Female thermal sensitivity and behaviour across the lifespan: A unique journey.

Women are a group of individuals that undergo unique anatomical, physiological and hormonal changes across the lifespan. For example, consider the impact of the menstrual cycle, pregnancy and menopause, all of which are accompanied by both short- and long-term effects on female body morphology (e.g., changes in breast size) and temperature regulation, heat tolerance, thermal sensitivity and comfort. However, empirical evidence on how skin thermal and wetness sensitivity might change across the lifespan of women, and the implications that this has for female-specific thermal behaviours, continues to be lacking. This paper is based on a symposium presentation given at Physiology 2023 in Harrogate, UK. It aims to review new evidence on anatomical and physiological mechanisms underpinning differences in skin thermal and wetness sensitivity amongst women varying in breast size and age, in addition to their role in driving female thermal behaviours. It is hoped that this brief overview will stimulate the development of testable hypotheses to increase our understanding of the behavioural thermal physiology of women across the lifespan and at a time of climate change.

Biophysical, thermo-physiological and perceptual determinants of cool-seeking behaviour during exercise in younger and older women.

Women continue to be under-represented in thermoregulatory research despite their undergoing unique physiological changes across the lifespan. This study investigated the biophysical, thermo-physiological, and perceptual determinants of cool-seeking behaviour during exercise in younger and older women. Eleven younger (25 ± 5 years; 1.7 ± 0.1 m; 63.1 ± 5.2 kg) and 11 older women (53 ± 6 years; 1.7 ± 0.1 m; 65.4 ± 13.9 kg) performed a 40-min incremental cycling test in a thermoneutral environment (22 ± 1.7°C; 36 ± 4% relative humidity). Throughout the test, participants freely adjusted the temperature of a cooling probe applied to their wrists to offset their thermal discomfort. We continuously recorded the probe-wrist interface temperature to quantify participants' cool-seeking behaviour. We also measured changes in participants' rate of metabolic heat production, core and mean skin temperatures, and skin wetness. Finally, we body-mapped participants' skin heat, cold and wetness sensitivity. Our results indicated that: (1) older and younger women exhibited similar onset and magnitude of cool-seeking behaviour, despite older women presented reduced autonomic heat-dissipation responses (i.e., whole-body sweat losses); (2) older women's thermal behaviour was less determined by changes in core temperature (this being a key driver in younger women), and more by changes in multiple thermo-physiological and biophysical parameters (i.e., physical skin wetness, temperature and heat production); (3) older women did not present lower regional skin thermal and wetness sensitivity than younger women. We conclude that predictions of female cool-seeking behaviours based on thermo-physiological variables should consider the effects of ageing. These findings are relevant for the design of wearable cooling systems and sports garments that meet the thermal needs of women across the lifespan.

The effect of female breast surface area on skin stiffness and tactile sensitivity at rest and following exercise in the heat.

Female development includes significant morphological changes across the breast. Yet, whether differences in breast surface area (BrSA) modify breast skin stiffness and tactile sensitivity at rest and after exercise in the heat remain unclear. We investigated the relationship between BrSA and skin stiffness and tactile sensitivity in 20 young to middle-aged women (27 ± 8 years of age) of varying breast sizes (BrSA range: 147-502 cm2) at rest and after a submaximal run in a warm climatic chamber (32 C ${\mathrm{C}}$  ±  0 . 6 C ; ${\mathrm{0}}{\mathrm{.6C;}}$ 53% ± 1.7% relative humidity). Skin stiffness above and below the nipple and tactile sensitivity from the nipple down were measured. Associations between BrSA and both skin stiffness and tactile sensitivity at rest were determined via correlation analyses. Effects of exercise and test site were assessed by a two-way ANOVA. Skin stiffness was positively correlated with BrSA 3 cm above the areola edge (r = 0.61, P = 0.005) and at the superior areola border (r = 0.54, P = 0.016), but not below the nipple (P > 0.05). The area 3 cm below the areola was also significantly stiffer than all other test sites (P < 0.043). Tactile sensitivity did not vary with BrSA (P > 0.09), but it varied across the breast (i.e., the area 3 cm below the areola was more sensitive than the inferior areola edge; P = 0.018). Skin stiffness and tactile sensitivity across the breast decreased after exercise by ∼37% (P < 0.001) and ∼45% (P = 0.008), respectively. These findings expand our fundamental understanding of the mechanosensory properties of the female breast, and they could help to inform sportswear innovation to better meet the support needs of women of different breast sizes at rest and following exercise.

The effect of female breast surface area on heat-activated sweat gland density and output.

Female development includes significant morphological changes across the breast. Yet, whether differences in breast surface area (BrSA) modify sweat gland density and output remains unclear. The present study investigated the relationship between BrSA and sweat gland density and output in 22 young to middle-aged women (28 ± $\ \pm \ $ 10 years) of varying breast sizes (BrSA range: 147-561 cm2) during a submaximal run in a warm environment (32  ± $ \pm \ $ 0.6°C; 53  ± $ \pm \ $ 1.7% relative humidity). Local sweat gland density and local sweat rate (LSR) above and below the nipple and at the bra triangle were measured. Expired gases were monitored for the estimation of evaporative requirements for heat balance (Ereq, in W/m2). Associations between BrSA and (i) sweat gland density; (ii) LSR; and (iii) sweat output per gland for the breast sites were determined via correlation and regression analyses. Our results indicated that breast sweat gland density decreased linearly as BrSA increased (r = -0.76, P < 0.001), whereas sweat output per gland remained constant irrespective of BrSA (r = 0.29, P = 0.28). This resulted in LSR decreasing linearly as BrSA increased (r = -0.62, P = 0.01). Compared to the bra triangle, the breast had a 64% lower sweat gland density (P < 0.001), 83% lower LSR (P < 0.001) and 53% lower output per gland (P < 0.001). BrSA (R2 = 0.33, P = 0.015) explained a greater proportion of variance in LSR than Ereq (in W/m2) (R2 = 0.07, P = 0.538). These novel findings extend the known relationship between body morphology and sweat gland density and LSR, to the female breast. This knowledge could innovate user-centred design of sports bras by accommodating breast size-specific needs for sweat management, skin wetness perception and comfort.

Ageing reduces skin wetness sensitivity across the body.

NEW FINDINGS: What is the central question of this study? Ageing impairs the skin's thermal and tactile sensitivity: does ageing also induce loss of skin wetness sensitivity? What is the main finding and its importance? Older adults show an average 15% loss of skin wetness sensitivity, with this sensory deficit being mediated by a combination of reductions in skin's tactile sensing and hydration status. These findings increase knowledge of wetness sensing mechanisms across the lifespan. ABSTRACT: Humans use sensory integration mechanisms to sense skin wetness based on thermal and mechanical cues. Ageing impairs the skin's thermal and tactile sensitivity, yet we lack evidence on whether wetness sensing also changes with ageing. We mapped local skin wetness and temperature sensitivity in response to cold-, neutral- and warm-wet stimuli applied to the forehead, neck, lower back, dorsal foot, index finger and thumb, in 10 Younger (22.4 ± 1.1 years) and 10 Older (58.2 ± 5.1 years) males. We measured local skin temperature and conductance (i.e., a marker of hydration status) at the tested sites, to establish the role of skin's thermal and mechanical parameters in ageing-induced changes in wetness sensing. Irrespective of body site, Older reported overall lower wetness perceptions than Younger across all wet-stimulus temperatures (mean difference: -14.6 mm; 95% CI: -4.3, -24.9; P = 0.008; ∼15% difference). When considering regional wetness sensitivity, the effect of ageing was more pronounced in response to the cold-wet stimulus over the lover back (mean difference Older vs. Younger: -36.8 mm; 95% CI: -68.4, -5.2; P = 0.014; ∼37% difference) and dorsal foot (mean difference: -37.1 mm; 95% CI: -68.7, -5.5; P = 0.013; ∼37% difference). We found no differences between age groups on overall thermal sensations (P = 0.744) nor local skin temperature (P = 0.372); however, we found that Older presented overall lower skin conductance than Younger (mean difference: -1.56 µS; 95% CI: -0.49, -2.62; P = 0.005), which corresponded to an ∼78% reduction in skin hydration. We conclude that skin wetness sensing decreases with ageing primarily due to age-induced changes in skin mechanics and tactile sensitivity.

Effect of the COVID-19 pandemic and the lockdown measures on the local stroke network.

INTRODUCTION: The COVID-19 outbreak highly impacted the acute ischemic stroke care management. The primary end point of the study was to evaluate the impact of the COVID-19 outbreak and the following lockdown measures on our hub-and-spoke network; the secondary end point was to evaluate if the impact of the COVID-19 outbreak was different in hub-and-spoke centers. METHODS: This was a retrospective multicenter observational study conducted at the Stroke Units of Policlinico Gemelli, Ospedale San Filippo Neri, Ospedale di Belcolle, and Ospedale San Camillo de Lellis. We collected clinical reports of all consecutive patients admitted with diagnosis of acute ischemic stroke or transient ischemic attack (TIA) during the phase 1 of the lockdown period (11 March 2020-4 May 2020). As controls, we used all consecutive patients admitted for acute ischemic stroke or TIA in the same period of the previous year. RESULTS: A total of 156 and 142 clinical reports were collected in 2019 and 2020, respectively. During the COVID-19 outbreak, we observed a reduction of number of thrombolysis, a reduction of the length of hospitalization, and an increase of pneumonia. Regarding performance indicators, we observed an increase in onset-to-door time and in door-to-groin time. We did not observe any statistically significant interaction between year (2019 vs 2020) and facility of admission (hub vs spoke) on all variables analyzed. DISCUSSION: Our observational study, involving hub-and-spoke stroke network of a wide regional area, indicates that the COVID-19 outbreak impacted on the acute stroke management. This impact was equally observed in hub as well as in spoke centers.

Independent and interactive effects of thermal stress and mental fatigue on manual dexterity.

Many occupations and sports require high levels of manual dexterity under thermal stress and mental fatigue. Yet, multistressor studies remain scarce. We quantified the interactive effects of thermal stress and mental fatigue on manual dexterity. Seven males (21.1 ± 1.3 yr) underwent six separate 60-min trials characterized by a combination of three air temperatures (hot, 37°C; neutral, 21°C; cold, 7°C) and two mental fatigue states (MF, mental fatigue induced by a 35-min cognitive battery; no-MF, no mental fatigue). Participants performed complex (O'Connor test) and simple (hand-tool test) manual tasks pre- and posttrial to determine stressor-induced performance changes. We monitored participants' rectal temperature and hand skin temperature (Thand) continuously and assessed the reaction time (hand-click test) and subjective mental fatigue (5-point scale). Thermal stress (P < 0.0001), but not mental fatigue (P = 0.290), modulated Thand (heat, +3.3°C [95% CI: +0.2, +6.5]; cold, -7.5°C [-10.7, -4.4]). Mental fatigue (P = 0.021), but not thermal stress (P = 0.646), slowed the reaction time (∼10%) and increased subjective fatigue. Thermal stress and mental fatigue had an interactive effect on the complex manual task (P = 0.040), with cold-no-MF decreasing the performance by -22% [-39, -5], whereas neutral-MF, cold-MF, and heat-MF by -36% [-53, -19], -34% [-52, -17], and -36% [-53, -19], respectively. Only mental fatigue decreased the performance in the simple manual task (-30% [-43, -16] across all thermal conditions; P = 0.002). Cold stress-induced impairments in complex manipulation increase with mental fatigue; yet combined stressors' effects are no greater than those of mental fatigue alone, which also impairs simple manipulation. Mental fatigue poses a greater challenge to manual dexterity than thermal stress.

Thermosensory mapping of skin wetness sensitivity across the body of young males and females at rest and following maximal incremental running.

KEY POINTS: Humans lack skin receptors for wetness (i.e. hygroreceptors), yet we present a remarkable wetness sensitivity. Afferent inputs from skin cold-sensitive thermoreceptors are key for sensing wetness; yet, it is unknown whether males and females differ in their wetness sensitivity across their body and whether high intensity exercise modulates this sensitivity. We mapped sensitivity to cold, neutral and warm wetness across five body regions and show that females are more sensitive to skin wetness than males, and that this difference is greater for cold than warm wetness sensitivity. We also show that a single bout of maximal exercise reduced the sensitivity to skin wetness (i.e. hygro-hypoesthesia) of both sexes as a result of concurrent decreases in thermal sensitivity. These novel findings clarify the physiological mechanisms underpinning this fundamental human sensory experience. In addition, they indicate sex differences in thermoregulatory responses and will inform the design of more effective sport and protective clothing, as well as thermoregulatory models. ABSTRACT: Humans lack skin hygroreceptors and we rely on integrating cold and tactile inputs from A-type skin nerve fibres to sense wetness. Yet, it is unknown whether sex and exercise independently modulate skin wetness sensitivity across the body. We mapped local sensitivity to cold, neutral and warm wetness of the forehead, neck, underarm, lower back and dorsal foot in 10 males (27.8 ± 2.7 years; 1.92 ± 0.1 m2 body surface area) and 10 females (25.4 ± 3.9 years; 1.68 ± 0.1 m2 body surface area), at rest and post maximal incremental running. Participants underwent our quantitative sensory test where they reported the magnitude of thermal and wetness perceptions (visual analogue scale) resulting from the application of a cold (5°C below skin temperature) wet (0.8 mL of water), neutral wet and warm wet (5°C above skin temperature) thermal probe (1.32 cm2 ) to five skin sites. We found that: (i) females were ∼14% to ∼17% more sensitive to cold-wetness than males, yet both sexes were as sensitive to neutral- and warm-wetness; (ii) regional differences were present for cold-wetness only, and these followed a craniocaudal increase that was more pronounced in males (i.e. the foot was ∼31% more sensitive than the forehead); and (iii) maximal exercise reduced cold-wetness sensitivity over specific regions in males (i.e. ∼40% decrease in foot sensitivity), and also induced a generalized reduction in warm-wetness sensitivity in both sexes (i.e. ∼4% to ∼6%). For the first time, we show that females are more sensitive to cold wetness than males and that maximal exercise induce hygro-hypoesthesia. These novel findings expand our knowledge on sex differences in thermoregulatory physiology.

A case report on the physiological responses to extreme heat during Sicily's July 2023 heatwave.

July 2023 has been confirmed as Earth's hottest month on record, and it was characterized by extraordinary heatwaves across southern Europe. Field data collected under real heatwave periods could add important evidence to understand human adaptability to extreme heat. However, field studies on human physiological responses to heatwave periods remain limited. We performed field thermo-physiological measurements in a healthy 37-years male undergoing resting and physical activity in an outdoor environment in the capital of Sicily, Palermo, during (July 21; highest level of local heat-health alert) and following (August 10; lowest level of local heat-health alert) the peak of Sicily's July 2023 heatwave. Results indicated that ~40 min of outdoor walking and light running in 33.8°C Wet Bulb Globe Temperature (WBGT) conditions (July 21) resulted in significant physiological stress (i.e., peak heart rate: 209 bpm; core temperature: 39.13°C; mean skin temperature: 37.2°C; whole-body sweat losses: 1.7 kg). Importantly, significant physiological stress was also observed during less severe heat conditions (August 10; WBGT: 29.1°C; peak heart rate: 190 bpm; core temperature: 38.48°C; whole-body sweat losses: 2 kg). These observations highlight the physiological strain that current heatwave conditions pose on healthy young individuals. This ecologically-valid empirical evidence could inform more accurate heat-health planning.

Assessing the Long-Term (48-Week) Effectiveness, Safety, and Tolerability of Fremanezumab in Migraine in Real Life: Insights from the Multicenter, Prospective, FRIEND3 Study.

INTRODUCTION: Long-term (1-year) fremanezumab treatment proved to be effective, safe, and well tolerated in individuals with migraine and < 2 medication clusters in a randomized controlled trial (RCT). We aimed to assess real-world evidence (RWE), long-term effectiveness, tolerability, and safety of fremanezumab in people with high-frequency episodic migraine (HFEM) or chronic migraine (CM) with > 3 treatment failures and various comorbidities. METHODS: A 48-week, prospective, multicenter (n = 26), cohort study assessed fremanezumab's effectiveness, safety, and tolerability in consecutive adults with HFEM or CM with > 3 treatment failures. Primary endpoint was variation from baseline in monthly migraine days (MMD) in HFEM and monthly headache days (MHD) in CM at weeks 45-48. Secondary endpoints were changes in monthly analgesic medications, Numerical Rating Scale (NRS), Headache Impact Test (HIT-6), and the Migraine Disability Assessment Scale (MIDAS) scores and ≥ 50%, ≥ 75%, and 100% responder rates. RESULTS: Of 533 participants who had received ≥ 1 fremanezumab dose, 130 were treated for ≥ 48 weeks and considered for effectiveness analysis. No participant missed any treatment dosage every other consecutive month during the 12-month period. PRIMARY ENDPOINT: fremanezumab significantly (p < 0.001) reduced both MMD (- 6.4) in HFEM and MHD (- 14.5) in CM. Secondary endpoints: a significant reduction (p < 0.001) was observed in monthly analgesic medications (HFEM - 6.0; CM -16.5), NRS (HFEM - 3.4; CM - 3.4), HIT-6 (HFEM - 16.9; CM - 17.9) and MIDAS score (HFEM - 50.4; CM - 76.6). The ≥ 50%, ≥ 75%, and 100% response rates to fremanezumab were 75.5%, 36.7%, and 2% in HFEM and 71.6%, 44.4%, and 3.7% in CM. Corresponding response rates were 60.5%, 37.2%, and 2.3% in individuals with psychiatric comorbidities, 74.2%, 50%, and 4.8% in CM with medication overuse, and 60.9%, 39.1%, and 4.3% in CM with medication overuse and psychiatric comorbidities. Mild and transient treatment-emergent adverse events occurred in 7.8% of the participants. No subject discontinued the treatment for any reason. CONCLUSION: This RWE study documents that long-term fremanezumab treatment is highly effective and remarkably well tolerated in subjects with HFEM or CM with multiple (> 3) therapeutic failures, even in the presence of concomitant medication overuse, psychiatric comorbidities, or both. The effectiveness-to-tolerability ratio appears to be better in RWE than in RCTs.

Cutaneous thermosensory mapping of the female breast and pelvis.

Differences in skin thermal sensitivity have been extensively mapped across areas of the human body, including the torso, limbs, and extremities. Yet, there are parts of the female body, such as the breast and the pelvis for which we have limited thermal sensitivity data. The aim of this study was to map cutaneous warm and cold sensitivity across skin areas of the breast and pelvis that are commonly covered by female underwear. Twelve young females (21.9 ± 3.2 years) reported on a 200 mm visual analogue scale the perceived magnitude of local thermal sensations arising from short-duration (10 s) static application of a cold [5 °C below local skin temperature (Tsk)] or warm (5 °C above local Tsk) thermal probe (25 cm2) in seventeen locations over the breast and pelvis regions. The data revealed that thermal sensitivity to the warm probe, but not the cold probe, varied by up to 25% across the breast [mean difference between lowest and highest sensitivity location was 51 mm (95% CI:14, 89; p < 0.001)] and up to 23% across the pelvis [mean difference between lowest and highest sensitivity location: 46 mm (95% CI:9, 84; p = 0.001)]. The regional differences in baseline Tsk did not account for variance in warm thermal sensitivity. Inter-individual variability in thermal sensitivity ranged between 24 and 101% depending on skin location. We conclude that the skin across the female breast and pelvis presents a heterogenous distribution of warm, but not cold, thermal sensitivity. These findings may inform the design of more comfortable clothing that are mapped to the thermal needs of the female body.

Thermal modulation of skin friction at the finger pad.

Preliminary human studies show that reduced skin temperature minimises the risk of mechanically induced skin damage. However, the mechanisms by which cooling enhances skin tolerance to pressure and shear remain poorly understood. We hypothesized that skin cooling below thermo-neutral conditions will decrease kinetic friction at the skin-material interface. To test our hypothesis, we measured the friction coefficient of a thermally pre-conditioned index finger pad sliding at a normal load (5N) across a plate maintained at three different temperatures (38, 24, and 16 °C) in 8 healthy young adults (29±5y). To quantify the temperature distribution of the skin tissue, we used 3D surface scanning and Optical Coherence Tomography to develop an anatomically representative thermal model of the finger. Our group-level data indicated that the sliding finger with thermally affected tissues (up to 8 mm depth) experienced significantly lower frictional forces (p<0.01) at plate temperatures of 16 °C (i.e. 32% decrease) and 24 °C (i.e. 13% decrease) than at 38 °C, respectively. This phenomenon occurred consistently across participants (i.e. N = 6/8, 75%) and without large changes in skin hydration during sliding. Our complementary experimental and theoretical results provide new insights into thermal modulation of skin friction that can be employed for developing thermal technologies to maintain skin integrity under mechanical loading and shearing.

Effects of Cycling on Spine: A Case-Control Study Using a 3D Scanning Method.

BACKGROUND: Few studies have investigated the effects of adopting a specific and prolonged posture on cyclists. This study aimed to evaluate the upright spine in a sample of recreational cyclists and compare it with a sample of non-cyclists, though still athletes, through a 3D scanning method. METHODS: Forty-eight participants were enrolled in this observational study. The sample consisted of 25 cyclists for the cycling group and 23 non-cyclist athletes for the control group. The Spine3D device (Sensor Medica, Guidonia Montecelio, Rome, Italy) was used to evaluate the spine of the participants in both groups. RESULTS: The results showed significantly greater spine inclination in the cycling group compared to the control group (p < 0.01). Furthermore, there was a significant decrease in lumbar lordosis in the cycling group compared to the control group (p < 0.01). CONCLUSIONS: This case-control study raises the possibility that the onset of lower back pain in cyclists may be due to a reduction in lumbar lordosis. Furthermore, this study demonstrated that the Spine3D device can be used in sports to monitor the spine of athletes to prevent and reduce musculoskeletal deficits.

Probable Alzheimer's disease patients presenting as "focal temporal lobe dysfunction" show a slow rate of cognitive decline.

Several authors have recently shown that anterograde amnesia is often associated with semantic memory impairment in amnesic MCI patients. Similarly, after the MCI condition, some patients who convert to Alzheimer's disease (AD) show the classic onset (cAD) characterized by the impairment of memory and executive functions, whereas other AD patients show isolated defects of episodic and semantic memory without deficits in other cognitive domains. The latter have been considered an AD variant characterized by 'focal Temporal Lobe Dysfunction' (TLD). The aim of the present study was to assess the differences in disease progression between cAD and TLD. For this purpose a continuous series of newly diagnosed probable AD patients presenting as cAD (n = 30) and TLD (n = 25), matched for severity, and 65 healthy controls underwent a comprehensive neuropsychological evaluation at baseline; TLD and cAD were re-evaluated at a 24-month follow-up. At follow-up, TLD patients showed no significant worsening of cognitive functions, whereas cAD subjects displayed a significant worsening in all explored cognitive domains. In conclusion, our results confirm that probable AD presenting as TLD represents a specific onset of AD characterized by a slower rate of progression.

An observational study on electrolyte disorders in the acute phase of ischemic stroke and their prognostic value.

Data on electrolyte disorders in neurological conditions and in acute stroke are somewhat scanty and not easily compared. In our Stroke Unit we studied patients hospitalized within six hours of the onset of an acute ischemic stroke and recorded their demographic and clinical data. Blood test results were recorded before any pharmacological therapy. A total of 475 individuals (256 M, 219 F; range: 14-96 years) treated over a period of 18 consecutive months, were selected. According to multiple logistic regression analysis, the baseline National Institute of Health Stroke Scale (NIHSS) score (odds ratio [OR]=1.33; 95% confidence interval [CI]: 1.22-1.44) and natremia alterations (OR=6.89; 95% CI=1.94-24.40) were associated with higher odds of death. Based on the ordinal logistic regression analysis, the baseline NIHSS score (OR=1.07; 95% CI=1.03-1.10) and baseline hypernatremia (OR=9.69; 95% CI=1.55-60.69) were related to early neurological worsening. Our work suggests an association between serum sodium alterations and mortality, and between high sodium levels and neurological clinical impairment, in the acute phase of an ischemic stroke.

Apolipoprotein E epsilon4 allele differently affects the patterns of neuropsychological presentation in early- and late-onset Alzheimer's disease patients.

The presence of the apolipoprotein E (APOE) epsilon4 allele is a definite risk factor for the onset of Alzheimer's disease (AD). Its presence seems to affect especially the memory in the early stage of the disease, but the effect on the progression of the disease and survival is still controversial. Some longitudinal studies could be influenced by variables other than APOE, such as the response to medical treatment, rehabilitation therapy and inclusion of patients at different stages of progression at baseline. Moreover, the inclusion in the same study sample of patients of different ages at onset of the disease (below 65 or above 80 years) appears arbitrary. In our study, we evaluated a population of newly diagnosed untreated AD patients at their first neuropsychological examination and with the onset of their first symptoms not longer than 3 years ago. In order to analyse the different effects of the APOE epsilon4 allele on the different ages at the onset of the disease, we split the study sample into two groups: (1) subjects under 65 years [early-onset AD (EOAD); n = 30] and subjects over 70 years [late-onset AD (LOAD); n = 41], excluding subjects with an age of onset between 66 and 69 years. Our results show that the APOE epsilon4 allele carriers are characterised by a different neuropsychological pattern at the disease onset; however, only in the EOAD group is this effect significant: in EOAD, the epsilon4 allele carriers obtained worse performances in learning, long-term verbal memory and general intelligence tasks. On the contrary, in LOAD patients, the pattern of cognitive impairment at the onset is not dependent on the possession of an epsilon4 allele in the genotype. Such data could suggest a careful control of the study sample concerning age at the onset of the disease since APOE could play a different role in EOAD and LOAD mainly due to the different pathogenic mechanism at the onset and evolution of AD.