Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease
Open accessAbstract
The objective of this manuscript is to provide a comprehensive review of the epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with Alzheimer's disease. The mechanisms for these associations remain to be elucidated, but may include direct actions from insulin, advanced products of glycosilation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of Alzheimer's disease. The evidence relating adiposity in old age to Alzheimer's disease is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of Alzheimer's disease. Hyperinsulinemia is a risk factor for diabetes, and numerous studies have shown a relation of diabetes with higher Alzheimer's disease risk. Most studies fail the take into account the continuum linking these risk factors which may result in underestimation of their importance in Alzheimer's disease. The implication of these associations is that a large proportion of the world population may be at increased risk of Alzheimer's disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes. However, if proven causal, these associations also present a unique opportunity for prevention and treatment of Alzheimer's disease.
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TL;DR
This narrative review argues that adiposity, hyperinsulinemia, and diabetes form a continuum associated with higher Alzheimer’s disease risk, though mechanisms and causality remain unresolved. It synthesizes prospective epidemiologic evidence and Washington Heights Inwood Columbia Aging Project (WHICAP) findings, reporting elevated risks for hyperinsulinemia and diabetes but conflicting findings for adiposity in old age.
Key findings
- In WHICAP, Alzheimer’s disease risk doubled in the 39% of the sample with hyperinsulinemia (hazard ratio = 2.1; 95% CI: 1.5, 2.9); the highest insulin quartile had HR = 1.7 (95% CI: 1.0, 2.7; p for trend = 0.009), and hyperinsulinemia or diabetes had HR = 2.2 (95% CI: 1.5, 3.1). The risk of Alzheimer’s disease attributable to hyperinsulinemia or diabetes was 39%.
- Diabetes was related to higher risk of all-cause mild cognitive impairment (HR = 1.4; 95% CI: 1.0, 1.8), amnestic mild cognitive impairment (HR = 1.5; 95% CI: 1.0, 2.2), and Alzheimer’s disease (HR = 2.4; 95% CI: 1.8, 3.2) in WHICAP; a reanalysis with longer follow-up reported RR = 4, independent of other vascular conditions.
- Elevated adiposity in middle age is related to higher dementia risk, but evidence in old age is conflicting; WHICAP found a U-shaped BMI association with Alzheimer’s disease in persons 65–75 years and no association in those 76 years and older, while higher waist circumference was related to Alzheimer’s disease in the younger elderly but not the oldest.
- The metabolic syndrome was not associated with incident dementia in WHICAP, but its components diabetes and hyperinsulinemia were associated with increased Alzheimer’s disease risk (HR = 1.4; 95% CI: 1.0–2.1 and HR = 1.4; 95% CI: 0.9–2.7, respectively) and vascular dementia risk (HR = 1.9; 95% CI: 1.1–3.1 and HR = 2.3; 95% CI: 1.1–4.7).
Methods
- Narrative review, not a primary study, providing a comprehensive review of epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with Alzheimer’s disease.
- Data include prospective epidemiologic studies and findings from WHICAP, a longitudinal study of aging in persons 65 years and older in New York City; outcomes include memory impairment or decline, amnestic mild cognitive impairment, and Alzheimer’s dementia.
- Main analysis is qualitative synthesis of cited studies and WHICAP results; no formal systematic search, meta-analysis, or quantitative pooling is described.
Limitations
- Stated: mechanisms remain to be elucidated; evidence falls short of proof of causation; old-age adiposity findings are conflicting; definitions of normal for adiposity, hyperinsulinemia, and diabetes are arbitrary and may cause misclassification; survival bias is an issue in elderly cohorts; the conditions may be heterogeneous and a reductionistic separation of their effects is difficult if not impossible.
- Evident from the text: as a narrative review, it lacks a systematic search strategy, formal risk-of-bias assessment, and quantitative synthesis; conclusions depend on the selected cited studies and WHICAP findings rather than new primary data.
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Claims the paper makes
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- Findingcitation§ 8. Putting it all together
In the WHICAP cohort, higher waist circumference is associated with Alzheimer's disease in persons aged 65 to 75 years.
“We found that higher waist circumference was associated with Alzheimer’s disease also in persons 65 to 75 years, while there was no association in persons 76 years and older.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Luchsinger et al., 2007a
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- Findingcitation§ 8. Putting it all together
Diabetes is associated with a higher risk of Alzheimer's disease.
“Diabetes has been related to a higher risk of amnestic mild cognitive impairment, non-amnestic mild cognitive impairment, Alzheimer’s disease, and vascular dementia (Luchsinger et al., 2005; Luchsinger et al., 2007b; Luchsinger et al., 2001).”
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- cites Luchsinger et al., 2007b
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- Findingcitation§ 8. Putting it all together
The 4th quartile of waist circumference was related to a higher vascular dementia risk in the whole sample.
“The 4 th quartile of waist circumference was related to a higher vascular dementia risk in the whole sample, and to dementia and Alzheimer’s disease in persons < 76 years.”
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- Findingcitation§ 8. Putting it all together
Compared to persons in the first quartile of body mass index, persons in the third quartile had a lower dementia and Alzheimer's disease risk.
“Compared to persons in the first quartile of body mass index, persons in the third quartile had a lower dementia and Alzheimer’s disease risk, and persons in the second quartile had a lower vascular dementia (vascular dementia) risk.”
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- Findingcitation§ 8. Putting it all together
Diabetes is associated with a higher risk of non-amnestic mild cognitive impairment.
“Diabetes has been related to a higher risk of amnestic mild cognitive impairment, non-amnestic mild cognitive impairment, Alzheimer’s disease, and vascular dementia (Luchsinger et al., 2005; Luchsinger et al., 2007b; Luchsinger et al., 2001).”
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- cites Luchsinger et al., 2007b
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- Findingcitation§ 8. Putting it all together
Diabetes is associated with a higher risk of vascular dementia.
“Diabetes has been related to a higher risk of amnestic mild cognitive impairment, non-amnestic mild cognitive impairment, Alzheimer’s disease, and vascular dementia (Luchsinger et al., 2005; Luchsinger et al., 2007b; Luchsinger et al., 2001).”
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- cites Luchsinger et al., 2007b
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- cites Luchsinger et al., 2001
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- Findingcitation§ 8. Putting it all together
Compared to persons in the first quartile of body mass index, persons in the second quartile had a lower vascular dementia risk.
“Compared to persons in the first quartile of body mass index, persons in the third quartile had a lower dementia and Alzheimer’s disease risk, and persons in the second quartile had a lower vascular dementia (vascular dementia) risk.”
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- Findingown data§ 8. Putting it all together
In the WHICAP cohort, elevated waist circumference is a stronger risk factor for vascular dementia than for Alzheimer's disease.
“We found that elevated waist circumference was a stronger risk factor for vascular dementia than for Alzheimer’s disease.”
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- Findingcitation§ 8. Putting it all together
The association between body mass index and dementia resembled a U-shape in those younger than 76 years.
“The association between body mass index and dementia resembled a U-shape in those < 76 years, while dementia risk decreased with higher body mass index in those ≥ 76 years.”
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- Findingcitation§ 8. Putting it all together
The individual components of hyperinsulinemia and diabetes as defined within the metabolic syndrome definition are associated with a higher risk of Alzheimer's disease.
“However, the individual components of hyperinsulinemia and diabetes as defined within the metabolic syndrome definition were associated with a higher risk of Alzheimer’s disease.”
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- Findingcitation§ 8. Putting it all together
In the WHICAP cohort, Alzheimer's disease risk increases with higher insulin quartile.
“For hyperinsulinemia we found that Alzheimer’s disease risk increased with higher insulin quartile, and that this association was stronger for persons with the APOE-ε4 allele (Luchsinger et al., 2004).”
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- Findingcitation§ 8. Putting it all together
The 4th quartile of waist circumference was related to dementia and Alzheimer's disease in persons younger than 76 years.
“The 4 th quartile of waist circumference was related to a higher vascular dementia risk in the whole sample, and to dementia and Alzheimer’s disease in persons < 76 years.”
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- Findingcitation§ 8. Putting it all together
In the WHICAP cohort, higher body mass index has a U-shaped association with Alzheimer's disease in persons aged 65 to 75 years.
“We found that higher body mass index has a U-shape association with Alzheimer’s disease in persons 65 to 75 years, while there is no association in persons 76 years and older (Luchsinger et al., 2007a).”
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- Findingcitation§ 8. Putting it all together
The risk of Alzheimer's disease doubled in the 39% of the sample with hyperinsulinemia (hazard ratio = 2.1; 95% CI: 1.5, 2.9).
“The risk of Alzheimer’s disease doubled in the 39% of the sample with hyperinsulinemia (hazard ratio = 2.1; 95% CI: 1.5, 2.9) and was highest in people without diabetes.”
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- Findingcitation§ 8. Putting it all together
In the WHICAP cohort, the association between hyperinsulinemia and Alzheimer's disease risk is stronger in persons with the APOE-ε4 allele.
“For hyperinsulinemia we found that Alzheimer’s disease risk increased with higher insulin quartile, and that this association was stronger for persons with the APOE-ε4 allele (Luchsinger et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Luchsinger et al., 2004
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- Findingcitation§ 8. Putting it all together
In the WHICAP cohort, waist circumference is not associated with Alzheimer's disease in persons aged 76 years and older.
“We found that higher waist circumference was associated with Alzheimer’s disease also in persons 65 to 75 years, while there was no association in persons 76 years and older.”
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- Findingcitation§ 8. Putting it all together
Two definitions of the metabolic syndrome, one including diabetes and one including hyperinsulinemia, are not related to Alzheimer's disease risk.
“We found that two definitions of the metabolic syndrome, one that included diabetes and one that included hyperinsulinemia, were not related to Alzheimer’s disease risk (Muller et al., 2007).”
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- Findingcitation§ 8. Putting it all together
In the WHICAP cohort, body mass index is not associated with Alzheimer's disease in persons aged 76 years and older.
“We found that higher body mass index has a U-shape association with Alzheimer’s disease in persons 65 to 75 years, while there is no association in persons 76 years and older (Luchsinger et al., 2007a).”
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- Findingcitation§ 8. Putting it all together
Diabetes is associated with a higher risk of amnestic mild cognitive impairment.
“Diabetes has been related to a higher risk of amnestic mild cognitive impairment, non-amnestic mild cognitive impairment, Alzheimer’s disease, and vascular dementia (Luchsinger et al., 2005; Luchsinger et al., 2007b; Luchsinger et al., 2001).”
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- cites Luchsinger et al., 2007b
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- Findingcitation§ 8. Putting it all together
Dementia risk decreased with higher body mass index in those aged 76 years and older.
“The association between body mass index and dementia resembled a U-shape in those < 76 years, while dementia risk decreased with higher body mass index in those ≥ 76 years.”
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- Findingcitation§ 8. Putting it all together
Diabetes was associated with an increased incident vascular dementia risk (hazard ratio = 1.9; 95% CI: 1.1-3.1).
“Of the components of the metabolic syndrome, diabetes and hyperinsulinemia were associated with an increased incident Alzheimer’s disease (hazard ratio; 95%CI respectively 1.4; 1.0–2.1 and 1.4; 0.9–2.7) and vascular dementia risk(hazard ratio; 95%CI respectively 1.9; 1.1–3.1 and 2.3; 1.1–4.7).”
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- Findingcitation§ 8. Putting it all together
The risk of Alzheimer's disease associated with hyperinsulinemia was highest in people without diabetes.
“The risk of Alzheimer’s disease doubled in the 39% of the sample with hyperinsulinemia (hazard ratio = 2.1; 95% CI: 1.5, 2.9) and was highest in people without diabetes.”
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- Findingcitation§ 8. Putting it all together
In New York City elderly, the risk of Alzheimer's disease attributable to the presence of hyperinsulinemia or diabetes was 39%.
“The risk of Alzheimer’s disease attributable to the presence of hyperinsulinemia or diabetes was 39%.”
- Also stated in: § 9. Implications for prevention and treatment of Alzheimer’s disease · hedged
“We estimated that in New York City the presence of diabetes or hyperinsulinemia in elderly people could account for 39% of cases of Alzheimer’s disease (Luchsinger et al., 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Luchsinger et al., 2004
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- Rests on an assumption: The WHICAP cohort is representative of the elderly population in New York City for estimating the population attributable risk of Alzheimer's disease due to diabetes or hyperinsulinemia.
- Also stated in: § 9. Implications for prevention and treatment of Alzheimer’s disease · hedged
- Findingcitation§ 8. Putting it all together
Diabetes was associated with an increased incident Alzheimer's disease (hazard ratio = 1.4; 95% CI: 1.0-2.1).
“Of the components of the metabolic syndrome, diabetes and hyperinsulinemia were associated with an increased incident Alzheimer’s disease (hazard ratio; 95%CI respectively 1.4; 1.0–2.1 and 1.4; 0.9–2.7) and vascular dementia risk(hazard ratio; 95%CI respectively 1.9; 1.1–3.1 and 2.3; 1.1–4.7).”
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- Findingcitation§ 8. Putting it all together
Diabetes was related to a significantly higher risk of all-cause mild cognitive impairment (hazard ratio = 1.4; 95% CI: 1.0, 1.8) after adjustment for all covariates.
“Diabetes was related to a significantly higher risk of all-cause mild cognitive impairment (hazard ratio= 1.4; 95% CI: 1.0,1.8) and amnestic mild cognitive impairment (hazard ratio= 1.5; 95% CI: 1.0,2.2) after adjustment for all covariates.”
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- Findingcitation§ 8. Putting it all together
Hyperinsulinemia was not related to decline in other cognitive domains.
“Hyperinsulinemia was also related to a statistically significant decline in memory related cognitive scores, but not to decline in other cognitive domains.”
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- Findingcitation§ 8. Putting it all together
The hazard ratio relating presence of hyperinsulinemia or diabetes in 50% of our sample to Alzheimer's disease was 2.2 (95% CI: 1.5, 3.1).
“The hazard ratio relating presence of hyperinsulinemia or diabetes in 50% of our sample to Alzheimer’s disease was 2.2 (95% CI: 1.5,3.1).”
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- Findingcitation§ 8. Putting it all together
The hazard ratio of Alzheimer's disease for the highest quartile of insulin compared to the lowest was 1.7 (95% CI: 1.0, 2.7; p for trend = 0.009).
“The hazard ratio of Alzheimer’s disease for the highest quartile of insulin compared to the lowest was 1.7 (95% CI: 1.0,2.7; p for trend = 0.009).”
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- Findingcitation§ 8. Putting it all together
Hyperinsulinemia was related to a statistically significant decline in memory-related cognitive scores.
“Hyperinsulinemia was also related to a statistically significant decline in memory related cognitive scores, but not to decline in other cognitive domains.”
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- Findingcitation§ 8. Putting it all together
Metabolic syndrome was not associated with incident dementia.
“metabolic syndrome was not associated with incident dementia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Muller et al., 2007 source
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- Findingcitation§ 8. Putting it all together
Hyperinsulinemia was associated with an increased incident vascular dementia risk (hazard ratio = 2.3; 95% CI: 1.1-4.7).
“Of the components of the metabolic syndrome, diabetes and hyperinsulinemia were associated with an increased incident Alzheimer’s disease (hazard ratio; 95%CI respectively 1.4; 1.0–2.1 and 1.4; 0.9–2.7) and vascular dementia risk(hazard ratio; 95%CI respectively 1.9; 1.1–3.1 and 2.3; 1.1–4.7).”
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- Findingcitation§ 8. Putting it all together
Diabetes was related to a higher risk of non-amnestic mild cognitive impairment (hazard ratio = 1.4; 95% CI: 1.0, 1.9).
“Diabetes was also related to a higher risk of non-amnestic mild cognitive impairment (1.4; 95% CI: 1.0,1.9), but this association was appreciably attenuated after adjustment for socio-economic variables and vascular risk factors (1.2; 95% CI: 0.9,1.8).”
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- cites Luchsinger et al., 2007b
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- Findingcitation§ 8. Putting it all together
The association between diabetes and non-amnestic mild cognitive impairment was appreciably attenuated after adjustment for socio-economic variables and vascular risk factors (hazard ratio = 1.2; 95% CI: 0.9, 1.8).
“Diabetes was also related to a higher risk of non-amnestic mild cognitive impairment (1.4; 95% CI: 1.0,1.9), but this association was appreciably attenuated after adjustment for socio-economic variables and vascular risk factors (1.2; 95% CI: 0.9,1.8).”
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- cites Luchsinger et al., 2007b
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- Findingcitation§ 8. Putting it all together
Hyperinsulinemia was associated with an increased incident Alzheimer's disease (hazard ratio = 1.4; 95% CI: 0.9-2.7).
“Of the components of the metabolic syndrome, diabetes and hyperinsulinemia were associated with an increased incident Alzheimer’s disease (hazard ratio; 95%CI respectively 1.4; 1.0–2.1 and 1.4; 0.9–2.7) and vascular dementia risk(hazard ratio; 95%CI respectively 1.9; 1.1–3.1 and 2.3; 1.1–4.7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Muller et al., 2007 source
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- Findingcitation§ 8. Putting it all together
Diabetes was related to a significantly higher risk of amnestic mild cognitive impairment (hazard ratio = 1.5; 95% CI: 1.0, 2.2) after adjustment for all covariates.
“Diabetes was related to a significantly higher risk of all-cause mild cognitive impairment (hazard ratio= 1.4; 95% CI: 1.0,1.8) and amnestic mild cognitive impairment (hazard ratio= 1.5; 95% CI: 1.0,2.2) after adjustment for all covariates.”
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- cites Luchsinger et al., 2007b
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- Findingcitation§ 8. Putting it all together
The hazard ratio relating diabetes with Alzheimer's disease was 2.4 (95% CI: 1.8, 3.2).
“The hazard ratio relating diabetes with Alzheimer’s disease was 2.4 (95 % CI: 1.8, 3.2).”
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- cites Luchsinger et al., 2007b
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- Interpretationcitation§ Abstract
Diabetes is related to a higher risk of Alzheimer's disease.
“Hyperinsulinemia is a risk factor for diabetes, and numerous studies have shown a relation of diabetes with higher Alzheimer’s disease risk.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation§ Abstract
Elevated adiposity in middle age is related to a higher risk of Alzheimer's disease.
“Elevated adiposity in middle age is related to a higher risk of Alzheimer’s disease.”
- Also stated in: § 6.1. Adiposity · plain
“Elevated body mass index (overweight and obesity) in middle age is associated with higher dementia risk (Kivipelto et al., 2005; Whitmer et al., 2005a).”
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- cites Whitmer et al., 2005a
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- Also stated in: § 6.1. Adiposity · plain
- Interpretationcitation§ Abstract
Hyperinsulinemia is related to a higher risk of Alzheimer's disease.
“Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of Alzheimer’s disease.”
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- cites Luchsinger et al., 2004
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- Interpretationcitation§ Abstract
The evidence relating adiposity in old age to Alzheimer's disease is conflicting.
“The evidence relating adiposity in old age to Alzheimer’s disease is conflicting.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 3. The continuum of adiposity, hyperinsulinemia, glucose intolerance and diabetes
The most frequent modifiable determinant of insulin resistance and hyperinsulinemia is adiposity.
“The most frequent modifiable determinant of insulin resistance and hyperinsulinemia is adiposity (Reaven, 2005; Reaven and Laws, 1999), although adipose tissue is not the only factor.”
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- cites Reaven and Laws, 1999
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- Interpretationreasoning§ 3. The continuum of adiposity, hyperinsulinemia, glucose intolerance and diabetes
When an epidemiologic study finds a relation between components of the continuum and Alzheimer's disease, it cannot be certain whether the relation reflects a surrogate marker of another component or the examined exposure itself.
“Another implication of the continuum described above is that when an epidemiologic study finds a relation between the components of this continuum and Alzheimer’s disease we cannot be certain if we are looking at a surrogate marker of one of the other components (e.g. diabetes is a marker of past adiposity or hyperinsulinemia, obesity is a marker of hyperinsulinemia) or if the important exposure”
Quote in the paperSubstantial claim - Interpretationreasoning
Adiposity, hyperinsulinemia, and diabetes may affect Alzheimer's disease risk indirectly through vascular risk factors and cerebrovascular disease.
“Thus, adiposity, hyperinsulinemia, and diabetes may affect Alzheimer’s disease risk indirectly through vascular risk factors and cerebrovascular disease.”
Quote in the paperSubstantial claim - Interpretationown data§ 8. Putting it all together
Misclassification of vascular dementia as Alzheimer's disease did not explain the positive findings.
“In general these findings were robust when only probable Alzheimer’s disease was examined as the outcome, suggesting that misclassification of vascular dementia as Alzheimer’s disease did not explain the positive findings.”
Quote in the paperSubstantial claim - Study design and conductown data§ 8. Putting it all together
The positive findings were robust when only probable Alzheimer's disease was examined as the outcome.
“In general these findings were robust when only probable Alzheimer’s disease was examined as the outcome, suggesting that misclassification of vascular dementia as Alzheimer’s disease did not explain the positive findings.”
Quote in the paperSubstantial claim - Premisecitation§ 8. Putting it all together
Measures of adiposity lose their predictive ability with aging.
“It is known that measures of adiposity lose their predictive ability with aging (Stevens et al., 1998) and our results by age group reflect that.”
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- Interpretationreasoning§ Abstract
A large proportion of the world population may be at increased risk of Alzheimer's disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes.
“The implication of these associations is that a large proportion of the world population may be at increased risk of Alzheimer’s disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes.”
Quote in the paperSubstantial claim - Premisecitation§ 9. Implications for prevention and treatment of Alzheimer’s disease
Large intervention studies with lifestyle interventions and drugs like metformin have shown that it is feasible to decrease hyperinsulinemia and the risk of diabetes.
“Large intervention studies with lifestyle interventions and drugs like metformin have shown that it is feasible to decrease hyperinsulinemia and the risk of diabetes (The Diabetes Prevention Program Research, 2005) and is possible that these interventions could extend to decreasing the risk of Alzheimer’s disease.”
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- Interpretationreasoning§ 9. Implications for prevention and treatment of Alzheimer’s disease
It is possible that interventions that decrease hyperinsulinemia and diabetes risk could extend to decreasing the risk of Alzheimer's disease.
“Large intervention studies with lifestyle interventions and drugs like metformin have shown that it is feasible to decrease hyperinsulinemia and the risk of diabetes (The Diabetes Prevention Program Research, 2005) and is possible that these interventions could extend to decreasing the risk of Alzheimer’s disease.”
Quote in the paperSubstantial claim - Interpretationreasoning§ 9. Implications for prevention and treatment of Alzheimer’s disease
A large proportion of cases of Alzheimer's disease could be preventable or treatable.
“However, the other implication is that a large proportion of cases of Alzheimer’s disease could be preventable or treatable.”
Quote in the paperSubstantial claim - Interpretationreasoning§ 9. Implications for prevention and treatment of Alzheimer’s disease
The evidence that adiposity, hyperinsulinemia, and diabetes are related to Alzheimer's disease falls short of proof of causation until mechanisms and caveats are understood.
“However, this evidence comes short of being considered as proof of causation until we understand the mechanisms and some of the caveats discussed in this review.”
Quote in the paperSubstantial claim - Premisecitation§ 9. Implications for prevention and treatment of Alzheimer’s disease
Concerns about rosiglitazone's safety may limit its usefulness.
“On this basis, drugs like rosiglitazone have shown preliminary (Watson et al., 2005) promise in the treatment of Alzheimer’s disease, although concerns about its safety may make limit this drug’s usefulness (Nathan, 2007; Nathan and Berkwits, 2007).”
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- Interpretationreasoning§ 9. Implications for prevention and treatment of Alzheimer’s disease
With increasing life expectancy, we are likely to increasingly see the cognitive consequences of increased adiposity, hyperinsulinemia, and diabetes in old age.
“With increasing life expectancy we are likely to increasingly see the cognitive consequences of increased adiposity, hyperinsulinemia, and diabetes in old age.”
Quote in the paperSubstantial claim - Premisecitation§ 9. Implications for prevention and treatment of Alzheimer’s disease
Drugs like rosiglitazone have shown preliminary promise in the treatment of Alzheimer's disease.
“On this basis, drugs like rosiglitazone have shown preliminary (Watson et al., 2005) promise in the treatment of Alzheimer’s disease, although concerns about its safety may make limit this drug’s usefulness (Nathan, 2007; Nathan and Berkwits, 2007).”
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- May combine two claims. 7
- Classified as probably not a substantial claim. 3
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Findingown data§ 8. Putting it all togetherDiabetes and hyperinsulinemia are robust predictors for Alzheimer's disease in our data.
“In fact, diabetes and hyperinsulinemia, which are robust predictors for Alzheimer’s disease in our data, are the very constructs that the metabolic syndrome tries to capture.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationDiabetes is consistently related to vascular dementia, but its relation to Alzheimer's disease is less clear.
“Diabetes has been found consistently to be related to vascular dementia (vascular dementia), but its relation to Alzheimer’s disease is less clear.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Yoshitake et al., 1995
Not checked in the free run.
- cites Luchsinger et al., 2001
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ AbstractMost studies fail to take into account the continuum linking adiposity, hyperinsulinemia, and diabetes, which may result in underestimation of their importance in Alzheimer's disease.
“Most studies fail the take into account the continuum linking these risk factors which may result in underestimation of their importance in Alzheimer’s disease.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ 3. The continuum of adiposity, hyperinsulinemia, glucose intolerance and diabetesAdiposity, hyperinsulinemia, glucose intolerance, and diabetes are related sequentially and often occur simultaneously.
“However, they are related sequentially and often occur simultaneously, and understanding this relationship is fundamental in the study of the role of adiposity, insulin resistance, and diabetes in Alzheimer’s disease.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Festa et al., 2006
Not checked in the free run.
- cites DeFronzo, 2000
Not checked in the free run.
May combine two claims.
Premisecitation§ 8. Putting it all togetherThe metabolic syndrome is a useful concept in middle age but its use may be limited in the elderly.
“In terms of the metabolic syndrome, it is a useful concept in middle age but its use may be limited in the elderly (Luchsinger, 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Luchsinger, 2006
Not checked in the free run.
May combine two claims.
Premisecitation§ 3. The continuum of adiposity, hyperinsulinemia, glucose intolerance and diabetesElevations of adiposity result in insulin resistance, causing the pancreas to increase insulin to abnormal levels to sustain normal glucose, and if the pancreas can no longer sustain hyperinsulinemia, glucose intolerance and diabetes will ensue.
“Elevations of adiposity result in insulin resistance, causing the pancreas to increase insulin to abnormal levels to sustain normal glucose, and if and when the pancreas can no longer sustain hyperinsulinemia, glucose intolerance and diabetes will ensue.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Festa et al., 2006
Not checked in the free run.
- Rests on an assumption: Some adults develop diabetes without going through insulin resistance and hyperinsulinemia, but most adults who develop diabetes do go through insulin resistance and hyperinsulinemia.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ AbstractIf proven causal, the associations between adiposity, hyperinsulinemia, diabetes and Alzheimer's disease present a unique opportunity for prevention and treatment of Alzheimer's disease.
“However, if proven causal, these associations also present a unique opportunity for prevention and treatment of Alzheimer’s disease.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ 9. Implications for prevention and treatment of Alzheimer’s diseaseElucidating the mechanisms linking adiposity, hyperinsulinemia and diabetes to Alzheimer's disease will help identify specific targets for treatment.
“Elucidating the mechanisms linking adiposity, hyperinsulinemia and diabetes to Alzheimer’s disease will help identify specific targets for treatment and more research is needed in this regard.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Interpretationreasoning§ 9. Implications for prevention and treatment of Alzheimer’s diseaseIf the relation between adiposity, hyperinsulinemia, and diabetes and Alzheimer's disease were causal, the public health implications would be enormous.
“If the relation between these conditions and Alzheimer’s disease were to be causal, the public health implications are enormous.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone given§ 9. Implications for prevention and treatment of Alzheimer’s diseaseThere is very strong evidence that adiposity, hyperinsulinemia, and diabetes are related to Alzheimer's disease.
“There is very strong evidence that adiposity, hyperinsulinemia, and diabetes are related to Alzheimer’s disease.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Some adults develop diabetes without going through insulin resistance and hyperinsulinemia, but most adults who develop diabetes do go through insulin resistance and hyperinsulinemia.
“Some adults develop diabetes without going through insulin resistance and hyperinsulinemia, but it is thought that most will.”
The paper relies on this without support.
The WHICAP cohort is representative of the elderly population in New York City for estimating the population attributable risk of Alzheimer's disease due to diabetes or hyperinsulinemia.
“We estimated that in New York City the presence of diabetes or hyperinsulinemia in elderly people could account for 39% of cases of Alzheimer’s disease (Luchsinger et al., 2004).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Dyslipidemias are associated with obesity, which has been linked to insulin resistance/hyperinsulinemia in the development of Alzheimer's disease.
“Dyslipidemias are also associated with obesity, which has been linked to insulin resistance/hyperinsulinemia in the development of AD [108,109].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [108]
Individuals with type 2 diabetes have an elevated AD risk.
“For example, individuals with type2 diabetes have an elevated AD risk (Luchsinger, 2008).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Luchsinger, 2008
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting findings for BMI and Alzheimer's disease in the oldest group
MajorThe review describes the same cited cohort as showing a lower Alzheimer's disease risk with higher BMI in the oldest group, but later says there was no association in that group. The stated age cutoffs also differ, though the groups overlap above age 76.
“while in the oldest old (> 76 years) higher body mass index is related to a lower Alzheimer’s disease risk.”
“We found that higher body mass index has a U-shape association with Alzheimer’s disease in persons 65 to 75 years, while there is no association in persons 76 years and older (Luchsinger et al., 2007a).”
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Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease
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“Complex diseases such as late-onset Alzheimer’s disease (LOAD) arise from the downstream interplay of DNA-sequence variants and nongenetic factors that act through molecular networks to confer disease risk (Schadt, 2009).”
BackgroundInfluentialMicroglia in neurodegenerative disease
Perry, V. H., Nicoll, J. A. R., & Holmes, C. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.17 · Cited by 1,543 · see citing works
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“Physical inactivity in the teenage years is also associated with obesity and diabetes;(168) both are risk factors for AD.(169) Physical activity and exercise are much more strongly”
The effects of aging in the hippocampus and cognitive decline
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Is Alzheimer’s disease a type 3 diabetes? A critical appraisal
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“Dyslipidemias are also associated with obesity, which has been linked to insulin resistance/hyperinsulinemia in the development of AD [108,109].”
BackgroundThe Role of Metabolic Disorders in Alzheimer Disease and Vascular Dementia: Two Roads Converged
Craft, S. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.27 · Cited by 547 · see citing works
“The relationship between diabetes and increased AD and VaD risk has recently been discussed in several excellent reviews.(13,14) The weight of evidence suggests that diabetes increases the risk of both AD and VaD, and that this risk occurs regardless of the age at which diabetes occurs.”
BackgroundBiessels, G. J., Strachan, M. W. J., Visseren, F. L. J., Kappelle, L. J., & Whitmer, R. A. (2013) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(13)70088-3 · Cited by 555 · see citing works
Hippocampal insulin resistance and cognitive dysfunction
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Diabetes and Cognitive Impairment
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Estrogen: A master regulator of bioenergetic systems in the brain and body
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“001 insulin to induce glucose uptake (Luchsinger, 2008).”
The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Ferreira, S. T., & Klein, W. L. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.003 · Cited by 442 · see citing works
Promising Strategies for the Prevention of Dementia
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“Specifically, in vitro studies indicate that insulin causes a significant increase in extracellular -amyloid levels.(6) Consequently, people with insulin resistance, such as those with type 2 diabetes mellitus or those with precursor hyperinsulinemia, may have insulin-caused increases in -amyloid levels.”
BackgroundResultInfluentialMiddleton, L. E., Barnes, D. E., Lui, L., & Yaffe, K. (2010) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2010.02903.x · Cited by 339 · see citing works
“In addition, youth who are physically inactive have higher rates of obesity and type II diabetes mellitus,(12) which are risk factors for cognitive impairment in late life.(13,14) The objective of the current study was to examine how physical activity at several points over the life course is related to cognitive perf…”
BackgroundInsulin metabolism and the risk of Alzheimer disease: The Rotterdam Study
Schrijvers, E. M. C., Witteman, J. C. M., Sijbrands, E. J. G., Hofman, A., Koudstaal, P. J., & Breteler, M. M. B. (2010) · Neurology · doi:10.1212/wnl.0b013e3181ffe4f6 · Cited by 328 · see citing works
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“Epidemiological studies provide evidence that in addition to the established association of obesity and metabolic disease with cerebrovascular lesions and vascular cognitive impairment, there is a direct relationship between obesity and pathogenesis of AD (reviewed in (7)).”
BackgroundMammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration
Querfurth, H., & Lee, H.-K. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00428-5 · Cited by 288 · see citing works
Adiponectin receptor signalling in the brain
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“…and the correspondingly high level of adiponectin during the same period, could point to a role for adiponectin during the pro-dromal state of AD by altering the CNS control of energy homeostatsis and body weight (Aziz et al., 2008; Luchsinger, 2008; Luchsinger and Gustafson, 2009a,b) (Figure 5).”
BackgroundContribution of systemic inflammation to chronic neurodegeneration
Perry, V. H. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0722-x · Cited by 283 · see citing works
“It is also notable that reported risk factors for AD include conditions such as obesity [69], diabetes [60], vascular disease [18], periodontitis [56, 57] and smoking [84] that are all associated with chronic low-grade systemic inflammation.”
BackgroundPal, K., Mukadam, N., Petersen, I., & Cooper, C. (2018) · Social Psychiatry and Psychiatric Epidemiology · doi:10.1007/s00127-018-1581-3 · Cited by 276 · see citing works
Insulin, cognition, and dementia
Cholerton, B., Baker, L. D., & Craft, S. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.08.008 · Cited by 229 · see citing works
“increased risk of both Alzheimer's disease and vascular dementia (Luchsinger, 2008; Strachan et al., 2008).”
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Higher normal fasting plasma glucose is associated with hippocampal atrophy
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Insulin resistance and pathological brain ageing
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Activation of mTOR: a culprit of Alzheimer&rsquo;s disease?
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Activity Energy Expenditure and Incident Cognitive Impairment in Older Adults
Middleton, L. E. (2011) · Archives of Internal Medicine · doi:10.1001/archinternmed.2011.277 · Cited by 160 · see citing works
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Neuroprotective properties of GLP-1: theoretical and practical applications
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Central Obesity in the Elderly is Related to Late-onset Alzheimer Disease
Luchsinger, J. A., Cheng, D., Tang, M. X., Schupf, N., & Mayeux, R. P. (2011) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e318222f0d4 · Cited by 140 · see citing works
“Obesity is a risk factor for hyperinsulinemia and T2D,(24) and both are risk factors in our cohort(25) and in other studies.(12) Obesity is also related to other vascular risk factors such as hypertension and dyslipidemia, heart disease, and stroke,(24) which have also been reported to be associated with LOAD in isola…”
BackgroundSelf-citationType 2 Diabetes and Late-Onset Alzheimer’s Disease
Cheng, D., Noble, J. M., Tang, M. ‐., Schupf, N., Mayeux, R. P., & Luchsinger, J. A. (2011) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000324134 · Cited by 134 · see citing works
Self-citationLifestyle and neurocognition in older adults with cognitive impairments
Blumenthal, J. A., Smith, P. J., Mabe, S., Hinderliter, A. L., Lin, P., Liao, L., Welsh-Bohmer, K. A., Browndyke, J. N., Kraus, W. E., Doraiswamy, P. M., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000006784 · Cited by 134 · see citing works
“Current smoker, n (%) 3 (8) 1 (3) 0 (0) 2 (3) 6 (4) 0.”
Bhat, N. R., & Thirumangalakudi, L. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121030 · Cited by 116 · see citing works
“It is also thought that cognitive decline and dementia often observed in patients with diabetes may be the result of insulin/IGF-I resistance and/or deficiency [26, 27].”
BackgroundObesity-induced Cognitive Impairment in Older Adults: a Microvascular Perspective.
Balasubramanian, P., Kiss, T., Tarantini, S., Nyúl-Tóth, Á., Ahire, C., Yabluchanskiy, A., Csípő, T., Lipécz, Á., Tabák, Á., Institoris, A., et al. (2020) · American Journal of Physiology. Heart and Circulatory Physiology · doi:10.1152/ajpheart.00736.2020 · Cited by 106 · see citing works
“The current view is that obesity both promotes the 74 development of vascular cognitive impairment (VCI)(110) (the most important form of Alzheimer's 75 disease related dementia [ADRD]) and also increases the incidence of Alzheimer’s disease (AD)(169).”
BackgroundBohnen, N. I., Kotagal, V., Müller, M. L. T. M., Koeppe, R. A., Scott, P. J. H., Albin, R. L., Frey, K. A., & Petrou, M. (2014) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2014.10.008 · Cited by 114 · see citing works
“Diabetes mellitus (DM) contributes to cognitive impairment in the elderly (1, 2) and constitutes a risk factor for dementia, possibly including Alzheimer disease (3, 4).”
BackgroundGenetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease
Reitz, C., Tosto, G., Mayeux, R. P., Luchsinger, J. A., & the NIA-LOAD/NCRAD Family Study Group and the Alzheimer's Disease Neuroimaging Initiative (2012) · PLoS ONE · doi:10.1371/journal.pone.0050354 · Cited by 109 · see citing works
“Explanations for the conflicting data include reversed causation, residual confounding, potential survival bias, and decreased validity of body mass index (BMI) as a measure of obesity in the elderly [10].”
BackgroundSelf-citationObesity as a risk factor for Alzheimer’s disease: the role of adipocytokines
Letra, L., Santana, I. J., & Seiça, R. M. F. (2014) · Metabolic Brain Disease · doi:10.1007/s11011-014-9501-z · Cited by 92 · see citing works
“Other measures of adiposity are waist circumference and waist-to-hip ratio, the first being more related to visceral fat deposits and with stronger correlation with adverse metabolic outcomes (Luchsinger 2008).”
BackgroundInfluentialObesity: What is an elderly population growing into?
Salihu, H. M., Bonnema, S. M., & Alio, A. P. (2009) · Maturitas · doi:10.1016/j.maturitas.2009.02.010 · Cited by 90 · see citing works
Zhao, R. R., O’Sullivan, A. J., & Fiatarone Singh, M. A. (2018) · European Review of Aging and Physical Activity · doi:10.1186/s11556-018-0190-1 · Cited by 88 · see citing works
“Cerebral neuropathological changes are believed to begin in the early stages of diabetes, consistent with deficits in cognitive performance for adults with prediabetes as well [47, 48].”
BackgroundThe role of PI3K signaling pathway in Alzheimer’s disease
Pan, J., Yao, Q., Wang, Y., Chang, S., Li, C., Wu, Y., Shen, J., & Yang, R. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1459025 · Cited by 89 · see citing works
“On the one hand, dysregulated mTOR activation can exacerbate A β generation and deposition, either by inhibiting A β clearance or by increasing A β generation via pathways such as insulin resistance (Luchsinger, 2008).”
BackgroundCheng, D., Yang, S., Zhao, X., & Wang, G. (2022) · Drug Design, Development and Therapy · doi:10.2147/dddt.s348055 · Cited by 84 · see citing works
“Among these mechanisms, brain IR may play a primary role, and it is worth noting that neurologic complications may already occur with prediabetes IR.(12) Oxidative stress,(13) mitochondrial”
BackgroundInfluentialImproved diabetes control in the elderly delays global cognitive decline
Luchsinger, J. A., Palmas, W., Teresi, J. A., Silver, S., Kong, J., Eimicke, J. P., Weinstock, R. S., & Shea, S. (2011) · The journal of nutrition health & aging · doi:10.1007/s12603-011-0057-x · Cited by 85 · see citing works
Self-citationSchuur, M., Henneman, P., Swieten, J. C. V., Zillikens, M. C., de Koning, I., Janssens, A. C. J. W., Witteman, J. C. M., Aulchenko, Y. S., Frants, R. R., Oostra, B. A., et al. (2010) · European Journal of Epidemiology · doi:10.1007/s10654-010-9476-y · Cited by 83 · see citing works
“Several groups have suggested that in particular adiponectin might be a promising biomarker for MetS [17–19].”
BackgroundOverlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes
Ahmad, W. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8352-z · Cited by 80 · see citing works
“with diabetes as well AD [39].”
Adiponectin protects rat hippocampal neurons against excitotoxicity
Qiu, G., Wan, R., Hu, J., Mattson, M. P., Spangler, E. L., Liu, S., Yau, S., Lee, T. M. C., Gleichmann, M., Ingram, D. K., et al. (2010) · AGE · doi:10.1007/s11357-010-9173-5 · Cited by 80 · see citing works
“Interestingly, obesity which suppresses circulating adiponectin levels has now been identified as a risk factor for AD (Luchsinger 2008).”
BackgroundWang, H., Chen, F., Du, Y., Long, Y., Reed, M. N., Hu, M. Y., Suppiramaniam, V. D., Hong, H., & Tang, S. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.026 · Cited by 79 · see citing works
“Peripheral hyperinsulinemia may down-regulate insulin transport into the brain and inhibit brain insulin production, followed by reduced the CNS insulin and signaling events resulting in deficits in brain oxidative metabolism and accumulation of Aβ (Luchsinger, 2008; Reger et al., 2006).”
Park, H.-S., Park, S.-S., Kim, C., Shin, M., & Kim, T.-W. (2019) · Nutrients · doi:10.3390/nu11071603 · Cited by 76 · see citing works
Family History and APOE-4 Genetic Risk in Alzheimer’s Disease
Donix, M., Small, G. W., & Bookheimer, S. Y. (2012) · Neuropsychology Review · doi:10.1007/s11065-012-9193-2 · Cited by 69 · see citing works
“Strategies aimed at enhancing vascular health could be important for the prevention of Alzheimer's disease (Luchsinger 2008 ).”
Toro, P., Schönknecht, P., & Schröder, J. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0981 · Cited by 71 · see citing works
“Although the relationship between T2DM, hyperinsulinemia, and dementia has been addressed in a number of studies (for a review see [2]), most of them used samples comprising a wide range of age (i.e., 60–75 years) and showed divergent findings: some relating T2DM to AD and MCI [3–5] and others…”
Physiological role of adiponectin in different tissues: a review
Esmaili, S., Hemmati, M., & Karamian, M. (2018) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2018.1493606 · Cited by 71 · see citing works
“This is due to the change of CNS control in energy homeostasis and body weight (Aziz et al. 2008, Luchsinger 2008, Luchsinger and Gustafson 2009).”
BackgroundBhat, N. R. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06978.x · Cited by 70 · see citing works
“Prominently, insulin resistance (or insulin deficiency in T1DM) is now thought to underlie diabetes-associated cognitive decline and dementia (Luchsinger 2008; Freude et al. 2009; de la Monte 2009; Zhao and Townsend 2009).”
BackgroundBroadening the definition of brain insulin resistance in aging and Alzheimer's disease
Frazier, H. N., Ghoweri, A. O., Anderson, K. L., Lin, R., Porter, N. M., & Thibault, O. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.12.007 · Cited by 67 · see citing works
“Furthermore, a large body of evidence supports the hypothesis that peripheral metabolic dysregulation contributes to cognitive decline in T2DM and obesity, suggesting the presence of parallel mechanisms between neuronal and chronic peripheral insulin resistance (Arnold et al., 2018; Benedict and Grillo, 2018; Biessels…”
Substrate Competitive GSK-3 Inhibitors strategy and Implications
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West, R. K., Ravona‐Springer, R., Schmeidler, J., LeRoith, D., Koifman, K., Guerrero‐Berroa, E., Preiss, R., Hoffman, H., Silverman, J. M., Heymann, A. D., et al. (2014) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2014.01.010 · Cited by 62 · see citing works
“Duration of T2D and poor glycemic control are major contributors to the impact of T2D on cognitive impairment.(2) Disentangling the underlying basis of these associations is important because T2D management may reduce the risk of cognitive decline and dementia.”
BackgroundNam, G. E., Park, Y. G., Han, K., Kim, M. K., Koh, E. S., Kim, E. S., Lee, M., Kim, B., Hong, O., & Kwon, H. (2019) · Diabetes Care · doi:10.2337/dc18-1667 · Cited by 62 · see citing works
“unclear, it has been hypothesized that cerebrovascular pathologies are influenced by hyperglycemia and insulin resistance (9,10).”
BackgroundGanguli, M., Albanese, E., Seshadri, S. S., Bennett, D. A., Lyketsos, C. G., Kukull, W. A., Skoog, I. G., & Hendrie, H. C. (2018) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000237 · Cited by 55 · see citing works
The link between iron, metabolic syndrome, and Alzheimer’s disease
Grünblatt, E., Bartl, J., & Riederer, P. F. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0426-3 · Cited by 56 · see citing works
“15, 97080 Würzburg, Germany These subjects already present with insulin resistance as a pathophysiological mechanism that is often associated with MetS (Yaffe et al. 2004; Luchsinger 2008).”
BackgroundInfluentialSilymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms
Haddadi, R., Shahidi, Z., & Brooshghalan, S. E. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153320 · Cited by 55 · see citing works
Increased GABA concentrations in type 2 diabetes mellitus are related to lower cognitive functioning
van Bussel, F. C. G., Backes, W. H., Hofman, P. A. M., Puts, N. A. J., Edden, R. A. E., van Boxtel, M. P. J., Schram, M. T., Stehouwer, C. D. A., Wildberger, J. E., & Jansen, J. F. A. (2016) · Medicine · doi:10.1097/md.0000000000004803 · Cited by 54 · see citing works
“Higher GABA+ levels were found in participants with type 2 diabetes, in participants with higher fasting blood glucose levels, and in participants with both higher HbA1c levels and less cognitive performance.”
BackgroundInfluentialThe association of diabetes and dementia and possible implications for nondiabetic populations
Ravona‐Springer, R., & Beeri, M. S. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.11.152 · Cited by 52 · see citing works
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Meusel, L.-A., Kansal, N., Tchistiakova, E., Yuen, W., MacIntosh, B. J., Greenwood, C. E., & Anderson, N. D. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00148 · Cited by 46 · see citing works
“It is here that we see the link between T2DM and Alzheimer disease pathology: brain insulin deficiency results in the down-regulation of insulin degrading enzyme (IDE; Luchsinger, 2008), which also has a role in degrading Aβ (Carlsson, 2010).”
BackgroundAltered Hippocampal White Matter Connectivity in Type 2 Diabetes Mellitus and Memory Decrements
van Bussel, F. C. G., Backes, W. H., Hofman, P. A. M., van Boxtel, M. P. J., Schram, M. T., Stehouwer, C. D. A., Wildberger, J. E., & Jansen, J. F. A. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12366 · Cited by 45 · see citing works
Glycemia, Diabetes Status, and Cognition in Hispanic Adults Aged 55–64 Years
Luchsinger, J. A., Cabral, R., Eimicke, J. P., Manly, J. J., & Teresi, J. A. (2015) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000208 · Cited by 46 · see citing works
“However, most cognition studies enroll elderly participants with a mean age around 75 years (23), andmany studies that relatemiddle-age risk factors such as diabetes to dementia in older age do not have concurrent midlife cognitive data (24–26).”
BackgroundSelf-citationLonger Term Effects of Diet and Exercise on Neurocognition: 1‐Year Follow‐up of the ENLIGHTEN Trial
Blumenthal, J. A., Smith, P. J., Mabe, S., Hinderliter, A. L., Welsh-Bohmer, K. A., Browndyke, J. N., Doraiswamy, P. M., Lin, P., Kraus, W. E., Burke, J. R., et al. (2019) · Journal of the American Geriatrics Society · doi:10.1111/jgs.16252 · Cited by 46 · see citing works
“Single, never married 2 (5) 2 (5) 4 (10) 3 (8) 11 (7)”
Alzheimer's disease: brain expression of a metabolic disorder?
Merlo, S., Spampinato, S. F., Canonico, P. L., Copani, A., & Sortino, M. A. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.05.005 · Cited by 47 · see citing works
Luo, D., Hou, X., Hou, L., Wang, M., Xu, S., Dong, C., & Liu, X. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.04.045 · Cited by 42 · see citing works
Plasma leptin levels and free leptin index in women with Alzheimer's disease
Baranowska-Bik, A., Bik, W., Styczyńska, M., Chodakowska-Żebrowska, M., Barcikowska, M., Wolińska‐Witort, E., Kalisz, M., Martyńska, L., & Baranowska, B. (2015) · Neuropeptides · doi:10.1016/j.npep.2015.05.006 · Cited by 41 · see citing works
“Despite the fact that correlation between obesity and AD is still controversial (Luchsinger, 2008), data from study by Whitmer et al.”
On the Interplay of Microvasculature, Parenchyma, and Memory in Type 2 Diabetes
van Bussel, F. C. G., Backes, W. H., Hofman, P. A. M., van Oostenbrugge, R. J., Kessels, A. G. H., van Boxtel, M. P. J., Schram, M. T., Stehouwer, C. D. A., Wildberger, J. E., & Jansen, J. F. A. (2015) · Diabetes Care · doi:10.2337/dc14-2043 · Cited by 39 · see citing works
Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease
Morabito, M. V., Berman, D. E., Schneider, R. T., Zhang, Y., Leibel, R. L., & Small, S. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.12.017 · Cited by 39 · see citing works
“Type 2 diabetes (T2D) and AD are associated epidemiologically (Luchsinger et al., 2001), specifically via T2D-associated phenotypes such as hyperinsulinemia, hyperglycemia, and obesity (Luchsinger, 2008).”
Amyloid precursor protein modulates macrophage phenotype and diet-dependent weight gain
Puig, K. L., Brose, S. A., Zhou, X.-D., Sens, M., Combs, G., Jensen, M., Golovko, M., & Combs, C. (2017) · Scientific Reports · doi:10.1038/srep43725 · Cited by 35 · see citing works
Navigating the intersection: Diabetes and Alzheimer's intertwined relationship
Kale, M. B., Bhondge, H. M., Wankhede, N. L., Shende, P. V., Thanekar, R., Aglawe, M. M., Rahangdale, S. R., Taksande, B. G., Pandit, S. B., Upaganlawar, A. B., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102415 · Cited by 38 · see citing works
Blood glucose levels and cortical thinning in cognitively normal, middle-aged adults
Wennberg, A. M. V., Spira, A. P., Pettigrew, C. A., Soldan, A., Zipunnikov, V. M., Rebok, G. W., Roses, A. D., Lutz, M. W., Miller, M. M., Thambisetty, M., et al. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.04.017 · Cited by 39 · see citing works
“Although BMI has been linked to brain atrophy [31], this association may be through hyperglycemia [43].”
BackgroundMohamed, H. E., Abo–Elmatty, D. M., Mesbah, N. M., Saleh, S. M., Ali, A. A., & Sakr, A. T. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.08.034 · Cited by 37 · see citing works
Hieke, M., Neß, J., Steri, R., Dittrich, M., Greiner, C., Werz, O., Baumann, K., Schubert‐Zsilavecz, M., Weggen, S., & Zettl, H. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm1003073 · Cited by 36 · see citing works
The Aging Brain and Neurodegenerative Diseases
Duncan, G. W. (2011) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2011.07.008 · Cited by 36 · see citing works
Sayed, N. S. E., Kandil, E. A., & Ghoneum, M. H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.666502 · Cited by 36 · see citing works
“For Aβ aggregation, hyperinsulinemia results in the downregulation of insulin receptors with consequent alteration in insulin signaling in the brain, which in turn elevates the generation of Aβ and decreases its clearance by hampering the production of the enzyme required for its degradation, IDE, as well as competing…”
BackgroundGetting the iron out: Phlebotomy for Alzheimer’s disease?
Dwyer, B. E., Zacharski, L. R., Balestra, D. J., Lerner, A. J., Perry, G. L., Zhu, X., & Smith, M. A. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2008.12.029 · Cited by 35 · see citing works
“resistance, hypo- and hyperglycemia, atherosclerosis and microvascular disease, and cognitive dysfunction [1].”
BackgroundInfluentialTian, Y., Jing, G., Ma, M., Yin, R., & Zhang, M. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105848 · Cited by 38 · see citing works
“Epidemiological studies show that insulin resistance, especially in the prediabetes stage, significantly increases the risk of cognitive impairment (Kiliaan et al., 2014; Luchsinger, 2008).”
Backgroundde la Torre, J. C. (2009) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2008.11.014 · Cited by 34 · see citing works
Caldérari, S., Ria, M., Gérard, C., Nogueira, T. C., Villate, O., Collins, S. C., Neil, H., Gervasi, N., Hue, C., Suárez-Zamorano, N., et al. (2017) · Genomics · doi:10.1016/j.ygeno.2017.09.001 · Cited by 32 · see citing works
Sluiman, A. J., McLachlan, S., Forster, R., Strachan, M. W. J., Deary, I. J., & Price, J. F. (2021) · Diabetologia · doi:10.1007/s00125-021-05634-w · Cited by 33 · see citing works
“A number of key vascular risk factors have been identified including impaired fasting glucose and insulin [12, 13], hypertension and macrovascular disease [14, 15].”
BackgroundArtichoke Leaf Extract‐Mediated Neuroprotection against Effects of Aflatoxin in Male Rats
Ibrahim, E. A., Yousef, M. I., Ghareeb, D. A., Augustyniak, M., Giesy, J. P., Aboul‐Soud, M. A. M., & Wakil, A. E. (2022) · BioMed Research International · doi:10.1155/2022/4421828 · Cited by 33 · see citing works
“The latter is a state in which tissues that require glucose have a diminished response to insulin, and the subsequently reduced clearance of glucose from the blood feeds back onto the pancreas to increase secretion of insulin to induce glucose uptake [35].”
Short-term mechanisms influencing volumetric brain dynamics
Dieleman, N., Koek, H. L., & Hendrikse, J. (2017) · NeuroImage Clinical · doi:10.1016/j.nicl.2017.09.002 · Cited by 32 · see citing works
“Moreover, an indirect pathway leads to increased levels in amyloid beta and tau caused by down-regulation of insulin degrading enzyme (Luchsinger, 2008).”
Repositioning leptin as a therapy for Alzheimer’s disease
Johnston, J. M., Greco, S. J., Hamzelou, A., Ashford, J. W., & Tezapsidis, N. (2011) · Therapy · doi:10.2217/thy.11.57 · Cited by 32 · see citing works
“Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J. Biol. Chem. 283(3), 1754–1763 (2008).”
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The total alkaloids from Coptis chinensis Franch improve cognitive deficits in type 2 diabetic rats
Li, J.-C., Shen, X., Shao, J.-A., Tao, M., Gu, J. P., Li, J., & Huang, N. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s171025 · Cited by 28 · see citing works
“The incidence rate of diabetes and related cognitive deficits increases steadily together with the changes of lifestyle and population aging.(3,4) Thus, identification of treatment strategies for diabetesinduced cognitive deficits has been an important research goal.”
Hazar, N., Seddigh, L., Rampisheh, Z., & Nojomi, M. (2016) · Europe PMC (PubMed Central) · Cited by 26 · see citing works
Arginase as a Potential Target in the Treatment of Alzheimer’s Disease
Polis, B., & Samson, A. O. (2018) · Advances in Alzheimer s Disease · doi:10.4236/aad.2018.74009 · Cited by 23 · see citing works
“The latest epidemiological studies indicate the comorbidity of AD and diabetes mellitus beyond any doubt [4].”
BackgroundYoo, J. E., Han, K., Kim, B., Park, S. H., Kim, S. M., Park, H. S., & Nam, G. E. (2022) · Diabetes Care · doi:10.2337/dc21-1597 · Cited by 24 · see citing works
Carmichael, O. T., Stuchlik, P. M., Pillai, S. R., Biessels, G. J., Dhullipudi, R., Madden‐Rusnak, A., Martin, S., Hsia, D. S., Fonseca, V. A., & Bazzano, L. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02750 · Cited by 23 · see citing works
Links Between Adiponectin and Dementia: From Risk Factors to Pathophysiology
Chen, R., Shu, Y., & Zeng, Y. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00356 · Cited by 22 · see citing works
“Significant increase in abdominal circumference means central adiposity or abdominal obesity, which is more associated with visceral fat deposits and has a stronger relationship with adverse metabolic outcomes (Luchsinger, 2008).”
BackgroundEffects of glucose and insulin on secretion of amyloid‐β by human adipose tissue cells
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Ginsenoside Ameliorates Cognitive Dysfunction in Type 2 Diabetic Goto-Kakizaki Rats
Tian, Z., Ren, N., Wang, J., Zhang, D., & Zhou, Y. (2018) · Medical Science Monitor · doi:10.12659/msm.907417 · Cited by 19 · see citing works
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- Authors
- Luchsinger, J. A.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 585
- Issue
- 1
- Pages
- 119-129
- ISSN
- 0014-2999 (ISSN-L)
- PMC
- PMC2474785
- OpenAlex
- W1566564316
- Semantic Scholar
- 8a430b274834dd5ab4279dd6eb5eb66eb9b113ec
- Cited by
- 171
- References
- 122
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 12 · 2023: 6 · 2022: 7 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 13 · 2017: 11 · 2016: 12 · 2015: 7 · 2014: 14 · 2013: 9 · 2012: 9
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P01AG007232, AG 07232)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- Alzheimer's disease, adiposity, hyperinsulinemia, diabetes mellitus, insulin resistance, obesity, advanced glycation end products, cerebrovascular disease, adipose tissue metabolism, middle age (human life stage), old age, Alzheimer's disease risk factors, Alzheimer's disease prevention
- MeSH terms
- Alzheimer Disease, Diabetes Mellitus, Type 2, Humans, Hyperinsulinism, Insulin Resistance, Obesity, Risk Factors, Adiposity
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