Genetics of Dementia

 

Alzheimer’s disease is often discussed as a general condition occurring at any time in a person’s life span. However, Alzheimer’s disease can be classified more specifically based on age of occurrence, as early-onset or late-onset Alzheimer’s. Early-onset Alzheimer’s disease is generally defined as Alzheimer’s disease diagnosed before age 65, and late-onset diagnosed at age 65 or older. Alzheimer’s disease usually manifests itself as amnestic mild cognitive impairment (MCI) first and then progresses to dementia, including memory impairment as the primary cognitive deficit. The cerebral atrophy in Alzheimer’s disease is accompanied by amyloid plaques composed of Aβ, and neurofibrillary tangles composed of the protein tau.

 

The reviewers identified that in four recent genome-wide association studies of Alzheimer’s disease, APOE was identified as a powerful genetic risk factor for Alzheimer’s disease, confirming this previously known association. The ApoE2 allele is associated with a reduced risk of late onset Alzheimer’s disease and ApoE4 with an increased risk of late onset Alzheimer’s disease. However, people with ApoE4 sometimes do not develop Alzheimer’s disease and people without ApoE4 sometimes still develop Alzheimer’s disease. The recent genomic studies have also identified multiple additional susceptibility genes, which group into several functional categories. These categories suggest specific biologic areas that contribute to disease pathogenesis, including the immune system, synaptic dysfunction, membrane recycling, and lipid metabolism.

 

In addition to early- or late-onset, Alzheimer’s disease can also be classified as familial or non-familial. The term ‘familial’ Alzheimer’s disease is typically used to describe cases associated with an autosomal-dominant, highly penetrant genetic variation, in particular variants (or mutations) of the genes APP (amyloid precursor protein), PS1 (presenilin-1), or PS-2, although genetic factors involving other genes also play a role in many other cases of Alzheimer’s.  Familial Alzheimer’s (i.e. cases involving APP, PS1 or PS2 mutations) are usually early-onset, although many (in fact most) cases of early-onset Alzheimer’s do not involve these familial genetic mutations, which are relatively rare.  PS1 mutations are the most common cause of familial Alzheimer’s disease. APP mutations are more rare, and PS2 even rarer still. Collectively, familial Alzheimer’s disease from these three disease genes compromise only about 2% of all Alzheimer’s disease, but their discovery has helped the understanding of the pathophysiology of all Alzheimer’s disease.

The majority of Alzheimer’s disease is late-onset, meaning after age 65. Even though late-onset Alzheimer’s disease is not usually ‘familial’ in the sense described above, genetic factors nevertheless play a significant role in many cases within this category. The most powerful genetic factor is Apolipoprotein E (ApoE). The ApoE E2 allele is associated with a reduced risk of late onset Alzheimer’s disease and ApoE E4 with an increased risk of late onset Alzheimer’s disease. However, people with ApoE E4 sometimes do not develop Alzheimer’s disease and people without ApoE E4 sometimes still develop Alzheimer’s disease.

The reviewers identify that in four recent genome-wide association studies of Alzheimer’s disease, APOE was identified as a powerful genetic risk factor for Alzheimer’s disease, as well as 9 new loci for which there is compelling evidence (CLU, PICALM, CR1, BIN1, ABCA7, MS4A cluster, CD2AP, CD33, and EPHA1). These identified factors are related to a small risk for Alzheimer’s disease (increased risk odds ratio of 1.1 to 1.15) as compared to APOE E4 allele (odds ratio is 3.0 to 4.0). However, the importance of these newly identified susceptibility genes is they suggest new mechanisms contributing to disease pathogenesis that may not be linked to the production, oligomerization or clearance of B-amyloid. These pathways include the immune system and complement activation, synaptic dysfunction, membrane recycling, and lipid metabolism.

Notably, several of the late-onset Alzheimer’s disease genes (APOE, CLU, CR1, CD33, ABCA7, and MS4A) are involved either directly or indirectly in the regulation of inflammatory mechanisms. This supports the previously hypothesized role of the immune system and neuroinflammation in Alzheimer’s disease pathogenesis.

The researchers conclude that recent results from biomarker studies, and failures thus far to find a preventive treatment, have led physicians and scientists to begin to view Alzheimer’s disease as a process that extends over decades, rather than as the symptomatic dementia that presents itself well into the progression of the disease. Evidence suggests that we can identify biomarkers of ongoing disease well before the patient shows cognitive symptoms and try to employ potential preventive therapies early in the process to hopefully slow the rate of the disease or stop it all together.

 

  1. Paulson, HL, Igo, I. Genetics of Dementia. Seminars in Neurology. November 2011;31(5):449-460.

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