Mild cognitive impairment

Mild cognitive impairment (MCI) refers to a decrease in memory and cognitive ability. It is thought to be a precursor to dementia-related diseases like Alzheimer's,¹ but it could also be caused by old age or injury.² The cognitive impairments are severe enough to cause noticeable changes compared to what is expected for their age, but people with MCI can continue to live independently and do not have a significant impact on daily life.^1,2 Genetic factors may play a role in the predisposition to MCI, and ongoing research is exploring this connection.

MCI symptoms and diagnosis

 MCI symptoms can be categorised into three distinct types: amnesic, non-memory single domain, and multiple domain:³

Amnesic MCI

Amnesic MCI primarily affects memory-related brain functions. Including memory storage and retrieval. Symptoms Include:

• Increased forgetfulness, both short- and long-term
• Forgetting appointments, meetings, and events
• Difficulty recognizing familiar places and locations

Non-Memory MCI 

This type affects cognitive functions other than memory and may appear in single or multiple domains. Symptoms include:

• Losing train of thought or difficulty following conversations
• Challenges with task initiation, completion, and decision-making
• Poor judgment and difficulty making sound decisions
• Impaired visual perception

Multi-domain MCI

Symptoms span across various cognitive functions, not just memory. Individuals with this type of MCI experience impairments in several domains simultaneously, such as:

• Memory issues, including forgetting recent events or conversations
• Language difficulties, like trouble finding words or following conversations
• Executive function deficits, such as difficulty planning, organising tasks, or making decisions
• Visuospatial challenges, including trouble understanding visual information or navigating familiar places

Diagnosis of MCI involves a comprehensive evaluation by a healthcare professional, who will assess symptoms, and physical health, and may conduct memory and cognitive tests. This is often supplemented by PET scans and blood tests to determine underlying causes such as brain injury, tumors, elevated amyloid-beta levels (a marker for Alzheimer's), or changes in brain areas like the hippocampus and ventricles.²

Approximately 10-15% of individuals with MCI are diagnosed with dementia each year, although many cases remain stable.³ The progression to dementia occurs at a higher rate in those with MCI compared to those without.⁴ An accurate diagnosis ensures timely support to help manage symptoms and maintain quality of life, potentially slowing further cognitive decline.

Causes

MCI is believed to be caused by changes and abnormalities in brain structures. However, many factors have been identified, rather than a single one.^2,3

MCI in other pathologies frequently affects the same areas as various types of dementia, however to a much lesser extent. Degenerative disorders like progressive MCIs are progressive whereas stable MCI is not.³

Age seems to be the most common factor, either developing a degenerative disease or simply the effects of old age on memory being more extreme than predicted.

Injuries and tumours both are capable of causing MCI temporarily or permanently. Strokes can cause severe localised brain injuries resulting in MCIs.²

Other risk factors: Obesity, high cholesterol, high blood pressure, diabetes, lack of exercise, smoking, regular alcohol consumption, depression, reduced stimulatory activities both prior and during ranging from cognitive to simply being able to see and hear, and sleep disorders.^3,4

Areas affected by MCIs are:

• Decreased hippocampal size – Important in memory formation and recollection
• Larger ventricles – Increased volume of fluid in the brain
• Decreased glucose use in neurons
• Degeneration and dysfunction of other key areas⁵

Prevention methods can be employed beforehand to help reduce the risk of MCIs, Advice can be found here

Genetic predisposition

Inherited genes are the primary factor in predicted susceptibility to various diseases, and dementia and MCIs are no exception, with increased susceptibility resulting from various gene mutations/polymorphisms. While most cases are spontaneous, there has been evidence of familial genetic variation in several genes, many of which have been extensively studied.

If a family member is known to be more likely to develop or has developed dementia, you are also more likely to develop it. However, because of the number of genes required and their roles in various pathways, the development of the disease is not always evident.⁶

Genetic factors affected

Due to the commonality of MCI with dementias such as Alzheimer’s disease, many genetic factors that have been explored are genetic factors associated with Alzheimer's.

Polygenic risk

This is when there are minor mutations in many genes that affect pathways and mechanisms increasing the risk of certain developing certain diseases/disorders. Each of the genes may have minor or even minuscule effects alone, but when the collection of risk genes increases it may result in the development of the disease/disorder. Due to the vast number of polygenic combinations, size, and severity, while it is a major contributor to the number of patients with MCI and dementias it is difficult to treat and target.

Apolipoprotein E polymorphism e4 (APOE ε4)

APOE ε4 is one of the most studied genetic variations found in Alzheimer’s disease due to its frequency and severity. APOE ε4 is found in plasma. It is involved in transportation of lipids, like cholesterol, into cells. The polymorphism ε4 results in promotion of αβ monomer binding and retention in the brain – the driving force of Alzheimer’s disease.⁸ This can cause onset of progressive MCI due to degeneration. Promoter genes associated with APOE ε4 have also been implicated in MCI development.

APOE ε4 also has been found to interact with proteins and neurochemical communicators such as BDNF or COMT. Interaction with this polymorphism expands the effects of the changes that APOE ε4 is responsible for.

Although this only accounts for some MCI developments, meaning there are more genes involved than just APOE ε4.⁷

Methylenetetrahydrofolate reductase (MTHFR)

This enzyme is key to the metabolism of tHcy (total homocysteine). tHcy has been heavily implicated in cognitive impairments and dementia. It shows neurotoxic actions in the hippocampus leading to apoptosis and mediates impairment of several key methylation reactions.

A tyrosine polymorphism of MTHFR results in reduced reductase activity, resulting in reduced metabolism and increased tHcy concentrations. Higher tHcy concentrations often lead to lower cognitive function (not memory). APOE ε4 with the MTHFR mutation causes impaired executive functions, but not with memory – Non-memory MCI.⁹

Bridging integrator protein-1(BIN1)

This gene helps with physiological processes like cell-endocytosis and actin activation. Mutation of this gene is heavily associated with AD pathology, namely tau pathology and neurofibrillary tangles, although the way it affects the pathways isn’t obvious as of yet.¹⁰

BIN1 mutations have been associated with a loss in episodic memory performance. It is an important risk factor for MCI as age increases.¹¹

Recombinant human Spi-1 proto-oncogene (SPI1)

This gene is responsible for assisting myeloid cell development and functions. These myeloid cells assist in functions associated with microglia phagocytosis.

SPI1 directly moderates Alzheimer’s risk genes in myeloid cells, polymorphisms of this gene upset its moderation and shift the balance causing promotion of Alzheimer phenotypes within microglia.¹⁰

Microglia function is also associated with other neurodegenerative diseases such as Parkinson’s. Dysfunction of genetic presentation and cell activity may also play a role in MCI, stable and progressive, unrelated to Alzheimer’s.¹²

Steroidogenic acute regulatory-related lipid transfer domain 6 (STARD6)

STARD6 binds testosterone and is present within the hippocampus. Other START domain proteins have similar binding pockets for cholesterols but are localised differently. STARD6 polymorphism has been shown to have a higher incidence of MCI due to its effects on neurosteroids, such as testosterone, and cholesterol with the hippocampus.^10,13

Other genes

There are many other genes associated with neurodegenerative diseases that often can precede with MCIs.^7,11

Some of these genes include: TOMM40, PSEN1, PSEN2, and CR1.

Summary

Mild cognitive impairments are a condition that causes a decline in cognitive function, affecting executive function and/or memory. They are most common in the elderly population. It is caused by advancing age, injury, tumours, high cholesterol, a lack of stimulation, and other factors. However, genetic polymorphisms found in a variety of genes associated with MCI are a major factor that is both independent and caused by lifestyle.

MCIs, which frequently precede dementia, have a number of genetic risk factors as people age. Genetic variations in one or more risk genes increase the likelihood of developing MCIs. The most common gene is APOE ε4, which increases the risk of all types of MCIs by interacting with proteins and messengers that mediate different cellular mechanisms. Other genes studied, such as BIN1 and MTHFR, have unique mechanisms for increasing MCIs.

Research into MCI risk genes is far from complete, and much work remains to be done; however, with a better understanding of these genes, we may be able to alleviate MCI symptoms and slow the progression of degenerative diseases.