Most rapid cognitive decline in APOE ε4 negative Alzheimer's disease with early onset

BackgroundWe aimed to compare the rate of cognitive decline in patients with early and late onset Alzheimer's disease (AD) and to investigate the potentially modifying influence of the apolipoprotein E (APOE) genotype.MethodWe included 99 patients with early onset AD (age ⩽65 years) and 192 patients with late onset AD (age >65 years) who had at least two scores on the Mini-Mental State Examination (MMSE) (range 2–14) obtained at least 1 year apart. Linear mixed models were performed to investigate the rate of cognitive decline dependent on age at onset (AAO) and APOE genotype.ResultsThe mean (s.d.) age for patients with early onset AD was 57.7 (4.5) years, and 74.5 (5.1) years for patients with late onset AD. AAO was not associated with baseline MMSE [β (s.e.)=0.8 (0.5), p=0.14]. However, patients with early onset showed a faster decline on the MMSE [β (s.e.)=2.4 (0.1) points/year] than those with late onset [β (s.e.)=1.7 (0.1) points/year, p=0.00]. After stratification according to APOE genotype, APOE ε4 non-carriers with early onset showed faster cognitive decline than non-carriers with late onset [2.4 (0.3) v. 1.3 (0.3) points/year, p=0.01]. In APOE ε4 carriers, no difference in rate of cognitive decline was found between patients with early and late onset [β (s.e.)=0.2 (0.2), p=0.47].ConclusionPatients with early onset AD show more rapid cognitive decline than patients with late onset, suggesting that early onset AD follows a more aggressive course. Furthermore, this effect seems to be most prominent in patients with early onset who do not carry the genetic APOE ε4 risk factor for AD.

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The clinical utility of gene testing for Alzheimer’s disease

Neurology International ◽

10.4081/ni.2011.e1 ◽

2011 ◽

Vol 3 (1) ◽

pp. 1 ◽

Cited By ~ 8

Author(s):

Emily R. Atkins ◽

Peter K. Panegyres

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Association Studies ◽

Susceptibility Gene ◽

Genome Wide Association Studies ◽

Apoe Ε4 ◽

Gene Testing ◽

A Genome

Alzheimer’s disease (AD) is the largest cause of dementia, affecting 35.6 million people in 2010. Amyloid precursor protein, presenilin 1 and presenilin 2 mutations are known to cause familial early-onset AD, whereas apolipoprotein E (APOE) ε4 is a susceptibility gene for late-onset AD. The genes for phosphatidylinositol- binding clathrin assembly protein, clusterin and complement receptor 1 have recently been described by genome-wide association studies as potential risk factors for lateonset AD. Also, a genome association study using single neucleotide polymorphisms has identified an association of neuronal sortilin related receptor and late-onset AD. Gene testing, and also predictive gene testing, may be of benefit in suspected familial early-onset AD however it adds little to the diagnosis of lateonset AD and does not alter the treatment. We do not recommend APOE ε4 genotyping.

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Late Onset Alzheimer Dementia in Patients with Genotype E3/E4: A Case Report

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2021.5583 ◽

2021 ◽

Vol 9 (C) ◽

pp. 5-9

Author(s):

Anak Agung Ayu Putri Laksmidewi ◽

Chiquita Putri Vania Rau

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Case Report ◽

Mini Mental State Examination ◽

Late Onset ◽

Apoe Genotype ◽

Time Orientation ◽

Alzheimer Dementia ◽

The Family ◽

State Examination

BACKGROUND: Dementia is one of the leading causes of disability and dependence in elderly worldwide. Epidemiological statistics indicate that data show that at about 60–80%, Alzheimer’s is the most common type of dementia. Alzheimer’s is also the third-most prominent cause of death in elderly. CASE REPORT: A 72-years-old male patient, complained by the family often forgets about things that have just been done for 3 years ago. According to the family, patient also often discussing the same things repeatedly. Patients tend not to have the initiative to start his daily activities. The family admitted that patient also became often angry and felt suspicious for the last 2 years. From the mini mental state examination showed disturbances in time orientation and recall; from Montreal Cognitive Assessment Ina found disturbances in visuospatial, fluency, abstraction, delayed memory, and time orientation; accompanied by activities of daily living (ADL) and instrumental ADL disorders. Patient also performed a molecular examination of the apolipoprotein E (APOE) genotype and the genotype E3/E4 was detected. CONCLUSION: The function of the APOE gene, in particular APOE4, is the most emphasized genetic relationship in late onset Alzheimer’s disease. It is proposed that blocking the action of APOE4 can delay or stop Alzheimer’s disease progression.

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O2-04-07: Most rapid cognitive decline in APOE4 negative Alzheimer's disease with early onset

Alzheimer s & Dementia ◽

10.1016/j.jalz.2009.05.349 ◽

2009 ◽

Vol 5 (4S_Part_4) ◽

pp. P111-P112

Author(s):

Wiesje M. van der Flier ◽

Annelies E. van der Vlies ◽

Esther L. Koedam ◽

Yolande A.L. Pijnenburg ◽

Jos W.R. Twisk ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Early Onset ◽

Rapid Cognitive Decline

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Trajectories of cognitive decline in Alzheimer's disease

International Psychogeriatrics ◽

10.1017/s1041610209991001 ◽

2009 ◽

Vol 22 (2) ◽

pp. 281-290 ◽

Cited By ~ 78

Author(s):

Patricia A. Wilkosz ◽

Howard J. Seltman ◽

Bernie Devlin ◽

Elise A. Weamer ◽

Oscar L. Lopez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Complex Disease ◽

Latent Class ◽

Rating Scale ◽

Late Onset ◽

Psychotic Symptoms ◽

Concomitant Variables ◽

Rapid Cognitive Decline

ABSTRACTBackground: Late-onset Alzheimer disease (LOAD) is a clinically heterogeneous complex disease defined by progressively disabling cognitive impairment. Psychotic symptoms which affect approximately one-half of LOAD subjects have been associated with more rapid cognitive decline. However, the variety of cognitive trajectories in LOAD, and their correlates, have not been well defined. We therefore used latent class modeling to characterize trajectories of cognitive and behavioral decline in a cohort of AD subjects.Methods: 201 Caucasian subjects with possible or probable Alzheimer's disease (AD) were evaluated for cognitive and psychotic symptoms at regular intervals for up to 13.5 years. Cognitive symptoms were evaluated serially with the Mini-mental State Examination (MMSE), and psychotic symptoms were rated using the CERAD behavioral rating scale (CBRS). Analyses undertaken were latent class mixture models of quadratic trajectories including a random intercept with initial MMSE score, age, gender, education, and APOE ϵ4 count modeled as concomitant variables. In a secondary analysis, psychosis status was also included.Results: AD subjects showed six trajectories with significantly different courses and rates of cognitive decline. The concomitant variables included in the best latent class trajectory model were initial MMSE and age. Greater burden of psychotic symptoms increased the probability of following a trajectory of more rapid cognitive decline in all age and initial MMSE groups. APOE ϵ4 was not associated with any trajectory.Conclusion: Trajectory modeling of longitudinal cognitive and behavioral data may provide enhanced resolution of phenotypic variation in AD.

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Genomics and Functional Genomics of Alzheimer’s Disease

Neurotherapeutics ◽

10.1007/s13311-021-01152-0 ◽

2021 ◽

Author(s):

M. Ilyas Kamboh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Genomics ◽

Early Onset ◽

Late Onset ◽

Association Studies ◽

Age At Onset ◽

Significant Risk ◽

Major Public Health Problem ◽

Genome Wide Association Studies

AbstractAlzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5–10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.

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Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets

Brain ◽

10.1093/brain/awz289 ◽

2019 ◽

Vol 142 (11) ◽

pp. 3375-3381 ◽

Cited By ~ 1

Author(s):

Ming Zhang ◽

Allison A Dilliott ◽

Roaa Khallaf ◽

John F Robinson ◽

Robert A Hegele ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Accelerated Ageing ◽

Disease Phenotypes ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Disease Family

Zhang, Dilliott et al. examine a unique family with early- and late-onset Alzheimer’s disease phenotypes, as well as disease-discordant monozygotic triplets. The triplets and the patient with early-onset disease are carriers of the APOE ε4-allele plus rare substitutions in other genes. Epigenetic analyses suggest accelerated ageing in the early-onset patient.

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Differential effects of risk factors on the cognitive trajectory of early- and late-onset Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00857-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jaeho Kim ◽

Sook-Young Woo ◽

Seonwoo Kim ◽

Hyemin Jang ◽

Junpyo Kim ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Cognitive Decline ◽

Late Onset ◽

Low Education ◽

Rapid Cognitive Decline ◽

Function Language ◽

The Impact

Abstract Background Although few studies have shown that risk factors for Alzheimer’s disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset < 65 years of age) versus late-onset AD (LOAD). Therefore, we evaluated whether the impact of Alzheimer’s disease (AD) risk factors on cognitive trajectories differ in EOAD and LOAD. Methods We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories. Results APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD. Conclusions Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.

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The National Institute on Aging Late Onset Alzheimer's Disease Family Based Study: A Critical Component of the International Effort to Understand Alzheimer's Disease

10.1101/2021.04.12.21255332 ◽

2021 ◽

Author(s):

Dolly Reyes-Dumeyer ◽

Kelley Faber ◽

Badri N. Vardarajan ◽

Alison Goate ◽

Alan Renton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Age At Onset ◽

Apoe Genotype ◽

Alzheimers Disease ◽

Genetic Etiology ◽

Wide Range ◽

Family Based ◽

Disease Family

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimers Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimers disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained as was neuropathology, when possible. APOE genotypes, genome-wide SNP arrays and sequencing was completed in the majority of families. RESULTS: A wide range in the age-at-onset in many large families was related to APOE genotype, but not in all. Variants typically associated with early-onset AD and frontotemporal dementia were also found. DISCUSSION: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 126 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.

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Cognitive Decline in Alzheimer’s Disease Is Not Associated with APOE

Journal of Alzheimer s Disease ◽

10.3233/jad-210685 ◽

2021 ◽

pp. 1-9

Author(s):

Ioanna Katzourou ◽

Ganna Leonenko ◽

Dobril Ivanov ◽

Alun Meggy ◽

Rachel Marshall ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Mini Mental State Examination ◽

Linear Models ◽

Apoe Genotype ◽

Clinical Information ◽

Mixed Effect ◽

Rate Of Decline ◽

State Examination

Background: The rate of cognitive decline in Alzheimer’s disease (AD) has been found to vary widely between individuals, with numerous factors driving this heterogeneity. Objective: This study aimed to compute a measure of cognitive decline in patients with AD based on clinical information and to utilize this measure to explore the genetic architecture of cognitive decline in AD. Methods: An in-house cohort of 616 individuals, hereby termed the Cardiff Genetic Resource for AD, as well as a subset of 577 individuals from the publicly available ADNI dataset, that have been assessed at multiple timepoints, were used in this study. Measures of cognitive decline were computed using various mixed effect linear models of Mini-Mental State Examination (MMSE). After an optimal model was selected, a metric of cognitive decline for each individual was estimated as the random slope derived from this model. This metric was subsequently used for testing the association of cognitive decline with apolipoprotein E (APOE) genotype. Results: No association was found between the number of APOE ɛ2 or ɛ4 alleles and the rate of cognitive decline in either of the datasets examined. Conclusion: Further exploration is required to uncover possible genetic variants that affect the rate of decline in patients with AD.

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Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05669-6 ◽

2022 ◽

Author(s):

Denise Visser ◽

Sander C. J. Verfaillie ◽

Emma E. Wolters ◽

Emma M. Coomans ◽

Tessa Timmers ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Cognitive Deficits ◽

Early Onset ◽

Late Onset ◽

Age At Onset ◽

Region Of Interest ◽

Tau Pathology

Abstract Purpose Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. Methods Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition. Results Both region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND − 0.76 ≤ stβ ≤ − 0.48 vs LOAD − 0.18 ≤ stβ ≤ − 0.02; EOAD R1 0.37 ≤ stβ ≤ 0.84 vs LOAD − 0.25 ≤ stβ ≤ 0.16). Conclusions Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.

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