Higher Incidence of Mild Cognitive Impairment in Familial Hypercholesterolemia

Article Outline

• Abstract
• Methods
  • Diagnosis of Familial Hypercholesterolemia
  • Subjects and Design
  • Clinical and Laboratory Determinations
  • Neuropsychologic Evaluation
  • Definitions of Cognitive Abnormalities and Mild Cognitive Impairment
  • Imaging Studies
  • Data Analysis
• Results
  • Participant Characteristics
  • Cognitive Function
  • Imaging Studies
• Discussion
• Conclusions
• Acknowledgments
• References
• Copyright

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: Alzheimer's disease, Hypercholesterolemia, Lipoprotein receptors, Mild cognitive impairment

Alzheimer's disease is a progressive neurodegenerative disorder characterized by global deterioration of cognition and behavior.¹ Development of dementia in Alzheimer's disease is usually preceded by a prodromal stage of abnormal cognitive performance known as mild cognitive impairment.² A major neuropathologic feature of Alzheimer's disease is the increase in insoluble amyloid fibrils composed of 40-42 amino acid peptides known as the amyloid beta protein.³, ⁴

Recent studies suggest a connection between cholesterol metabolism and the pathogenesis of Alzheimer's disease.⁵, ⁶, ⁷, ⁸, ⁹ We reported that hypercholesterolemia accelerates amyloid beta protein production in the brain of transgenic mice⁷, ⁸ and associates with higher levels of amyloid beta protein amyloid in the human brain.¹⁰ On the basis of apparently controversial epidemiologic studies,¹¹ some investigators have argued that this relationship might be spurious. However, the discrepancies might be more apparent than real for the following reasons. Most positive studies have typically measured serum cholesterol levels early in life and then correlated these levels prospectively to development of dementia later in life.¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶ In contrast, most negative reports have examined cohorts of older patients and for short follow-up periods, and concluded that there was no association between cognitive decline and higher cholesterolemia.¹¹, ¹⁶ Taken together, the studies suggest that hypercholesterolemia is only an early (not a late) risk factor for Alzheimer's disease. In addition, the negative studies inadvertently missed gradual declines in cholesterolemia that precede by years the development of dementia in most affected patients;¹⁵ this phenomenon could obscure abnormalities that might have occurred earlier in life. Last, subjects with the highest levels of cholesterolemia generally die of cardiovascular events at younger ages and are lost from the samples of elderly subjects (ie, comparative studies of patients with Alzheimer's disease vs controls), introducing a bias known as survivor effect.¹⁷ The hypothesis that hypercholesterolemia represents an early risk factor for Alzheimer's disease was recently tested and substantiated by us in a neuropathologic study.¹⁰ Hypercholesterolemia was strongly correlated with the presence of brain amyloid but only in subjects aged 40 to 55 years (P=.00). The differences in cholesterolemia between amyloid-bearing and amyloid-free brains disappeared as the subjects' age increased beyond 55 years. With the foregoing mechanisms in mind, one also can explain most studies negating a role for statins in Alzheimer's disease prevention because they have been conducted in samples of patients older than 65 years, failing to consider the mentioned age-related dynamics in the populations' risk.¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶

The aim of the current study was to determine whether patients who have familial hypercholesterolemia exhibit cognitive abnormalities. Patients with familial hypercholesterolemia offer a unique window into the role of cholesterol metabolism in cognition because the afflicted patients are exposed to hypercholesterolemia from early in life and also carry a dysfunction of low-density lipoprotein (LDL) receptors. Members of the LDL receptor family, including LDL receptors themselves, have been implicated in synaptic function and Alzheimer's disease pathogenesis.¹⁸ There are no studies examining cognition in this population, independently of cerebrovascular disease, because statins have only been widely available since the early 1990s.

Familial hypercholesterolemia is characterized by hypercholesterolemia since birth and is caused by inherited genetic abnormalities that directly or indirectly affect the function of the LDL receptors.¹⁹ The resulting condition carries a high risk of early-onset coronary heart disease and decreased survival if untreated.¹⁹

Back to Article Outline

Methods 

Diagnosis of Familial Hypercholesterolemia 

We used the Dutch Lipid Clinic Network criteria.²⁰ Briefly, these criteria are based on LDL-cholesterol levels above the age- and gender-specific 95th percentiles of a reference population, vertical transmission of hypercholesterolemia, early-onset coronary heart disease in the index case or first-degree relatives, and presence of tendon xanthomas.²¹ Each of these variables was scored, and an overall score was constructed to indicate the diagnostic probability of familial hypercholesterolemia (possible 3-5, probable 6-7, and certain ≥8). Only individuals with a score of≥8 were included in the familial hypercholesterolemia group.

Patients with clinical familial hypercholesterolemia were then recruited into the Spanish Familial Hypercholesterolemia Register²² and subjected to DNA testing for identification of LDL receptor mutations and the apolipoprotein B R3500G mutation following standard protocols. Briefly, genomic DNA was screened by a microarray system (Lipochip, Progenika Biopharma, Derio, Spain).²³, ²⁴ DNA samples from those patients in whom no mutation was identified by the microarray method were further sequenced after polymerase chain reaction amplification of the promoter region, the translated exon sequences, and the exon-intron boundaries of the LDL receptors gene. Large rearrangements were analyzed using a method based on quantitative fluorescent multiplex polymerase chain reaction. Nucleotide positions were numbered as suggested by Yamamoto and colleagues.²³ By these methods (microarray and sequencing), LDL receptor gene mutations were identified in 24 patients (∼50% of patients), a proportion that is in agreement with other studies.²⁹, ³¹, ³², ³³

Subjects and Design 

Between August 2005 and May 2007, 47 patients with a diagnosis of familial hypercholesterolemia, aged more than 50 years, and without history of stroke or transient ischemic attacks were recruited from 2 Lipid Clinics (University of Barcelona and the Spanish Familial Hypercholesterolemia Foundation, Madrid, Spain). Patients without familial hypercholesterolemia were recruited from the Internal Medicine Service of the University of Barcelona. None of the patients were referred to any of these clinics for cognitive problems. The patients with familial hypercholesterolemia were self-referred or referred for neurologically unrelated conditions for lipid management or to establish primary care. Patients with clinical evidence of psychiatric or neurologic disorders (including history of stroke or transient ischemic attack), any metabolic disease that could affect cognitive performance, illiteracy, history of excessive alcohol use (consumption>50 g/d), or drug abuse were excluded from the study. In addition, patients with history of hypertension, diabetes, or prior coronary artery bypass graft surgery also were excluded from both the familial hypercholesterolemia and the no-familial hypercholesterolemia groups because these conditions might adversely affect cognitive performance and potentially bias the results. Comprehensive medical histories and neurologic examinations were obtained from all participating subjects, including visual capacity, history of alcohol consumption, and administration of the Hamilton Depression Rating Scale.²⁴ All subjects were outpatients. Comparison subjects without familial hypercholesterolemia underwent a similar screening process as detailed above; however, the criteria for inclusion of control subjects also was conditioned on the absence of hypercholesterolemia (LDL cholesterol level<160 mg/dL). The latter was necessary to avoid inadvertent inclusion of patients with familial hypercholesterolemia into the comparison group because not all mutations associated with familial hypercholesterolemia are known and the genetic screen detects only approximately 50% of the mutations. All study participants underwent detailed neuropsychologic studies and laboratory investigations. Brain magnetic resonance imaging (MRI) was performed in all patients meeting criteria for mild cognitive impairment in the familial hypercholesterolemia group; 2 patients with mild cognitive impairment in the no-familial hypercholesterolemia group refused the MRI study. All subjects provided informed consent to a protocol approved by the institutional review boards at each location.

Clinical and Laboratory Determinations 

All subjects' medical records were thoroughly reviewed, and each patient was clinically assessed for family history of early coronary heart disease (<55 years for men and <60 years for women), medication use, demographic characteristics, standard cardiovascular risk factors, and presence of tendon xanthomas.²¹ Serum glucose, cholesterol, and triglycerides were measured by standard automated enzymatic procedures. LDL-cholesterol was estimated with the Friedewald equation.²⁵ Baseline lipid profiles were obtained from patients who had not received hypolipemic therapy for at least 4 weeks before drawing fasting glucose samples. Apolipoprotein E genotyping was performed by the polymerase chain reaction followed by restriction digestion with 5 U of Hha I. Digested products were separated by electrophoresis as described.²⁶

Neuropsychologic Evaluation 

The neuropsychologic examination was conducted by 2 experienced neuropsychologists blinded to the patients' diagnosis. We selected 13 well-established neuropsychologic instruments for screening of all cognitive domains.²⁷ The tests selected included the Mini-Mental State Examination, Buschke Memory Impairment Screen, semantic verbal category fluency for animals, Benton temporal orientation, clock drawing test (copy and command forms), Rey Auditory Verbal Learning test, Verbal Paired Associates, Boston Naming Test, digit span (forward and backward), Digit Symbol Substitution Test, Trail Making Test (Parts A and B), and Stroop test. Other measures incorporated in the assessment were the Global Dementia Scale and Hamilton Depression Rating Scale.

Definitions of Cognitive Abnormalities and Mild Cognitive Impairment 

The diagnosis of mild cognitive impairment was made using the criteria outlined by Petersen et al,² recently endorsed by US²⁸ and European expert groups.²⁹ Briefly, amnestic mild cognitive impairment was defined as having a positive history of memory complaints and abnormal memory function on at least 2 neuropsychologic instruments tapping on the memory domain and normal performance on instruments tapping mainly on domains other than memory. However, patients with abnormal memory performance on 2 instruments plus only isolated deficits in a single instrument tapping on another domain also were classified as having amnestic mild cognitive impairment. Patients with mild cognitive impairment also were required to have intact activities of daily living and not to be demented. For the results to be considered abnormal, the scores were required to be less than 1.5 standard deviations of the controls. Patients were classified as affected with the multiple-domain form of mild cognitive impairment if they exhibited memory complaints and abnormal memory on neuropsychologic testing as defined above plus abnormal scores (<1.5 standard deviations of the controls) in at least 2 additional instruments tapping on cognitive domains other than memory. Patients with deficits in other cognitive domains as identified by poor performance on 2 instruments (tapping primarily in such domains) were considered for the diagnosis of non-amnestic mild cognitive impairment (ie, dysexecutive syndrome) (2), but these subtypes were not encountered in our cohorts.

Imaging Studies 

Brain MRI was carried out in patients with mild cognitive impairment. The scans were performed by using a 1.5 Tesla Sigma apparatus (General Electric, Fairfield, Conn), according to a pre-established protocol that included coronal T1, axial T1, fast spin echo, diffusion-T2, and Flair and coronal fast spin gradient. All scans were read by an experienced neuroradiologist.

Data Analysis 

Demographics, clinical features, apolipoprotein E status, and neuropsychologic test scores were compared between familial hypercholesterolemia and control (no-familial hypercholesterolemia) groups using independent sample t tests for continuous variables and chi-square tests for categoric values. All tests were 2-sided using P less than .05 as the threshold for statistical significance. Of primary interest was the difference between familial hypercholesterolemia and no-familial hypercholesterolemia groups in the proportion of patients with mild cognitive impairment. Power calculations for the chi-square test (2-sided, alpha=0.05, 45 patients with familial hypercholesterolemia, 70 patients with no familial hypercholesterolemia) yielded 80% power to detect a difference in mild cognitive impairment proportions of 3% in the no-familial hypercholesterolemia group (lowest reported proportion) and 20% in the familial hypercholesterolemia group.

In addition to direct familial hypercholesterolemia versus no-familial hypercholesterolemia group comparisons, factors associated with cognitive test scores were explored using separate stepwise multiple linear regression models for the Mini-Mental State Examination, Verbal Paired Associates, Rey Auditory Verbal Learning, and Trail Making Test. The dependent variable in each model was the test score, with the following independent variables allowed to enter: familial hypercholesterolemia group, age per 10 years, gender, education per 5 years, family history of premature coronary heart disease, ever tobacco use, body mass index, total cholesterol, and presence of apolipoprotein E4 and E2 alleles. SPSS software version 12.0 (SPSS Inc, Chicago, Ill) was used for all analyses.

Back to Article Outline

Results 

Participant Characteristics 

Participant characteristics are presented in Table 1.

Table 1. Participant Characteristics

	FH N=47	No FH N=70	P Value
Men (No., %)	21(44.7)	32(45.7)	1.00
Age, y (mean, SD)	60.1(6.7)	61.0(7.0)	.49
Education, y (mean, SD)	10.1(5.2)	9.7(5.2)	.65
Family history of premature CHD (No., %)	15(31.9)	7(10.0)	.00
Ever smoked (No., %)	14(29.8)	35(50.0)	.04
Body mass index, kg/m2 (mean, SD)	26.5(3.5)	25.6(3.2)	.15
Baseline glucose (mean, SD)	91.5(8.7)	91.5(10.3)	1.00
Mild cognitive impairment (No., %)	10(21.3)	2(2.9)	.00
Baseline lipid profile, mg/dL
Total cholesterol (mean, SD)	386.3(65.7)	214.8(23.3)	.00
LDL cholesterol (mean, SD)	300.4(66.9)	136.1(17.8)	.00
HDL cholesterol (mean, SD)	60.7(12.8)	61.7(13.1)	.70
Triglycerides, (mean, SD)	128.2(40.3)	84.5(29.2)	.00
Apolipoprotein E status (FH n=46, Comp n=63)
ε4 carrier (No., %)	9(19.6)	11(17.5)	.81
ε2 carrier (No., %)	0(0.0)	9(14.3)	.01

CHD=coronary heart disease; FH=familial hypercholesterolemia; SD=standard deviation; LDL=low-density lipoprotein; HDL=high-density lipoprotein.

Demographic and clinical characteristics of the study subjects.

Cognitive Function 

None of the patients with familial hypercholesterolemia and mild cognitive impairment had a history of coronary events. Patients in the familial hypercholesterolemia group were significantly more likely than those in the no-familial hypercholesterolemia group to have developed mild cognitive impairment (relative risk 7.45; 95% confidence interval, 1.71-32.47). Ten subjects (21.3%) from the familial hypercholesterolemia group met criteria for mild cognitive impairment and exhibited neuropsychologic findings supporting this diagnosis. Of these patients, 7 were classified as having amnestic mild cognitive impairment and 3 were classified as having the multiple-domain form. On the other hand, only 2 subjects (2.9%) from the no-familial hypercholesterolemia group met the criteria for mild cognitive impairment (1 patient had the amnestic type, and 1 patient had the multiple-domain form).

There were significant differences between the familial hypercholesterolemia and the no-familial hypercholesterolemia groups in a number of individual cognitive measures, all in the direction of worse cognitive performance for those with familial hypercholesterolemia, as summarized in Table 2.

Table 2. Neuropsychologic Test Results

Neuropsychologic Tests	FH	No FH	P Value
MMSEa	28.6(1.6)	29.2(1.1)	.027
Benton Temporal Orientation test	0.38(2.0)	0.02(0.1)	.230
Memory impairment screen	6.8(1.6)	7.1(1.0)	.351
Verbal category fluency	19.5(4.8)	18.9(4.4)	.548
Clock drawing test
Order	9.3(1.3)	9.9(0.4)	.005
Copy	9.9(0.4)	10.0(0.2)	.102
Boston Naming Test	50.1(6.2)	50.9(6.7)	.528
RAVL test
A1	4.9(1.5)	4.8(1.5)	.784
A2	7.2(1.7)	7.3(1.5)	.949
A3	8.4(2.1)	9.1(1.5)	.048
A4	9.4(2.2)	10.2(2.1)	.075
A5	10.0(2.3)	11.2(2.0)	.014
Total	39.9(8.4)	42.7(7.1)	.085
Interference	7.6(2.9)	8.8(2.2)	.021
Delayed recall	7.3(2.9)	8.3(2.4)	.076
Digit span
Forward	5.6(0.8)	5.8(0.9)	.268
Backward	3.9(1.0)	4.2(1.0)	.271
VPA
Easy	16.3(2.1)	17.6(0.9)	<.001
Difficult	6.7(2.9)	8.9(2.2)	<.001
Total	15.8(3.5)	18.5(2.7)	<.001
TMT
Part A	50.9(21.9)	49.2(24.1)	.720
Part B	99.1(39.7)	84.5(28.4)	.053
Symbol Digit Modality	49.6(19.5)	52.8(20.6)	.456
Stroop test(Interference)	−2.1(8.8)	0.1(7.3)	.218
Global Deterioration Scale	2.13(0.4)	1.98(0.1)	.033
Hamilton Depression Rating Scale	2.2(2.6)	2.8(3.1)	.329

FH=Familial hypercholesterolemia; MMSE=Mini-Mental State Examination; RAVL=Rey Auditory Verbal Learning; TMT=Trail Making Test; VPA=Verbal Paired Associates.

Neuropsychologic assessment: standardized tests scores for FH and No-FH groups. Data are expressed as mean and SD.

Factors associated with cognitive functioning were explored using stepwise linear regression separately for each test (Table 3). Membership in the familial hypercholesterolemia group was independently associated with worse scores on the Mini-Mental State Examination (P=.01), Verbal Paired Associates (P=.00), and Rey Auditory Verbal Learning Interference (P=.049) tests. Cholesterol level was independently associated only with worse scores in the Trail Making Test Part B (P=.01). As expected, younger age and higher education years were independent predictors of better scores in several neuropsychologic measures. Finally, women scored significantly better than men in the Rey Auditory Verbal Learning Total (P=.049) and Delayed Recall (P=.01) tests. In the familial hypercholesterolemia group, the presence of memory complaints was associated with significantly decreased performance on neuropsychologic testing (Table 4). However, whether this clinical subjective marker of such lower performance will extend to larger samples is unknown.

Table 3. Independent Determinants of Cognitive Test Scores by Stepwise Multiple Linear Regression Analysis^a

Cognitive Tests	Independent Variables	Regression Coefficient B	Standardized Coefficient Beta	R2 for Model	Coefficient P Value
MMSEb	Constant	29.383	—	0.072	—
	FH group	−0.731	−0.269	—	.005
VPA	Constant	16.700	—	0.408	—
	Education per 5 y	0.709	0.221	—	.016
	FH group	−2.339	−0.355	—	<.001
RAVL
Total (A1-A5)	Constant	35.288	—	0.304	—
	Education per 5 y	2.128	0.280	—	.004
	Gender (female)	2.979	0.192	—	.049
Interference	Constant	8.600	—	0.037	—
	FH Group	−0.991	−0.192		.049
Delayed recall	Constant	12.611	—	0.093	—
	Age per 10 y	−0.942	−0.237	—	.018
	Gender (female)	1.436	0.273	—	.006
TMT Part B	Constant	31.433	—	0.399	—
	Age per 10 y	12.274	0.240	—	.006
	Education per 5 y	−16.541	−0.471	—	<.001
	Cholesterol	0.072	0.206		.013

MMSE=Mini Mental State Examination; RAVL=Rey Auditory Verbal Learning; FH=familial hypercholesterolemia; VPA=Verbal Paired Associates; TMT=Trail Making Test.

Table 4. Group Statistics within the Familial Hypercholesterolemia Group: Mild Cognitive Impairment versus No Mild Cognitive Impairment

FH=familial hypercholesterolemia; MCI=mild cognitive impairment; SD=standard deviation; MMSE=Mini Mental State Examination; VPA=Verbal Paired Associates; AVLT=Auditory Verbal Learning Test; TMT B=Trail Making Test Part B.

Intra-group comparison of neuropsychologic performance between patients with mild cognitive impairment and without mild cognitive impairment within the FH group analyzed by a 2-sided, 2-group independent samples t test for equality of means.

Imaging Studies 

Brain MRI studies were obtained from 10 patients with familial hypercholesterolemia and mild cognitive impairment and in neither of the 2 subjects with no familial hypercholesterolemia with mild cognitive impairment. None of the scans showed significant vascular lesions. A small lacunar pontine infarction was present in 2 of the patients with familial hypercholesterolemia; 1 patient had a small T2 hyperintense area in the subcortical parieto-occipital white matter. No areas of leukoaraiosis, T2 hyperintense white matter lesions (except for few minute T2 hyperintense periventricular white matter lesions in 2 patients), or other significant structural abnormalities were identified.

Back to Article Outline

Discussion 

In this study, we found an association between familial hypercholesterolemia and mild cognitive impairment. The proportion of patients with familial hypercholesterolemia exhibiting abnormal cognitive function and meeting criteria for mild cognitive impairment (21.3%) was significantly higher than that observed in the control group (2.9%; P=.00) and far exceeded the age-specific prevalence predicted from either epidemiologic studies in the general population or the prevalence observed in follow-up of large cohorts with milder sporadic hypercholesterolemia.², ³⁰, ³¹, ³² All 10 patients from the mild cognitive impairment group had history of memory complaints, and all of them had neuropsychologic profiles meeting the criteria for mild cognitive impairment. Therefore, the clinical presence of a memory complaint seemed to be (at least in this small sample) an important marker for mild cognitive impairment. In the non-familial hypercholesterolemia control group, however, there were 4 patients with memory complaints. The diagnosis of mild cognitive impairment, however, could be confirmed in only 2 of these 4 patients in the non-familial hypercholesterolemia group by neuropsychologic examination. When comparing the familial hypercholesterolemia group with the non-familial hypercholesterolemia group, score differences were more conspicuous with the Mini-Mental State Examination (P=.03), clock test (order: P=.01), Verbal Paired Associates (P=.00), and Rey Auditory Verbal Learning (A3: P=.048; A5: P=.01; interference: P=.02). The Trail Making Test Part B was almost significant at P=.053. There also were significant differences in the Global Deterioration Scale (P=.03). Our findings cannot be explained solely by large vessel cerebrovascular disease because this possibility was excluded clinically and by imaging. We were surprised, however, by the relative lack of white matter disease in patients with mild cognitive impairment.

The term “mild cognitive impairment” is generally used to define a transitional stage between normal cognitive function and dementia.^2,39-41 Estimates of its progression rate to Alzheimer's disease range from 10% to 15% per year compared with 1% to 2% for cognitively intact subjects.² There are disagreements on which tests are most accurate for the diagnosis of mild cognitive impairment; however, instruments that assess learning and retention of information seem to be best as predictors for progression to Alzheimer's disease.³³

We became interested in familial hypercholesterolemia because this condition may offer a unique window into the role of cholesterol metabolism in cognition. Two aspects of familial hypercholesterolemia may be of particular relevance to Alzheimer's disease. The first is that patients who have this disorder are exposed to higher cholesterol levels from early in life. This is important because as mentioned, hypercholesterolemia may be an early risk factor for Alzheimer's disease.¹⁰, ¹⁵ The second feature is the involvement of LDL receptors in familial hypercholesterolemia. LDL receptors have been implicated in synaptic maintenance and Alzheimer's disease pathogenesis. Members of the LDL receptors family are involved in amyloid beta clearance¹⁸, ³⁴ and synaptic plasticity from the brain, as supported by a growing body of literature.¹⁸ One study showed that when an Alzheimer's disease mouse model of amyloidosis was crossed into an LDL receptor-deficient background, the mice not only developed exacerbated age-dependent cerebral beta-amyloidosis but also developed more severe behavioral abnormalities than observed in mice with LDL receptor-intact Alzheimer's disease.³⁴

On the basis of the results of the current study, we propose the hypotheses that either early exposure to cholesterol or dysfunction of LDL receptors contributes to cognitive dysfunction in patients with familial hypercholesterolemia and that it is possible that similar mechanisms may be involved in mild cognitive impairment not associated with familial hypercholesterolemia. These hypotheses also might explain the apparently divergent results between our data and those from longitudinal studies of patients aged more than 65 years in whom (sporadic) hypercholesterolemia was not associated with increased risk of developing incident mild cognitive impairment. Presumably, these patients were neither exposed to high cholesterol levels early in life nor affected by LDL receptor mutations.

As in other populations with familial hypercholesterolemia who have been studied, only 50% of our patients had detectable LDL receptor mutations. Although this rate was higher among patients with familial hypercholesterolemia with mild cognitive impairment, it would be premature to make conclusions on this finding because of the small sample size. The possibility still stands, however, that in association with or independently of the lipid abnormalities, dysfunctions of LDL receptors or other unknown defects causing the familial hypercholesterolemia phenotype are linked to cognitive decline as patients grow older. The sample size in our study also was insufficient to dissect the effect of cholesterol from the effect of the LDL receptor mutations or their subtypes. Likewise, additional effects of lipoprotein E isoforms could not be fully assessed, although stepwise linear regression analysis suggested that the apolipoprotein E2 or E4 status did not affect cognitive performance (Table 3).

Back to Article Outline

Conclusions 

Cognitive impairment in familial hypercholesterolemia was unrecognized before this report probably because statins became widely available only in the early 1990s. Before that time, many patients with familial hypercholesterolemia would die of cardiovascular disease early before cognitive impairment could become manifest. Studies of larger samples of patients with familial hypercholesterolemia will allow further insights into the mechanisms and rates of conversion to dementia in this disorder.

Back to Article Outline

Acknowledgments 

We thank the participants in this study.

Back to Article Outline

References 

1. Masters CL, Beyreuther K. Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway. Brain. 2006;129:2823–2839
   • View In Article
   • CrossRef
2. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–308
   • View In Article
   • MEDLINE
   • CrossRef
3. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–890
   • View In Article
   • MEDLINE
   • CrossRef
4. Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J Clin Invest. 2005;115:1121–1129
   • View In Article
   • MEDLINE
   • CrossRef
5. Pappolla MA, Smith MA, 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
   • View In Article
   • MEDLINE
   • CrossRef
6. Refolo LM, Malester B, LaFrancois J, et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000;7:321–331
   • View In Article
   • MEDLINE
   • CrossRef
7. Refolo LM, Pappolla MA, 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
   • View In Article
   • MEDLINE
   • CrossRef
8. 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
   • View In Article
   • MEDLINE
   • CrossRef
9. Sparks DL, Martin TA, Gross DR, Hunsaker JC. Link between heart disease, cholesterol, and Alzheimer's disease: a review. Microsc Res Tech. 2000;50:287–290
   • View In Article
   • MEDLINE
   • CrossRef
10. Pappolla MA, Bryant-Thomas TK, Herbert D, et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. 2003;61:199–205
    • View In Article
    • CrossRef
11. Kivipelto M, Solomon A. Cholesterol as a risk factor for Alzheimer's disease—epidemiological evidence. Acta Neurol Scand Suppl. 2006;185:50–57
    • View In Article
    • MEDLINE
12. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men (The Honolulu-Asia aging study). Arterioscler Thromb Vasc Biol. 2000;20:2255–2260
    • View In Article
    • CrossRef
13. Notkola IL, Sulkava R, Pekkanen J, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;17:14–20
    • View In Article
    • MEDLINE
    • CrossRef
14. Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005;64:277–281
    • View In Article
    • CrossRef
15. Kivipelto M, Helkala EL, Laakso MP, 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
    • View In Article
16. Arvanitakis Z, Schneider JA, Wilson RS, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 2008;70(19 Pt 2):1795–1802Epub 2008 Jan 16
    • View In Article
    • CrossRef
17. Newschaffer CJ, Bush TL, Hale WE. Aging and total cholesterol levels: cohort, period, and survivorship effects. Am J Epidemiol. 1992;136:23–34
    • View In Article
    • MEDLINE
18. Zlokovic BV, Yamada S, Holtzman D, et al. Clearance of amyloid beta-peptide from brain: transport or metabolism?. Nat Med. 2000;6:718
    • View In Article
    • MEDLINE
    • CrossRef
19. Civeira F. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004;173:55–68
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (204 KB)
    • CrossRef
20. Damgaard D, Larsen ML, Nissen PH, et al. The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis. 2005;180:155–160
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (76 KB)
    • CrossRef
21. 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
    • View In Article
    • CrossRef
22. 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
    • View In Article
    • MEDLINE
    • CrossRef
23. Yamamoto T, Davis CG, Brown MS, et al. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984;39:27–38
    • View In Article
    • MEDLINE
    • CrossRef
24. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278–296
    • View In Article
    • MEDLINE
    • CrossRef
25. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502
    • View In Article
    • MEDLINE
26. Wenham PR, Price WH, Blandell G. Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991;337:1158–1159
    • View In Article
    • CrossRef
27. Otfried Spreen ES. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. New York: Oxford University Press; 1998;
    • View In Article
28. Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet. 2006;367:1262–1270
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (152 KB)
    • CrossRef
29. Portet F, Ousset PJ, Visser PJ, et al. Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure (Report of the MCI Working Group of the European Consortium on Alzheimer's Disease). J Neurol Neurosurg Psychiatry. 2006;77:714–718
    • View In Article
    • CrossRef
30. Canevari L, Clark JB. Alzheimer's disease and cholesterol: the fat connection. Neurochem Res. 2007;32:739–750
    • View In Article
    • MEDLINE
    • CrossRef
31. 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
    • View In Article
    • CrossRef
32. Stewart R, White LR, Xue QL, Launer LJ. Twenty-six-year change in total cholesterol levels and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol. 2007;64:103–107
    • View In Article
    • MEDLINE
    • CrossRef
33. Elias MF, Beiser A, Wolf PA, et al. The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch Neurol. 2000;57:808–813
    • View In Article
    • MEDLINE
    • CrossRef
34. 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
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (600 KB)
    • CrossRef