Abstract
Background: Mothers transmit Alzheimer’s disease (AD) more frequently than fathers. Factors other than female longevity may be at work to promote maternal transmission of AD. Among these are the X chromosome, mitochondrial DNA, and AD comorbidities, especially depression. A recent study associated mitochondrial SNP rs2853499 with AD. Materials and Methods: We used UK Biobank (UKBB) data to investigate the relation of mitochondrial SNP rs2853499, with AD. To identify cases of AD we used ICD10 code G30.9. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used PLINK, a whole-genome association analysis toolset, to analyze the UKB22418 mitochondrial hard-called chromosome file. Results: Of 953 AD cases, 493 were male (51.7%) and 460 were female (48.3%). Mothers were twice as likely to transmit AD compared to fathers. We found that in individuals with AD, 22.3% (n=201) carried the A allele of SNP rs2853499, 77.7% (n=700) carried the G allele. In individuals without AD, 22.2% (n=10,7726) carried the A allele of SNP rs2853499, 77.8% (n=378,535) carried the G allele. This difference was not significant (p=0.91, two-tailed Fisher exact test). Therefore, factors other than mitochondrial SNP rs2853499 may be at work to promote maternal transmission of AD. Conclusion: We conclude that depression, a multigenic illness, in the mother is most likely the basis for the fact that mothers transmit AD twice as often as fathers.
Mothers transmit Alzheimer’s disease (AD) more frequently than fathers (1, 2). Even after accounting for age, Heggeli et al. found that mothers of patients with AD and of controls were more frequently affected than fathers (1). Yet the mothers of those with AD did not more frequently have dementia than mothers of the controls. Mosconi et al. linked maternal AD transmission to a relationship between reduced cerebral metabolic rate of glucose in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals (3). Honea et al. demonstrated progressive regional atrophy and AD biomarkers in adults without AD but with mothers with AD (4, 5).
Another source of maternal AD transmission may be the mitochondria. Nuclear genomes on chromosomes 1-22 are inherited equally from both parents, whereas the mitochondrial mode of transmission is entirely maternal. As a result, mutations linked to diseases affecting mitochondria are always inherited from the mother, who transmits a circular single-stranded mitochondrial chromosome to her offspring (6). Among the most common mitochondrial diseases are mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome, Leber hereditary optic neuropathy, Leigh syndrome, myoclonic epilepsy, ragged-red fiber disease, and Kearns-Sayre syndrome. Mitochondrial diseases occur about once in 5,000 people.
The hallmark of AD is increasing neuronal dysfunction, and mitochondria play a crucial part in maintaining healthy neuronal function and longevity. Mitochondrial dysfunction, which develops upstream and can cause many downstream signs, such as amyloid β and tau pathology, might be an underlying factor in AD. Abundant data suggest that oxidative damage and metabolic abnormalities are both present in AD [reviewed in (7)].
Yet mitochondrial DNA variants have been inconsistently associated with AD [reviewed in (8)]. The most recent is mitochondrial SNP rs2853499 that was mapped to a novel small mitochondrial open-reading frame called SHMOOSE with microprotein-encoding potential. Levels of SHMOOSE in cerebrospinal fluid in humans correlated with age, cerebrospinal fluid tau, and brain white matter volume (9).
To further elucidate mitochondrial AD transmission, we examined parental transmission of AD in UK Biobank data to assess the allelic frequency of mitochondrial SNP rs2853499 in patients with AD versus individuals without AD.
Materials and Methods
The UK Biobank is a large, prospective observational study of men and women. Participants were recruited from across 22 centers located throughout England, Wales, and Scotland between 2006 and 2010 and continue to be longitudinally followed for capture of subsequent health events (10). Follow-up health information is provided by linkage to primary care electronic health records, death and cancer registries, and hospital admission records (11).
Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). To identify cases of AD, we used the ICD10 code G30.9.
Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used PLINK, a whole-genome association analysis toolset, to analyze the UKB22418 mitochondrial hard-called chromosome file (12). These data were derived directly from Affymetrix DNA microarrays. SNP rs2853499 is in position chrMT:12372 (GRCh38.p14), with alleles G>A, a single nucleotide variant, with minor allelic (A) frequency of 0.417 in the UK Biobank. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 from UKBB were used to determine apolipoprotein E (APOE) genotype (E2, E3, E4) (13). We used the UK Biobank Data Parser (UKBB parser), a python-based package that allows easy interfacing with the large UK Biobank dataset. Statistical analyses were carried out with SPSS 26 (IBM, New York, NY, USA). SNP/allelic frequency were evaluated with two-tailed Fisher’s exact test. Acceptable level of significance was p=0.05.
Results
Of 953 AD cases, 493 were male (51.7%) and 460 were female (48.3%). The mean age was 57±8 years, and 95% were White. Mothers were twice as likely to transmit AD as fathers (Figure 1). APOE genotype was not significantly different in those with AD with or without a mother with AD (p=0.512, two-tailed Fisher’s exact test, Table I).
Alzheimer’s disease heritability in 259 patients with Alzheimer’s disease in the UK Biobank. Mothers were twice as likely as fathers to transmit Alzheimer’s disease.
Apolipoprotein E (APOE) genotype in 385 patients with Alzheimer’s disease according to family history of Alzheimer’s disease in their mothers. The variability was insignificant (p=0.512, two-tail Fisher’s exact test).
We found that in individuals with AD, 22.3% (n=201) carried the A allele of mitochondrial SNP rs2853499 and 77.7% (n=700) carried the G allele. In individuals without AD, 22.2% (107,726) carried the A allele of SNP rs2853499 and 77.8% (378,535) carried the G allele. This difference was not significant (p=0.91, two-tailed Fisher exact test).
Therefore, factors other than mitochondrial SNP rs2853499 may be at work to promote maternal transmission of AD. These other factors might be increased AD incidence in women, effects associated with the X chromosome and AD comorbidities, especially depression.
Discussion
Increased incidence of AD in women. While female longevity is a contributing factor to increased AD in women, it is not solely responsible (14). Another cause may be a stronger immune system in females (15). Women are twice as likely as men to have autoimmune disease (16). The amyloid plaques characteristic of AD may be the ‘output’ of part of the brain’s immune system (17). Due to their stronger immune systems, women may end up having more amyloid plaques than men. As a result, women may have a greater risk of developing AD and so more mothers than fathers of AD patients would have AD.
Mitochondrial DNA. Our analysis of mitochondrial SNP rs2853499 (above) suggests that mitochondrial DNA is unrelated to maternal AD transmission. These results agree with another assessment: The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of AD or is secondary to other phenomena [reviewed in (18)].
X Chromosome. The mother’s X chromosome is home to 867 known genes, many of which are crucial for the development of tissues such as bone, brain, blood, hepatic, renal, retina, ears, cardiac, skin, and teeth. At least 533 illnesses are caused by X chromosome-related genes. When an X-linked recessive inheritance pattern exists, the X chromosome is the site of a damaged (mutated) gene. Duchenne muscular dystrophy, various types of colorblindness, and hemophilia A are examples of X-linked recessive illnesses (19).
A link between the X chromosome and AD was recently identified in mice. In comparison to brains of males, those of females have higher production of X-linked ubiquitin-specific peptidase 11 (USP11), which leads to greater accumulation of tau protein (20). Tauopathies, a group of neurodegenerative disorders that include AD, are characterized by tau accumulation in the central nervous system. But a relationship between the X chromosome and AD has not turned up in numerous genome-wide association studies of AD, even when family history was included (21, 22).
Comorbidities in patients with AD. Epidemiological and molecular investigations have shown that several illnesses, in particular type 2 diabetes, cardiovascular disease, depression and gastrointestinal disorders, may raise the risk of AD (23, 24). Of these four, type 2 diabetes, cardiovascular disease and gastrointestinal disorders are approximately equally distributed between men and women. Cardiovascular disease is more common in younger men, but after menopause women, are heavily affected as well. Only depression, especially major depression, predominates in women.
Major depressive illness will affect at least 10% of Americans at some point in their lives. Major depression affects twice as many women as men. Major depression is quite heritable, more so in women than in men (25). Unrelated twins (also known as fraternal or dizygotic) share 50% of their DNA, whereas identical (monozygotic) twins share 100% of their genes. If genes have a role in the causation of depression, the identical twin of a patient should be at significantly higher risk for the disease than the non-identical twin, which applies to severe depression. The inheritability of depression is 19% in dizygotic twins, 76% in monozygotic twins, and may be higher in severe depression. Like hypertension and type 2 diabetes, depression and risk of depression are polygenic, many genes having been implicated (26, 27).
Depression and AD. Depression is a chronic psychiatric and neurological condition associated with a range of other medical problems, from alcoholism to heart disease. Psychiatric and neurological conditions have little impact on lifespan, accounting for 1.4% of all deaths. But these conditions represent 28% of all disabilities, with depression the leading cause of disability worldwide (28).
People with AD frequently experience depression, especially in the early and middle stages. According to a recent meta-analysis of clinical investigations, depression may be a risk factor for cognitive impairment and AD (29). Depression symptoms in cognitively healthy older individuals, together with brain amyloid, can incite changes in memory and thinking over time (30).
The same genetic risk factors that cause depression may also be responsible for some cases of AD (31). In one study, a correlation existed between the single nucleotide polymorphisms (SNPs) carried by people with AD and those in persons with depression. The SNPs linked to depression increase a person’s likelihood of getting AD. The opposite, though, was not true: the chance of developing depression was not increased by the SNPs linked to AD (32). This observation is consistent with Heggeli et al.’s findings, noted above, that dementia was not more frequent in mothers of AD cases than in the mothers of controls.
The fact that AD is polygenic, like depression, means that several different variants might work together to increase disease vulnerability. Apolipoprotein E ε4 (APOE4) is the largest genetic risk factor for development of sporadic AD. Evaluating depression and depression-related genetics with deep learning neural network models for polygenic risk may improve AD predictability (33).
Conclusion
Increased AD in women is not fully accounted for by increased maternal AD transmission, nor autoimmunity, X chromosome or mitochondrial transmission. We conclude that depression in the mother, a polygenic illness, is most likely the basis for the fact that mothers transmit AD twice as often as fathers.
Acknowledgements
This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was also supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the Authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Authors’ Contributions
Dr. Lehrer and Dr. Rheinstein contributed equally to the conception, writing, and data analysis of this study.
Data Availability
Data sources described in article publicly available or available after approved application to UK Biobank.
Conflicts of Interest
None.
- Received July 4, 2023.
- Revision received September 5, 2023.
- Accepted September 6, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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