From the Internal Medicine-Pediatrics Residency Program (M.S.G.), Departments of Medicine and Pediatrics, Department of Public Health Sciences (K.E.W., L.P.S.), Department of Psychology and Institute for Mind and Biology (M.K.M.), and Section of Otolaryngology-Head and Neck Surgery (J.M.P.), Department of Surgery, The University of Chicago, IL.
Neurology. 2023 Sep 26;101(13):e1341-e1350. doi: 10.1212/WNL.0000000000207659. Epub 2023 Jul 26.
The ε4 allele confers susceptibility to faster decline in odor identification and subsequently to Alzheimer disease (AD). Odor identification requires recognizing and naming odors and detecting them (odor sensitivity). Whether ε4 is associated with decline of odor sensitivity and whether such decline serves as a harbinger of cognitive decline and AD remains unclear. We determined whether and when ε4 affects decline in odor sensitivity, odor identification, and cognition in the National Social Life Health and Aging Project (NSHAP).
We used data from NSHAP, a nationally representative survey study of home-dwelling US older adults. Olfaction was measured over time (odor identification in 2005, 2010, and 2015; odor sensitivity in 2010 and 2015; both using validated tests). Cognition was measured with a modified version of the Montreal Cognitive Assessment in 2010 and 2015. Genotyping was performed using DNA samples collected in 2010. Odor sensitivity and identification were compared among ε4 carriers and noncarriers stratified by age. Relationships between ε4, odor sensitivity, odor identification, and cognition were analyzed in cross-section using ordinal logistic regression and longitudinally using mixed-effects models adjusted for confounders.
Odor sensitivity was measured in 865 respondents, odor identification in 1,156 respondents, and cognition in 864 respondents; all these respondents had genetic data available. Odor sensitivity deficits in ε4 carriers were apparent at ages 65-69 years, whereas odor identification deficits did not appear until ages 75-79 years. Subsequently, odor sensitivity did not decline more rapidly with aging in ε4 carriers compared with that in noncarriers (carrier status and aging interaction: odds ratio [OR] 1.44, 95% CI 0.94-2.19, = 0.092), whereas odor identification declined more rapidly in carriers (aging 10 years interaction: OR 0.26, 95% CI 0.13-0.52, < 0.001). As expected, and in parallel to odor identification, cognition declined more rapidly in ε4 carriers (interaction: OR 0.55, 95% CI 0.34-0.89, = 0.015).
ε4 affects decline of odor sensitivity earlier than odor identification or cognition. Thus, testing odor sensitivity may be useful to predict future impaired cognitive function. Identifying the mechanism underlying these relationships will elucidate the key role of olfaction in neurodegeneration during aging.
ε4 等位基因使嗅觉识别能力下降更快，进而导致阿尔茨海默病（AD）。嗅觉识别需要识别和命名气味，并检测它们（嗅觉敏感度）。ε4 是否与嗅觉敏感度下降有关，以及这种下降是否预示着认知能力下降和 AD，目前尚不清楚。我们在全国社会生活、健康和老龄化项目（NSHAP）中确定了 ε4 是否以及何时会影响嗅觉敏感度、嗅觉识别和认知能力的下降。
我们使用了来自 NSHAP 的数据，这是一项针对美国居住在家中的老年成年人的全国代表性调查研究。嗅觉随时间推移进行测量（2005 年、2010 年和 2015 年进行嗅觉识别；2010 年和 2015 年进行嗅觉敏感度测量，均使用经过验证的测试）。认知功能使用改良版蒙特利尔认知评估量表在 2010 年和 2015 年进行测量。2010 年采集 DNA 样本进行基因分型。根据年龄对 ε4 携带者和非携带者进行分层，比较嗅觉敏感度和识别能力。使用有序逻辑回归分析横断面关系，使用混合效应模型调整混杂因素进行纵向分析。
865 名受访者接受了嗅觉敏感度测试，1156 名受访者接受了嗅觉识别测试，864 名受访者接受了认知测试；所有这些受访者都有可用的遗传数据。在 65-69 岁的 ε4 携带者中出现嗅觉敏感度缺陷，而在 75-79 岁的 ε4 携带者中才出现嗅觉识别缺陷。随后，与非携带者相比，ε4 携带者的嗅觉敏感度不会随年龄增长而更快下降（携带者状态和衰老交互作用：比值比 [OR] 1.44，95%CI 0.94-2.19， = 0.092），而嗅觉识别能力在携带者中下降更快（衰老 10 年交互作用：OR 0.26，95%CI 0.13-0.52， < 0.001）。正如预期的那样，与嗅觉识别能力平行，ε4 携带者的认知能力下降更快（交互作用：OR 0.55，95%CI 0.34-0.89， = 0.015）。
ε4 影响嗅觉敏感度的下降早于嗅觉识别或认知能力下降。因此，测试嗅觉敏感度可能有助于预测未来认知功能受损。确定这些关系背后的机制将阐明嗅觉在衰老过程中对神经退行性变的关键作用。
