Alzheimer's disease and type 2 diabetes mellitus (T2DM)

Last edited 12/2022 and last reviewed 03/2023

T2DM is associated with cognitive impairments and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related Late onset Alzheimer's disease (1):

• most common form of the disease, is characterized by AD that becomes apparent after the age of 60
• athough the apolipoprotein E e4 allele (APOE e4) is the most consistently replicated genetic variant influencing the risk of late-onset Alzheimer disease (LOAD)
• explains only 20% of the attributable genetic risk (2,3)

The most common types of dementia are Alzheimer’s disease (AD) and vascular dementia (VaD)

• less severe forms of cognitive dysfunction that precede the development of dementia affect many more people, with mild cognitive impairment (MCI) affect 6% of the population, and 1 in 5 people aged 65 or older
• MCI is a condition that lies between age-appropriate cognition and dementia
• defined as objective cognitive impairment relative to the person’s age, with concern about the cognitive symptoms, in a person with essentially normal functional activities who does not have dementia

Diabetes has been identified as a key risk factor for dementia and MCI

• the growing prevalence of glycaemic disorders has the potential to further increase the burden of MCI and dementia on healthcare systems (4)

Type 2 diabetes (T2D) has been associated with a modest increased risk in cognitive dysfunction across all cognitive domains

• effect appears to be consistent across all age groups and mimics an accelerated ageing of brain function - however there is also an increased risk of more severe impairment of cognition and developing dementia in older age groups that would appear to be a different phenomenon (4)
• diabetes, prediabetes and metabolic syndrome were all associated with increased risks of progression of MCI to dementia
• pooled odds ratio for progression in people with diabetes was 1.53 (95% CI 1.20–1.97) while the pooled odds ratio in people with MetS was 2.95 (95% CI 1.23–7.05)
• in T2D, a longer duration of diabetes and the presence of retinopathy were associated with an increased risk of progression from MCI to dementia, while statins and oral hypoglycaemic agents appeared to reduce the risk
• onset of dementia in people with T2D is on average 2.5 years earlier than in comparable populations without diabetes
• vascular damage and dysfunctions in glucose, insulin and amyloid metabolism in T2D have been proposed as mechanisms underlying this increased risk - likely that T2D reduces cognitive reserve and increases brain susceptibility to significant insults from cerebrovascular events or dysfunctional amyloid processing (4)

A population based cohort study suggested that (5):

• development of hypertension, hyperlipidemia, or both, following a diagnosis of incident diabetes is secondary to diabetes onset and likely mediated through insulin resistance associated with diabetes, which does not further accentuate dementia risk. DM itself (i.e., the systemic influence of hyperglycemia) might be the main driver of increased dementia risk
• however, hypertension and hyperlipidemia increased the dementia risk in the non-DM cohort

Cognitive decline is also reflected in macroscopic brain changes like global cerebral and white matter atrophy in T2D (6):

• evidence showed 2% lower brain volumes in diabetic patients
• duration of diabetes has been linked to grey matter atrophy (1% decrease for every additional 10 years)
  • white matter atrophy and infarct volume was also associated with the disease duration
• studies have shown that antidiabetic agents, especially metformin, glitazones, and GLP-1 receptor agonists, have a potential therapeutic role in the prevention or treatment of dementia and Alzheimer's disease (6)

Reference:

• Hayden MR.Type 2 Diabetes Mellitus Increases the Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy.Brain Sci. 2019, 9, 262.
• Lee JH et al. Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family StudyImplication of Additional Loci Arch Neurol. 2008;65(11):1518-1526
• Slooter  AJCruts  MKalmijn  S  et al.  Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study.  Arch Neurol 1998;55 (7) 964- 968
• Pal K et al. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-nalysis. Social Psychiatry and Psychiatric Epidemiology 2018;53:1149–1160.
• Fan et al.Increased dementia risk predominantly in diabetes mellitus rather than in hypertension or hyperlipidemia: a population-based cohort study Alzheimer's Research & Therapy (2017) 9:7
• Papazafiropoulou AK, Koros C, Melidonis A, Antonopoulos S. Diabetes and dementia - the two faces of Janus. Arch Med Sci Atheroscler Dis. 2020 Jul 21;5:e186-e197.