The Complicated Interplay of Alzheimer’s Risk and Genetics

Alzheimer’s dementia is expected to affect nearly 14 million people by 2050 (Herbert et al. 2013). The primary genetic factor associated with Alzheimer’s disease (AD) is the ε4 allele, which is one of the three common isoforms of the ApoE gene (Kim et al. 2009). The three isoforms of this gene are ApoE2, ApoE3, and ApoE4. ApoE2 appears to be protective against the development of Alzheimer’s disease by delaying the potential onset by about five years, whereas those presenting ApoE4 typically experience onset about 10 years earlier (Corder et al. 1994). The ApoE gene is expressed primarily in liver followed by macrophages and brain tissues as evidenced in mice models (Xu et al. 2006). Interestingly, ApoE appears to protect against neurodegeneration in mice when fed high-fat diets, yet is often associated with an increased risk of cardiovascular disease, particularly in males. It is also important to note that although 40%–65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease; at least a third of patients with AD are ApoE4 negative, and some ApoE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD (Hauser and Ryan 2013).

In Alzheimer’s disease, it may be that ApoE only alters risk by lowering the age of onset of the disease, with ApoE4 carriers acquiring the disease earliest (around age 60) and ApoE2 carriers the latest (Meyer et al. 1998). Most studies indicate AD does not initially present after the age of 85. The mechanism by which ApoE alters risk does not appear to be well known or understood; ApoE 2/3/4 variants appear to mediate cholesterol levels, and so the risk may not directly involve the brain at all. It is important to note that ApoE only modulates the risk and does not cause the disease (Lovestone 2009).

Genotype-phenotype interactions and environmental risk factors complicate the interpretation of potential ApoE effects. While ApoE4 has been found to increase the odds that an individual will develop Alzheimer’s, any combination of ApoE isoforms, high serum total cholesterol, and high blood pressure in midlife together can nearly triple the risk that the individual will later develop AD (Kivipelto et al. 2002). These data suggest that lowering serum cholesterol levels may reduce a person’s risk for AD, even if they have two ApoE4 alleles, thus reducing the risk from nine or 10 times the odds of developing this disease down to just two times the odds.

An array of inheritable and lifestyle factors complicate the risks associated with developing AD and related dementias (Kivipelto et al. 2008, Farrer et al. 1997). For example, females are significantly over-represented in all cohorts of Alzheimer’s patients, which may reflect greater longevity among women and postmenopausal hormone shifts that contribute to a decline in neuroprotective effects of estrogen and related hormones. Statistically, assessments of physical inactivity, moderate dietary fat and polyunsaturated fat intake, frequent alcohol drinking, and smoking at midlife indicate these variables may be associated with the risk of dementia and AD, especially among the ApoE ε4 carriers.

Family-based studies confirm age of onset is shared by siblings but that not all of the sharing is accounted for by ApoE (Tunstall et al. 2000). Additional findings suggest ethnicity may be another risk factor. For example, among 497 African-Americans with and without ApoE4, a slightly elevated serum cholesterol suggested a possible interaction between serum total cholesterol, ApoE 4, and Alzheimer’s disease risk (Evans et al. 2000). On the other hand, Nigerians have the highest observed frequency of the ApoE4 allele in world populations, but AD is rare among them (Sepehrnia et al. 1989). Among 444 Finnish survivors of the Seven Countries Study, high cholesterol (mean level 251 mg/dL) appeared to be an independent risk factor for developing AD (Notkola et al. 1998). Additional evidence from animal studies suggests that the elevated distribution of cholesterol among different regions of the brain may contribute to the development of the disease (Puglielli et al. 2003).

The ApoE4 allele, which is profoundly involved in cholesterol metabolism, has been established as a significant genetic risk factor for AD in the general population. Whether the associations of elevated level of serum total cholesterol and ApoE polymorphism with AD are independent or interrelated is unknown at this time. The impact that a spectrum of lifestyle factors may have on the development of AD and other forms of dementia and ultimately public health requires additional research.

Roger Clemens, DrPH, CFS, Contributing Editor
Adjunct Professor, Univ. of Southern California’s School of Pharmacy, Los Angeles, Calif.
[email protected]