New insights on Preclinical Dementia

Historically, research on Alzheimer’s disease has focused on symptomatic stages of the disease, particularly mild cognitive impairment (MCI) and dementia. However, recent advancements have shifted attention to the preclinical phase of AD, which can precede overt symptoms by years or even decades¹. This phase offers a critical window for intervention, with the potential to delay or prevent the onset of clinical symptoms.

Identifying reliable biomarkers for the preclinical phase of AD is crucial for early diagnosis and intervention¹. Current research has focused on a combination of imaging, Cerebrospinal (CSF), and blood-based biomarkers.

1.  Imaging Biomarkers²: PET imaging has been instrumental in detecting amyloid and tau deposits in the brain. Additionally, structural MRI can reveal hippocampal atrophy and other brain changes associated with early AD.
    
2. Cerebrospinal Fluid (CSF) Biomarkers: CSF levels of Aβ42, total tau, and phosphorylated tau are widely used to identify preclinical AD. A decreased Aβ42/tau ratio in CSF indicates amyloid pathology and neurodegeneration³. Moreover, neurofilament light (NfL, a marker of neurodegeneration) and neurogranin (a marker of synaptic damage) have garnered significant attention, as elevated levels of both NfL and neurogranin are correlated with Alzheimer's disease pathology^4-6.
    
3. Blood-Based Biomarkers⁷: Recent advances in blood-based biomarkers, such as plasma Aβ42/Aβ40 ratios and p-tau217, offer a less invasive, cost-effective, and more accessible approach to detecting preclinical AD. These biomarkers are still under investigation but show promise for widespread screening. Furthermore, plasma pTau-217 and ratio pTau-217/total-tau (%p-Tau) are now being investigated thoroughly for their potential to be a confirmatory/diagnostic test for AD⁸. Elevated plasma NfL levels can be detected in the preclinical stages of Alzheimer's disease, even before the onset of cognitive symptoms. This makes NfL a valuable biomarker for identifying individuals at risk for AD⁹. Given the major capacity constraints and drawbacks of amyloid PET and CSF testing, integration of high-performance blood-based biomarker tests in a clinical setting could enable many more people with pre-clinical AD to receive an accurate and timely diagnosis and to benefit from new disease-modifying therapies for early symptomatic AD.
    
4. Other non-brain markers of preclinical AD: sarcopenic level muscle mass is associated with thinner cortex, smaller hippocampal volume, and more cerebral small vessel disease¹⁰; faster gait speed associated with better cognitive performance; higher accumulation of visceral fat is associated with thinner cortex and more small vessel disease burden¹¹; individuals with ApoEe4 with poor sleep is associated with higher CSF t-tau, p-tau, and neurogranin, as well as lower CSF Aβ42¹².

The preclinical phase of Alzheimer's disease represents a critical period for research and intervention. Advances in understanding the pathophysiological mechanisms, coupled with the development of sensitive biomarkers, have opened new avenues for early diagnosis and treatment. While therapeutic strategies targeting amyloid and tau are still in development, the potential to intervene during the preclinical phase offers hope for altering the trajectory of Alzheimer's disease. Future research should focus on refining these approaches and exploring the role of lifestyle modifications in preventing the progression of symptomatic dementia.

Implement Dementia Risk Reduction Strategies with Brain Equity in Mind

The concept of brain health equity in Alzheimer's disease (AD) refers to ensuring that all individuals, regardless of their socioeconomic status, race, ethnicity, or geographic location, have equal opportunities to maintain brain health and access care, prevention, and treatment for Alzheimer's disease¹³. The road to brain health equity in Alzheimer's disease is winding, marked by significant challenges rooted in historical, social, and economic disparities, as well as early- and mid-life lifestyle and physiological risk factors¹³. Therefore, implementation of dementia risk reduction strategies is very crucial.

The 2024 Lancet Commission Report on Dementia Prevention, Intervention, and Care identifies two new modifiable risk factors for dementia: untreated vision loss and high LDL cholesterol, adding to the previously identified 12 risk factors¹⁴.

The report adopts a life-course perspective, emphasizing the importance of early and sustained interventions to mitigate dementia risk. Key strategies include improving education, managing cardiovascular health, treating hearing loss, and reducing exposure to air pollution. Hearing loss treatment, particularly through hearing aids, is highlighted as an increasingly supported intervention for reducing dementia risk¹⁴.

The report also addresses the unequal burden of dementia risk factors across different populations, particularly in low-income and minority groups, and stresses the need for targeted prevention strategies in these communities. Depression is identified as a significant midlife risk factor for dementia, with evidence suggesting that its treatment can lower the likelihood of developing dementia¹⁴.

Overall, the report provides hopeful evidence that dementia risk can be modified and highlights the importance of both individual and policy-level interventions in reducing the global burden of dementia.

Policymakers can drive brain health equity by taking 4 steps¹³:

1. Invest in public health, treatment, and research infrastructure in communities hard-hit by Alzheimer’s and related dementias 
2. Invest in educational and economic opportunity to reduce social inequities 
3. Establish a national goal to prevent Alzheimer’s disease and related dementia and address disparities in early intervention and diagnosis 
4. Collect better data to identify and address gaps in access to Alzheimer’s health services and research for underserved communities

Vascular dementia and cognitive reserve

Vascular dementia (VaD), Alzheimer's disease (AD), and cognitive reserve are intricately linked in the context of neurodegenerative disorders. While VaD and AD have distinct pathological processes, they often coexist, leading to complex interactions that influence cognitive outcomes. Diagnosing a VaD involves two steps, establishing the presence of a cognitive disorder and determining that this directly results from cerebrovascular pathology¹⁵.

Cognitive reserve plays a crucial role in modulating the impact of these diseases on cognitive function, offering a potential avenue for intervention and prevention. Cognitive reserve (CR) refers to the brain's ability to compensate for damage and maintain cognitive function despite the presence of neuropathology. The concept of CR is based on the observation that individuals with similar levels of brain pathology can exhibit different levels of cognitive impairment, depending on their cognitive reserve^16,17.

Factors Influencing Cognitive Reserve^16,17:

1. Education: Higher levels of education are consistently associated with greater CR and a lower risk of dementia.
2. Occupation: Engaging in mentally stimulating work and activities throughout life contributes to CR. 
3. Lifestyle Factors: Physical activity, social engagement, and intellectually stimulating activities (e.g., reading, playing musical instruments) enhance CR.
4. Genetics: Genetic factors may also play a role in determining an individual's CR, for instance, a common single nucleotide polymorphism in the BDNF gene, specifically a valine-to-methionine substitution at codon 66 (Val66Met), has an influence on LTP as well as activity-dependent BDNF secretion¹⁸

Future research should focus on identifying strategies to enhance CR and exploring its role in mitigating the effects of mixed dementia (AD and VaD), to improve clinical outcomes and reduce the burden of dementia on individuals and society.