Perimenopausal Cognitive Changes (Brain Fog): A Comprehensive, Evidence-Informed Clinical Approach in a Patient with APOE4

A case-based, integrative strategy for addressing brain fog, executive dysfunction, and long-term cognitive risk in perimenopausal women, including those with APOE4 genetic risk.

Dr. Nicole Roberts, ND

Abstract

In this case report, we see a 48-year-old female, over one year after a partial hysterectomy, struggling with executive function, sleep, and emotional regulation to the point that she is worried her job is in jeopardy.

There is an element of fear for the patient as she knows she is a carrier for APOE4, a genetic polymorphism that increases her risk of late-onset Alzheimer’s disease. She has seen an older family member develop dementia, which is not a trajectory she wants for herself.

With in-office assessments and blood work, we are able to identify and create a thoughtful, concise treatment plan that provides significant results to the patient symptom picture within three months and then use that improved sense of well-being to build into a plan that supports cognitive health and cognitive trajectory over the long term.

The interventions utilized in this patient case represent a multimodal approach to an individual in perimenopause, combining supplement recommendations, a hormone therapy prescription, and targeted diet and exercise interventions.

At over six months since beginning to work together, the patient now feels significant relief in her original symptoms and confident in the plan created to support her cognitive health as she ages.

Introduction

As high-quality evidence has continued to develop our understanding of standards for the treatment of perimenopause and menopause, we are seeing more focus and an influx of discussion around key symptoms associated with a decline in estrogen. The use of hormone therapy for women in their forties and fifties is becoming more common treatment approach as clinicians feel more confident in the safety of well-applied hormone therapy regimens. There still exists a need to recognize individuality in a woman’s perimenopause to menopause transition and to ensure we look beyond the role of hormone therapy as an exclusive treatment avenue to avoid missing other critical elements in her care.

A woman’s physiology from a metabolic and cognitive standpoint, is under rapid change during the late perimenopause to menopause transition. Within this case study, we see an intersection between what may be a transient shift in cognitive function, including executive function, focus, and memory, associated with a natural decline in estrogen production from the ovaries, laid on top of the patient carrying a genetic polymorphism that increases her risk of late onset Alzheimer’s disease, the most common form of dementia.

Exploring how to navigate cognitive changes in the present, but also consider cognitive trajectory over time,  allows for the development of good treatment plans that allay patient fear. This is an important skill as it allows clinicians to broach and discuss early intervention to stabilize cognitive trajectory. There appears to be a critical window in which we need to begin applying these preventative strategies to reduce the risk of age-related cognitive decline.1 It is important to address these preventative strategies by midlife.

This case report examines multiple overlapping influences on female cognition, while including objective assessments that allow us to assess for progress and cognitive stability over time. In Canada, we see 76,000 new cases of Alzheimer’s Disease diagnosed annually.2 Primary care providers do not routinely feel confident in the ability of the health system’s infrastructure in which they work, to allow for adequate resources to be dedicated toward cognitive health and dementia management.3 This can negatively impact patient assessment and cognitive trajectory. This case study provides one lens for speaking candidly and engaging the patient in her own cognitive management. 

“If a hypothetical intervention was initiated that delayed the onset of Alzheimer’s disease by just five years, this would lead to a 57% reduction in the number of patients with Alzheimer’s disease dementia.”4 This quote, from National Institute on Aging / Alzheimer’s Association 2011 paper, underscores the need to be proactive when it comes to cognitive health. 

Case Presentation

Initial Visit and Case Set Up: 

48-year-old female

Patient initials for reference (changed to preserve anonymity) are NF

Relevant History

• Had a partial hysterectomy at the age of 47 due to multiple very large fibroids and menorrhagia. 
• Menstrual cycle was regular into her 40s but she had very long bleeding windows with 10-day long periods. 
• Works full-time with two kids age 10 and 15, one of which is in a rep level sport with lots of travel on weeknights and weekends. 
• Most recent blood work was prior to the partial hysterectomy, revealing normal CBC, TSH, creatinine, ALT, and electrolyte levels.
• Former cigarette smoker: quit when she got pregnant with her first baby, 16 years ago.
• Medications: None
• Allergies: None known
  

Symptoms: 

• Within the past six months, night sweats that occur approximately 50% of the time. Denies hot flashes. 
• Disrupted sleep from both night sweats and a restless feeling in her legs that began or intensified after her hysterectomy. She reports her hips can ache sometimes and this might make it harder to fall back to sleep. 
• Fatigue upon waking. Energy is okay throughout the day until approximately 3 p.m. when it drops significantly and she struggles to get to bedtime. 
• Denies vaginal dryness or vulvovaginal symptoms.  
• Has been noticing a thinning hair across the scalp  and was told by a dermatologist it was androgenetic alopecia or female pattern hair loss. 

Chief Concern: Cognitive Function

NF’s primary concern is that she is having a very difficult time focusing and getting things done at work. She feels there has been a net negative change to her cognition, and she thinks this has probably happened over the past year. She is not sure if it worsened as her sleep deteriorated or just before. She feels scared about this change because NF watched her mother manage her grandmother’s declining cognitive health. NF’s grandmother was diagnosed with dementia at the age of 76, but she can’t recall if the term Alzheimer’s disease was used. NF doesn’t want to have the same cognitive trajectory. She’s worried that the brain fog she feels is a sign of cognitive decline and eventual dementia. She’s also worried she may lose her job as she has had a performance report recently that indicated improvement was needed. NF has a history of anxiety (self-reported) since she was in her late teens, but an anxiety disorder has never been formally diagnosed. Overall, she is feeling very overwhelmed, confused, and unsure of what to do next.

Of note, NF did have a genetic test done in the past that showed she was a carrier of the APOE4 polymorphism. She has read about APOE4 playing a role in Alzheimer’s disease risk.

NF reports that she used to be quite physically active with multiple sports and training sessions at the gym prior to having children 15 years ago. The demands on her time and the amount of fatigue she feels have been barriers to returning to regular exercise. She does not currently have a regular exercise regimen. She would like to be more active but feels tired and achy and with her busy schedule, she hasn’t gotten around to starting something regularly.

NF would consider her diet to be healthy overall, particularly compared to the way she sees people eat around her. She admits that she often skips breakfast, grazes throughout the day, and that her only regular meal is typically dinner, which consists of a protein, a vegetable, and a carbohydrate. Weight has not historically been a concern for her, but she has noticed over the past year that her pants are beginning to fit tighter, and she would like to see this change. She stands at 5’7″ and doesn’t regularly weigh herself.

Family History

• Mother had multiple uterine leiomyomas that led to a hysterectomy in her mid-40s. Recently diagnosed with prediabetes. 
• Father was diagnosed with high blood pressure in his 60s and has been on medication ever since. 
• Has two siblings. Her younger brother was diagnosed with ADHD as a child. Her 51-year-old sister was diagnosed with hypothyroidism after having children and has been on medication ever since.
• No one else in her family has ever been tested for their APOE4 polymorphisms.

In Office Physical Exam: Initial Appointment

NF appeared alert and oriented to person, place, and time. 

She was able to discuss her past medical history without confusion. 

Affect was positive. 

Blood pressure right arm sitting was 127 over 84 mmHg. Blood pressure left arm sitting was 129 over 85 mmHg. 

Waist circumference was 34.6 inches.

A Discussion of Differential Diagnoses 

Perimenopause to Menopause Transition: In reviewing the information obtained within the initial visit, it would seem logical to consider a Late Perimenopause to Menopause Transition as the underlying contributor to cognitive symptoms, vasomotor symptoms, the night sweats, sleep changes, hair thinning, and current anxiety levels. A partial hysterectomy does not cause surgical menopause but does remove menstrual tracking from the data pool we have when considering hormonal changes in perimenopause.

However, to jump into exclusive treatment of perimenopause/menopause without further consideration may be hasty, as there remain a number of additional differential diagnoses and questions that need to be explored if we are going to give NF the most concise and effective individualized treatment plan. 

Nutritional Deficiencies: NF is a busy working mom and doesn’t eat 3 regular meals per day.
Prior to her partial hysterectomy, NF had very large fibroids and menorrhagia. Her iron status has not recently been checked, and it is possible that she is still iron-deficient after years of heavy blood loss. Her not currently menstruating doesn’t negate her history of heavy menses.

The Impact of Insomnia: Poor quality sleep for months on end could explain cognitive and mood changes. Sleep is being affected by 3 key symptoms as reported by NF: restless legs, night sweats and aching in her hips. Solving barriers to NF’s sleep may lead to significant improvement in other symptoms and seems like a key place to begin. NF doesn’t report any routine changes that have affected sleep, but she has reported an increase in her anxiety which may both affect, and be affected by poor sleep. Notably, sleep changes are a key symptom on the Menopause rating scale and this is often a place female patients will struggle with the menopausal transition. 

Considering Anxiety; A History of Anxiety and Recent Intensification:

NF reports she is an anxious person and always has been. As discussed above, sleep deficits can impact anxiety. Low iron has been correlated with anxiety and psychiatric effects.5 Anxiety is known to increase in the years before a woman’s final period.6 We also know that cognitive changes are anxiety-inducing for many patients. There may be a vicious cycle occurring between these symptoms.

Family History of ADHD: The fact that NF’s sibling, particularly NF’s male sibling, was diagnosed with ADHD as a child is interesting. While a diagnosis of ADHD cannot be made within my office as a naturopathic doctor, it is a piece of her history that I would like to remain aware of. Females growing up in NF’s generation may not have fit the current era understanding for ADHD, and thus a childhood diagnosis may have been missed. Coping mechanisms that NF may have had in place to help her function throughout the years, may now be affected by inadequate sleep, fatigue and hormonal transitions.

APOE4 Carriership: APOE4 is a genetic variant that significantly increases the risk of developing late-onset Alzheimer’s disease. The risk associated with APOE4 is dose-dependent, with heterozygotes having a 2-to-3-fold higher risk of developing Alzheimer’s disease compared to those with the neutral E3/E3 genotype.7

Carrying the APOE4 variant is not deterministic for Alzheimer’s Disease, and this is VERY important to note. While APOE4 increases risk, it does not guarantee that an individual will develop Alzheimer’s disease. The “AD risk triad” consists of genes [APOE4 carriership], age [being over 65 years old] and sex [being female].8 

The fact that NF discusses having the ApoE4 polymorphism does not immediately increase my suspicion of her, at the age of 48, as having cognitive changes related to the eventual development of dementia. My first assessment based on age and history is that she is experiencing transient changes in cognitive function associated with the late perimenopause to menopause transition, and that this, along with the impact of inadequate sleep, is affecting her executive function, focus and mood. 

However, NF carrying the E4 allele, coupled with her family history, does increase her risk of developing late-onset Alzheimer’s disease. What the APOE4 polymorphism does is inform my treatment of NF in the present and allow me to make choices with her that may differ if she did not carry this allele.

The triad of risk for Alzheimer’s disease is increasing age, APOE status, and particularly APOE4 carriership and the female sex, which means NF currently exists at a critical time to assess and attempt to mitigate risk of a decline in her cognitive trajectory.

The Question of Metabolic Syndrome: NF’s waist circumference that comes in just under the 35-inch mark increases my suspicion of an earlier developing presentation of metabolic syndrome. I plan to assess this with blood work. Menopause increases the risk of developing metabolic syndrome and can exacerbate an increase in central body fat as sleep quality declines, MSK pain goes up and the balance of caloric intake vs utilization shifts. Metabolic syndrome exists as a risk factor for Alzheimer’s disease, which makes early identification important for in this clinical case.9

Other Explanations for Symptoms Associated with Declining Estrogen: Last but not least, when patients experience symptoms that seem to indicate perimenopausal hormonal shifts or menopausal changes, and thus best seem explained by a decline in estrogen, I always look or screen to see if there is anything else that may act to decrease estrogen outside of natural decline of ovarian production. This would include screening for hypothalamic amenorrhea, which is difficult to assess in a patient who does not have a monthly bleed. NF does report an overall increase in stress (primarily related to the symptoms she is feeling), but no decrease in food intake, or a sudden increase or relative increase in exercise, which makes this condition less likely.

NF and I discussed the utility in testing for hormones including follicle stimulating hormone, estradiol, and prolactin. We acknowledge that assessing FSH and estradiol levels is not always (and often not) necessary to treat perimenopausal symptoms. FSH and estradiol fluctuate throughout a cycle, and can vary widely in late perimenopause. Without a menstrual cycle to assign more context to these levels, any serum FSH and Estradiol testing that came back in expected mid-ranges (i.e. no extremes) would not offer us much insight. Due to NF’s partial hysterectomy, we decided to test these markers to create a baseline and to assess whether levels aligned with the working diagnosis that we would eventually come to, as we did not have cycle duration to aid us in decision-making.

Next Steps

Following this assessment of potential diagnoses, our next step was to conduct additional blood work, the results of which would be reviewed at our second appointment. NF was instructed to do the blood work first thing in the morning after a 12-hour fast but well hydrated with water.

Laboratory Results

 – CBC: within normal limits
– Ferritin: 25 ug/L (L)
– Vitamin D25OH: 64 nmol/L (L)
– HbA1c: 5.7%
– TSH: 1.24 mIU/L
– Vitamin B12: 230 pmol/L
– Total cholesterol: 5.4 mmol/L (H)
– LDL cholesterol: 3.8 mmol/L (H)
– HDL cholesterol: 0.95 mmol/L (L)
– Fasting triglycerides: 1.5 mmol/L
– Apolipoprotein B: 1.2 g/L (H)
– Fasting insulin: 140 pmol/L
– Fasting glucose: 5.6 mmol/L
– HOMA IR score: 5.8 (calculated) (H)
– Creatinine: within normal limits
– Liver panel: within normal limits
– Sodium, potassium, calcium: within normal limits
– C-reactive protein: 4.5 mg/L
– Follicle Stimulating Hormone: 15.4 IU/L
– Estradiol: 152 pmol/L
– Prolactin 19 ug/L

Summary:
1. Nutritional deficiencies are likely impacting energy, hair loss, and cognitive function. Plan to correct iron deficiency, Vitamin D deficiency and suboptimal B12 status.
2. Metabolic profile showing risk of insulin resistance and emerging metabolic syndrome.
3. Atherosclerotic risk if values remain unchanged or worsen over time. Cardiovascular risk compounded by emerging metabolic syndrome.
4. Hormonal profile consistent with late perimenopause or perimenopause to menopause transition, ruling out other hormonal causes of symptoms

In Office Screening Within the 2nd Appointment: 

1. Menopause Rating Scale: Total Score of 18 (See addendum). Highest scores were in sleep disruption, irritability, cognitive changes, anxiety with some physical symptoms including muscular and joint discomfort. 
2. American College of Cardiology ASCVD Risk Estimator: 1.9% 10 Year Risk (Low)
3. NIH Breast Cancer Risk Assessment Tool: Lifetime Risk of Developing Breast Cancer: 12.5% (Average risk 11.5%)

Interventions

Supplementation: Initiation of a combination supplement containing 75 mg of elemental iron, 1000 mcg of methylcobalamin and 400 mcg of folate to be taken once daily for an initial period of four months before reassessment. 

A vitamin D3 prescription was initiated at 5000 IU once daily for a period of 30 days, after which vitamin D3 would be taken in a dose of 2500 IU once daily for an additional 60 days, at which time serum vitamin D and serum calcium would be re-tested. The goal was to raise vitamin D above 75 nmol/L quickly and then maintain a sufficient level. This prescription was made in late fall in Canada knowing the patient would not be exposed to a significant amount of sunlight over the ensuing few months.

Hormone Therapy: A prescription for topical estradiol gel was initiated at a total daily dose of 0.75 mg of estradiol. The rationale for this dose was that the patient appeared to be experiencing symptoms associated with a decline in estrogen and she was over the critical age of 45. Thus, estrogen was being initiated primarily to improve her quality of life and the symptoms assessed by the menopause rating scale – it was not being utilized to specifically replace necessary estradiol exposure. Additionally, the patient was experiencing limited and more isolated vasomotor symptoms compared to consistent, frequent and intense daily vasomotor symptoms. Reassessment at three months was recommended, though if the patient was not feeling significantly better within 2 months, she should follow up sooner.  A progestogen was not recommended due to the patient’s history of a partial hysterectomy. 

The relationship between ApoE4 carriership and hormone therapy, particularly estradiol dosing, in the context of Alzheimer’s risk, is not yet well flushed out and does appear to be complex. We do know at this time that hormone therapy is not recommended for the sole purpose of preventing dementia.

Studies suggest that hormone therapy may have a more protective effect for APOE4 carriers, particularly if initiated very close to menopause or within late perimenopause.10 This is very important to note for there does appear to be a critical window in which estradiol initiation for menopausal symptoms would be of more benefit to an APOE4 carrier’s cognitive trajectory and lifetime Alzheimer’s disease risk, compared to non-carriers.

I obtained consent from NF to send a letter to update her family doctor of both her Vitamin D and estradiol prescriptions.

Dietary Counselling: The patient was introduced to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diet. The existing literature has found that greater adherence to the MIND diet is associated with a decreased risk of cognitive impairment, and that this may be of particular benefit to females.11

The MIND diet incorporates a significant amount of the metabolically healthy recommendations found in the Mediterranean diet and may have its most significant impact on a patient’s cognitive trajectory if adopted within midlife. For this reason, the MIND diet was chosen as the template for this patient because it covered the cardiovascular, cognitive, and anti-inflammatory dietary principles that would help NF in a multifaceted and synergistic way.

A discussion was had around alcohol consumption. NF reported that she was not a regular or heavy drinker, but in social situations, she could have up to four or five alcoholic drinks. We discussed that either alcohol abstinence or staying within moderation if drinking, which meant ideally no more than one alcoholic drink per day, was associated with better cognitive outcomes. The interaction between ApoE4 and alcohol consumption seems to become greater as a patient ages. One study found that light and moderate alcohol consumption in late life was associated with a decline in learning and memory, only for APOE4 carriers.12

NF was encouraged to consume more phytonutrients in her beverages including organic green tea, matcha, and very small amounts of an unsweetened dark berry juice such as grape or pomegranate coupled with bubbly water for a non-alcoholic spritz. We agreed to make these changes over a period of three months and then reassess.

The goals for our next check-in, particularly if symptoms such as fatigue and body pain significantly stabilized while on the iron supplement, the vitamin D supplement, and HT regimen, would be to talk more in depth about an exercise regimen that NF could begin implementing that would further address cognitive stability and metabolic resiliency as she faced her menopause transition.

Outcome and Follow-Up

3 Month Follow Up: 

NF came in for follow-up at the three-month mark. She denied any side effects associated with estradiol gel – no breast tenderness, no headaches, no increase in moodiness. She tolerated her iron supplement well as long as she took it with food. The most notable improvement was a complete resolution of night sweats, leading to improved sleep. Her daytime cognitive function and executive function had significantly improved, and she was feeling very confident at work. She had began to notice some regrowth of hair around her hairline. Upon reassessment, her menopause rating scale total score had gone down from 18 to 6. Her musculoskeletal and joint discomfort had significantly improved. Her daytime energy was improved. 

NF reported she felt ready to begin talking about an exercise regimen. The Nurses Health Study found that vigorous exercise maintained throughout midlife had a significant stabilizing effect on cognitive trajectory as females aged into their 70s, and that this was particularly pronounced in APOE4 carriers.13

Blood work requisition was prepared for ferritin, vitamin D, and B12 testing to be done within a month, and additional metabolic testing was deferred until our 6 month follow up.

In-office blood pressure was 121/79 mmHg RAS. 

In-office waist circumference had decreased to 33.5 inches. 

The patient reported enjoying the MIND diet and an adherence of approximately 80 to 90%. She found her treatment plan sustainable and cost effective. 

The patient felt well enough to engage in an in-office cognitive assessment as she felt her current cognitive state was better representative of her capability now that she had been having much improved sleep. A mini mental state examination (MMSE) was done as this was the cognitive test most suited to the time and resources available in office. She scored 29 out of 30, which fell into the normal cognitive range. Future use of the Montreal Cognitive Assessment was discussed, which is considered superior in identifying mild cognitive impairment. It was also discussed that longitudinal cognitive evaluations would be more helpful than a single evaluation to understand cognitive change over time.Long-Term Follow-Up: 

Within 6 months, NF had begun resistance training twice weekly, with an additional 2 high-intensity cardio sessions per week. She ate 3 meals and one snack daily. She was able to get 7.5 to 8 hours of restful sleep nightly.

Her waist circumference continued to decrease as she gained lean muscle mass, her Apo B fell below 1 g/L, her HOMA IR score reduced to 2.7 and she was able to maintain a serum ferritin of about 100 without ongoing supplementation.

NF initiated a discussion with her family doctor about her cognitive trajectory and now felt much more supported in her proactive approach to cognitive health. She no longer reported feeling fearful of future health outcomes, and her anxiety felt significantly more manageable once these fears had alleviated. 

We decided on a quarterly follow up plan where we focus on maintaining results, troubleshooting new symptoms and preventing exercise-induced injury, assessing the progression of metabolic health, screening for changes to iron status as NFs activity level continues to increase, and discussing interventional literature updates on APOE4 carriers and cognitive health. 

Discussion

This case report draws on an understanding of the overlapping factors that can affect female cognitive and metabolic health in midlife. Here we see a combined treatment approach of nutritional supplements with hormone therapy and lifestyle changes creating a sustainable and cost-effective plan that gave the patient significant symptom relief in the short term and set her up on a path towards better cognitive and cardiovascular health over the long run. The patient came in feeling overwhelmed, confused, and scared.

Managing her case with clear objective goals obtained from physical exams and blood work allowed both her and I to feel confident that the results she was seeing were significant and were affecting her physiology in such a way that she would have a lasting benefit. My goal was for her to be able to look back one year after beginning to work with me and feel that she was in a much better place physically, cognitively, and mentally. I also wanted her to learn throughout our work together and feel prepared to advocate for her metabolic and cognitive health both now and in the future. We discussed a number of the studies that were referenced in this case report today so that she had an understanding of the evidence base I was pulling treatment from.

Limitations to this approach primarily fall around the initiation of hormone therapy. I was able to work directly with NF regarding hormone therapy, because she had had a partial hysterectomy and did not require oral progestogen therapy, which currently falls outside the scope of naturopathic prescribing in the jurisdiction I practice. If NF had had her uterus, we would have been triangulating care with a nurse practitioner or medical doctor. This can create some barriers, financial implications and delays in care, but it can also create a supportive healthcare team that functions to help an individual patient.

This case, while NF is one patient in this case report, this case presentation is very similar to a number of others I see on a regular basis. And I believe NF’s treatment trajectory can offer a supportive roadmap for many similar patients in perimenopause.

The key takeaways from this case report was thinking through the differential diagnosis intentionally, creating objective biomarkers to track progress, applying the current evidence base to an individual patient in a clinical setting, and creating a confident, sustainable treatment plan that was not overwhelming from either a time or cost factor for the individual patient. I believe this combination of factors is what led to NF’s success.

Conclusion

Methodical, evidence-informed assessment and treatment of perimenopausal cognitive changes, all began with a thorough patient intake and formed the base of this multimodal approach. Within 3 months we were able to effectively address the patient’s perimenopausal cognitive changes in the present with a cost-effective approach that the patient could sustain and then build upon, while ensuring we remained proactive in supporting her cognitive trajectory as she aged. This was the kind of comprehensive care the patient expressed she needed to reduce her fears about dementia. 

Early identification of cognitive risk factors in females in midlife including emerging metabolic syndrome, particularly for those that are at an increased genetic risk of developing Alzheimer’s dementia, is an impactful way for naturopathic doctors to make a difference not only in an individual patient’s health and quality of life, but in the broader community.

A naturopathic doctor’s ability to critically assess the current available literature and spend time breaking this down for a patient in their office can lead to adherence to dietary and supplement changes that can lead to years of better health.

Delaying chronic disease may be as important as preventing it entirely when we think about the impact of a condition like cognitive impairment on a family and a community. We have resources at our disposal in the present to enact important and effective changes as long as we feel confident to address these concerns in a clinical setting.

Dr. Nicole Roberts, ND, BScH is a licensed naturopathic doctor practicing in Ontario, Canada, specializing in brain health, women’s health across the lifespan, and preventive, evidence-informed care. She trained at the Canadian College of Naturopathic Medicine and helps patients connect symptoms with whole-body function to optimize cognitive, hormonal, and metabolic health. Dr. Roberts focuses on sustainable, personalized strategies for conditions including perimenopausal cognitive changes, mood disorders, metabolic imbalance, and chronic disease risk, blending lifestyle medicine, targeted therapeutics, and integrative diagnostics to enhance health span and resilience.

References

1. B.B. Antal, H. van Nieuwenhuizen, A.G. Chesebro, H.H. Strey, D.T. Jones, K. Clarke, C. Weistuch, E. Ratai, K.A. Dill, & L.R. Mujica-Parodi, Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention, Proc. Natl. Acad. Sci. U.S.A. 122 (10) e2416433122, https://doi.org/10.1073/pnas.2416433122 (2025).
2. Alzheimer’s Society of Canada. Landmark Study Volume 2; The Many Faces of Dementia in Canada. 2024. https://alzheimer.ca/sites/default/files/documents/ASC_The%20Many%20Faces%20of%20Dementia%20In%20Canada_Landmark%20Study_Vol2.pdf
3. Sideman AB, Ma M, Hernandez de Jesus A, et al. Primary Care Practitioner Perspectives on the Role of Primary Care in Dementia Diagnosis and Care. JAMA Netw Open. 2023;6(9):e2336030. doi:10.1001/jamanetworkopen.2023.36030
4. Wilson D, Peters R, Ritchie K, Ritchie CW. Latest Advances on Interventions that May Prevent, Delay or Ameliorate Dementia. Ther Adv Chronic Dis. 2011 May;2(3):161-73. doi: 10.1177/2040622310397636. PMID: 23251748; PMCID: PMC3513883.
5. Arshad H, Arshad A, Hafiz MY, Muhammad G, Khatri S, Arain F. Psychiatric Manifestations of Iron Deficiency Anemia-A Literature Review. Eur Psychiatry. 2023 Jul 19;66(Suppl 1):S243–4. doi: 10.1192/j.eurpsy.2023.560. PMCID: PMC10595923.
6. Bromberger JT, Kravitz HM, Chang Y, Randolph JF Jr, Avis NE, Gold EB, Matthews KA. Does risk for anxiety increase during the menopausal transition? Study of women’s health across the nation. Menopause. 2013 May;20(5):488-95. doi: 10.1097/GME.0b013e3182730599. PMID: 23615639; PMCID: PMC3641149.
7. Benjamin R. Troutwine, Laylan Hamid, Colton R. Lysaker, Taylor A. Strope, Heather M. Wilkins,Apolipoprotein E and Alzheimer’s disease,Acta Pharmaceutica Sinica B,Volume 12, Issue 2,2022,Pages 496-510,ISSN 2211-3835,https://doi.org/10.1016/j.apsb.2021.10.002.(https://www.sciencedirect.com/science/article/pii/S2211383521003944)
8. Riedel BC, Thompson PM, Brinton RD. Age, APOE and sex: Triad of risk of Alzheimer’s disease. J Steroid Biochem Mol Biol. 2016 Jun;160:134-47. doi: 10.1016/j.jsbmb.2016.03.012. Epub 2016 Mar 8. PMID: 26969397; PMCID: PMC4905558.
9. Ezkurdia A, Ramírez MJ, Solas M. Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance. Int J Mol Sci. 2023 Feb 22;24(5):4354. doi: 10.3390/ijms24054354. PMID: 36901787; PMCID: PMC10001958.
10. Saleh RNM, Hornberger M, Ritchie CW, Minihane AM. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. Alzheimers Res Ther. 2023 Jan 9;15(1):10. doi: 10.1186/s13195-022-01121-5. PMID: 36624497; PMCID: PMC9830747.
11. Sawyer RP, Blair J, Shatz R, Manly JJ, Judd SE. Association of Adherence to a MIND-Style Diet With the Risk of Cognitive Impairment and Decline in the REGARDS Cohort. Neurology. 2024 Oct 22;103(8):e209817. doi: 10.1212/WNL.0000000000209817. Epub 2024 Sep 18. PMID: 39292985; PMCID: PMC11413742.
12. Downer B, Zanjani F, Fardo DW. The relationship between midlife and late life alcohol consumption, APOE e4 and the decline in learning and memory among older adults. Alcohol Alcohol. 2014 Jan-Feb;49(1):17-22. doi: 10.1093/alcalc/agt144. Epub 2013 Sep 18. PMID: 24049153; PMCID: PMC3865814.
13. Fassier P, Kang JH, Lee IM, Grodstein F, Vercambre MN. Vigorous Physical Activity and Cognitive Trajectory Later in Life: Prospective Association and Interaction by Apolipoprotein E e4 in the Nurses’ Health Study. J Gerontol A Biol Sci Med Sci. 2022 Apr 1;77(4):817-825. doi: 10.1093/gerona/glab169. PMID: 34125204; PMCID: PMC8974346.