Age at onset of dementia and age of menopause in women with Down's syndrome

Menstrual status and the age of menopause were investigated in 143 Irish females with Down's syndrome (DS). The average age of menopause in 42 subjects (44.7 years) was younger than in the general population. The age at onset of dementia correlated with the age of menopause. This finding may be a manifestation of accelerated ageing in DS or point to oestrogen deficiency being an independent risk factor for the development of Alzheimer's dementia in DS. The implications of this finding for possible treatments are discussed.     

Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age

We examined the relation between oestrogen containing hormone therapy (HT) used for more than 6 months and Alzheimer's disease (AD) risk in 971 postmenopausal women (426 AD patients, 545 relatives without dementia). There was a significant interaction between age and HT use on AD risk (p = 0.03). In stratified analyses, a significant protective association was seen only in the youngest age tertile (50-63 years; odds ratio = 0.35, 95% confidence interval = 0.19 to 0.66). Results must be considered cautiously in light of recent clinical trial evidence that oestrogen plus progestin increases dementia incidence in older postmenopausal women. However, our observational findings are consistent with the view that HT may protect younger women from AD or reduce the risk of early onset forms of AD, or that HT used during the early postmenopause may reduce AD risk.     

Risk factors in Alzheimer's disease: a clinicopathologic study.

We investigated potential risk factors for Alzheimer's disease (AD) in a clinicopathologic study of 407 patients with definite AD, 100 non-Alzheimer dementia patients, and 50 normal subjects. The AD patients had more first-degree relatives with dementia than the non-AD dementia group (odds ratio of 1.85, 95% confidence interval of 1.07-3.20) or the normal elderly (odds ratio of 3.60, 95% confidence interval of 1.50-8.64) but did not have significantly more head injuries, medical and psychiatric illnesses, or relatives with Down's syndrome. The AD patients with a family history of dementia had their dementia at a later age than those without an affected relative. These findings indicate a familial risk for AD that is greater than for other dementing illnesses and has age-related penetrance. This study does not support other putative risk factors for AD such as head trauma and familial Down's syndrome.     

The natural history of dementia in Down's syndrome

In a prospective longitudinal study with death as the end point in 17 middle-aged patients with Down's syndrome, dementia was clinically diagnosed in 15 patients, by means of careful observations in daily circumstances. Autopsies were performed in 10 cases: 8 demented patients and 2 nondemented patients. Neuropathologically, Alzheimer-type abnormalities were demonstrated in 9 patients, both demented and nondemented, and combined Alzheimer-type abnormalities with infarctions were demonstrated in 1 patient. In the 14 demented patients who did not show evidence of cerebrovascular or systemic vascular disease, dementia had an early onset and was rapidly progressive (mean age at onset, 51.3 years in the moderately retarded patients and 52.6 years in the severely retarded patients; mean duration of symptoms, respectively, 4.9 and 5.2 years). Cognitive and behavioral decline corresponded to symptoms of dementia of the Alzheimer's type in patients without Down's syndrome, but often were not recognized early. In the present group of patients, there was a remarkably high incidence of gait and speech deterioration. Also, the incidence of epileptic seizures and myoclonus was about eightfold, as compared with dementia of the Alzheimer's type in patients without Down's syndrome.     

Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down's syndrome: implications for the prodromal phase of Alzheimer's disease.

OBJECTIVE: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. METHOD: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume. RESULTS: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. CONCLUSIONS: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.     

Alzheimer's disease: genetic aspects and associated clinical disorders

Genetic aspects and associated clinical disorders were studied in a consecutive series of 68 men and women in whom Alzheimer's disease appeared at or before age 70. Secondary cases of dementia were found in 17 (25%) of the families, affecting 22 of the probands' siblings and parents. The cumulative incidence of Alzheimer's disease in these relatives was approximately 14% at age 75. An increased frequency of Down's syndrome was observed among relatives of the probands: a rate of 3.6 per 1,000, as compared with an expected rate of 1.3 per 1,000. A history of thyroid disease was established in 9 (19.6%) of the 46 female probands, a frequency greater than that reported in the general population. There was no excess of hematological malignancies among the blood relatives, and parental age at the time of birth of the probands did not differ from the norm. The results of this study indicate that early-onset Alzheimer's disease is associated with a genetic factor manifested in a substantial familial aggregation of dementia, a probable excess of Down's syndrome in the probands' relatives, and a possible association with thyroid dysfunction in women with this form of dementia.     

Preventing dementia

Primary prevention will become increasingly important as dementia prevalence increases and effective retardive therapies are developed. To date, only one randomized controlled trial (involving treatment of systolic hypertension) has demonstrated that the incidence of dementia can be reduced. Physicians should remain alert to possible secondary causes of dementia and correct these whenever possible. Primary and secondary prevention of stroke should reduce dementia related to cerebrovascular disease either directly or as a comorbid factor in Alzheimer's disease (AD). Epidemiological studies have revealed a number of risk factors for AD including genetic mutation, susceptibility genes, positive family history, Down's syndrome, age, sex, years of education, head trauma and neurotoxins. In case-control studies non-steroidal anti-inflammatory medication and estrogen replacement therapy appear to decrease the relative risk of developing AD. Further research to develop and test preventative therapies in AD and other dementias should be strongly encouraged.     

Use of electroencephalography to detect Alzheimer's disease in Down's syndrome

We studied the role of electroencephalography (EEG) in the diagnosis of Alzheimer-type dementia in patients with Down's syndrome. 197 patients with Down's syndrome were monitored for 5 to 8 years. Aspects of cognitive functioning were assessed twice yearly. EEGs were scored in a blind fashion, and changes in the EEG were compared to changes in cognitive functioning. When possible, a neuropathological post-mortem examination was performed. Cognitive functioning was drastically reduced in 29 patients. The dominant occipital rhythm became slower at the onset of the cognitive deterioration, and eventually disappeared. In 11 of these patients neuropathological examination showed a severe form of Alzheimer's disease. Changes in the frequency of the dominant occipital rhythm could distinguish between Alzheimer's disease or other causes as underlying the cognitive decline. Slowing of the dominant occipital rhythm seems to be related to Alzheimer's disease in patients with Down's syndrome, and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration. The EEG is thus an important tool in the clinical diagnosis of Alzheimer-type dementia in patients with Down's syndrome.     

The development of Alzheimer's disease in Down's syndrome assessed by auditory event-related potentials

ABSTRACT. Several studies have reported changes in auditory event-related potentials in patients with Alzheimer's type dementia, These include an increase in latency and a reduction in amplitude of the P300 (P3) response, a late positive component generated about 300 ms after an unexpected stimulus. Alzheimer's type dementia is an almost invariable acompaniment of ageing in Down's syndrome. This study was designed to assess the usefulness of the auditory P300 response as a measure of the onset of dementia in Down's subjects, who because of poor language development may be difficult to assess by psychological tests. Auditory event-related potentials were recorded from 89 Down's subjects, aged 16–66 years. A control group of 29 mentally retarded subjects with fragile-X syndrome and 83 normal volunteer controls were also tesled. Clinical psychological testing found evidence of dementia in 16 Down's subjects and none with fragile-X. Furthermore, in the Down's population but not the fragile-X or control groups, there was a marked increase in P300 latency with age starting around 37 years. In controls, the effect of age on P300 latency became significant some 17 years later around the age of 54 years. The premature effect of age on P300 in Down's syndrome was due to the prolonged P300 latency in the 16 subjects showing signs of dementia. It was confirmed that P300 latency increase reflects the development of Alzheimer's dementia in Down's subjects.     

Down syndrome, Alzheimer's disease and seizures

Neuropathologically, Alzheimer-type abnormalities are demonstrated in patients with Down syndrome (DS), both demented and nondemented and more than a half of patients with DS above 50 years develop Alzheimer's disease (AD). The apolipoprotein E epsilon4 allele, oestrogen deficiency, high levels of Abeta1-42 peptide, elevated expression of BACE2, and valine polymorphism of prion protein gene are associated with earlier onset of dementia in DS individuals. Advanced AD alone may be an important risk factor for new-onset seizures in older adults and age above 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. DS patients aged over 45 years are significantly more likely to develop Alzheimer's disease than those less than 45 years and up to 84% demented individuals with DS develop seizures. Late-onset epilepsy in DS is associated with AD, while early-onset epilepsy is associated with an absence of dementia. In AD patients with a younger age of dementia onset are particularly susceptible to seizures. DS adults with epilepsy score significantly higher overall on the adaptive behaviour profile. Language function declined significantly more rapidly in AD patients with seizures and there is a good correlation between the severity of EEG abnormalities and cognitive impairment whereas in DS slowing of the dominant occipital rhythm is related to AD and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration.     

ALZHEIMER''S PRESENILE DEMENTIA, SENILE DEMENTIA OF ALZHEIMER TYPE AND DOWN''S SYNDROME IN MIDDLE AGE FORM AN AGE RELATED CONTINUUM OF PATHOLOGICAL CHANGES

A loss of nerve cells from the nucleus basalis of Meynert and the locus caeruleus together with a reduction in nucleolar volume in surviving cells was measured in twenty-two patients with Alzheimer's disease who ranged in age from 48-92 years, and in six patients over 50 years of age with Down's syndrome who also showed extensive formation of senile plaques and neurofibrillary tangles within their cerebral cortex. When compared with age matched controls the severity of these changes was greatest in the younger patients with Alzheimer's disease, but this fell with age such that by 90 years the level of change in Alzheimer's disease approached that in old age alone. There were only slight differences in the extent of these pathological changes in those patients with Down's syndrome when compared with others of similar age with Alzheimer's disease. It is concluded that the presenile dementia of Alzheimer's disease, the senile dementia of Alzheimer type and Down's syndrome in middle age all form an age-related continuum of pathological change.     

A prospective study of menopause in women with Down's syndrome

The present study prospectively examined the age at menopause of 92 women with Down's syndrome (DS) and the influence of hypothyroidism on the age of menopause. Three methods were used to determine the distribution and median age at onset of menopause: (1) Kaplan–Meier life tables; (2) Cox proportional hazards modelling; and (3) maximum likelihood logistic regression. All three methods provided distributions and similar estimates of the median age at menopause, which was ≈46 years. The presence of hypothyroidism did not influence age at menopause. The earlier‐than‐expected age at onset of menopause suggests that women with DS are at an increased risk for post‐menopausal health disorders.     

A Highly Selective and Specific PET Tracer for Imaging of Tau Pathologies

CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.     

Calcification of the basal ganglia in Down's syndrome and Alzheimer's disease

Summary The prevalance and severity of calcification in the basal ganglia (BGC) has been examined histopathologically in 194 patients divided into ten diagnostic categories. The prevalence and severity of BGC was greater (for age) in Down's syndrome and in patients under 75 years of age with Alzheimer's disease. The severity, but not the prevalance, of BGC was greater in Down's syndrome than in patients of similar age with Alzheimer's disease. Both the prevalence and the severity of BGC in patients over 75 years of age with Alzheimer's disease were as expected for age alone. The increased prevalence and severity of BGC in Down's syndrome and in younger patients with Alzheimer's disease appeared not to be related to the presence of dementia or degenerative disease per se, nor was it affected by the presence of cerebral infarction. BGC may result from an age-related disturbance of the structure of arteries within the globus pallidus, which is accelerated (or occurs prematurely) in Down's syndrome and in younger patients with Alzheimer's disease, but probably does not form part of that spectrum of changes that constitutes the pathological basis of Alzheimer's disease.     

APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome.

BACKGROUND: Alzheimer disease (AD) neuropathology is present in Down syndrome (DS) after age 35, but dementia onset varies from ages 40 to 70 years. Because of small sample sizes and nonuniform determination of dementia, previous studies produced differing results on the influence of APOE subtypes on AD in DS. OBJECTIVE: To determine the influence of the APOE genotype and gender on development of AD in adults with DS to ascertain similarities with AD in the general population. METHODS: A total of 100 adults with DS (ages 35 to 79 years), almost all of whom were longitudinally assessed by neurologists, underwent APOE genotyping. Dementia onset was determined using criteria applied from the Tenth International Classification of Mental and Behavioral Disorders. This cohort contains the largest number of DS subjects with dementia (n = 57) in a single study, thus increasing reliability of the results. RESULTS: The epsilon2 allele frequency was 4% in those with dementia versus 13% in those without dementia (p = 0.03); epsilon4 allele frequency was 18% in those with dementia versus 13% in those without dementia (p = 0.45). Using APOE-epsilon3/3 as the reference group, the risk ratio for the development of AD at any given time was 0.34 for the APOE-epsilon2/3 group (p = 0.04) and 1.44 for the APOE-epsilon(3/4,4/4) group (p = 0.25). Women were 1.77 times as likely to dement as men at any given point in time (p = 0.04). CONCLUSIONS: The epsilon2 allele confers a protective effect, and women with DS have an increased risk for AD, as in the general population. In this sample, epsilon4 does not confer a significantly increased risk for AD in DS.     

Are sex and educational level independent predictors of dementia and Alzheimer's disease? Incidence data from the PAQUID project

OBJECTIVES: To examine the age specific risk of Alzheimer's disease according to sex, and to explore the role of education in a cohort of elderly community residents aged 65 years and older. METHODS: A community based cohort of elderly people was studied longitudinally for 5 years for the development of dementia. Dementia diagnoses were made according to the DSM III R criteria and Alzheimer's disease was assessed using the NINCDS-ADRDA criteria. Among the 3675 non-demented subjects initially included in the cohort, 2881 participated in the follow up. Hazard ratios of dementia were estimated using a Cox model with delayed entry in which the time scale is the age of the subjects. RESULTS: During the 5 year follow up, 190 incident cases of dementia, including 140 cases of Alzheimer's disease were identified. The incidence rates of Alzheimer's disease were 0.8/100 person-years in men and 1.4/100 person-years in women. However, the incidence was higher in men than in women before the age of 80 and higher in women than in men after this age. A significant interaction between sex and age was found. The hazard ratio of Alzheimer's disease in women compared with men was estimated to be 0.8 at 75 years and 1.7 at 85 years. The risks of dementia and Alzheimer's disease were associated with a lower educational attainment (hazard ratio=1.8, p<0.001). The increased risk of Alzheimer's disease in women was not changed after adjustment for education. CONCLUSION: Women have a higher risk of developing dementia after the age of 80 than men. Low educational attainment is associated with a higher risk of Alzheimer's disease. However, the increased risk in women is not explained by a lower educational level.     

Estrogen alters amyloid precursor protein as well as dendritic and cholinergic markers in a mouse model of Down syndrome

Individuals with Down syndrome (DS) develop the pathological hallmarks of Alzheimer's disease at an early age, later followed by memory decline and dementia. Women with DS are twice as likely to undergo early menopause, and levels of estradiol correlate with onset of cognitive decline in these women. We have demonstrated that a mouse model of DS, mice with segmental trisomy of chromosome 16 (Ts65Dn), develop a significant deficit in both reference and working memory as young adults (6-10 months of age), coupled with phenotypic loss of cholinergic neurons in the basal forebrain and altered growth factor levels. In the present study we examined cholinergic and dendritic markers in the hippocampal formation and levels of the amyloid precursor protein (APP) in different brain regions of Ts65Dn mice treated with estradiol for 60 days. The density of the dendritic marker Map2 was significantly decreased in the hippocampal formation of middle-aged trisomic mice (9-15 months old), and the density of cholinergic neurites (acetylcholinesterase [AChE] histochemistry) was also decreased in specific layers of the hippocampus. Treatment with 17beta-estradiol alleviated the decreases in Map2 and AChE staining, but had no effect on full-length APP levels in the hippocampus. In contrast, a main effect of treatment on APP levels in the striatum was noted, with significant elevations observed in controls and trisomics. These findings demonstrate that estrogen can alleviate deficits in cholinergic and dendritic elements in the hippocampal formation and further strengthens the rationale to explore estrogen replacement therapy in women with DS.     

Physical disorders and causes of death in relatives of Alzheimer's disease patients

BACKGROUND: Genetic risk factors are important in Alzheimer's disease (AD). These risk factors might also predispose for other disorders. This might lead to a familial coaggregation of AD and other disorders, e.g. Down's syndrome or Parkinson's disease. In the present study the risk of physical disorders in relatives of AD patients, of depressed patients and of control subjects were compared. METHODS: Family history and, if possible, interview information on physical disorders and causes of death in relatives of 146 patients with AD, 168 patients with major depression (MD) and 136 controls was collected. Statistical comparisons were performed using chi-square tests and, if necessary, logistic regression analysis accounting for age, gender and interview status. RESULTS: In contrast to our hypotheses, there was no increased risk of cerebrovascular disease, Down's syndrome, haematological malignancies or Parkinson's disease in relatives of AD patients compared with relatives of patients with MD and of controls. The explorative analysis revealed that congenital malformations, i.e. malformations of the heart or of the extremities, were slightly increased in relatives of AD patients. Relatives of patients with AD or MD were at increased risk of dying as a result of accidents, in most cases falls in advanced age, and relatives of patients with MD were at slightly increased risk of dying from gastroenterologic diseases, in most cases complications of peptic ulcers. CONCLUSION: The results do not support a major overlap between the genetic risk of AD and the genetic risk of cerebrovascular disease, Down's syndrome, haematological malignancies or Parkinson's disease. The finding of an increased risk of congenital malformations in relatives of AD patients needs further replication before it can be stated. The increased risk of dementia or depression with cognitive impairment in elderly relatives of patients with AD or MD increases the risk of accidents like falls. The genetic risk of depression in relatives of patients with MD could have a negative influence on the prognosis of peptic ulcera.     

Endogenous sex hormones, cognitive decline, and future dementia in old men

OBJECTIVE: To estimate the association of endogenous levels of bioavailable testosterone and estradiol with risk for cognitive decline and dementia in old men. METHODS: Within the population-based, prospective Honolulu-Asia Aging Study, 2,974 men, aged 71 to 93 years, without dementia were reexamined 3 times over an average of 6 years for development of dementia and cognitive decline. Cognitive decline was measured with the Cognitive Abilities Screening Instrument. Incident dementia was diagnosed according to standard criteria. A total of 134 men experienced development of Alzheimer's disease (AD; including 40 cases with contributing cerebrovascular disease) and 44 experienced development of vascular dementia. RESULTS: Adjusting for age and other covariates, testosterone was not associated with risk for dementia (using Cox regression analyses) or cognitive decline (using random coefficient analyses). However, higher levels of estradiol were associated with risk for AD (hazard ratio per standard deviation increase, 1.25; 95% confidence interval, 1.05-1.47) and AD with cerebrovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.38). Also, compared with the lowest tertile of estradiol, men in the middle and highest tertile of estradiol had 0.24 and 0.28 points lower Cognitive Abilities Screening Instrument scores, respectively, for each year increase in age. INTERPRETATION: In old men, endogenous testosterone levels are not associated with risk for cognitive decline and AD, whereas higher estrogen levels increase risk for cognitive decline and AD.