14th May 2023, Dr Chee L Khoo
When we think about diabetic complications, we usually think about microvascular and macrovascular complications. We don’t often think about dementia as a diabetic complication. Diabetes has consistently been associated with an increased risk of dementia and its subtypes (Alzheimer’s disease and vascular dementia (1). As many with diabetes, especially T2D, are being diagnosed at a younger age, dementia relating to diabetes will increasingly be diagnosed and diagnosed at a younger age. There is also evidence demonstrating that diabetes onset at an early stage of lifespan is associated with the largest cognitive decrements (2). In many of these patients, diabetes is not the only risk factor for dementia.
The onset of dementia in diabetes patients is gradual. It starts with subtle cognitive impairment, which, in progressive patients, develops into mild cognitive impairment followed by frank dementia, often times as Alzheimer’s disease. This progressive cognitive impairment occurs in parallel with structural brain changes, as revealed by MRI.
We are all familial with diabetes causing damage to neurological structure. Peripheral neuropathy and autonomic neuropathy (cardiac or gastrointestinal) are evidence of nerve damage and it is not surprising that diabetes can cause damage to central nerves leading to cognitive impairment. Indeed, clinical studies underscore a correlation between presence of peripheral neuropathy with the development of cognitive impairment (3,4).
PREDIMED-Plus is a multicentre, randomised, single-blinded clinical trial conducted in Spain to evaluate the effects of a special intervention including: a) energy-reduced MedDiet; b) physical activity; and c) a behavioural therapy for weight loss (5). Mallorqui-Bague et al performed a cross-sectional analysis on the baseline data in PREDIMED-Plus trial to explore the association between T2D and cognitive performance and the influence of sleep disorders, depression and glycaemic control on cognitive function (6). They found that participants with T2D performed worse in executive function (EF) than non-diabetic, depression, sleep disorders and higher BMI had a negative effect on EF. Further, patients with higher diabetes duration and higher HbA1c performed worse in EF.
Similar associations of diabetes, diabetes duration and glycaemic control with cognitive dysfunction were demonstrated in the longitudinal assessment of the Atherosclerosis Risk in Communities (ARIC) trial (7) and Japan Public Health Center- Based Prospective Study (8).
Dementia shares many pathophysiological features with diabetes – insulin resistance, obesity, dyslipidaemia and hypertension. Brian Callaghan et al recruited 138 severely obese before bariatric surgery and compared their cognitive function with 46 lean individuals. Cognitive deficits were found in 6.5% of lean individuals, 22% of obese individuals without diabetes, 18% of obese individuals with prediabetes and 26% of obese individuals with diabetes. They suggested that obesity alone is sufficient to account for the cognitive deficits (9).
The association between hypertension and dementia is a little more complicated. Numerous studies have investigated the association between hypertension and the risk of dementia (10) but clear consensus on the impact of age on this association has not been achieved (11-14). Early life (<35 years old) seems to have an impact on cognitive deficit although the association with dementia is less clear. Further, the association of later life hypertension and dementia is even less consistent (15).
Power et al found that elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides in midlife were associated with greater 20-year cognitive decline (16).
Thus, it is not surprising that dementia is associated with diabetes and the other metabolic derangements that come with diabetes. Biomarkers including amyloid deposition, vascular changes, inflammation, neuronal degeneration and glucose metabolism may help to understand mechanisms of the association between diabetes and cognitive impairment (17).
There are many modifiable risk factors at our disposal to reduce the future incidence of dementia. To estimate the contribution to dementia burden from diabetes, obesity, and hypertension, the Lancet Commission estimated the population attributable fraction (PAF), which represents the percentage of new cases that could be avoided if a specific risk factor was removed (6,7). Their analysis leveraged risks from institutional guidelines, primary studies, and meta-analyses to calculate PAF for various risks on all-cause dementia. PAF for diabetes in later life was calculated as 1.1 %, 0.7 % for midlife obesity, and 1.9 % for hypertension. Additionally, physical inactivity, which is an aspect of poor metabolism and the modern sedentary lifestyle, has a PAF of 1.6 % for all-cause dementia.
Tentative evidence indicates that controlling hypertension with anti-hypertensive medications or exercise to battle inactivity may reduce dementia incidence; however, data regarding anti-diabetic medications and the long-term effects of weight loss are sparser and inconclusive. The reasons anti-diabetic medications may not effectively lower dementia incidence may be manifold; possibly, once the diabetes disease process has started, it may already be too late to mitigate dementia risk due to irreversible damage to the brain.
During a median follow up of 11.9 years, Shang et al. found that individuals with T1D or T2D diagnosed at younger age are at larger excessive risk of brain volume reduction and dementia (21). Shang et al also found that hypertension diagnosed in young adulthood or mid-life, but not late life is associated with smaller brain volumes and an increased risk of dementia (15).
Early interventions to prevent diabetes, rather than treating it once the disease has started, may more effectively prevent dementia since prediabetes (and other metabolic derangements) is also associated with decline in executive dysfunction. Thus, a multi-pronged approach targeting multiple elements of the metabolic syndrome, and not just diabetes, may be needed.
References:
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