Do synaptic changes occur before old age in people at high genetic risk of Alzheimer's disease?

In this case control study, we examined the retinal thickness of the different layers in the macular region and peripapillary retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT) in healthy cognitive subjects (from 51 to 74 years old) at high genetic risk for developing Alzheimer’s disease (AD). Thirty-five subjects with a family history of Alzheimer disease (AD) (FH+) and ApoE ɛ4 carriers and 29 age-matched control subjects without a family history of AD (FH−) and ApoE ɛ4 non-carriers were included. Compared to FH− ApoE ɛ4 non-carriers, in FH+ ApoE ɛ4 carriers, there were statistically significant decreases (p < 0.05) in (i) the foveal area of mRNFL; (ii) the inferior and nasal sectors in the outer and inner macular ring in the inner plexiform layer (IPL); (iii) the foveal area and the inferior sector in the outer macular ring in the inner nuclear layer (INL); and (iv) the inferior sector of the outer macular ring in the outer plexiform layer (OPL). However, no statistically significant differences were found in the peripapillary thickness of RNFL between both study groups. In subjects with cognitive health and high genetic risk for the development of AD, initial changes appeared in the macular area. OCT could be a promising, cost-effective and non-invasive test useful in early AD, before the onset of clinical symptoms.

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Genetic studies in Alzheimer's disease

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2003.5.1/yptang ◽

2003 ◽

Vol 5 (1) ◽

pp. 17-226 ◽

Cited By ~ 2

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Genetic Risk ◽

Late Onset ◽

Association Studies ◽

Genetic Associations ◽

Coding Region ◽

Genetic Studies ◽

High Genetic Risk

Alzheimer's disease (AD), the most common cause of dementia in aged populations, is believed to be caused by both environmental factors and genetic variations. Extensive linkage and association studies have established that a broad range of loci are associated with AD, including both causative and susceptibility (risk factor) genes. So far, at least three genes, APP, PS1, and PS2, have been identified as causative genes. Mutations in these genes have been found to cause mainly early-onset AD. On the other hand, APOE has been identified to be the most common high genetic risk factor for late-onset AD. Polymorphisms in the coding region, intron, and promoter region of certain genes constitute another kind of genetic variation associated with AD. A number of other genes or loci have been reported to have linkage with AD, but many show only a weak linkage or the results are not well reproduced. Currently, the measurable genetic associations account for about 50% of the population risk for AD. It is believed that more new loci will be found to associate with AD, either as causative genes or genetic risk factors, and that eventually the understanding of genetic factors in the pathogenesis of AD will be important for our efforts to cure this illness.

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Ocular vascular changes in relatives at high genetic risk for developing Alzheimer’s disease: foveal avascular zone and choroidal thickness

Acta Ophthalmologica ◽

10.1111/j.1755-3768.2022.194 ◽

2022 ◽

Vol 100 (S267) ◽

Author(s):

Inés López‐Cuenca ◽

Elena Salobrar‐Garcia ◽

Celia Alcántara‐Rey ◽

Lorena Elvira‐Hurtado ◽

José A. Fernández‐Albarral ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Choroidal Thickness ◽

Foveal Avascular Zone ◽

Vascular Changes ◽

High Genetic Risk ◽

Avascular Zone

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Case Studies in Dementia-Related Anxiety

GeroPsych ◽

10.1024/1662-9647/a000243 ◽

2020 ◽

pp. 1-6

Author(s):

Molly Maxfield ◽

Jennifer R. Roberts ◽

JoAnna Dieker

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Social Withdrawal ◽

Cognitive Status ◽

Generalized Anxiety ◽

Neurocognitive Disorder ◽

High Genetic Risk ◽

Disease Case ◽

Negative Perceptions

Abstract. Two clients seeking neuropsychological assessment reported anxiety about their cognitive status. We review the cases to increase our understanding of factors contributing to dementia-related anxiety. Case 1 met the criteria for mild neurocognitive disorder; the client’s memory was impaired, and she had a high genetic risk for Alzheimer’s disease. The client reported anxiety about negative perceptions of quality of life among individuals diagnosed with Alzheimer’s disease. Case 2 did not meet the criteria for a neurocognitive disorder. Anxiety about this client’s cognitive status appeared attributable to generalized anxiety disorder, given his anxiety about diverse topics. Both clients reported embarrassment about forgetfulness and social withdrawal. Dementia-related anxiety is believed to be relatively common, to exist on a continuum, to have unique social implications, and to stem from various sources, necessitating differing interventions.

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Genetic risk for Alzheimer's disease, cognition, and mild behavioral impairment in healthy older adults

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring ◽

10.1002/dad2.12164 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Byron Creese ◽

Ryan Arathimos ◽

Helen Brooker ◽

Dag Aarsland ◽

Anne Corbett ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Behavioral Impairment ◽

Healthy Older Adults

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Interaction of Alzheimer’s Disease-Associated Genetic Risk with Indicators of Socioeconomic Position on Mild Cognitive Impairment in the Heinz Nixdorf Recall Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210244 ◽

2021 ◽

pp. 1-11

Author(s):

Mirjam Frank ◽

Jonas Hensel ◽

Lisa Baak ◽

Sara Schramm ◽

Nico Dragano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Socioeconomic Position ◽

Genetic Risk ◽

Late Onset ◽

Heinz Nixdorf Recall Study ◽

Low Education ◽

Additive Scale

Background: The apolipoprotein E (APOE) ɛ4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ4 and low education on MCI (RERI: 0.52 [95% -confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% -CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% -CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ4 expression on MCI, especially among women.

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Circulating levels of Irisin in obese individuals at genetic risk for Alzheimer’s disease: Correlations with amyloid-β, metabolic, and neurocognitive indices

Behavioural Brain Research ◽

10.1016/j.bbr.2020.113013 ◽

2020 ◽

pp. 113013

Author(s):

Chia-Liang Tsai ◽

Ming-Chyi Pai

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Amyloid Β ◽

Circulating Levels

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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.

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