将近五年后，一项 12 月研究估计，全球多达 400 million 人正承受 SARS-CoV-2 感染的长期后果；而一项 11 月分析估计其年度经济代价为 $1 trillion（约 $1,000 billion），接近全球国内生产总值的 1%。UK Biobank 对比感染前后的脑部扫描发现，即使是轻症感染，与规划和记忆相关区域也有细微流失；英国社区研究则发现认知分数出现小幅但可测量的下降。在一项英国人体挑战研究中，受试者为无既往免疫力、感染原始毒株的健康年轻成人，多数病情轻微且无人回报持续问题；但在 1 year 后，他们在记忆与决策测试中的表现略差，差距大致相当于 6 IQ points；该实验追踪参与者 12 months。
到疫情第 3 年，汇总观察性研究与大型人口资料集回报，Covid 后出现认知受损的风险在统计上更高；在较高龄族群中，与匹配对照相比可见失智程度的衰退，且可出现在感染后数月或数年。1 月的一项研究追踪了 Covid 前后皆有血液样本的必要工作者，结果显示：有持续神经症状的参与者其 phosphorylated tau 明显上升，尤其在症状超过 1 year 时更为明显；作者并未宣称 Covid 会导致 Alzheimer’s，但表示此生物学模式令人忧虑。11 月发表的一项韩国研究扫描了数百名多为轻症感染后约 1 year 的个体，发现仍有认知问题者在与注意力、情绪、记忆相关区域出现轻微变薄、异常铁沉积、一个与脑部废物清除及免疫调节相关结构的扩大，以及血检显示持续脑细胞压力与损伤，且相同异常在另一组患者中得到重现。
In the spring of 2020, Avindra Nath helped investigate unexplained deaths in New York City where victims stopped breathing and died suddenly at home, with no lung or heart damage explaining the cause. After high-resolution magnetic resonance imaging and microscope examination, tissue in brain-stem regions controlling breathing had lost neurons, and months later recovering patients reported Ondine-like episodes in which breathing no longer felt automatic and some could not sleep for days. In June 2020, Nath said thousands of patients were reporting persistent symptoms, and by fall 2020 he was focusing on long Covid and describing broad social effects, including impacts on people in their 40s.
Almost five years later, a December study estimated as many as 400 million people worldwide were living with long-term consequences of SARS-CoV-2 infection, and a November analysis estimated an annual economic toll of $1 trillion (about $1,000 billion), close to 1% of global gross domestic product. UK Biobank comparisons of pre- and post-Covid brain scans found subtle loss in regions involved in planning and memory even after mild infection, and UK community studies found a small but measurable downward shift in cognitive scores. In a UK human challenge study of healthy young adults with no prior immunity infected with the original strain, most had mild illness and none reported lasting problems, but after 1 year they performed slightly worse on memory and decision-making tests, with a difference roughly comparable to 6 IQ points; the experiment followed participants for 12 months.
By the third year of the pandemic, pooled observational research and large population datasets reported a statistically higher risk of cognitive impairment after Covid, and in older age groups dementia-level decline versus matched controls, including months or years after infection. In a January study of essential workers with blood samples from before and after Covid, participants with persistent neurological symptoms showed a clear rise in phosphorylated tau, especially when symptoms lasted more than 1 year; the authors did not claim Covid causes Alzheimer’s but said the biological pattern was concerning. A Korean study published in November scanned hundreds of people about 1 year after mostly mild infections and found that those with lingering cognitive problems had slightly thinner regions linked to attention, emotion, and memory, unusual iron buildup, enlargement of a brain waste-clearance and immune-regulation structure, and blood-test signs of ongoing brain-cell stress and injury, with the same abnormalities replicated in a separate patient group.