Alzheimer's Disease In People Research Articles

Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer's Disease Risk: A Retrospective Cohort Proof-of-Concept Study.

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted.

Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-β1 (TGF-β1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-β1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35years) and older DS subjects without AD (35-60years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-β1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-β1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-β1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1µM for 24h) were able to rescue TGF-β1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-β1 concentrations in DS subjects at higher risk to develop cognitive decline.

Diagnostic Sensitivity and Specificity of Cognitive Tests for Mild Cognitive Impairment and Alzheimer's Disease in Patients with Down Syndrome: A Systematic Review and Meta-Analysis.

Improved health care for people with Down syndrome (DS) has resulted in an increase in their life expectancy therefore increasing comorbidities associated with age-related problems in this population, the most frequent being Alzheimer's disease (AD). To date, several cognitive tests have been developed to evaluate cognitive changes related to the development of mild cognitive impairment (MCI) and AD in people with DS. Identify and evaluate available cognitive tests for the diagnosis of MCI and AD in people with DS. A systematic search of the Pubmed and PsycInfo databases was performed to identify articles published from January 1, 2000 and July 1, 2022. Keysearch terms were DS, AD or MCI, cognition, and assessment. Relevant studies assessing the diagnostic accuracy of cognitive tests for AD or MCI with standard clinical evaluation were extracted. Risk of bias was assessed using the QUADAS 2. We identified 15 batteries, 2 intelligence scales, 14 memory tests, 11 executive, functioning tests, 11 motor and visuospatial functioning tests, 5 language tests, 3 attention tests, and 2 orientation tests. Analysis showed that the CAMCOG-DS present a fair to excellent diagnostic accuracy for detecting AD in patients with DS. However, for the diagnosis of MCI, this battery showed poor to good diagnostic accuracy. The findings highlight important limitations of the current assessment available for the screening of mild cognitive impairment and AD in patients with DS and support the need for more clinical trials to ensure better screening for this highly at-risk population.

Cerebrolysin Treatment Reduces the Risk of Mild Cognitive Decline to Dementia in 1st-Degree Relatives of Alzheimer's Patients: A Prospective Comparative Study

To evaluate the long-term effects of annual course therapy with Cerebrolysin on cognitive functioning and the risk of transition to dementia in relatives of patients with Alzheimer's disease (AD) with amnestic-type mild cognitive decline syndrome (aMCI) in comparison with the same group untreated relatives. The cohort included 88 first-degree relatives of BA patients with aMCI syndrome aged 50 to 82 years (mean age 65.0±9.9 years) of which 46 people received course therapy with Cerebrolysin and 42 people were not treated. Clinical, neuropsychological, statistical methods were used. Conducted annual course therapy with Cerebrolysin (a total of 3 courses of infusion therapy: for a course of 20 intravenous infusions of 20 ml of Cerebrolysin in 100 ml of isotonic saline) followed by a follow-up study after 3 months after the end of the therapeutic period. The dynamics of cognitive functioning in the therapeutic group was compared with the corresponding dynamics in the comparison group over the same period. The assessment was carried out on day 0, by the end of 1, 14, 27 and 30 months research. In the therapeutic group, according to the CGI-I scale, by the end of the 3rd course of therapy, in 95.7% of cases, a pronounced or moderate improvement was achieved after each of the courses on all scales and tests. In this group, by the end of the therapeutic period, a significant improvement in the initial mean group scores was established. According to the all scales and tests, a significant improvement of the initial average group scores was found after each course of therapy (p<0.05). In the comparison group there was a significant deterioration (p<0.05) of the average group scores of most of the cognitive scales and test by the end of the observation. The annual conversion from aMCI to dementia due to probable AD was 9.5% only in the comparison group. The average group indicators of all scales and tests significantly worsened starting from the 14th month of observation in the comparison group. The absence of cases of aMCI conversion to dementia in the treated patients for 2.5 years of observation can serve as confirmation of a disease-modifying effect in Cerebrolysin. These results indicate the need for more extensive clinical studies of the preventive effects of Cerebrolysin and to explore the possibility of including such therapy in drug prevention programs for AD in people at high risk for this disease.

Exploring the role of sex differences in Alzheimer's disease pathogenesis in Down syndrome.

Women are disproportionately affected by Alzheimer's disease (AD), yet little is known about sex-specific effects on the development of AD in the Down syndrome (DS) population. DS is caused by a full or partial triplication of chromosome 21, which harbors the amyloid precursor protein (APP) gene, among others. The majority of people with DS in their early- to mid-40s will accumulate sufficient amyloid-beta (Aβ) in their brains along with neurofibrillary tangles (NFT) for a neuropathological diagnosis of AD, and the triplication of the APP gene is regarded as the main cause. Studies addressing sex differences with age and impact on dementia in people with DS are inconsistent. However, women with DS experience earlier age of onset of menopause, marked by a drop in estrogen, than women without DS. This review focuses on key sex differences observed with age and AD in people with DS and a discussion of possible underlying mechanisms that could be driving or protecting from AD development in DS. Understanding how biological sex influences the brain will lead to development of dedicated therapeutics and interventions to improve the quality of life for people with DS and AD.

Prevalence and characteristics of psychiatric morbidity treated in specialized health care in a nationwide cohort of people with newly diagnosed Alzheimer's disease.

ObjectivePsychiatric disorders have been implied as both risk factors and prodromal symptoms of Alzheimer's disease (AD). A better understanding of the history of psychiatric morbidity in people with AD may aid with understanding this relationship and highlight challenges in diagnosing AD in people with concomitant psychiatric disorders.MethodsMedication use and Alzheimer's disease (MEDALZ) study is a nationwide register‐based cohort of people (n = 70,718) who received a clinically verified AD diagnosis in Finland in 2005–2011 and were community‐dwelling at the time of diagnosis. The study population was divided into four groups based on psychiatric morbidity treated in specialized health care. We characterized the groups using data of psychiatric and somatic illnesses, psychotropic drug use, and socioeconomic factors and investigated factors associated with prodromal AD.ResultsAltogether, 4.3% of cohort members had a psychiatric diagnosis at least five years before AD diagnosis, 3.1% had a psychiatric diagnosis only up to five years before AD diagnosis, and 1.1% had a psychiatric diagnosis both less and more than 5 years before AD. Belonging to the Prodromal group (psychiatric diagnosis within 5 years before AD diagnosis) was most strongly associated with substance abuse (RR 65.06, 95%CI 55.54–76.22). Other associated factors with the Prodromal group were female gender, use of psychotropics, stroke, and asthma/COPD.ConclusionSubstance abuse and psychotropic drug use are common five years before AD diagnosis. These can be potential markers of possible prodromal symptoms of AD and should be acknowledged in clinical work.

TRISOMY 21 CAUSES A DEFICIT IN LYSOSOMAL CATHEPSINS AND ALTERS APP/Aβ PROCESSING INDEPENDENTLY OF AN EXTRA COPY OF APP

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and increases the risk of Alzheimer disease (AD). People who have DS universally develop AD pathology by the age of 40 and the majority develop early-onset dementia (AD-DS). Three copies of the Hsa21 gene APP are sufficient to cause early-onset AD but how trisomy of other Hsa21 genes influences disease development is unclear. We analysed cathepsin activity in patient fibroblasts, post-mortem brain material from people who have DS and AD pathology and a novel mouse model of AD-DS (progeny of the cross of the Tc1 model of Hsa21 trisomy with the J20 APP transgenic model). To understand how changes in cathepsin activity may affect APP and Aβ processing in vitro and in vivo in our AD-DS animal model, we used a combination of pulse-chase analysis, western blotting, immunohistochemistry, ELISA, mass-spectrometry, enzymatic activity assays and in vivo Aβ clearance studies. Additionally we undertook behavioural phenotyping and an aging study of our mouse model of AD-DS to understand how changes in APP/Aβ processing due to trisomy of Hsa21 effect learning and aging. Here we show that triplication of Hsa21 sequences, other than APP, cause cysteine cathepsin deficits that result in failure to activate these proteases in DS. We successfully modelled these enzymatic changes in a novel AD-DS mouse model system, and found that they occur independently of gross-enlargement of the endo-lysosomes. Using our AD-DS mouse model, we show that trisomy of Hsa21 sequences, other than APP, also alter the metabolism of APP/Aβ. These changes decrease the soluble Aβ38/42 ratio and are associated with an increase in Aβ aggregation and deposition, and result in exacerbation of APP/Aβ-associated hyper-activity and specific deficits in two tests of short-term memory. We also show that the trisomy-associated changes in APP/Aβ metabolism we observe occur independently of alterations in α-, β- or γ-secretase activity or changes in the rate of extracellular Aβ-clearance in vivo. We propose that trisomy Hsa21-associated cathepsin deficits are a novel AD-DS pathomechanism that alter APP/Aβ processing and may contribute to the development of AD in people who have DS.

Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer’s Disease

Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in DS patients. Here, we investigated the association between the calcineurin-NFAT signaling pathway and AD using neuronal cells. Short-term pharmacological stimulation decreased gene expression of tau and neprilysin, and long-term inhibition of the signaling pathway decreased that of amyloid precursor protein. Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide levels. Taken together, our results suggest that a dysregulation in calcineurin-NFAT signaling may contribute to the early onset of AD in people with DS.

Finding chemopreventatives to reduce amyloid beta in yeast.

Finding chemopreventatives to reduce amyloid beta in yeast.

Cerebrovascular contributions to aging and Alzheimer's disease in Down syndrome

Down syndrome (DS) is a common cause of intellectual disability and is also associated with early age of onset of Alzheimer's disease (AD). Due to an extra copy of chromosome 21, most adults over 40years old with DS have beta-amyloid plaques as a result of overexpression of the amyloid precursor protein. Cerebrovascular pathology may also be a significant contributor to neuropathology observed in the brains of adults with DS. This review describes the features of cardiovascular dysfunction and cerebrovascular pathology in DS that may be modifiable risk factors and thus targets for interventions. We will describe cerebrovascular pathology, the role of co-morbidities, imaging studies indicating vascular pathology and the possible consequences. It is clear that our understanding of aging and AD in people with DS will benefit from further studies to determine the role that cerebrovascular dysfunction contributes to cognitive health. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

Hippocampal glutamate-glutamine (Glx) in adults with Down syndrome: a preliminary study using in vivo proton magnetic resonance spectroscopy ((1)H MRS).

BackgroundDown syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. People with DS have intellectual disability (ID) and are at significantly increased risk of developing Alzheimer’s disease (AD). The biological associates of both ID and AD in DS are poorly understood, but glutamate has been proposed to play a key role. In non-DS populations, glutamate is essential to learning and memory and glutamate-mediated excitotoxicity has been implicated in AD. However, the concentration of hippocampal glutamate in DS individuals with and without dementia has not previously been directly investigated. Proton magnetic resonance spectroscopy (1H MRS) can be used to measure in vivo the concentrations of glutamate-glutamine (Glx). The objective of the current study was to examine the hippocampal Glx concentration in non-demented DS (DS-) and demented DS (DS+) individuals.MethodsWe examined 46 adults with DS (35 without dementia and 11 with dementia) and 39 healthy controls (HC) using 1H MRS and measured their hippocampal Glx concentrations.ResultsThere was no significant difference in the hippocampal Glx concentration between DS+ and DS-, or between either of the DS groups and the healthy controls. Also, within DS, there was no significant correlation between hippocampal Glx concentration and measures of overall cognitive ability. Last, a sample size calculation based on the effect sizes from this study showed that it would have required 6,257 participants to provide 80% power to detect a significant difference between the groups which would indicate that there is a very low likelihood of a type 2 error accounting for the findings in this study.ConclusionsIndividuals with DS do not have clinically detectable differences in hippocampal Glx concentration. Other pathophysiological processes likely account for ID and AD in people with DS.

Safety and Efficacy of Memantine Extended-Release in the Management of Alzheimer's Disease

Alzheimer's disease (AD) affects the majority of the 35 million people with dementia worldwide. Four pharmacological treatment options are available for this patient group, of which memantine is licensed for treatment of people with moderate to severe stages of the condition. Memantine acts through its function as an NMDA-glutamate receptor blocker and has an established safety profile. The evidence supporting its efficacy in people with AD includes a number of large randomized clinical trials showing benefit to cognition, function, and overall clinical outcome. Additional favorable health economics analyses have confirmed the clinical and cost-effectiveness of this drug. More recently an extended-release formulation has been developed. This review outlines the key evidence base supporting memantine as a treatment for moderate to severe AD, in addition to discussing the conditions under which it may provide additional value in combination with other drugs. The review also discusses the use of memantine to address behavioral and psychological symptoms of dementia (BPSD) arising in people with AD and the limited evidence around its use in AD in people with Down's syndrome. Finally the review considers the potential value of the extended release formulation in AD.

Cognitive dysfunction syndrome in dogs and cats.

Abstract Some ageing pets developed cognitive dysfunction syndrome (CDS), which is equivalent to dementia or Alzheimer's disease (AD) in people. Both CDS and AD share similar pathological changes including cortical atrophy with irreversible loss of brain cells, cerebral amyloid angiopathy and ventricular enlargement. Clinical signs of CDS include disorientation, social interaction changes, sleep/wake disturbances, house soiling and general activity changes. The risk factors and causes of CDS in dogs and cats have not been fully investigated, but age, gender, oxidative stress and sex hormone deficiency appear to be associated with increased risk of CDS in dogs. Both AD and CDS are incurable diseases currently, therefore greater efforts should be focused on preventing or reducing brain atrophy, and minimizing the risk of AD in people and CDS in pets. A number of nutritional approaches for enhancing cognitive function and promoting healthy brain ageing are briefly discussed.

Poor Sleep as a Precursor to Cognitive Decline in Down Syndrome : A Hypothesis

We propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be an overlooked way to improve cognitive outcomes in this population. This article is a contribution to a Special Issue on Down Syndrome curated by the editors of the Journal of Alzheimer’s Disease & Parkinsonism.

Herpes simplex virus type I induces the accumulation of intracellular β-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells

Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD). Epidemiological analyses have shown that HSV-1 is a risk factor for AD in people with at least 1 type 4 allele of the apolipoprotein E gene. Recent studies have also suggested that HSV-1 contributes to the appearance of the biochemical anomalies characteristic of AD brains. In addition, autophagic activity appears to be reduced with aging, and the final stages of autophagy in neurodegenerative process appear to be impaired. The present work reports that HSV-1 provokes the strong intracellular accumulation of both the main species of β-amyloid (Aβ) in the autophagic compartments and that it is associated with a marked inhibition of Aβ secretion. Autophagosomes containing Aβ failed to fuse with lysosomes in HSV-1-infected cells, indicating the impaired degradation of Aβ localized in the autophagic vesicles. In addition, HSV-1 infection was associated with the inhibition of the nonamyloidogenic pathway of amyloid precursor protein (APP) processing without significantly affecting the activity of the secretases involved in the amyloidogenic pathway. Taken together, these data suggest that HSV-1 infection modulates autophagy and amyloid precursor protein processing, contributing to the accumulation of Aβ characteristic of AD.

Docosahexaenoic Acid Protects from Amyloid and Dendritic Pathology in an Alzheimer's Disease Mouse Model

Genetic data argues that Alzheimer's disease (AD) can be initiated by aggregates of a 42 amino acid beta amyloid peptide (Abeta42). The Abeta aggregates, notably small oligomer species, cause a cascade of events including oxidative damage, inflammation, synaptic toxicity and accumulation of intraneuronal inclusions; notably neurofibrillary tangles. Cognitive deficits are likely to begin with a failure of synaptogenesis and synaptic plasticity with dendritic spine loss and dying back of dendritic arbor. This is followed by neuron loss in key areas involved in learning and memory. Significant prevention or delay of clinical onset may be achievable by modifying environmental risk factors that impact the underlying pathogenic pathways. Because low fish intake and low blood levels of the marine lipid, docosahexaenoic acid (DHA) have been associated with increased AD risk we have tested the impact of depleting or supplementing with dietary DHA on AD pathogenesis in transgenic mice bearing a mutant human gene known to cause AD in people. We reported that even with intervention late in life dietary DHA depletion dramatically enhanced oxidative damage and the loss of dendritic markers, while DHA supplementation markedly reduced Abeta42 accumulation and oxidative damage, corrected many synaptic deficits and improved cognitive function. Loss of brain DHA was exacerbated in mice expressing the mutant human AD transgene, this is consistent with evidence for increased oxidative attack on DHA oxidation in AD. Treatment with the curry spice extract curcumin, a polyphenolic antioxidant that inhibits AP aggregation, has been strongly protective in the same mouse model. Many Western diets are typically deficient in DHA and low in polyphenolic antioxidant intake. These and other data argue that increasing dietary intake of both DHA and polyphenolic antioxidants may be useful for AD prevention.

Brain-imaging surrogate markers for detection and prevention of age-related memory loss.

Recent evidence points to the importance of neuropathological and cognitive changes preceding Alzheimer's disease (AD), and clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of AD in people with age-associated memory impairment (AAMI). Studying subjects with few deficits leads to diagnostic heterogeneity and a need for larger samples in order to detect active drug effects. In this report, I review results of recent studies designed to address such issues. Middle-aged and older adults with mild memory complaints were studied using brain imaging and measures of the major known genetic risk for AD, the apolipoprotein E-4 (APOE-4) allele. In a study of positron emission tomography during mental rest, glucose metabolic rates were significantly lower in APOE-4 carriers in brain regions affected by AD. Another study using functional magnetic resonance imaging showed increased brain activation during memory tasks in APOE-4 carriers in similar brain regions. Longitudinal follow-up after 2 yr indicated the potential utility of such brain-imaging measures, combined with genetic-risk information, as surrogate markers in treatment trials for AAMI to prevent further cognitive decline. Current development focuses on novel technologies using positron emission tomography to directly image the neuritic plaques and neurofibrillary tangles of AD in order to provide more specific measures of disease progression in future clinical trials.

Presenilin 1 and α‐1‐antichymotrypsin polymorphisms in down syndrome: No effect on the presence of dementia

As people with Down syndrome (DS) age, they are at greater risk for Alzheimer disease (AD) than the general population. It has been suggested that polymorphisms at the genes for presenilin-1 (PS-1) and α-1-antichymotrypsin (ACT) confer an increased risk for AD in the general population, and therefore potentially to AD in people with DS. We obtained DNA from 231 individuals with DS and 233 population controls. People with DS were evaluated for dementia. Allele frequencies at PS-1 and ACT polymorphisms in people with DS were compared to those in age-matched controls. There were no frequency differences between the control sample and DS sample for PS-1 or ACT alleles or genotypes. Similarly, there were no differences in allele frequencies between the demented and age-matched non-demented DS samples. However a higher frequency of PS-1 heterozygotes in the demented DS group was noted. We conclude that unlike the general population, neither PS-1 nor ACT polymorphisms appear to have a similar detrimental effect on dementia in DS. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:616–620, 1999. © 1999 Wiley-Liss, Inc.

Presenilin 1 and ?-1-antichymotrypsin polymorphisms in down syndrome: No effect on the presence of dementia

As people with Down syndrome (DS) age, they are at greater risk for Alzheimer disease (AD) than the general population. It has been suggested that polymorphisms at the genes for presenilin-1 (PS-1) and alpha-1-antichymotrypsin (ACT) confer an increased risk for AD in the general population, and therefore potentially to AD in people with DS. We obtained DNA from 231 individuals with DS and 233 population controls. People with DS were evaluated for dementia. Allele frequencies at PS-1 and ACT polymorphisms in people with DS were compared to those in age-matched controls. There were no frequency differences between the control sample and DS sample for PS-1 or ACT alleles or genotypes. Similarly, there were no differences in allele frequencies between the demented and age-matched non-demented DS samples. However a higher frequency of PS-1 heterozygotes in the demented DS group was noted. We conclude that unlike the general population, neither PS-1 nor ACT polymorphisms appear to have a similar detrimental effect on dementia in DS. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:616-620, 1999.