Alzheimer's disease is a chronic progressive degenerative disease of the brain characterised by declining memory and other cognitive functions. It is characterised by deposition of abnormal protein complexes in the brain called amyloid and tau. Even though we understand Alzheimer's as primarily a brain disease, we now know that cardiac, metabolic and circulatory changes that occur with ageing can significantly influence the functioning of the brain and contribute to the pathogenesis of this disease decades later. Diabetes, high blood pressure and abnormal cholesterol levels, three extremely common conditions, are increasingly recognised as potentially modifiable risk factors for dementia in general, and especially Alzheimer's disease, which is the most common form of dementia worldwide.

This does not mean that everyone with these conditions will develop Alzheimer's disease. The pathogenesis is a complex interplay of age, genetics and several acquired diseases and lifestyle factors, and the relative contribution of each factor varies in individual patients. However, good cardiovascular health appears to be an important component of maintaining brain health.

Although the brain represents only about 2% of body weight, it requires 20% of the cardiac output. Its network of small blood vessels supplies neurons with oxygen and glucose and helps maintain the environment necessary for normal brain function.

Long-standing hypertension, diabetes and high cholesterol can affect both large and small blood vessels. As a person ages, this can lead to cerebral small-vessel disease, microscopic infarcts, disruption of the blood-brain barrier and reduced ability of cerebral blood vessels to respond appropriately to changing metabolic demands of the brain.

Importantly, Alzheimer's disease and vascular brain injury frequently coexist. Vascular damage may therefore lower the brain's "reserve", making the clinical effects of Alzheimer pathology more apparent and early.

The relationship between blood pressure and dementia is particularly strong when hypertension occurs during midlife.

Long-term observational studies show that elevated blood pressure during middle age is associated with greater subsequent risk of dementia and Alzheimer's disease. Hypertension contributes to arterial stiffness, small-vessel damage, white-matter injury and stroke.

There is also evidence that treating hypertension can protect cognition. The landmark SPRINT-MIND randomised trial demonstrated that intensive blood-pressure treatment significantly reduced the incidence of mild cognitive impairment compared with standard treatment. It also reduced the combined outcome of mild cognitive impairment or probable dementia.

Thus, controlling hypertension may have benefits extending well beyond prevention of heart attacks and protect the brain from cognitive impairment and dementia.

Type 2 diabetes is another important dementia risk factor. Meta-analysis studies suggests that people with type 2 diabetes have approximately a 50-60% higher risk of developing Alzheimer's dementia than those without diabetes.

Several mechanisms may explain this association. Chronic hyperglycemia injures small blood vessels and promotes oxidative stress and inflammation. Insulin resistance may also influence neuronal metabolism and signaling pathways in amyloid and tau biology. Diabetes also increases the risk of stroke, kidney disease, hypertension and dyslipidemia, which offers multiple overlapping pathways through which brain health can be impacted.

The relationship is therefore probably not attributable to glucose alone but to a broader metabolic and vascular environment.

The relationship between cholesterol and dementia is more complicated because cholesterol levels can change with ageing and illness. Nevertheless, evidence increasingly points towards high LDL cholesterol during aging as a dementia risk factor.

A systematic review of cohort studies found evidence linking midlife dyslipidaemia with later dementia, while a meta-analysis found that elevated LDL cholesterol was associated with Alzheimer's disease, particularly in people aged approximately 60-70 years.

Reflecting this evidence, the 2024 Lancet Commission on dementia prevention added high LDL cholesterol in midlife to its list of potentially modifiable dementia risk factors.

Cholesterol contributes to atherosclerosis and cerebrovascular disease, but researchers are also investigating more direct interactions between lipid metabolism, APOE, amyloid processing and neuroinflammation.

The important message is not that Alzheimer's disease is simply caused by diabetes, hypertension or cholesterol. It is that brain ageing occurs within the same vascular system that supplies the heart, kidneys and other organs.

The 2024 Lancet Commission estimated that addressing 14 potentially modifiable factors across the lifespan could prevent or delay around 45% of dementia cases at a population level. These factors include hypertension, diabetes, high LDL cholesterol, smoking, obesity, physical inactivity, hearing loss and several others. This estimate should not be interpreted as guaranteeing prevention for an individual, but it highlights the substantial potential of risk reduction.

For someone in their 40s, 50s or 60s, therefore, checking blood pressure, controlling diabetes, treating high LDL cholesterol, exercising regularly, avoiding smoking and maintaining a healthy weight should not be considered only "heart-health" measures.

Taking care of your heart and blood vessels is also one of the most practical ways we currently have to take care of your ageing brain.

(By Dr Pramod Krishnan, HOD & Consultant - Neurology Epileptology & Sleep Medicine, Manipal Hospital Old Airport Road)

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