Advertisement

Higher Incidence of Mild Cognitive Impairment in Familial Hypercholesterolemia

      Abstract

      Objective

      Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia.

      Methods

      By using a cohort study design, patients with familial hypercholesterolemia (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment.

      Results

      Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P=.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia.

      Conclusion

      Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Masters C.L.
        • Beyreuther K.
        Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway.
        Brain. 2006; 129: 2823-2839
        • Petersen R.C.
        • Smith G.E.
        • Waring S.C.
        • et al.
        Mild cognitive impairment: clinical characterization and outcome.
        Arch Neurol. 1999; 56: 303-308
        • Glenner G.G.
        • Wong C.W.
        Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
        Biochem Biophys Res Commun. 1984; 120: 885-890
        • Gandy S.
        The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease.
        J Clin Invest. 2005; 115: 1121-1129
        • Pappolla M.A.
        • Smith M.A.
        • Bryant-Thomas T.
        • et al.
        Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis.
        Free Radic Biol Med. 2002; 33: 173-181
        • Refolo L.M.
        • Malester B.
        • LaFrancois J.
        • et al.
        Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.
        Neurobiol Dis. 2000; 7: 321-331
        • Refolo L.M.
        • Pappolla M.A.
        • LaFrancois J.
        • et al.
        A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease.
        Neurobiol Dis. 2001; 8: 890-899
        • Simons M.
        • Keller P.
        • De Strooper B.
        • et al.
        Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons.
        Proc Natl Acad Sci U S A. 1998; 95: 6460-6464
        • Sparks D.L.
        • Martin T.A.
        • Gross D.R.
        • Hunsaker 3rd, J.C.
        Link between heart disease, cholesterol, and Alzheimer's disease: a review.
        Microsc Res Tech. 2000; 50: 287-290
        • Pappolla M.A.
        • Bryant-Thomas T.K.
        • Herbert D.
        • et al.
        Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.
        Neurology. 2003; 61: 199-205
        • Kivipelto M.
        • Solomon A.
        Cholesterol as a risk factor for Alzheimer's disease—epidemiological evidence.
        Acta Neurol Scand Suppl. 2006; 185: 50-57
        • Kalmijn S.
        • Foley D.
        • White L.
        • et al.
        Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2255-2260
        • Notkola I.L.
        • Sulkava R.
        • Pekkanen J.
        • et al.
        Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease.
        Neuroepidemiology. 1998; 17: 14-20
        • Whitmer R.A.
        • Sidney S.
        • Selby J.
        • et al.
        Midlife cardiovascular risk factors and risk of dementia in late life.
        Neurology. 2005; 64: 277-281
        • Kivipelto M.
        • Helkala E.L.
        • Laakso M.P.
        • et al.
        Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease.
        Ann Intern Med. 2002; 137: 149-155
        • Arvanitakis Z.
        • Schneider J.A.
        • Wilson R.S.
        • et al.
        Statins, incident Alzheimer disease, change in cognitive function, and neuropathology.
        Neurology. 2008; 70 (Epub 2008 Jan 16): 1795-1802
        • Newschaffer C.J.
        • Bush T.L.
        • Hale W.E.
        Aging and total cholesterol levels: cohort, period, and survivorship effects.
        Am J Epidemiol. 1992; 136: 23-34
        • Zlokovic B.V.
        • Yamada S.
        • Holtzman D.
        • et al.
        Clearance of amyloid beta-peptide from brain: transport or metabolism?.
        Nat Med. 2000; 6: 718
        • Civeira F.
        Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia.
        Atherosclerosis. 2004; 173: 55-68
        • Damgaard D.
        • Larsen M.L.
        • Nissen P.H.
        • et al.
        The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.
        Atherosclerosis. 2005; 180: 155-160
        • Junyent M.
        • Gilabert R.
        • Zambon D.
        • et al.
        The use of Achilles tendon sonography to distinguish familial hypercholesterolemia from other genetic dyslipidemias.
        Arterioscler Thromb Vasc Biol. 2005; 25: 2203-2208
        • Pocovi M.
        • Civeira F.
        • Alonso R.
        • Mata P.
        Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic aspects.
        Semin Vasc Med. 2004; 4: 67-74
        • Yamamoto T.
        • Davis C.G.
        • Brown M.S.
        • et al.
        The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.
        Cell. 1984; 39: 27-38
        • Hamilton M.
        Development of a rating scale for primary depressive illness.
        Br J Soc Clin Psychol. 1967; 6: 278-296
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Wenham P.R.
        • Price W.H.
        • Blandell G.
        Apolipoprotein E genotyping by one-stage PCR.
        Lancet. 1991; 337: 1158-1159
        • Otfried Spreen E.S.
        A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary.
        Oxford University Press, New York1998
        • Gauthier S.
        • Reisberg B.
        • Zaudig M.
        • et al.
        Mild cognitive impairment.
        Lancet. 2006; 367: 1262-1270
        • Portet F.
        • Ousset P.J.
        • Visser P.J.
        • et al.
        Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure.
        J Neurol Neurosurg Psychiatry. 2006; 77: 714-718
        • Canevari L.
        • Clark J.B.
        Alzheimer's disease and cholesterol: the fat connection.
        Neurochem Res. 2007; 32: 739-750
        • Solomon A.
        • Kareholt I.
        • Ngandu T.
        • et al.
        Serum cholesterol changes after midlife and late-life cognition: twenty-one-year follow-up study.
        Neurology. 2007; 68: 751-756
        • Stewart R.
        • White L.R.
        • Xue Q.L.
        • Launer L.J.
        Twenty-six-year change in total cholesterol levels and incident dementia: the Honolulu-Asia Aging Study.
        Arch Neurol. 2007; 64: 103-107
        • Elias M.F.
        • Beiser A.
        • Wolf P.A.
        • et al.
        The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham Cohort.
        Arch Neurol. 2000; 57: 808-813
        • Cao D.
        • Fukuchi K.
        • Wan H.
        • et al.
        Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice.
        Neurobiol Aging. 2006; 27: 1632-1643