The relationship between cardiovascular diseases and the family history of Alzheimer’s disease: results from NHANES (1999-2004)

doi:10.21203/rs.3.rs-3230800/v1

Patients with cardiovascular diseases (CVDs) have a notably high Alzheimer’s disease (AD) risk in the previous finding. Both CVDs and AD are genetic related disorders. While seldom data concerning the risk of CVDs in individuals with AD family history. The present study aimed to examine the relationship between CVDs and family history of AD. A total of 15019 participants were enrolled and analyzed. Logistic regression analysis indicated that individuals with AD family history had 0.173 higher odds of CVDs than those without AD relatives (OR = 1.173 (1.029-1.338), p < 0.05). The odds ratio of CVDs in the adjudged model was 1.184 (95%CI 0.987-1.421) for individuals with maternal line family history of AD after taking into account age, gender, BMI, race, education and family income. AD family history was positively associated with CVDs, while maternal origin AD family history is more likely to be a risk factor for CVDs than paternal origins. Further prospective studies are needed to confirm the relationship between AD family history and CVDs.

Cardiovascular diseases

Alzheimer’s disease

NHANES

family history

The relationship between Alzheimer’s disease (AD) and Cardiovascular Diseases (CVDs) has been proposed in recent years[1]. AD is a severe progressive neurodegenerative disorder characterized by memory loss, impaired cognitive function and deposition of tau neural fibrillary tangles and β-amyloid plaques in the brain[2]. Nevertheless, emerging evidence has suggested the potential relationship between AD and various CVDs, which include heart failure, atrial fibrillation, atherosclerosis, coronary artery diseases and hypertension.

The mechanisms of AD are still complex, elusive and lack clear understanding. There is various hypothesis attempted to explain the onset and progress of AD. Hypoperfusion is one of the possible pathogenesis of AD. The brain is a voracious consumer of energy in the human body, and any inadequate blood supplement to the brain would probably affect its function. A previous study suggested that the cerebral blood flow or pulse pressure was reduced in AD patients[3]. Indeed, atherosclerosis is also associated with AD as provided by the fact that AD patients have a more thicken vascular wall and higher cerebral artery occlusion rate[4]. However, hypertension which seems to have higher cerebral perfusion is also connected with AD. Hypertension seems to promote AD by inducing oxidative stress, inflammation and deposition of Aβ[5]. In addition, hypertension is a traditional risk factor for heart failure. Heart failure, the end stage of various CVDs, is a general public health problem in the aging population in the 21st century[6]. Heart failure patients have similar epidemiological characteristics as obesity and age[1]. In addition, heart failure patients commonly have a lower cardiac output which contributes to hypoperfusion of the brain, causing abnormality in energy metabolism and accelerating the formation of β-amyloid plaque[7].

Although various CVDs are linked with the progress of AD, there is no research concerning the connection between the family history of AD and CVDs. Whether the AD history of a lineal relative would increase the risk of CVDs is still unknown. Herein, we provide a potential connection between these two states by exploring the data from National Health and Nutrition Examination Survey (NHANES).

2.1 Study population

We obtained the NHANES data and conducted this cross-sectional study of individuals who participated in the six cycles (NHANE 1999–2004). NHANES, a program that accesses the nutritional and health status of America, is performed by the Centers for Disease Control and Prevention (CDC). Briefly, NHANES aims to collect a variety of health information from the American population by conducting interviews, medical examinations, and laboratory tests of blood, urine and other samples. First, we obtained data from individuals who took part in NHANES 1999–2004 cycle and responded to the questionnaires (N = 31126). Then 16107 participants were excluded due to missing the Alzheimer’s data. Finally, there were remain a total of 15019 individuals enrolled in this study, which were then divided into CVDs (N = 5303) and Non-CVDs (N = 9716) groups (Fig. 1).

2.2 Covariates of Interest

Our demographic characteristics included age (less than 30 years old, 30-year-old to 40-year-old and older than 40-year-old), gender (male or female), BMI (less than 20, 20 to 25, 25 to 30, larger than 30), Race (Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic black, Other Race or Multi-racial), education (lower than high school, high school, above high school), family income (higher or lower than 20000 USD per year), current smoking status (Yes or Not), blood pressure (systolic pressure and diastolic pressure) and the prevalence of CVDs. The CVDs analyzed in this study include hypertension, heart failure, angina, heart attack and coronary heart disease. Family history of AD was confirmed by the question “blood relatives including grandparents, parents, brothers, sisters ever told by a health professional that they had Alzheimer's disease” and “Which biological [blood] family member?”

2.3 Statistical Analysis

We conducted a Student t-test or ANOVA for the comparison of continuous variables followed by post hoc multiple comparisons, and the chi-square test was performed for the comparison of constituent ratios in each group. Then, logistic regression analyses were performed to assess the association between AD family history and CVDs. All the data were processed by SPSS 20.0, and the differences were considered statistically significant at a value of p < 0.05.

3.1 Characteristics of Participants with or without a family history of Alzheimer’s disease

After eliminating individuals without AD or CVDs information, a total of 15019 individuals were enrolled in the present study (Fig. 1). Then, we further explored the distribution of blood relatives with AD in enrolled individuals. Briefly, the red, yellow and orange symbols represent Alzheimer’s mom’s mother (N = 312), Alzheimer’s mom’s father (N = 168) and Alzheimer’s mother (N = 350), respectively. In addition, the symbols mentioned above were generalized to the maternally derived group. The blue, green and dark green symbols represent Alzheimer’s dad’s mother (N = 213), Alzheimer’s dad’s father (N = 97) and Alzheimer’s father (N = 197), respectively. While these symbols mentioned above were generalized to the paternal origin group (Fig. 2). The characteristics of the participants are displayed in Table 1. Overall, the prevalence of individuals with a family history of AD was 11.38%. The age distribution is similar in both individuals with or without AD family history by chi-squared test (p = 0.057), while females seem to have a higher rate of AD relatives (chi-squared, p < 0.001). However, there has no significance concerning BMI and smoking status. In addition, the features in a race, education and family income are different between these groups. Higher family income with higher education level in Non-Hispanic White people tends to have a higher rate of AD relatives. Additionally, the distribution of CVDs including hypertension, heart failure, angina, heart attack, and coronary artery disease are similar between these two groups. However, participants with AD relatives seem to have lower systolic blood pressure (SBP) (124.90 ± 21.01 vs. 126.95 ± 21.75mmHg, p < 0.001). (Table 1).

Table 1

**Demographics and characteristics of participants, from NHANES 1999–2004** Data are presented as N% (χ² test) and Mean ± SD (independent t-test) which are denoted by ^a and ^b, respectively.
Characteristic	With a family history of AD (N = 1709, 11.38%)	Without a family history of AD (N = 13310, 88.62%)	p value
Age, years, N (%)
< 30	330 (19.31%)	2412 (18.12%)	0.057^a
30–40	312 (18.26%)	2204 (16.56%)
>= 40	1067 (62.43%)	8694 (65.32%)
Mean ± SD	48.28 ± 18.50	50.64 ± 19.54	< 0.001^b
Gender, N (%)
Male	729 (42.66%)	6325 (47.52%)	< 0.001^a
female	980 (57.34%)	6985 (52.48%)
BMI, kg/m², Mean ± SD	28.41 ± 6.65	28.33 ± 6.19	0.641
Race, N (%)
Mexican American	182 (10.65%)	3148 (23.65%)	< 0.001^a
Other Hispanic	64 (3.74%)	623(4.68%)
Non-Hispanic White	1079 (63.14%)	6500 (48.84%)
Non-Hispanic black	337 (19.72%)	2534 (19.04%)
Other Race or Multi-racial	47 (2.75%)	505 (3.79%)
Education, N (%)
< High school	375 (21.94%)	4564 (34.29%)	< 0.001^a
High school	444 (25.98%)	3118 (23.42%)
> High school	885 (51.78%)	5583 (41.95%)
Missing	5 (0.29%)	45 (0.34%)
Annual family income, N (%)
< 20,000 USD	506 (29.61%)	4333 (32.55%)	< 0.01^a
≥ 20,000 USD	1143 (66.88%)	8344 (62.69%)
Missing	60 (3.51%)	633 (4.76%)
Current smoking status, N (%)
Smoking	409 (23.93%)	2825 (21.22%)	0.138^a
Non-smoking	459 (26.86%)	3530 (26.52%)
Missing	841 (49.21%)	6955 (52.25%)
Cardiovascular disease, N (%)	619 (36.22%)	4684 (35.19%)	0.402^a
Hypertension, N (%)	565 (33.06%)	4211 (31.64%)	0.343^a
Hearth failure, N (%)	65 (3.80%)	475 (3.57%)	0.616^a
Angina, N (%)	72 (4.21%)	510 (3.83%)	0.432^a
Heart attack, N (%)	94 (5.50%)	651 (4.89%)	0.274^a
Coronary heart disease, N (%)	68 (3.98%)	626 (4.70%)	0.184^a
SBP, Mean ± SD	124.90 ± 21.01	126.95 ± 21.75	< 0.001^b
DBP, Mean ± SD	70.76 ± 13.79	70.31 ± 14.43	0.252^b

3.2 Association between cardiovascular diseases and family history of Alzheimer’s disease

Then, we performed a logistics analysis to explore the relationship between CVDs and the family history of AD. Table 2 shows the crude and adjusted odds ratios for the association between AD family history and CVDs. There has no statistically significant in the crude model. However, after controlling for gender, age, BMI, race, education and annual family income, the association has significance. These individuals with AD relatives had 0.173 higher odds of CVDs than those without AD relatives (OR = 1.173 (1.029–1.338), p < 0.05).

Table 2

Association between AD family history and CVDs
	OR	95% CI	p values
Crude model
AD’s blood relatives			0.402
NO	Ref.	Ref.
YES	1.046	0.942–1.161
Adjudged model
AD’s blood relatives			< 0.05
NO	Ref.	Ref.
YES	1.173	1.029–1.338
Gender			0.692
Male	1.017	0.934–1.108
Female	Ref.	Ref.
Age, years	1.063	1.060–1.066	< 0.001
BMI, kg/m²	1.088	1.081–1.096	< 0.001
Race			< 0.001
Mexican American	0.698	0.543–0.899	< 0.01
Other Hispanic	0.837	0.613–1.144	0.265
Non-Hispanic White	0.924	0.727–1.174	0.516
Non-Hispanic black	1.351	1.052–1.735	< 0.05
Other Race or Multi-racial	Ref.	Ref.
Education			0.086
< High school	Ref.	Ref.
High school	0.991	0.877–1.118	0.879
> High school	0.897	0.801–1.003	0.057
Annual family income			< 0.001
< 20,000 USD	Ref.	Ref.
≥ 20,000 USD	0.797	0.723–0.877	< 0.001

3.3 Association between cardiovascular diseases and family history of Alzheimer’s disease from matrilineal and patrilineal sources

Next, we further compared the demographic characteristics of individuals with matrilineal and patrilineal sources of AD relatives (Table 3). Participants with matrilineal source AD relatives were significantly older than that from patrilineal sources (46.99 ± 17.22 vs. 42.96 ± 15.43, p < 0.001). In addition, individuals with a maternal AD family history seem to have a higher BMI (28.86 ± 7.15kg/m² vs 27.81 ± 6.83kg/m²), and a trend to have lower family income and lower smoking rate (23.31% vs. 29.63%, p < 0.01). However, almost half of the participants declined to answer the question concerning their smoking status. Additionally, there are no significant differences in gender, race, or education levels. An interesting finding is that individuals with matrilineal sources of AD relatives have a higher prevalence of CVDs (35.59% vs. 27.45%, p < 0.01), which seems possibly driven by the ratio of hypertension.

Table 3

**Demographics and characteristics of participants divided by matrilineal or patrilineal sources, from NHANES 1999–2004** Data are presented as N% (χ² test) and Mean ± SD (independent t-test) which are denoted by ^a and ^b, respectively.
Characteristic	Matrilineal family history of AD (N = 798, 63.48%)	Patrilineal family history of AD (N = 459, 36.51%)	p value
Age, years, N (%)
< 30	155 (19.42%)	99 (21.57%)	< 0.05^a
30–40	150 (18.80%)	113 (24.62%)
>= 40	493 (61.78%)	247 (53.81%)
Mean ± SD	46.99 ± 17.22	42.96 ± 15.43	< 0.001^b
Gender, N (%)
Male	344 (43.11%)	205 (44.66%)	0.593^a
female	454 (56.89%)	254 (55.34%)
BMI, kg/m², Mean ± SD	28.86 ± 7.15	27.81 ± 6.38	< 0.05^b
Race, N (%)
Mexican American	86 (10.78%)	59 (12.85%)	0.226^a
Other Hispanic	38 (4.76%)	14 (3.05%)
Non-Hispanic White	484 (60.65%)	294 (64.05%)
Non-Hispanic black	160 (20.05%)	79 (17.21%)
Other Race or Multi-racial	30 (3.76%)	13 (2.83%)
Education, N (%)
< High school	161 (20.18%)	86 (18.74%)	0.607^a
High school	204 (25.56%)	111 (24.18%)
> High school	430 (53.88%)	261 (56.86%)
Missing	3 (0.38%)	1 (0.22%)
Annual family income, N (%)
< 20,000 USD	252 (31.58%)	112 (24.40%)	< 0.01^a
≥ 20,000 USD	521 (65.29%)	330 (71.90%)
Missing	25 (3.13%)	17 (3.70%)
Current smoking status, N (%)
Smoking	186 (23.31%)	136 (29.63%)	< 0.01^a
Non-smoking	217 (27.19%)	101 (22.00%)
Missing	395 (49.50%)	222 (48.37%)
Cardiovascular disease, N (%)	284 (35.59%)	126 (27.45%)	< 0.01^a
Hypertension, N (%)	258 (32.33%)	119 (25.92%)	< 0.05^a
Hearth failure, N (%)	28 (3.51%)	8 (1.74%)	0.070^a
Angina, N (%)	35 (4.39%)	12 (2.61%)	0.107^a
Heart attack, N (%)	40 (5.01%)	19 (4.14%)	0.475^a
Coronary heart disease, N (%)	33 (4.14%)	13 (2.83%)	0.230^a
SBP, Mean ± SD	124.38 ± 21.06	119.44 ± 16.57	< 0.001^b
DBP, Mean ± SD	71.28 ± 13.01	71.56 ± 12.37	0.724^b

To further investigate the association between AD family history and CVDs, we explored their relationship by dividing the family history of AD into maternal and paternity sources (Table 4). In crude model, patrilineal sources had a lower odds ratio for CVDs (OR = 0.697, 95% CI = 0.566–0.858). Inversely, in an adjudged model, matrilineal sources had a slight difference ratio for CVDs (OR = 1.184, 95% CI = 0.987–1.421) with a p-value of 0.069. It is plausible that individuals with maternal source AD family history still have a risk of CVDs.

Table 4

Logistic regression analyses of AD family history on CVDs from matrilineal or patrilineal sources
	OR	95% CI	p values
Crude model
AD’s blood relatives			< 0.01
Maternal line	1.018	0.876–1.181	0.819
Paternal line	0.697	0.566–0.858	< 0.001
NO	Ref.	Ref.
Adjudged model
AD’s blood relatives			0.086
Maternal line	1.184	0.987–1.421	0.069
Paternal line	1.188	0.926–1.524	0.175
NO	Ref.	Ref.
Gender			0.578
Male	1.025	0.940–1.118	0.578
Female	Ref.	Ref.
Age, years	1.063	1.060–1.066	< 0.001
BMI, kg/m²	1.089	1.081–1.096	< 0.001
Race			< 0.001
Mexican American	0.703	0.545–0.907	< 0.01
Other Hispanic	0.834	0.609–1.143	0.260
Non-Hispanic White	0.929	0.730–1.183	0.553
Non-Hispanic black	1.359	1.056–1.749	< 0.05
Other Race or Multi-racial	Ref.	Ref.
Education			0.109
< High school	Ref.	Ref.
High school	0.981	0.867–1.110	0.760
> High school	0.896	0.799–1.004	0.059
Annual family income			< 0.01
< 20,000 USD	Ref.	Ref.
≥ 20,000 USD	0.798	0.723–0.880	< 0.001

In the present study, we explored the relationship between the family history of AD and CVDs. We found that individuals with a family history of AD might have a higher risk of CVDs. In addition, by dividing the family history of AD into matrilineal or patrilineal sources, we also found that the maternal line seems to be an important factor for the onset of CVDs rather than patrilineal sources.

Although various CVDs have been proved to increase the risk of AD, most cases of early-onset familial AD are inherited. Whether the family history of AD would inversely affect CVDs is seldom investigated. Indeed, there are some similarities between these two diseases. Besides similar epidemical characteristics like aging, diabetes and obesity between the heart and brain, the diets would be also important[8], as the Mediterranean is beneficial to both most CVDs and AD[9]. In addition, previous studies indicated that a ketogenic diet is a potential treatment and prevention strategy for AD[10, 11]. Similarly, ketone metabolism is crucial for the heart[12]. As relatives may share the same diet, the connection between CVDs and family history of AD is reasonable.

In addition, the heart and the brain share similar genetic profiles in the previous findings[13]. Researchers suggested amylin and amyloid aggregations in the heart of diabetic cardiomyopathy[14]. Another study indicated an amylin deposition in the brain would accompany a late onset AD[15]. Other studies also found some common genes or proteins between these two diseases, like PSEN1 or PSEN2 genes, and Cofilin[1]. Additionally, the mitochondrial function is also important. Mitochondria produces most of the energy for cells and its abnormality promotes oxidative stress and energy crisis.

Both the heart and brain are organs that desire an abundant of energy supplements. A failing heart is an engine out of energy, any mitochondrial dysfunction would promote heart failure. While mitochondria abnormality in the brain would also induce AD. Thus, there are various similarities and connections between AD and CVDs, from a clinical feature, protein, gene and ultrastructure.

Intriguingly, when all participants were enrolled, there has a significance between CVDs and the family history of AD. However, after we divided them into matrilineal and patrilineal sources, this connection disappeared in the paternal line and seemed still significant in the maternal line. A possible explanation is that the data is from a cross-sectional study and have various confounding factors. Another explanation is that mitochondria, which are essential in the onset of AD, are passed down its DNA through maternal lineage[16]. Thus, it is still possible that maternal AD family history is a risk of CVDs.

However, there are still some limitations to the study. First, the present study is a cross-sectional investigation, a prospective or animal study is needed. Second, although the data included the family history of AD, we cannot provide a direct connection between AD and CVDs, as we still lack the data on AD history in participants. Third, most cases of CVDs in the study are occupied by hypertension rather than heart failure or angina; therefore, the statistical significance might be driven by hypertension. Together, individuals with an AD family history tend to have cardiovascular disease, possibly hypertension.

In conclusion, the incidence of CVDns in individuals with AD relatives was higher than that in individuals without AD relatives. In addition, the demographic characteristics of individuals with maternal and paternal AD relatives were compared, and it was found that maternal source of AD family history rather than patrilineal was a risk factor for CVDs. Moreover, the exact mechanisms underlying the relationship between family history of AD and CVDs need to be further elucidated.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and analyzed during the current study are available in the Centers for Disease Control and Prevention repository, https://www.cdc.gov/nchs/nhanes/about_nhanes.htm

Competing interests

The authors declare that they have no competing interests.

Funding

This study was partly supported by grants from the Natural Science Foundation of Fujian Province (2021J05287, 2021J05283), the National Natural Science Foundation of China (82100385, 82202629, 81772287), Health Technology Project of Fujian Province (2021QNB016) and the grant of Xiamen High-level health talents.

Authors' contributions

LHY, ZB, MXB, HCY concept and design the study, WJY, YWZ, ZYX collected the data, LHY, ZGS, ZYQ, FLL analyzed and interpreted the data, LHY, YMM, CNN, LF drafted the manuscript, LHY, YMM, CNN critically revised the manuscript for important intellectual content. HGL, LZH provided financial support. All authors read and approved the final manuscript.

Acknowledgments

Not applicable.

Tublin JM, Adelstein JM, Del Monte F, et al. Getting to the Heart of Alzheimer Disease. Circ Res. 2019;124(1):142–9.
Tracy TE, Madero-Pérez J, Swaney DL, et al. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022;185(4):712–728e14.
Roher AE, Debbins JP, Malek-Ahmadi M, et al. Cerebral blood flow in Alzheimer's disease. Vasc Health Risk Manag. 2012;8:599–611.
Lathe R, Sapronova A, Kotelevtsev Y. Atherosclerosis and Alzheimer–diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr. 2014;14:36.
Gottesman RF, Seshadri S. Risk Factors, Lifestyle Behaviors, and Vascular Brain Health. Stroke. 2022;53(2):394–403.
Wei Y, Giunta S, Xia S. Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies. Int J Mol Sci, 2022. 23(15).
Ihara M, Washida K. Linking Atrial Fibrillation with Alzheimer's Disease: Epidemiological, Pathological, and Mechanistic Evidence. J Alzheimers Dis. 2018;62(1):61–72.
McGrattan AM, McGuinness B, McKinley MC, et al. Diet and Inflammation in Cognitive Ageing and Alzheimer's Disease. Curr Nutr Rep. 2019;8(2):53–65.
van den Brink AC, Brouwer-Brolsma EM, Berendsen AAM, et al. The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diets Are Associated with Less Cognitive Decline and a Lower Risk of Alzheimer's Disease-A Review. Adv Nutr. 2019;10(6):1040–65.
Broom GM, Shaw IC, Rucklidge JJ. The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease. Nutrition. 2019;60:118–21.
Rusek M, Pluta R, Ułamek-Kozioł M et al. Ketogenic Diet in Alzheimer's Disease. Int J Mol Sci, 2019. 20(16).
Guo Y, Liu X, Li T et al. Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver. Oxid Med Cell Longev, 2022. 2022: p. 4253651.
Li D, Parks SB, Kushner JD, et al. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006;79(6):1030–9.
Despa F, Decarli C. Amylin: what might be its role in Alzheimer's disease and how could this affect therapy? Expert Rev Proteomics. 2013;10(5):403–5.
Jackson K, Barisone GA, Diaz E, et al. Amylin deposition in the brain: A second amyloid in Alzheimer disease? Ann Neurol. 2013;74(4):517–26.
Chiaratti MR, Garcia BM, Carvalho KF, et al. The role of mitochondria in the female germline: Implications to fertility and inheritance of mitochondrial diseases. Cell Biol Int. 2018;42(6):711–24.

No competing interests reported.

The relationship between cardiovascular diseases and the family history of Alzheimer’s disease: results from NHANES (1999-2004)

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and Methods

2.1 Study population

2.2 Covariates of Interest

2.3 Statistical Analysis

3. Results

3.1 Characteristics of Participants with or without a family history of Alzheimer’s disease

3.2 Association between cardiovascular diseases and family history of Alzheimer’s disease

3.3 Association between cardiovascular diseases and family history of Alzheimer’s disease from matrilineal and patrilineal sources

4. Discussion

5.Conclusion

Declarations

References

Additional Declarations

Status:

Version 1