Chapter 99
Neurodegeneration — 5
Imust emphasize that genetic risk for late-onset Alzheimer’s extends well beyond APOE4. A polygenic risk score based on hundreds of genomic variants can accurately predict a doubling of the risk of developing Alzheimer’s. Notably, more than half of these risk genome variants involve the innate immune system, further framing Alzheimer’s as a neuro-inflammatory condition. The polygenic risk score complements the blood biomarker as a way to identify high-risk individuals, so if there is an effective intervention, we can prevent the disease from ever manifesting or significantly delay its presentation.
Once a person has reached an advanced age, a family history of Alzheimer’s is the most important risk factor for late-onset Alzheimer’s disease. The pattern of parental transmission to offspring by mothers, compared with fathers, is different. In a study with more than forty-four hundred participants with PET scans for β-amyloid, maternal history of memory impairment at any age was associated with increased β-amyloid in offspring, whereas for fathers that was only the case for early onset memory difficulties. The reason for this remains unclear; the potential role of transmission for the maternal X chromosome or mitochondria has been speculated.
The use of deep-learning AI of the MRI has been shown to improve accuracy of diagnosis of Alzheimer’s. A multimodal AI model performed exceptionally well for accurately classifying ten different types of dementia, exceeding neurologists. AI has even been able to help estimate how long until symptoms manifest based on abnormal imaging, genomics, and clinical data. That feeds into our infra potential prevention strategy.
LIFESTYLE+ FACTORS
For prevention or delaying the onset, we do know lifestyle+ factors play a vital role in our overall health. We’ve reviewed many of these, since the benefits of healthy lifestyle transcend the cardiovascular system and extend to promoting brain health. But it is worth emphasizing the difference that can be made to the onset of neurodegeneration.
Walking matters! To determine the relationship between steps and all-cause dementia, more than seventy-eight thousand UK Biobank participants with wrist accelerometers were followed for seven years: a daily dose up to ninety-eight hundred steps was linked to protection. There are nearly two thousand reports and eighty randomized trials that have studied the relationship between physical exercise and cognition. Overall, there is a consistent, though small, favorable effect of exercise for cognition. Some new studies have probed the mechanism for this benefit, such as improved clearance of Aβ thanks to our brain plumbing discussed above. In an animal model of aging, exercise rejuvenates microglia cells and reduces brain inflammation. Interestingly, an extensive gene expression analysis of over one thousand genes linked to Alzheimer’s identified “exercise as the top theoretical treatment.”
The Mediterranean-DASH Intervention for Neurodegenerative Delay diet randomized trial did not show benefit in 604 participants with a family history of Alzheimer’s compared with a control diet with mild caloric restriction. However, a prior double-blind randomized trial conducted in Finland with 1,260 participants, testing an intervention that included the Mediterranean diet, aerobic and strength training exercise, and cognitive training showed marked improvement to complex memory, executive functioning, and mental processing speed. In contrast, I’ve previously highlighted the risk of a diet high in ultra-processed foods for dementia.