P2-330: The High Prevalence of Alzheimer's Disease in Female APOE4 Allele Carriers is Contributed from a Combination of APOE4 Increased Activity and Female Sex Related High Expression of Bace1

Background: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

Download Full-text

Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200266 ◽

2021 ◽

Vol 5 (1) ◽

pp. 49-53

Author(s):

Steven Lehrer ◽

Peter H. Rheinstein

Keyword(s):

Breast Cancer ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apoe Genotype ◽

Uk Biobank ◽

Breast Cancer Patients ◽

Apoe4 Allele ◽

Significant Difference ◽

The Uk ◽

Cognitive Problems

Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.

Download Full-text

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510011112 ◽

2015 ◽

Vol 112 (38) ◽

pp. 11965-11970 ◽

Cited By ~ 64

Author(s):

Li Zhu ◽

Minghao Zhong ◽

Gregory A. Elder ◽

Mary Sano ◽

David M. Holtzman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Genetic Risk ◽

Primary Neurons ◽

Loss Of Function ◽

Sporadic Alzheimer’S Disease ◽

Postmortem Human Brain ◽

Apoe4 Allele ◽

Synaptojanin 1

The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

Download Full-text

Argyrophilic grain disease: An underestimated tauopathy

Dementia & Neuropsychologia ◽

10.1590/s1980-57642015dn91000002 ◽

2015 ◽

Vol 9 (1) ◽

pp. 2-8 ◽

Cited By ~ 19

Author(s):

Roberta Diehl Rodriguez ◽

Lea Tenenholz Grinberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Defense Mechanism ◽

Neuropsychiatric Symptoms ◽

Argyrophilic Grain Disease ◽

Coiled Bodies ◽

Pathologic Features ◽

High Prevalence ◽

Argyrophilic Grain ◽

Argyrophilic Grains

Argyrophilic grain disease (AGD) is an under-recognized, distinct, highly frequent sporadic tauopathy, with a prevalence reaching 31.3% in centenarians. The most common AGD manifestation is slowly progressive amnestic mild cognitive impairment, accompanied by a high prevalence of neuropsychiatric symptoms. AGD diagnosis can only be achieved postmortem based on the finding of its three main pathologic features: argyrophilic grains, oligodendrocytic coiled bodies and neuronal pretangles. AGD is frequently seen together with Alzheimer's disease-type pathology or in association with other neurodegenerative diseases. Recent studies suggest that AGD may be a defense mechanism against the spread of other neuropathological entities, particularly Alzheimer's disease. This review aims to provide an in-depth overview of the current understanding on AGD.

Download Full-text

The increased activity of BACE1 correlates with oxidative stress in Alzheimer's disease

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2006.05.004 ◽

2007 ◽

Vol 28 (7) ◽

pp. 1009-1014 ◽

Cited By ~ 50

Author(s):

Roberta Borghi ◽

Stefania Patriarca ◽

Nicola Traverso ◽

Alessandra Piccini ◽

Daniela Storace ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Increased Activity

Download Full-text

High Expression of Apolipoprotein E mRNA in the Brains with Sporadic Alzheimer’s Disease

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000051236 ◽

2001 ◽

Vol 12 (2) ◽

pp. 57-62 ◽

Cited By ~ 35

Author(s):

Kaoru Yamagata ◽

Katsuya Urakami ◽

Kazuyuki Ikeda ◽

Yong Ji ◽

Yoshiki Adachi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

High Expression ◽

Sporadic Alzheimer’S Disease

Download Full-text

Neurobiochemical Cross-talk Between COVID-19 and Alzheimer’s Disease

Molecular Neurobiology ◽

10.1007/s12035-020-02177-w ◽

2020 ◽

Cited By ~ 1

Author(s):

Mohammad Azizur Rahman ◽

Kamrul Islam ◽

Saidur Rahman ◽

Md Alamin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Markers ◽

Interleukin 1 ◽

Therapeutic Strategies ◽

Therapeutic Approaches ◽

Angiotensin Converting Enzyme 2 ◽

Apoe4 Allele ◽

The Common ◽

Global Threat

Abstract COVID-19, the global threat to humanity, shares etiological cofactors with multiple diseases including Alzheimer’s disease (AD). Understanding the common links between COVID-19 and AD would harness strategizing therapeutic approaches against both. Considering the urgency of formulating COVID-19 medication, its AD association and manifestations have been reviewed here, putting emphasis on memory and learning disruption. COVID-19 and AD share common links with respect to angiotensin-converting enzyme 2 (ACE2) receptors and pro-inflammatory markers such as interleukin-1 (IL-1), IL-6, cytoskeleton-associated protein 4 (CKAP4), galectin-9 (GAL-9 or Gal-9), and APOE4 allele. Common etiological factors and common manifestations described in this review would aid in developing therapeutic strategies for both COVID-19 and AD and thus impact on eradicating the ongoing global threat. Thus, people suffering from COVID-19 or who have come round of it as well as people at risk of developing AD or already suffering from AD, would be benefitted.

Download Full-text