangle because cleavage at this site can leave different C-terminal amino acids.
Figure 3
Figure 3. The γ secretase complex
The complex is composed of four membrane proteins: nicastrin, aph-1, Pen-2, and presenilin (1 or 2). The actual catalytic site is in presenilin. The gap in presenilin represents cleavage of the protein that is part of normal processing. Cleavage of APP and other substrates occurs in the membrane. As illustrated here, when there is an APP mutation that causes AD or related disease, the cleavage site is altered by approximately two amino acids (short yellow segment on the end of the red Aβ peptide). While only a single PSEN mutation is shown in the figure, as noted in the text, there are numerous PSEN1 and PSEN2 mutations that cause early-onset AD.
Figure 4
Figure 4. Photomicrograph of cotton wool plaques
Histologic section of frontal cortex from a patient with a strong family history of AD, who inherited PSEN1 mutation, and died of dementia. Hematoxylin and eosin stain (x200) of cerebral cortex shows marked neuron loss, vacuolization, gliosis, and large amorphous eosinophilic structures that are called cotton wool plaques. Modified Bielschowsky stain (inset) further highlights cotton wool plaques.
Figure 5
Figure 5. APOE gene structure and the ε2/ε3/ε4 allele system
The top of the figure shows the relationship between APOE and adjacent genes TOMM40 and APOC1 (not drawn to scale). Shown in the middle of the figure is the APOE exon structure and location of the polymorphic nucleotides that are responsible for the APOE ε2/ε3/ε4 allele system. At the bottom are the nucleotide and the resulting amino acid changes corresponding to these alleles.
Figure 6
Figure 6. Manhattan plot for AD association for the MS4A region of chromosome 11
The association plot is for P-values determined by a three-stage meta-analysis as reported in Naj et al. [114]. The X-axis is the genomic location (NCBI Build 37.1) and the y-axis is the − log10 of the P value. The black diamond is the P value for the SNP with the smallest P-value in the discovery phase (Stage 1). The purple diamond is the P-values for the same SNP for the first replication phase (stage 1 + 2). The red diamond is the P-value for the same SNP at the second replication phase (stage 1+2+3). The Color of the circles (orange, yellow, grey and white) indicate the estimated linkage disequilibrium with the top SNP and are r2 ≥ 0.8, 0.8 ≥ r2 ≥ 0.5, 0.5 > r2 > 0.2, and r2 < 0.2, respectively. Genes in the region are indicated by arrows at the bottom with the direction of the arrow indicating the direction of transcription and the length proportional to the size of the gene.
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