. Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med. 2010 Mar;123(3):267-74. PubMed.

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  1. This study is interesting in that it shows that patients with familial hypercholesterolemia have high incidence of mild cognitive impairment (MCI). The report suggests that exposure to elevated cholesterol during middle age or earlier or dysfunction of lipoprotein receptors are important risk factors for MCI. Since previous studies of MCI in the population at large (without LDL receptor mutations) have not shown increases in cholesterolemia, it certainly brings forward the question of whether dysfunction in LDL receptors or other related proteins may play a role in the development of MCI.

  2. This is a very important paper from Dr. Pappolla's group. It presents novel findings that may clarify a number of issues pertaining to the controversy between hypercholesterolemia and increase risk of Alzheimer disease. It is most interesting in that patients with familial hypercholesterolemia have high incidence of mild cognitive impairment (MCI) in the face of prior negative reports for “sporadic” MCI.

    Certainly, most patients with MCI do not have mutations in the LDL receptor and one wonders if an acquired dysfunction of this receptor during aging may be a mechanism at play for the development of MCI. If this turns out to be the case, then the complexity of the LDL receptor opens a myriad of interesting possibilities. This receptor binds to apoprotein B100 and to apoE but also binds a number of unrelated proteins including viruses. Next to the ligand-binding domain is an epidermal growth factor (EGF) precursor homology domain. The EGFP domain has been implicated in the release of ligands bound to the receptor, and this may have important implications for the transport of Abeta bound to chaperon proteins. It will be important to determine in future studies which is the neuropathological basis of the type of MCI associated with heterozygous familial hypercholesterolemia.

  3. Comment by George Perry, Xiongwei Zhu, Rudy J. Castellani, Clyde Phelix, Paula Moreira, Gemma Casadesus, Hyoung-gon Lee, and Mark A. Smith

    Evolution of the Cholesterol Story
    The finding that dysfunction of the low-density lipoprotein receptor (LDLr) drives an increase in the risk for MCI (Zambόn et al., 2010) raises the intriguing possibility that hypercholesterolemia is only a marker of dysfunction rather than the fundamental mechanistic basis for cognitive decline in Alzheimer disease. LDLr is an interesting new element in Alzheimer disease because it is intimately involved in cholesterol homeostasis, and it binds apolipoprotein E. Although genetic studies of the LDLr locus in Alzheimer disease were non-conclusive, one should keep in mind that, even in patients affected by Alzheimer disease meeting definite criteria for familial hypercholesterolemia, mutations affecting the LDLr itself can only be detected in approximately 50 percent of cases (Varret et al., 2008). This means that defects leading to dysfunction of this receptor system may not necessarily reside in the receptor protein itself but in any of several interacting factors that determine the functional integrity of the cholesterol homeostasis system (Valdez et al., 2010). Whether cholesterol biosynthesis in normal, aged human brain decreases is still uncertain (Thelen et al., 2006), and nearly a third of the cholesterol homeostasis markers (Valdez et al., 2010) show changes in gene expression along the spectrum of Alzheimer disease severity, suggesting enhanced cholesterol biosynthesis and metabolism as the disease progresses (Blalock et al., 2004). Future insights from human and animal studies will continue revealing the role of cholesterol homeostasis mechanisms in age-related memory impairments (Kadish et al., 2009). Interestingly, a recent study from David Holtzman showed that crossing mice that have increased LDLr in the brain with a mouse model of Alzheimer disease produced a line of mice with fewer amyloid plaques (Kim et al., 2009).

    Another important point is that in familial hypercholesterolemia, one frequently observes elevations of serum cholesterol from much younger ages than in the “sporadic” idiopathic form. Therefore, the results presented by these investigators may support the concept, as proposed by previous epidemiological and neuropathological studies, that hypercholesterolemia may only be an early risk factor for AD. Finally, an important caveat of this report is that the neuropathology underlying the newly recognized cognitive dysfunction present in patients with heterozygous familial hypercholesterolemia remains to be determined.

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    . Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med. 2010 Mar;123(3):267-74. PubMed.