PCOS and Dementia

Individuals with PCOS may be at up to 2x the risk of developing dementia compared to those without the condition.[1] Recent studies have found that individuals in mid-life with PCOS already demonstrate lower cognitive performance to those without PCOS.[2],[3]

This article explores PCOS and Dementia.

Dementia is the general term for a number of conditions associated with loss of memory, language, problem-solving and other cognitive abilities beyond what is associated with normal aging.[4],[5] These diseases destroy nerve cells over time, leading to damage to the brain.[6]

There are a variety of forms of Alzheimer’s Disease and Related Dementias (ADRD), including:[7],[8]

Alzheimer's disease (AD): most common form of dementia, accounting for 60-80% of all cases, and caused by the formation of two abnormal structures in the brain, beta-amyloid plaques between nerve cells and tau protein tangles within cells;[9]
Frontotemporal dementia (FTD): group of diseases accounting for 10-20% of all cases caused by damage to the frontal and temporal lobes of the brain, the control centers for behavior/emotion and language respectively;[10],[11],[12]
Dementia with Lewy bodies (DLB): caused by Lewy bodies, protein deposits made up primarily of Alpha-synuclein protein and names after Frederich H. Lewy, and associated with problems with thinking, reasoning and movement;[13],[14]
Vascular dementia: caused by restricted blood flow to the brain due to narrowing/blockage of blood vessels in the brain, a single stroke event where blood supply is suddenly shut off to part of the brain or a series of “mini strokes” (ischemic attacks or TIAs) causing small but distributed damage to the brain;[15]
Mixed dementia: dementia associated with more than one underlying cause;[16] and
Mild cognitive impairment (MCI): stage between decline in memory and thinking that naturally occurs with age and the onset of a more serious decline or dementia.[17]

Other disorders associated with dementia include:

Frontotemporal dementia and parkinsonism (FTDP-17): caused by mutations in the MAPT gene resulting in disruptions in the normal structure and function of tau proteins and leading to their buildup in the brain;[18]
Corticobasal degeneration: rare disease that causes areas of the brain in the frontal and temporal lobes to shrink (can be caused by Alzheimer’s, CJD, progressive supranuclear palsy or Pick’s disease);[19],[20]
Parkinson’s disease with dementia (PDD): c.80% of individuals with Parkinson’s disease develop dementia as the disease progresses as nerve cells break down[21] (collectively known as Lewy Body Dementia along with DLB as both are associated with Lewy bodies);[22]
Creutzfeldt-Jakob disease (CJD or prion disease): rare disease caused by a type of protein called a prion that folds in an abnormal way, transmits this abnormal folding pattern to proteins in neighboring cells and result in sponge-like holes in the brain;[23]
Huntington's disease: rare genetic disease where nerve cells in the brain decay over time;[24]
Normal pressure hydrocephalus (NPH): abnormal buildup of cerebrospinal fluid (CSF) in the brain’s ventricles putting pressure on the brain and often caused by physical damage through subarachnoid hemorrhage (bleeding in the space surrounding the brain)[25], traumatic brain injury, infection, brain tumor or complications from surgery;[26]

Individuals with PCOS have been found to have increased lesions on the white matter of the brain, the network of nerve fibers that allows the exchange of information, and cerebral infarcts, related to disrupted blood flow to the brain.[27] In addition, individuals with PCOS show reduced diffusion or transport of neuroactive substances such as hormones along the main axis of white matter fibers.[28],[29]

PCOS is believed to be linked to cognitive function and dementia through a number of potential mechanisms:[30]

Hormonal disruptions, including elevated androgens and lower estrogen and progesterone;
Metabolic changes and health complications, including insulin resistance, diabetes and obesity; and
Increased prevalence of sleep disorders, such as obstructive sleep apnea (OSA).

PCOS is associated with elevated levels of androgens[31], sex hormones that are produced in the ovaries, start at puberty and play a key role in reproductive health.[32] Learn more about PCOS and Androgen Excess.

High androgen levels stimulate the production of amyloid -beta (Aβ), a large protein involved in synaptic plasticity and learning;[33]
Increased production of Aβ leads to its accumulation within the brain;[34]
In Alzheimer’s these Aβ proteins clump together and form plaques;[35]
As above, these plaques cause damage to nerve cells and result in reduced executive function, the set of skills you use to manage every day such as making plans, solving problems and adapting to new situations.[36]

Interestingly, age-related loss in testosterone is associated with increasing risk of AD in men.[37] High circulating androgens in individuals with PCOS are conversely associated with improved verbal psychometer speed,[38] the rate at which you process verbal information.

PCOS can be associated with slightly elevated levels of estrogen where there is an accumulation of follicles in the ovaries.[39] Find out more about PCOS and Estrogen.

In general, estrogen is neuroprotective, playing a key role in various aspects of brain function, including: [40],[41]

Induces spinogenesis and synaptogenesis, the formation of spines and synapses in neuronal development and maintenance,[42] in the prefrontal cortex and hippocampus[43] increasing the level of neurotransmission or communication between cells;[44]
Initiates a complex set of signal transduction pathways, a series of cascading chemical reactions originating at the cell membrane,[45] via estrogen receptors (ERs) to induce spinogenesis and synaptogenesis across areas of the brain and beyond;[46]
Inhibits the action of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome,[47] a protein complex that constantly scans for signs of infection, toxins and metabolic imbalances,[48] to reduce neuroinflammation;[49]
Inhibits the production of mitochondrial superoxide,[50] formed when electrons leak and are captured by molecular oxygen and believed to play a key role in aging,[51] decreasing oxidative damage to the brain;
Supports the proper functioning of the cholinergic system, a branch of the autonomous nervous system that is critical for learning, memory formation and attention;[52] and
Supports the proper functioning of the serotonergic system, one of the key neurotransmitter systems in the brain regulating cognition, attention, emotion, pain, sleep and arousal.[53],[54]

However, estrogen can also be neuro-damaging, particularly when taken orally in combination with progestin:[55],[56],[57],[58]

Estrogen that is ingested orally is metabolized in the liver;[59]
Increased estrogen levels activate estrogen receptors (ERs) in the liver;
Increased ER activity increases the production of a variety of coagulating factors;
The increased level of coagulating factors increases the coagulation activity and therefore the risk of blood clots;[60] and
Increased risk of blood clots results in increased risk of stroke and therefore dementia.[61]

PCOS is associated with relatively high levels of luteinizing hormone (LH) relative to follicle stimulating hormone (FSH).[62] Learn more about PCOS and LH/FSH Ratio.

In individuals with PCOS, relatively high LH/FSH ratio has been shown to be correlated with reduced function in the right frontal lobe, the part of the brain that typically controls non-verbal abilities.[63],[64]

PCOS is associated with low levels of progesterone since, if ovulation does not happen, progesterone is not released.[65] Learn more about PCOS and Progesterone.

Lower progesterone is associated with decreased reactions in the amygdala, the main processing center for emotions,[66] and is therefore linked to lower emotional memory.[67] Low progesterone is also a risk factor sleep apnea as it plays a role in regulating respiratory pressure and the muscles’ function in dilating the upper airway.[68]

PCOS is associated with an increased prevalence of sleep disorders such as obstructive sleep apnea (OSA), a common and serious sleep disorder that causes you to briefly stop breathing during sleep.[69] Learn more about PCOS and Sleep Apnea.

Sleep apnea is associated with a significantly increased risk of various forms of dementia apart from vascular dementia.[70] It is believed that depriving the brain of oxygen during sleep causes the degeneration of some neurons.[71]

PCOS can be associated with elevated insulin resistance, where your body produces insulin but it cannot use the insulin effectively to balance your blood sugar.[72] Find out more about PCOS and Insulin Resistance.

In individuals with PCOS, increased insulin resistance has been shown to be correlated with an increased prevalence of AD.[73] Our brain accounts for only c. 2% of our body weight but consumes c. 20% of glucose-derived energy.[74] Individuals with PCOS were shown to have 9-14% lower metabolic rate in the frontal, parietal and temporal cortices of the brain than individuals without the condition.[75]

Risk factors for ADRD include:[76],[77]

Increasing age;
Genetics/family history of AD, CJD, Huntington's disease, FTDP-17 or several other kinds of dementia;
Genetics/family history of Gerstmann-Sträussler-Scheinker (GSS) syndrome or fatal familial insomnia (FFI), both extremely rare neurodegenerative brain disorders;[78],[79]
Having Down’s Syndrome with many individuals showing signs of AD by middle age;
Mild cognitive impairment, with one study finding that 40% of those over 65 with mild cognitive impairment developed dementia within 3 years;
Having had a traumatic brain injury (TBI), particularly athletes who experience repeated head injuries or older adults who experience falls;
Atherosclerosis, the buildup plaque, made up of fats, cholesterol and other substances, on the walls of your arteries[80] (AD and vascular dementia);
Hypertension, or high blood pressure;
Diabetes, particularly for those who develop Type 2 Diabetes in mid-life[81] (AD and vascular dementia);
Obesity in mid-life, also correlated with other risk factors such as hypertension and diabetes;
High cholesterol, a waxy substance found in your blood[82] (AD);
Having depression in mid- or later life;
Hearing loss, leading to social isolation and lack of independence;
Social isolation, also correlated with other risk factors such as hypertension and depression;
Physical inactivity, particularly in later life;
Vitamin D deficiency;[83]
Use of tobacco; and
Binge drinking, patterns of drinking alcohol that result in a blood alcohol concentration (BAC) of 0.08% or more, equivalent to a women drinking 4 of more drinks in 2 hours or less[84] (moderate drinking has been shown in some studies to reduce dementia risk).

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Reviewed by Dr. F, one of Neuraura’s friends and trusted advisors.

Sources

[1] https://www.sciencedirect.com/science/article/pii/S2589790X23003785

[2] https://www.neurology.org/doi/10.1212/WNL.0000000000208104

[3] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[27] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[28] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[29] https://www.sciencedirect.com/science/article/pii/S0969996122003734

[30] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[34] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[38] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[39] https://www.obgproject.com/2019/06/12/pcos-part-1-sensitive-care-of-the-pcos-patient/

[40] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480684/

[41] chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ogscience.org/upload/pdf/ogs-22165.pdf

[57] https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2013/04/postmenopausal-estrogen-therapy-route-of-administration-and-risk-of-venous-thromboembolism