Genetics of Alzheimer's Disease

Genetics involve looking at the DNA
Image Unavailable
Taken from

As with many neurodegenerative diseases, Alzheimer’s Disease (AD) can be associated with genetics. It is therefore important to study the role that genetics play in this disease with respect to its onset and progress, in order to better understand it and develop treatments. For instance, a specific allele (ApoE ε4) is known to increase one’s risk of getting AD in a dosage dependent manner. Namely, a person who has two copies of this allele has a much higher risk than one who has one copy of it; and a person who has no copy of these allele would have a lower risk than the aforementioned two [1]. Awareness of the presence of those alleles in one’s genome may influence the person to try to minimize their risk of acquiring AD or prolong their age of onset via other mechanisms, such as diet and lifestyle. Furthermore, other genes have also been found to contribute to AD onset albeit in a different way. Those genes follow Mendelian Genetics, and mutations in them account for a minority of the cases [1]. Yet, it is still important to study them, as they are linked to an earlier onset and more aggressive progression of the disease [1]. Studies looking at genes involved have furthered our knowledge in relation to Alzheimer’s Disease, ultimately aiding in the development of treatment strategies.

1.1 Background

1.1a Brief overview of pathology and symptoms

Alzhemier’s Disease is a condition that has sparked great interest and research over the recent decades. As a form of dementia, AD is accompanied by symptoms such as significant memory impairment and cognitive decline, which worsen as the disease progresses. In fact, the deficits caused by the progression of AD become severe enough to substantially impact quality of life and increase reliance on caregivers. Also, in addition to cognitive symptoms, neuropsychiatric symptoms (NPS) are known to arise in conjunction with and following Alzheimer’s. These symptoms include depression, aggression, agitation, anxiety and pyschosis [2].

In order to better understand why these symptoms arise and progress, one must take a closer look at the changes that occur in the brain as a result of AD. AD primarily affects the cerebral cortex (mainly frontal and temporal lobes) and, as a neurodegenerative disorder, causes massive loss of neurons and their connections in those regions[1]. In addition to the evident atrophy in neurons, AD is characterized by three components: the presence of neurofibrillary tangles (NFTs), amyloid plaques, and changes in the manufacturing of acetylcholine (ACh) – a neurotransmitter known to be important for learning and memory [3].

1.1b β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs)

β-amyloid (Aβ) plaques are extracellular accumulations of β-amyloid peptides [1], resulting from a pathogenic pathway of processing of the amyloid precursor protein (APP) [4]. Since these plaques are neurotoxic, they cause damage to neurons and initiate neuronal cell death [5], contributing to the observed loss of neurons. Neurofibrillary tangles (NFTs) result from the intracellular accumulation of a hyperphosphorylated form of a microtubule assembly protein – Tau protein. In its normal state, Tau functions to stabilize microtubules. However, when hyperphosphorylated (p-tau), it dissociates from microtubules, causing them to disassemble, leading to the overall loss of neuronal integrity [6], which also contributes to the vast loss of neurons. Both Aβ plaques as well as NFTs can be observed in a microscopic post-mortem analysis of an AD brain as can be seen in Figure 1

Post-mortem analysis of AD brain
Image Unavailable
Figure 1
Taken from

1.1c Epidemiology

Recent epidemiological data suggests that more than 26 million people worldwide are currently living with AD, including 5.3 million in the US alone [7]. Furthermore, it is estimated that the worldwide population will grow to over 106 million by the year 2050 [8]. Of these cases 98-99% are “sporadic”, demonstrating late onset of the disease, while the remaining 1-2% are familial, having early onset [4]. The two forms of the disease have distinct genetic components and progress at different rates.

1.2 Familial/ Early Onset AD

When it comes to this form of the disease, there is no controversy with respect to the genes that are implicated. Pathogenic autosomal dominant mutations of three genes – amyloid precursor protein gene (APP), presenilin 1 gene (PSEN1), and presenilin 2 gene (PSEN2) – have been found to cause the disease to appear at an age of onset younger than 60 years old [4].

1.2a Amyloid Precursor Protein Gene

This gene encodes the APP protein – a ubiquitously expressed transmembrane glycoprotein. As a result of alternative splicing of the APP gene, the protein exists in many different isoforms [4]. APP is processed through two mutually exclusive pathways (see Figure 2 [9]). The first is the constitutive pathway (also known as non-amyloidogenic cascade), wherein APP is first degraded by the enzyme α-secretase, producing soluble APP-α and membrane bound CTFα. The final products of this pathway are degraded and do not harm neurons. On the other hand, the second pathway, known as the amyloidogenic cascade is the pathogenic pathway. Here, instead of undergoing cleavage by α-secretase, APP is internalized by the cell and is cleaved by a different enzyme – β-secretase. The products of this proteolytic cleavage are soluble APP-β and CTFβ. Following that, γ-secretase cleaves CTFβ, producing Aβ peptides and Aβ intracellular domain (AICD). The AICD is degraded, however, the difference between this pathway and the non-pathogenic one is that in this case, the Aβ peptides produced aggregate outside the cells to form the β-amyloid plaques8. Mutations in the APP gene lead to more β-amyloid plaques. These mutations can be missense mutations or copy number variants as both have been identified in autosomal dominant early onset of AD [4].

Pathways of APP processing
Image Unavailable
Figure 2 [9]

1.2b Presenilin Genes

Presenilin 1 and 2 play a very similar role in Alzheimer’s as APP because they are also involved in APP processing. These two genes are extremely homologous and are important components of the γ-secretase enzyme, which upon proteolytic activity can produce the Aβ peptides that cause the Aβ plaques. Mutations of these genes are mostly missense mutations [4].

1.3 Sporadic/ Late Onset AD

As opposed to the familial form of AD, the sporadic form has a later onset in life (>65 years of age [1]) and has a more controversial genetic component. Large amounts of research have all linked the presence of ApoE ε4 allele to AD, yet other studies have found that the presence of this allele is neither necessary nor sufficient for the disease [1]. Consequently, it is safe to conclude that this form of the disease may have a genetic component, however it is more complex and is determined by several factors (ex: environmental factors), yielding variability in its incidence.

1.3a Apolipoprotein E and its alleles

Apolipoprotein E is a gene that encodes a glycoprotein found in the liver and the brain. This protein has several functions, including the mobilization and redistribution of cholesterol during neuronal growth and repair, as well as in nerve regeneration. Three major isoforms of the APOE differ in two sites of amino acid sequence [4] (see Figure 3 [10]). The three isoforms (APOEII, APOEIII, and APOEIV) come from three alleles: ApoE ε2, ApoE ε3, ApoE ε4. Different genotypes (combinations of these alleles) give rise to different outcomes in terms of the development and progression of AD and it has been proposed that this is due to the different APOE isoforms’ binding abilities to the Aβ peptide (faster binding leads to poorer outcomes) [4].

Schematic of APOE isoforms
Image Unavailable
Figure 3 [10]

1.3b (i) ApoE ε2, ApoE ε3, ApoE ε4

Of the three alleles, ApoE ε2 has been found to positively affect longevity and may even confer protection against developing the disease [4]. Similar conclusions are found with the ApoE ε3 allele. On the other hand, a recent metaanalysis report has labeled ApoE ε4 as the strongest known genetic risk factor of late onset AD [11]. In fact, a person’s risk of developing AD increases as the number of ApoE ε4 alleles in his/her genome increases. Having one copy of the allele is associated with a 2-3 fold increase in the risk, while 2 copies of the allele are associated with a 5 fold increase in risk [1]. Also, with every added copy of the allele, the age of onset of the disease is lowered by 6-7 years [1].

1.3b (ii) ApoE ε4’s connection to progression from (Mild Cognitive Impairment) MCI to Alzheimer’s

Furthermore, in a very recent paper Xu, L. et al., investigated the effect of having two copies of the ApoE ε4 allele on the progression from Mild Cognitive Impairment (MCI) to dementia [12]. As noted previously, AD is a form of dementia. Moreover, it is currently the most common form of dementia, however, one cannot assume that it is the only form of dementia investigated in this study. This is an advantage to the study, as it expands the question of the effects of homozygous ApoE ε4 carriers on more than one form of dementia. In their work, the authors define MCI as a transitional stage from where cognitive changes of early aging become cognitive changes of early dementia [12]. The authors followed the progression of individuals with MCI across a span of 10 years and found that ApoE ε4ε4 carriers had a much more accelerated progression from MCI to dementia than those that were heterozygotes, or homozygotes for ε3 [12].

1. Reitz, C., Brayne C., Mayeux R. Epidemiology of Alzheimer disease. Nature Reviews Neurology. 3, 137-152 (2011)
2. Panza, F. et al., Apolipoprotein E genotypes and neuropsychiatric symptoms and syndromes in late-onset Alzheimer’s disease. Aging Research Reviews. 11, 87-103 (2012)
3. Radvansky G. 2011. Human Memory. 2nd Edition. Boston (MA): Pearson Education Inc. 414p.
4. Guerreiro, R. J., Gustafson, D. R., & Hardy, J. The genetic architecture of Alzheimer’s disease: beyond APP, PSENs, and APOE. Neurobiology of Aging. 33, 437-456 (2012).
5. Niikura, T., Tajima, H., & Kita, Y. Neuronal cell death in Alzheimer’s disease and a neuroprotective factor, humanin. Current Pharmacology. 4, 139-147 (2006).
6. Morris, M., Maeda, S., Vossel, K., & Mucke, L. The many faces of Tau. Neuron. 70, 410-426 (2011).
7. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dementia. 6, 158–194 (2010).
8. Brookmeyer, R., Johnson, E., Ziegler-Graham, K., & Arrighi, H. M. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dementia. 3, 186–191 (2007).
9. Rivest, S. Regulation of innate immune responses in the brain. Nature Reviews Immunology. 9, 429-439 (2009).
10. Vance, J. E., & Hayashi, H. Formation and function of apolipoprotein E-containing lipoproteins in the nervous system. Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids. 1801, 806-818 (2010).
11. Elias-Sonnenschein, L. S., Viechtbauer, W., Inez H G B Ramakers, I., H., G., B., Verhey, F., R., J., & Visser, P., J. Predictive value of APOE-34 allele for progression from MCI to AD-type dementia: a meta-analysis. J Neurol Neurosurg Psychiatry. 82, 1149-1156 (2011)
12. Xu, L. et al., Accelerated progression from Mild Cognitive Impairment to dementia among APOE ε4ε4 carriers. Journal of Alzheimer’s Disease. 33, 507-515 (2013).

Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License