Symptom onset in autosomal dominant Alzheimer disease

Abstract

Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p , 10 216 , r 2 . 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research. Researchers have identified more than 230 different autosomal dominant Alzheimer disease (ADAD) mutations located in the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), including the canonical case discovered by Alois Alzheimer.1 There are significant differences between mutation types in age at symptom onset, and many result in onset as early as the third or fourth decade of life.2,3 Some families carrying an identical ADAD mutation can have significantly different ages at onset, suggesting the presence of other genetic or environmental modifiers of the disease process.4,5 APOE genotype was found to slightly modify age at onset in 2 ADAD kindreds, 5,6 although it is not yet clear whether this is the case for ADAD in general. The factors influencing symptom onset and progression in From the

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

“…While the processes that give rise to cortical amyloid-b accumulation are likely to differ between sporadic and autosomal dominant Alzheimer's disease, the effects of amyloid-b on neurodegeneration and cognition are similar, albeit occurring at markedly younger ages in autosomal dominant Alzheimer's disease (ADAD) (mean age of onset is 45 years) Jack and Holtzman, 2013;Ryman et al, 2014). Therefore the aim of this study was to investigate the effects of the BDNF Met 66 allele on episodic memory, hippocampal function, amyloid-b and tau in ADAD.…”

P2‐203: Phenotypic Similarities between Late‐Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single‐Family Case‐Control Study

“…7 Within PSEN1 families, this variance may be influenced by Aβ-independent effects resulting from disruption of other functions of PSEN1, including its role as an endoplasmic reticulum calcium leak channel. 46 These Aβ-independent effects could contribute to both the observed variability in AAO and phenotypic discordance between PSEN1 ADAD and LOAD.…”

“…[1][2][3][4][5] Longitudinal analyses of cohorts of individuals with ADAD have informed the understanding of the clinical and paraclinical disease phenotypes resulting from disrupted cerebral Aβ 42 metabolism. 6,7 However, compared with sporadic late-onset AD (LOAD), the symptomatic onset of ADAD usually begins at a much earlier age (46.2 versus 72.0 years). 7,8 Also, ADAD may be characterized by clinical features that are unusual in LOAD, including pyramidal signs, hypo/hyperkinetic movement disorders, ataxia, and early myoclonus and seizures.…”

“…6,7 However, compared with sporadic late-onset AD (LOAD), the symptomatic onset of ADAD usually begins at a much earlier age (46.2 versus 72.0 years). 7,8 Also, ADAD may be characterized by clinical features that are unusual in LOAD, including pyramidal signs, hypo/hyperkinetic movement disorders, ataxia, and early myoclonus and seizures. [9][10][11][12][13][14][15][16][17][18] Additional differences in the pattern of cerebral Aβ 42 deposition are reported in some ADAD cases, including 6,16,19,20 higher Aβ 42 burden and greater densities of neurofibrillary tangles; [21][22][23] increased Aβ 42 deposition within the cerebellum [24][25][26] and basal ganglia; 19,20 ; and higher prevalence of cerebral amyloid angiopathy and large diffuse so-called "cotton wool" plaques.…”

Effects of Detraining on Ach, AchE, β-amyloid, Apolipoprotein Expression and Cognitive Function in Brain Tissue of Memory Impairment Rats

“…The main risk factor is clearly age, though research has identified some genetic risk factors that may account for a small percentage of AD cases 6 . The most well established genetic component of AD risk is the APOE-ε 4 allele 7,8 . Epidemiological studies have reported a higher prevalence of AD in rural areas than in urban settings.…”