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February 01, 1996; 46 (2) ARTICLES

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease

Relation to apolipoprotein E polymorphism

M. Lehtovirta, H. Soininen, S. Helisalmi, A. Mannermaa, E.-L. Helkala, P. Hartikainen, T. Hanninen, M. Ryynanen, P. J. Riekkinen
First published February 1, 1996, DOI: https://doi.org/10.1212/WNL.46.2.413
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Abstract

Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease.In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon 4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (more than equals to 65 years), familial late-onset (FLO) (more than equals to 65 years), sporadic early-onset (SEO) (less than 65 years), and familial early-onset (FEO) (less than 65 years) patients and into three subgroups according to their ApoE genotype zero epsilon 4, one epsilon 4, and two epsilon 4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon 4 allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon 4 alleles had earlier age at onset of dementia than those with no epsilon 4 allele (63 plus minus 9 versus 68 plus minus 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon 4 allele in the delayed list learning (p less than 0.05) and from those with zero epsilon 4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon 4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon 4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon 4 allele.

NEUROLOGY 1996;46: 413-419

Clinical, genetic, pathologic, and neurochemical studies suggest that Alzheimer's disease (AD) is a heterogeneous entity. [1-4] In some pedigrees, it is autosomal dominant, usually an early-onset trait. [5] In a limited number of kindreds, there are specific missense mutations in the amyloid precursor protein gene on chromosome 21. [6-9] Most early-onset kindreds display evidence of genetic linkage on chromosome 14. [10-13] Recent studies about chromosome 14 kindreds show that these patients appear to have a shorter duration of the disease, more prominent aphasia, more prevalent and early appearing seizures, and myoclonus. [14,15] One study found a linkage of late-onset familial AD to the proximal long arm of chromosome 19 at the region where the apolipoprotein E (ApoE) gene is localized. [16] ApoE is a polymorphic lipoprotein defined by three alleles: epsilon 2, epsilon 3, and epsilon 4. Several studies suggested that the epsilon 4 allele is associated with an increased risk of developing AD in both late-onset familial and sporadic AD. [17-20] The epsilon 4 allele is also associated with an earlier age at onset of AD. [19,21] The subjects with the epsilon 4 allele have higher levels of total and low-density-lipoprotein cholesterol and a higher risk for myocardial infarction and coronary heart disease than those without the epsilon 4 allele. [22,23] ApoE is produced and secreted in the CNS by astrocytes. [24] Its presence in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid [25,26] and the in vitro binding of ApoE of the CSF to synthetic beta/A4 protein suggest a role in the pathogenesis of AD. [17]

The clinical characteristics and prognosis vary in AD. The most common feature is a loss of memory followed by dysfunction of visuospatial skills, language, and executive functions. An earlier study reported that AD patients with familial aggregation compared with sporadic cases had more marked impairment of language, praxia, and graphia, [27] but later studies have not been able to replicate these findings. [28-31]

We studied AD patients at the early stage of the disease and divided the patients into subgroups according to familial aggregation and age of onset and their ApoE genotype. We examined differences in the profile of cognitive deficits or clinical characteristics between the different subgroups.

Methods.

We studied 58 patients fulfilling the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association of probable AD. [32] Sixteen age- and sex-matched elderly subjects without signs of dementia or other neurologic diseases served as control subjects. Table 1 shows the clinical characteristics of the subjects. The ethics committee of University Hospital and University of Kuopio approved the study. All subjects and caregivers of demented patients gave their informed consent for participation in the study.

The AD patients underwent the following examinations: general physical and clinical neurologic examination; assessment of clinical severity using the Mini-Mental Status examination (MMSE) [33] and Brief Cognitive Rating Scale (BCRS), [34] assessment of extrapyramidal signs using Webster Parkinson Disease Scale, [35] assessment of depressive symptoms by Hamilton scale, [36] laboratory tests to exclude secondary causes of dementia, CSF analysis, neuropsychological tests, EEG and event-related evoked potentials, single photon emission CT, and MRI of the brain. All patients scored less than four in the modified ischemic scale. [37] The family history of dementia was obtained by asking the next of kin whether there were or had been other demented family members and by examining their medical records when available. If the existence of at least two first-degree relatives with dementia in two different generations was documented, the dementia was considered familial. We also recorded the occurrence of concomitant disease, such as coronary heart disease, hypertension, gastrointestinal disease, urogenital disease, malignancy, diabetes, and hypothyroidism or hyperthyroidism. The diagnosis of these disorders was accepted when it was present in the medical records. The presence of rigidity, hypokinesia, tremor at rest, orofacial dyskinesia, myoclonus, hallucinations, delusions, and different kinds of paresis was recorded in the neurologic examination. The occurrence of epileptic seizures, hallucinations, and delusions was also inquired from the caregivers. The use of medication was recorded. The AD subgroups did not differ significantly in the use of CNS active drugs; only four patients were on a neuroleptic regimen.

Neuropsychological testing.

Memory functions were examined with list learning test using shopping items. [38] A yes or no recognition of the words in the list was asked after a 30-minute delay filled with other psychometric tests. Immediate memory was also examined with Wechsler Logical Memory Test [39] using one story and with Heaton Visual Reproduction Test. [40] The delayed recall of the story and the figures were asked after a 30-minute delay again filled with other psychometric tests.

Verbal functions were examined with Boston Naming Test [41] and with the vocabulary subtest of Wechsler Adult Intelligence Scale, including every second item. [42]

Visuospatial functions were examined with copy-a-cube test. [43] The subject was asked to copy a two-dimensional drawing of a three-dimensional cube. The drawing was scored for correct number of lines, the presence and correctness of all angles, and the three-dimensionality of the drawing. In the clock setting test, [43] the subject was asked to draw the hour and minute hands on four clocks that have 12 indistinguishable slashes (instead of numbers) positioned symmetrically around the inner counter of their faces. The copy of figures of Heaton Visual Reproduction Test and the Block Design subtest of Wechsler Adult Intelligence Scale were also used. [42]

Praxic functions of the hand were investigated using a modification of Luria's method, choosing three examples of each functional area: simple movements, kinesthetic basis of movement, visuospatial organization, dynamic organization of motor act, and ideomotor praxia. The maximum score was 48. [38]

Executive functions were examined with Wisconsin Card Sorting Test using Nelson's version, [44] Trail-Making test A and B, [45] and the Verbal Fluency Test. The maximum time of 150 seconds for Trail-Making A and 300 seconds for Trail-Making B was allowed. If the test was not completed in the time allowed, the missing letters or numbers were scored as omissions. In the Verbal Fluency Test, the subject was asked to produce as many words as they could beginning with letters P, A, and S in 1 minute for each letter. In the Category Fluency Test, the subject was asked to generate as many names of animals as possible in 1 minute. In fluency tests, the score was number of words correctly named. [46]

Determination of ApoE genotype.

DNA was prepared from the venous blood of AD patients and control subjects by standard procedures. The ApoE genotypes were analyzed using the polymerase chain reaction (PCR) as described earlier [47,48] with slight modifications. The ApoE genotypes were identified using HhaI-digestion of the PCR-amplified samples. Digested DNA fragments were analyzed by polyacrylamide gel electrophoresis, and the separated DNA fragments were visualized by staining with ethidium bromide.

Statistical analysis.

We used ANOVA for independent samples to detect differences of means over the control subject and AD patient subgroups. All AD patients were classified first into those with sporadic late-onset (SLO, more than equals to 65 years, N equals 25), familial late-onset (FLO, more than equals to 65 years, N equals 15), sporadic early-onset (SEO, less than 65 years, N equals 9), and familial early-onset (FEO, less than 65 years, N equals 9) disease and second into those with two (N equals 13), one (N equals 24), and zero (N equals 21) ApoE epsilon 4 alleles. Duncan method was applied in the post-hoc analysis. If the data did not meet the assumptions of parametric methods, we used Kruskall-Wallis analysis of variance over the subgroups and Mann-Whitney U-test to determine which groups differed from each other. The subgroup analyses were made in two separate steps. Chi-square test was used for testing the differences in the categoric data. Differences in allele frequencies between the study groups were tested by Z-statistics for proportions. The level of significance was set at p less than 0.05.

Results.

AD patients did not differ in age or sex from control subjects. However, when AD patients were divided into different subgroups according to their ApoE genotypes, we found that the AD patients with the two epsilon 4 alleles had significantly earlier onset of the disease and were younger than the AD patients with one or zero epsilon 4 allele. The control subjects had longer education and higher MMSE than the AD patients. However, the AD subgroups did not differ in education, duration of dementia, clinical severity as assessed using MMSE and BCRS, scores of the Webster scale used for the evaluation of extrapyramidal signs, nor in the Hamilton depression scale Table 1.

View this table:

Table 1. Clinical characteristics of control subjects and Alzheimer patient subgroups

The ApoE genotypes and allele frequencies between the AD subgroups divided by familial aggregation and age of onset did not differ significantly. The allele frequencies for all AD patients and control subjects were epsilon 4 0.43 versus 0.13, epsilon 3 0.54 versus 0.88, and epsilon 2 0.03 versus 0. These differences were not statistically significant Table 2.

View this table:

Table 2. Apolipoprotein E genotypes and allele frequencies in AD patients and control subjects

In the statistical analyses of subgroups divided by familial aggregation, the occurrence of rigidity (present in 6/58 of all patients, 10%), hypokinesia (9, 16%), tremor at rest (6, 10%), myoclonus (1, 2%), hallucinations, delusions (4, 7%), and epileptic seizures (6, 10%) was similar in patients with SEO, FEO, SLO, and FLO. The FEO patients had more orofacial dyskinesia (2, 3%) than other subgroups (chi-square 11.3, df3, p equals 0.01) Figure 1 (A). After that, the same analyses were performed over the three ApoE subgroups. Hypokinesia was significantly more common in patients with one epsilon 4 allele than in other ApoE subgroups Figure 1 (B). These findings were not related to the use of neuroleptics, age, age at onset, duration, or clinical severity of dementia assessed using MMSE and BCRS. Hypokinesia in AD patients with one epsilon 4 allele was associated with excess of Webster's scores compared with patients with zero or two epsilon 4 alleles (5.7 versus 1.2). Presence of coronary heart disease (in 34% of all AD patients), hypertension (22%), gastrointestinal disease (10%), urogenital disease (9%), malignancy (2%), hypothyroidism or hyperthyroidism (0/2%), or type II diabetes mellitus (14%) did not differ significantly in AD subgroups.

Figure

Figure 1. The frequency of different neurologic symptoms in AD subgroups. (A) The data are presented as percent of the patients with a distinct finding within each AD subgroup. Subgroups SLO (more than equals to 65 years), FLO (more than equals to 65 years), SEO (less than 65 years), and FEO (less than 65 years). The only significant difference is a higher frequency of orofacial dyskinesia in FEO patients (chi-square test, p less than 0.05). (B) Subgroups stratified according to the ApoE epsilon 4 alleles. Patients with one epsilon 4 allele had significantly more often hypokinesia than those with zero or two epsilon 4 alleles (chi-square test, p less than 0.05).

The performance of all AD subgroups was significantly impaired compared with control subjects in all tests assessing memory and other cognitive functions. When education was used as a covariate in ANOVA, the results did not change. The familial and sporadic AD subgroups did not differ significantly from each other (data not shown). However, when the AD patients were divided into ApoE subgroups, patients with two epsilon 4 alleles had lowest scores on immediate and delayed memory tests. They differed significantly from those with zero epsilon 4 allele in delayed list learning. In addition, AD patients with one epsilon 4 and two epsilon 4 alleles differed significantly from those with zero epsilon 4 allele in immediate and delayed story recall. In immediate list learning, patients with zero epsilon 4 allele differed significantly from patients with one. When percent retention scores were calculated (how much the delayed memory was from the immediate memory), patients with two epsilon 4 alleles had significantly lower scores in list learning than the patients with zero or one (ANOVA, F(2,54) equals 7.2, p less than 0.01) and in story recall from patients with zero (ANOVA, F(2,39) equals 4.7, p less than 0.05). In visual reproduction, the subgroups did not differ from each other. In contrast, verbal functions were better preserved in the homozygous epsilon 4 patients; they differed significantly from the patients without epsilon 4 allele in the vocabulary test and from the heterozygous epsilon 4 patients in Boston naming Table 3

View this table:

Table 3. Scores of tests assessing memory and other cognitive functions for controls and AD patients with two, one, and zero apolipoprotein E epsilon 4 alleles

Discussion.

Previous studies reported an earlier age of dementia onset and more severe cognitive deficits, especially aphasia, agnosia, and apraxia, in familial than in sporadic AD. [2,27,50,51] We could not replicate these findings in our series of AD patients who were divided into four subgroups: SLO (more than equals to 65 years), FLO (more than equals to 65 years), SEO (less than 65 years), and FEO (less than 65 years). The AD patients of the present study were at the early stage of the disease and did not differ in global clinical severity, age, education, or sex. However, when we divided the AD patients according to ApoE genotype (two, one, and zero epsilon 4 alleles), we found that the AD patients with two epsilon 4 alleles had the lowest scores on immediate and delayed tests assessing verbal memory. In contrast, the verbal functions of the AD patients with two epsilon 4 alleles were better preserved than those of the AD patients with one or zero epsilon 4 allele; significant differences were observed in Boston naming and Vocabulary tests. Otherwise, the profile of cognitive dysfunctions did not differ between the AD subgroups with different ApoE genotypes. Even though the global disease severity was equal, the homozygous epsilon 4 patients seemed to have more severe memory dysfunction. This could indicate that ApoE epsilon 4 allele interferes with the course of AD and, especially, affects structures that are involved in the memory processing, such as the hippocampus.

The frequency of the epsilon 4 allele in a previous population-based study [52] from the same area was 0.40 in AD patients and 0.17 in control subjects (our epsilon 4 frequency among all AD patients was 0.43 and in control subjects 0.13). These frequencies are comparable with recently reported frequencies around the world. [16,17,53,54] The epsilon 4 allele frequencies did not differ between patients with sporadic and familial disease or early- (less than 65 years) and late-onset (more than equals to 65 years) AD. In this respect, the results disagree with earlier reports. This may be attributed to the populations studied, because the frequency of the ApoE alleles is dependent on the ethnic and genetic background as well as age of the population. The compiled data show differences in ApoE allele frequencies between caucasians, Japanese, Chinese, and black populations. The populations in southern Europe have the same frequencies as are found in Japanese populations; however, caucasian populations in northern Europe and the United States have a 1.5 to 2 times higher frequency of the epsilon 4 allele. [55] Previous studies reported a decrease in age at disease onset between 3.5 and 8 years for each epsilon 4 allele. [17,19,54] However, we did not find the decrease in age at onset to be linearly related to the number of epsilon 4 alleles as proposed earlier. In our study, the average decrease in age of onset was 5 years in the patients with two epsilon 4 alleles compared with those with one or zero epsilon 4 allele.

Others reported that the ApoE epsilon 4 allele was associated with a high risk for coronary artery disease. [23,56,57] We studied the medical records to determine whether the AD patients carrying the ApoE epsilon 4 allele have an increased frequency of hypertension or coronary heart disease and found no differences in the prevalence of these diseases across the ApoE subgroups. The evaluation of coincident diseases among AD subgroups did not reveal any other differences either.

The clinical examination included signs of rigidity, hypokinesia, tremor, orofacial dyskinesia, myoclonus, hallucinations, delusions, paresis, and epileptic seizures. Previous studies reported myoclonus to be present in frequencies between 4.3 and 9.9% and to relate to an earlier age of onset and greater severity of dementia. [1,2,50,58] In our series, myoclonus was present in only one patient (2%). Seizures develop in the clinical course of AD and the frequency averages 10% in different studies. [58-60] In our study, the frequency of seizures was 10%, but all the seizures of the patients were solitary; none of our patients had epileptic medication or irritative EEG activity. Earlier studies found extrapyramidal symptoms, especially rigidity and bradykinesia, to be frequent findings in patients with advanced AD [61,62] and patients older than 65 years. [63] The frequency varies between 13 and 67%. In addition, an early appearance of bradykinesia and rigidity seems to be associated with faster progression of cognitive symptoms and disability. [1,2,58,63] In our study, the frequency of rigidity was 10%, hypokinesia 16%, and tremor 10%, but our patients were at the early stage of the disease and that might explain lower frequencies than previously reported. There were no significant differences in the presence of rigidity and tremor over the subgroups, but the patients with one epsilon 4 allele had more hypokinesia that was not related to age or other clinical characteristics. Familial early-onset patients had more orofacial dyskinesia than other subgroups, which was not related to the use of neuroleptics, antidepressants, or psychiatric symptomatology (hallucinations, delusions, agitation, depression, or paranoia).

Recent studies reported in chromosome 14 linked familial AD patients early appearing myoclonus, seizures, early progressive aphasia, and more severe cognitive deterioration. The disease is also more rapid and shorter in duration than typical late-onset AD. [14,15] The AD patients with amyloid precursor protein mutations exhibit the age at onset around age 50 years; the initial symptom is most commonly memory impairment and later a global cognitive dysfunction develops. They do not usually have extrapyramidal symptoms or seizures at the early stage of the disease. [64,65] Our patients were at the early stage of AD, and none with familial AD had the age at onset at age 40 years as described in patients with linkage on chromosome 14. This might explain why we did not find more frequently myoclonus, seizures, or severe cognitive deficits in early-onset patients with familial AD.

In conclusion, we could not confirm the earlier results of severe aphasia, agnosia, and apraxia in AD patients with familial aggregation, but our AD subgroups were similar in the profile of neuropsychological deficits. In addition, we found that AD patients with two epsilon 4 alleles had earlier age at onset of dementia and lower scores on memory tests than those with one or zero epsilon 4 allele. The AD subgroups did not differ in global disease severity, education, or sex. The epsilon 4 allele may interfere with the course of AD, and further studies are required.

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