Executive functioning in cognitively normal middle-aged offspring of late-onset Alzheimer's disease patients

Amyloid plaques are the main signature of Alzheimer's disease (AD). Beta-amyloid (Aβ) concentration in cerebrospinal fluid (CSF-Aβ) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in Aβ metabolism of AD patients that underlie this difference using data from the Alzheimer's Disease Neuroimaging Initiative cohort. We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. Aβ cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.

Download Full-text

FDG and Amyloid PET in Cognitively Normal Individuals at Risk for Late-Onset Alzheimer’s Disease

Advances in Molecular Imaging ◽

10.4236/ami.2014.42003 ◽

2014 ◽

Vol 04 (02) ◽

pp. 15-26 ◽

Cited By ~ 18

Author(s):

John Murray ◽

Wai H. Tsui ◽

Yi Li ◽

Pauline McHugh ◽

Schantel Williams ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

At Risk ◽

Late Onset ◽

Amyloid Pet ◽

Cognitively Normal ◽

Normal Individuals

Download Full-text

Evidence for Reduced Autobiographical Memory Episodic Specificity in Cognitively Normal Middle-Aged and Older Individuals at Increased Risk for Alzheimer’s Disease Dementia

Journal of the International Neuropsychological Society ◽

10.1017/s1355617718000577 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1073-1083 ◽

Cited By ~ 14

Author(s):

Matthew D. Grilli ◽

Aubrey A. Wank ◽

John J. Bercel ◽

Lee Ryan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Older Individuals ◽

Autobiographical Memories ◽

Middle Aged ◽

Cognitively Normal ◽

Preclinical Ad ◽

Increased Risk ◽

And Gender

AbstractObjectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

Download Full-text

Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-170491 ◽

2017 ◽

Vol 60 (3) ◽

pp. 1183-1193 ◽

Cited By ~ 10

Author(s):

Stella M. Sánchez ◽

Carolina Abulafia ◽

Barbara Duarte-Abritta ◽

M. Soledad Ladrón de Guevara ◽

Mariana N. Castro ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Middle Aged ◽

Semantic Interference

Download Full-text

IC-02-01: Association between cerebral patterns of fibrillar beta-amyloid burden and glucose hypometabolism in cognitively normal older adults at three levels of genetic risk for late-onset Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2010.05.011 ◽

2010 ◽

Vol 6 ◽

pp. S4-S4

Author(s):

Adam S. Fleisher ◽

Kewei Chen ◽

Xiaofen Liu ◽

Napatkamon Ayutyanont ◽

Jessica B.S. Langbaum ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Late Onset ◽

Beta Amyloid ◽

Amyloid Burden ◽

Cognitively Normal ◽

Glucose Hypometabolism

Download Full-text

Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups

Molecular Psychiatry ◽

10.1038/s41380-018-0298-8 ◽

2018 ◽

Vol 25 (11) ◽

pp. 2942-2951 ◽

Cited By ~ 13

Author(s):

Shubhabrata Mukherjee ◽

◽

Jesse Mez ◽

Emily H. Trittschuh ◽

Andrew J. Saykin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Disease Diagnosis ◽

Single Nucleotide ◽

Cognitively Normal ◽

Snp Data ◽

Genotype Frequencies ◽

Genome Wide ◽

Ε4 Allele

Abstract Categorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10−5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10−27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10−5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

Download Full-text