Rodrigue KM, Rieck JR, Kennedy KM, Devous MD, Diaz-Arrastia R, Park DC.
Risk Factors for β-Amyloid Deposition in Healthy Aging: Vascular and Genetic Effects.
JAMA Neurol. 2013 May 1;70(5):600-6.
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Rodrigue et al. report exciting findings that suggest an interaction between hypertension and ApoE4. Individuals with hypertension and one or more ApoE4 alleles had a greater amyloid burden than those with no hypertension and no ApoE4 alleles. Further, breaking the sample down into controlled and uncontrolled hypertensives, they demonstrated the greatest risk of Aβ deposition in uncontrolled hypertensives with one or more ApoE4 alleles. Although the study begs follow-up and further replication in a larger sample, the implications are significant. These investigators have shed light not only on the association of a modifiable risk factor and AD pathology, but also a gene-by-environment interaction. Importantly, they have shown suggestive evidence that treatment of that modifiable factor is associated with reduced levels of AD pathology.
The determinants of amyloid deposition in the brain for most older individuals are not well understood. At least three hypotheses should be considered: 1) there are unique, important risk factors, such as hypertension, brain vascular disease, and inflammation; 2) genetic factors, including ApoE4, are the major determinants of amyloid deposition; and 3) amyloid deposition in the brain is primarily a function of normal aging.
It is very unlikely that genetic factors alone account for deposition of amyloid except in very rare genetic disorders. If aging is the primary factor, then prevention and possibly treatments should focus on aging and not necessarily on specific amyloid deposition in the brain. If risk factors such as hypertension increase amyloid deposition, then there is a great opportunity to decrease or postpone amyloid deposition and dementia. It is very unlikely that major advances in preventing and/or treating Alzheimer's disease, i.e., amyloid deposition, will occur until we have a better understanding of etiology (causes) in humans. The paper by Rodrigue et al. adds to a growing literature that brain vascular disease secondary to elevated blood pressure contributes to Alzheimer's disease and dementia. The unanswered question is whether prevention or treatment of hypertension will prevent dementia. It is also possible that specific antihypertensive drug(s) will be more effective in preventing dementia. The association with ApoE4 only in the current paper may just relate to small sample size or indicate that a genetic marker, ApoE4, interacts with a risk factor, elevated BP, to increase amyloid deposition.